Fentanyl Citrate Injection is indicated for:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is indicated for:" }

{ "type": "ul", "children": [ "analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises.\n ", "use as a narcotic analgesic supplement in general or regional anesthesia.\n ", "administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.\n ", "use as an anesthetic agent with oxygen in selected high-risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures." ], "text": "" }

Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

If Fentanyl Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product’s duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available [see Warnings and Precautions (5.4)].

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Premedication in Adults

50 mcg to 100 mcg may be administered intramuscularly 30 to 60 minutes prior to surgery.

Adjunct to General Anesthesia

See Dosage Range Charts below.

Table 1: Dosage Range Chart

<div class="scrollingtable"><table> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">Total Dosage</span> (expressed as fentanyl base)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Low Dose</span>—2 mcg/kg <br/> For use in minor, but painful, surgical procedures. <br/> May also provide some pain relief in the immediate postoperative period.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Moderate Dose</span>—2 mcg to 20 mcg/kg <br/> For use in more major surgical procedures, in addition to adequate analgesia, may abolish some of the stress response. <br/> Expect respiratory depression requiring artificial ventilation during anesthesia and careful observation of ventilation postoperatively is essential.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">High dose</span>—20 mcg to 50 mcg/kg <br/> For open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and the stress response to surgery would be detrimental to the well-being of the patient.<br/> In conjunction with nitrous oxide/oxygen has been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin.<br/> Expect the need of postoperative ventilation and observation due to extended post-operative respiratory depression.</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">Maintenance Dose</span> (expressed as fentanyl base)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Low Dose</span>—2 mcg/kg <br/> Additional dosages infrequently needed in these minor procedures. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Moderate Dose</span>—2 mcg to 20 mcg/kg <br/> 25 mcg to 100 mcg  <br/> Administer intravenously or intramuscularly as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">High Dose</span>—20 mcg to 50 mcg/kg <br/> Maintenance dosage [ranging from 25 mcg to one half the initial loading dose] as needed based on vital signs indicative of stress and lightening of analgesia. <br/> Individualize the dosage especially if the anticipated remaining operative time is short.</p> </td> </tr> </tbody> </table></div>

Adjunct to Regional Anesthesia

50 mcg to 100 mcg may be administered intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is required.

Postoperatively (recovery room)

50 mcg to 100 mcg may be administered intramuscularly for the control of pain, tachypnea and emergence delirium. The dose may be repeated in one to two hours as needed.

For Induction and Maintenance in Children 2 to 12 Years of Age

A reduced dose as low as 2 mcg to 3 mcg/kg is recommended.

As a General Anesthetic

As a technique to attenuate the responses to surgical stress without the use of additional anesthetic agents, doses of 50 mcg to 100 mcg/kg may be administered with oxygen and a muscle relaxant.  In certain cases, doses up to 150 mcg/kg may be necessary to produce this anesthetic effect. It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures.

Single-Dose Vials:

{ "type": "p", "children": [], "text": "Single-Dose Vials:" }

Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 2 mL, 5 mL and 50 mL single-dose glass vials.

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 2 mL, 5 mL and 50 mL single-dose glass vials." }

Fentanyl Citrate Injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Hypersensitivity to fentanyl (e.g., anaphylaxis) [See Adverse Reactions (6)]\n" ], "text": "" }

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioid are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential.  As with other potent opioids, the respiratory depressant effect of Fentanyl Citrate Injection may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves.  Through other mechanisms [see Clinical Pharmacology (12.2)] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these forms of anesthesia.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentanyl Citrate Injection.  Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.

Monitor such patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration (2.1)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.1)].

When benzodiazepines or other CNS depressants are used with Fentanyl Citrate Injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Fentanyl Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Fentanyl Citrate Injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha  adrenergic activity.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentanyl Citrate Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.  Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].     

If the decision is made to manage postoperative pain with Fentanyl Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate Injection-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentanyl Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentanyl Citrate Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations, decreased efficacy, or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using Fentanyl Citrate Injection with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider increasing the Fentanyl Citrate Injection dosage [see Dosage and Administration (2.1), Drug Interactions (7)].

Fentanyl Citrate Injection may cause muscle rigidity, particularly involving the muscles of respiration. The incidence and severity of muscle rigidity is dose related. These effects are related to the dose and speed of injection.  Skeletal muscle rigidity also has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration.  In addition, skeletal muscle movements of various groups in the extremities, neck, and external eye have been reported during induction of anesthesia with Fentanyl Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

These effects are related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Fentanyl Citrate Injection; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when Fentanyl Citrate Injection is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of Fentanyl Citrate Injection and a full paralyzing dose of a neuromuscular blocking agent when Fentanyl Citrate Injection is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status.

Fentanyl Citrate Injection may cause severe bradycardia, severe hypotension including orthostatic hypotension, and syncope.  There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)].  In patients with circulatory shock, Fentanyl Citrate Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Fentanyl Citrate Injection.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.  This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)].  Symptoms of OIH include (but may not be limited to) increased  levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).  These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. 

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.  Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.  Medical literature suggests a strong biological plausibility between opioid analgesics and OIH and allodynia.  If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2)]. 

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazadone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Fentanyl Citrate Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of increasing intracranial pressure. Monitor such patients closely, particularly when initiating and titrating Fentanyl Citrate Injection and when Fantanyl Citrate Injection is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)]. 

Fentanyl may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Fentanyl may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Fentanyl Citrate Injection therapy.

Fentanyl Citrate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery after Fentanyl Citrate Injection administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Fentanyl Citrate Injection and know how they will react to the medication.

Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. 

Administer neuroleptic agents with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI’s), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

When Fentanyl Citrate Injection is used with a neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern may return to normal slowly.

The following serious adverse reactions are described, or described in greater detail, in other sections:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described, or described in greater detail, in other sections:" }

{ "type": "ul", "children": [ "Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]\n", "Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]\n", "Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]\n", "Severe Cardiovascular Depression [see Warnings and Precautions (5.6)]\n", "Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)]\n", "Serotonin Syndrome [see Warnings and Precautions (5.8)]\n", "Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]\n", "Seizures [see Warnings and Precautions (5.12)]\n" ], "text": "" }

The following adverse reactions associated with the use of fentanyl were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of fentanyl were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

As with other opioid agonists, the most common serious adverse reactions reported to occur with fentanyl are respiratory depression, apnea, rigidity and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm, diaphoresis, serotonin syndrome, adrenal insufficiency, and anaphylaxis.

{ "type": "p", "children": [], "text": "As with other opioid agonists, the most common serious adverse reactions reported to occur with fentanyl are respiratory depression, apnea, rigidity and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm, diaphoresis, serotonin syndrome, adrenal insufficiency, and anaphylaxis." }

It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. When a tranquilizer is used with Fentanyl Citrate Injection, the following adverse reactions can occur: chills and/or shivering, restlessness and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with fentanyl citrate.

{ "type": "p", "children": [], "text": "It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. When a tranquilizer is used with Fentanyl Citrate Injection, the following adverse reactions can occur: chills and/or shivering, restlessness and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with fentanyl citrate." }

Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of fentanyl citrate with a neuroleptic agent.

{ "type": "p", "children": [], "text": "Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of fentanyl citrate with a neuroleptic agent." }

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

{ "type": "p", "children": [], "text": "\nSerotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs." }

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

{ "type": "p", "children": [], "text": "\nAdrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use." }

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Fentanyl Citrate Injection

{ "type": "p", "children": [], "text": "\nAnaphylaxis: Anaphylaxis has been reported with ingredients contained in Fentanyl Citrate Injection" }

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "\nAndrogen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)]." }

Hyperalgesia and Allodynia:  Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia:  Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7)]." }

Hypoglycemia:  Causes of hypoglycemia have been reported in patients taking opioids.  Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

{ "type": "p", "children": [], "text": "\nHypoglycemia:  Causes of hypoglycemia have been reported in patients taking opioids.  Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). " }

Table 2 includes clinically significant drug interactions with Fentanyl Citrate Injection.

{ "type": "p", "children": [], "text": "Table 2 includes clinically significant drug interactions with Fentanyl Citrate Injection." }

Table 2: Clinically Significant Drug Interactions with Fentanyl Citrate Injection

{ "type": "p", "children": [], "text": "\nTable 2: Clinically Significant Drug Interactions with Fentanyl Citrate Injection\n" }

<div class="scrollingtable"><table> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Inhibitors of CYP3A4</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact</span>:</td><td class="Botrule Lrule Rrule Toprule"> <p class="First">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved <span class="Italics">[see <a href="#LINK_e3cb22fc-df7c-456b-aa72-2043677b90f8">Warnings and Precautions (5.3)</a>]</span>.</p> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class="Italics">[see <a href="#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved <span class="Italics">[see <a href="#LINK_3d0b75be-a258-4057-813f-fcd4d55137a3">Dosage and Administration (2.1)</a>]</span>. Monitor patients for respiratory depression and sedation.</p> If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved.  Monitor for signs of opioid withdrawal<span class="Bold">.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see <a href="#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see <a href="#LINK_e3cb22fc-df7c-456b-aa72-2043677b90f8">Warnings and Precautions (5.3)</a>]</span>. </p> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see <a href="#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e">Clinical Pharmacology (12.3)</a>]</span>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Rifampin, carbamazepine, phenytoin</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of Fentanyl Citrate Injection with CNS depressants may result in decreased pulmonary artery pressure and may cause hypotension.  Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection.  As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death<span class="Bold">.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available <span class="Italics">[see <a href="#LINK_741fea65-586b-4281-85b2-e1ab6982304e">Warnings and Precautions (5.4)</a>]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see <a href="#LINK_ae54a748-3311-4fdc-a328-17c870455c98">Warnings and Precautions (5.8)</a>]</span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Monoamine Oxidase Inhibitors</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see <a href="#LINK_ae54a748-3311-4fdc-a328-17c870455c98">Warnings and Precautions (5.8)</a>]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see <a href="#LINK_6b4fcb6c-3629-405a-958c-6091b6048c22">Warnings and Precautions (5.2)</a>].</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Phenelzine, tranylcypromine, linezolid</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention</span>:</td><td class="Botrule Lrule Rrule Toprule">Avoid concomitant use.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Butorphanol, nalbuphine, pentazocine, buprenorphine.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Fentanyl Citrate Injection and/or the muscle relaxant as necessary.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Diuretics</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus<span class="Bold">.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention</span>:</td><td class="Botrule Lrule Rrule Toprule">Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs<span class="Bold">.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Neuroleptics</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic <span class="Italics">[see <a href="#LINK_ef9e08fe-586c-41c9-8638-5730637baf11">Warnings and Precautions (5.14)</a>]</span>.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Nitrous oxide</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection.</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact</span>:</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved <span class=\"Italics\">[see <a href=\"#LINK_e3cb22fc-df7c-456b-aa72-2043677b90f8\">Warnings and Precautions (5.3)</a>]</span>.</p>\n After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class=\"Italics\">[see <a href=\"#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e\">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved <span class=\"Italics\">[see <a href=\"#LINK_3d0b75be-a258-4057-813f-fcd4d55137a3\">Dosage and Administration (2.1)</a>]</span>. Monitor patients for respiratory depression and sedation.</p>\n If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved.  Monitor for signs of opioid withdrawal<span class=\"Bold\">.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class=\"Italics\">[see <a href=\"#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e\">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class=\"Italics\">[see <a href=\"#LINK_e3cb22fc-df7c-456b-aa72-2043677b90f8\">Warnings and Precautions (5.3)</a>]</span>. </p>\n After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class=\"Italics\">[see <a href=\"#LINK_160299a2-a050-48c5-a4c2-5cb0ebb7272e\">Clinical Pharmacology (12.3)</a>]</span>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Rifampin, carbamazepine, phenytoin</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of Fentanyl Citrate Injection with CNS depressants may result in decreased pulmonary artery pressure and may cause hypotension.  Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection.  As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death<span class=\"Bold\">.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available <span class=\"Italics\">[see <a href=\"#LINK_741fea65-586b-4281-85b2-e1ab6982304e\">Warnings and Precautions (5.4)</a>]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class=\"Italics\">[see <a href=\"#LINK_ae54a748-3311-4fdc-a328-17c870455c98\">Warnings and Precautions (5.8)</a>]</span>. </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Monoamine Oxidase Inhibitors</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">MAOI interactions with opioids may manifest as serotonin syndrome <span class=\"Italics\">[see <a href=\"#LINK_ae54a748-3311-4fdc-a328-17c870455c98\">Warnings and Precautions (5.8)</a>]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see <a href=\"#LINK_6b4fcb6c-3629-405a-958c-6091b6048c22\">Warnings and Precautions (5.2)</a>].</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention</span>:</td><td class=\"Botrule Lrule Rrule Toprule\">Avoid concomitant use.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Butorphanol, nalbuphine, pentazocine, buprenorphine.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Fentanyl Citrate Injection and/or the muscle relaxant as necessary.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus<span class=\"Bold\">.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention</span>:</td><td class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs<span class=\"Bold\">.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Neuroleptics</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic <span class=\"Italics\">[see <a href=\"#LINK_ef9e08fe-586c-41c9-8638-5730637baf11\">Warnings and Precautions (5.14)</a>]</span>.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Nitrous oxide</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection.</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Fentanyl Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

There are insufficient data to support the use of fentanyl in labor or delivery. Therefore, such use is not recommended. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl Citrate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Fentanyl Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m2 basis).  There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately

0.81 times the human dose of 100 mcg/kg on a mg/m2 basis.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.38%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fentanyl Citrate Injection and any potential adverse effects on the breastfed infant from Fentanyl Citrate Injection or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

The safety and efficacy of Fentanyl Citrate Injection in pediatric patients under two years of age has not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Fentanyl Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

Fentanyl Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of Fentanyl Citrate Injection and its metabolites. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled drug substance.

Fentanyl Citrate Injection contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.   

Misuse and abuse of Fentanyl Citrate Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death.  The risk is increased with concurrent abuse of Fentanyl Citrate Injection with alcohol and/or other CNS depressants.  Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence.  In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Fentanyl Citrate Injection abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use Fentanyl Citrate Injection in combination with other abused drugs. 

“Drug-seeking” behavior is very common in persons with substance use disorders.  Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical  records or contact information for other treating healthcare providers(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder.  Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Fentanyl Citrate Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispending and storage are appropriate measures to limit abuse of opioid drugs.

Risks Specific to Abuse of Fentanyl Citrate Injection

Abuse of Fentanyl Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Fentanyl Citrate Injection with alcohol and/or other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Both tolerance and physical dependence can develop during chronic opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). 

Physical dependence is a state that develops as a result of physiological adaptation in a response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dosage reduction of a drug.

Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Fentanyl Citrate Injection should not be abruptly discontinued in a physically dependent patient.  If Fentanyl Citrate Injection is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis.  Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)]. 

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]." }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

{ "type": "p", "children": [], "text": "In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. " }

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

{ "type": "p", "children": [], "text": "Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. " }

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information." }

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist." }

Fentanyl Citrate Injection is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration. Fentanyl citrate is chemically identified as N‑(1‑Phenethyl‑4‑piperidyl)propionanilide citrate (1:1) with the following structural formula:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration. Fentanyl citrate is chemically identified as N‑(1‑Phenethyl‑4‑piperidyl)propionanilide citrate (1:1) with the following structural formula:" }

Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection. Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. The pH range is 4.0 – 7.5. Contains no preservative.

{ "type": "p", "children": [], "text": "Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection. Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. The pH range is 4.0 – 7.5. Contains no preservative." }

Fentanyl Citrate Injection is an opioid agonist, whose principal actions of therapeutic value are analgesia and sedation.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritis, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and lutenizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration – Efficacy Relationships

A dose of 100 mcg of Fentanyl Citrate Injection is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1)].

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal analgesic effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg. Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours.

Concentration – Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1)].

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal respiratory depressant effect may not be noted for several minutes. As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of fentanyl may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of fentanyl citrate:

Fentanyl Citrate Injection is administered by the intravenous or intramuscular route. The pharmacokinetics of fentanyl can be described as a three-compartment model.

Distribution

Fentanyl plasma protein binding capacity increases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat and is released slowly into the blood. The volume of distribution for fentanyl is 4 L/kg. It has a distribution time of 1.7 minutes and redistribution time of 13 minutes.

Elimination

The terminal elimination half-life is 219 minutes.

Fentanyl, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of fentanyl citrate have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of fentanyl citrate have been conducted.

Impairment of Fertility

Decreased pregnancy rates occurred in a multigenerational study in which pregnant rats were treated subcutaneously during the first 21 days of pregnancy with 160 mcg/kg to 1250 mcg/kg fentanyl (0.26 times to 2.0 times a human dose of 100 mcg/kg based on body surface area).

Studies in animals to characterize the effect of fentanyl on male fertility have not been conducted.

Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows:" }

NDC 72572-170-25            2 mL Single Dose vials packaged in 25s NDC 72572-171-10            5 mL Single Dose vials packaged in 10s       NDC 72572-172-01            50 mL Single Dose vials packaged individually

{ "type": "p", "children": [], "text": "NDC 72572-170-25            2 mL Single Dose vials packaged in 25s \nNDC 72572-171-10            5 mL Single Dose vials packaged in 10s      \nNDC 72572-172-01            50 mL Single Dose vials packaged individually" }

PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20˚C to 25˚C (68˚F to 77˚F), excursions permitted to 15˚C to 30˚C (59˚F to 86˚F) [See USP Controlled Room Temperature]. Contains no preservative. DISCARD ANY UNUSED CONTENTS.

{ "type": "p", "children": [], "text": "PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20˚C to 25˚C (68˚F to 77˚F), excursions permitted to 15˚C to 30˚C (59˚F to 86˚F) [See USP Controlled Room Temperature]. Contains no preservative. DISCARD ANY UNUSED CONTENTS." }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit." }

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." }

For Product Inquiry call 1-877-845-0689.

{ "type": "p", "children": [], "text": "For Product Inquiry call 1-877-845-0689." }

Addiction, Abuse, and Misuse

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse \n" }

Inform patients that the use of Fentanyl Citrate Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. 

{ "type": "p", "children": [], "text": "Inform patients that the use of Fentanyl Citrate Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)].  " }

Life-Threatening Respiratory Depression

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n" }

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Fentanyl Citrate Injection or when the dosage is increased, and that it can occur even at recommended dosages.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Fentanyl Citrate Injection or when the dosage is increased, and that it can occur even at recommended dosages." }

Hyperalgesia and Allodynia 

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia  \n" }

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7); Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7); Adverse Reactions (6)]." }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.7), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.7), Drug Interactions (7)]." }

Constipation

{ "type": "p", "children": [], "text": "\nConstipation\n" }

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Clinical Pharmacology (12.2)]." }

Manufactured for: Civica, Inc. Lehi, Utah 84043

{ "type": "p", "children": [], "text": "Manufactured for:\nCivica, Inc.\nLehi, Utah 84043" }

Manufactured by: Hikma Pharmaceuticals USA Inc.  Cherry Hill, New Jersey 08003

{ "type": "p", "children": [], "text": "Manufactured by:\nHikma Pharmaceuticals USA Inc. \nCherry Hill, New Jersey 08003" }

Revised December 2023

{ "type": "p", "children": [], "text": "Revised December 2023" }

462-842-04

{ "type": "p", "children": [], "text": "462-842-04" }

72572-170-01   Rx Only Fentanyl Citrate Inj., USP    CII 100 mcg/2 mL (50 mcg/mL) For IV or IM use Protect From Light Destroy Unused Contents 2 mL Single Dose Vial

{ "type": "p", "children": [], "text": "72572-170-01   Rx Only\nFentanyl \nCitrate Inj., USP    CII\n100 mcg/2 mL\n(50 mcg/mL)\n\nFor IV or IM use\nProtect From Light\nDestroy Unused Contents\n2 mL Single Dose Vial" }

72572-170-25   Rx Only Fentanyl Citrate Injection, USP    CII 100 mcg/2 mL (50 mcg/mL) For IV or IM Use Preservative-free 25 x 2 mL Single Dose Vials

{ "type": "p", "children": [], "text": "72572-170-25   Rx Only\n\nFentanyl \nCitrate Injection, USP    CII\n100 mcg/2 mL\n(50 mcg/mL)\n\nFor IV or IM Use\nPreservative-free\n\n25 x 2 mL Single Dose Vials" }

72572-171-01   Rx Only Fentanyl Citrate Inj., USP    CII 250 mcg/5 mL (50 mcg/mL)     For IV or IM Use   Preservative-free 5 mL Single Dose Vial

{ "type": "p", "children": [], "text": "72572-171-01   Rx Only\nFentanyl \nCitrate Inj., USP    CII\n250 mcg/5 mL\n(50 mcg/mL)    \n\nFor IV or IM Use   Preservative-free\n\n5 mL Single Dose Vial" }

72572-171-10   Rx Only Fentanyl Citrate Injection, USP    CII 250 mcg/5 mL (50 mcg/mL)  For Intravenous or Intramuscular Use Preservative-free 10 x 5 mL Single Dose Vials

{ "type": "p", "children": [], "text": "72572-171-10   Rx Only\n\nFentanyl \nCitrate Injection, USP    CII\n250 mcg/5 mL\n(50 mcg/mL)  \nFor Intravenous or Intramuscular Use\nPreservative-free\n\n10 x 5 mL Single Dose Vials" }

72572-172-01   Rx Only Fentanyl Citrate Injection, USP    CII 2,500 mcg/50 mL                       Preservative- (50 mcg/mL)                                     free FOR SLOW INTRAVENOUS USE By Hospital Personnel Specifically Trained in the Use of Narcotic Analgesics 50 mL Single Dose Vial

{ "type": "p", "children": [], "text": "72572-172-01   Rx Only\nFentanyl \nCitrate Injection, USP    CII\n2,500 mcg/50 mL                       Preservative-\n\n(50 mcg/mL)                                     free\n\nFOR SLOW INTRAVENOUS USE\nBy Hospital Personnel Specifically Trained in the Use of\nNarcotic Analgesics\n\n50 mL Single Dose Vial\n" }

72572-172-01   Rx Only Fentanyl Citrate Injection, USP    CII 2,500 mcg/50 mL                      (50 mcg/mL)           FOR SLOW INTRAVENOUS USE By Hospital Personnel Specifically Trained in the Use of Narcotic Analgesics Preservative-free 50 mL Single Dose Vial

{ "type": "p", "children": [], "text": "72572-172-01   Rx Only\nFentanyl \nCitrate Injection, USP    CII\n2,500 mcg/50 mL                     \n(50 mcg/mL)          \nFOR SLOW INTRAVENOUS USE\nBy Hospital Personnel \nSpecifically Trained in the\nUse of Narcotic Analgesics\nPreservative-free\n50 mL Single Dose Vial" }

FENTORA is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

{ "type": "p", "children": [], "text": "FENTORA is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain." }

Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking FENTORA.

{ "type": "p", "children": [], "text": "Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking FENTORA." }

Limitations of Use:

{ "type": "p", "children": [], "text": "\nLimitations of Use:\n" }

{ "type": "ul", "children": [ "Not for use in opioid non-tolerant patients.", "Not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see Contraindications (4)].", "As a part of the TIRF REMS, FENTORA may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. For inpatient administration of FENTORA, patient and prescriber enrollment are not required." ], "text": "" }

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with FENTORA [see Warnings and Precautions (5.2)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.4)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

The initial dose of FENTORA is always 100 mcg with the only exception being patients already using ACTIQ.

Patients on ACTIQ

a. For patients being converted from ACTIQ, prescribers must use the Initial Dosing Recommendations for Patients on ACTIQ table below (Table 1). The doses of FENTORA in this table are starting doses and not intended to represent equianalgesic doses to ACTIQ. Patients must be instructed to stop the use of ACTIQ and dispose of any remaining units.

<div class="scrollingtable"><table> <caption> <span>Table 1. Initial Dosing Recommendations for Patients on ACTIQ</span> </caption> <col width="43%"/> <col width="57%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Current ACTIQ</span> </p> <p> <span class="Bold">Dose</span> </p> <p> <span class="Bold">(mcg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Initial FENTORA Dose*</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mcg tablet</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">400</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mcg tablet</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">600</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mcg tablet</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">800</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mcg tablet</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1200</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 x 200 mcg tablets</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1600</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 x 200 mcg tablets</p> </td> </tr> </tbody> </table></div>

*From this initial dose, titrate patient to effective dose.

b. For patients converting from ACTIQ doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg FENTORA tablet and should proceed using multiples of this tablet strength.

Repeat Dosing

Opening the Blister Package:

Tablet Administration:

Once the tablet is removed from the blister unit, the patient should immediately place the entire FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or place the entire FENTORA tablet under the tongue. Patients should not split the tablet.

The FENTORA tablet should not be crushed, sucked, chewed, or swallowed whole, as this will result in lower plasma concentrations than when taken as directed.

The FENTORA tablet should be left between the cheek and gum or under the tongue until it has disintegrated, which usually takes approximately 14-25 minutes.

After 30 minutes, if remnants from the FENTORA tablet remain, they may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when administering subsequent doses of FENTORA in the buccal cavity.

For patients no longer requiring opioid therapy, consider discontinuing FENTORA along with a gradual downward tapering (titration) of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, FENTORA therapy can usually be discontinued immediately [see Drug Abuse and Dependence (9.3)].

To dispose of unused FENTORA, remove FENTORA tablets from blister packages and flush down the toilet. Do not flush FENTORA blister packages or cartons down the toilet. If you need additional assistance with disposal of FENTORA, call Teva Pharmaceuticals at 1-888-483-8279.

FENTORA tablets are flat-faced, round, beveled-edge in shape; are white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. Each tablet strength is marked with a unique identifier [see How Supplied/Storage and Handling (16)].

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FENTORA is contraindicated in:

{ "type": "p", "children": [], "text": "\nFENTORA is contraindicated in:\n" }

{ "type": "ul", "children": [ "Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1), Warnings and Precautions (5.2)].\n", "Significant respiratory depression [see Warnings and Precautions (5.2)].\n", "Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see Indications and Usage (1)].", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.11)].\n", "Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.15)].\n", "Known hypersensitivity to fentanyl or components of FENTORA (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions (6.2)]." ], "text": "" }

FENTORA contains fentanyl, a Schedule II controlled substance. As an opioid, FENTORA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed FENTORA. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing FENTORA, and reassess all patients receiving FENTORA for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as FENTORA, but use in such patients necessitates intensive counseling about the risks and proper use of FENTORA along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing FENTORA. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of FENTORA, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of FENTORA are essential [see Dosage and Administration (2)]. Overestimating the FENTORA dosage can result in a fatal overdose with the first dose. The substitution of FENTORA for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

FENTORA could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion of even one dose of FENTORA, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions ( 5.3)].

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.7)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with FENTORA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.4), Overdosage (10)].

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.

Patients and their caregivers must be informed that FENTORA contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible.

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of FENTORA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when FENTORA is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

When prescribing, do not convert a patient to FENTORA from any other fentanyl product on a mcg per mcg basis as FENTORA and other fentanyl products are not equivalent on a microgram per microgram basis.

FENTORA is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a FENTORA prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and FENTORA are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of FENTORA for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Dosage and Administration (2.1)]. Therefore, for opioid-tolerant patients, the initial dose of FENTORA should always be 100 mcg. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.4)].

Concomitant use of FENTORA with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of FENTORA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in FENTORA-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using FENTORA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in FENTORA-treated patients, evaluate patients at frequent intervals and consider dosage reduction of FENTORA until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of FENTORA with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using FENTORA with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)], FENTORA is available only through a restricted program called the TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to outpatients, the outpatients themselves, and pharmacies are required to enroll in the program.

Notable requirements of the TIRF REMS are:

Further information, including a list of certified pharmacies and enrolled distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Use of FENTORA for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.7)].

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of FENTORA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue FENTORA if serotonin syndrome is suspected.

The use of FENTORA in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: FENTORA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of FENTORA [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Regularly evaluate patients, particularly when initiating and titrating FENTORA and when FENTORA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

FENTORA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of FENTORA. In patients with circulatory shock, FENTORA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of FENTORA in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), FENTORA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with FENTORA.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of FENTORA in patients with impaired consciousness or coma.

FENTORA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in FENTORA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

The fentanyl in FENTORA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during FENTORA therapy.

FENTORA may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of FENTORA and know how they will react to the medication.

Intravenous fentanyl may produce bradycardia. Therefore, use FENTORA with caution in patients with bradyarrhythmias.

Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see Adverse Reactions (6)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of FENTORA has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.

The clinical trials of FENTORA were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.

The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received FENTORA for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of FENTORA therapy or cancer-related symptoms.

Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.

<div class="scrollingtable"><table> <caption> <span>Table 2. Adverse Events Which Occurred During Titration at a Frequency of ≥5%</span> </caption> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">System Organ Class MeDRA preferred term, n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">100 mcg</span> </p> <p> <span class="Bold">(N=45)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> <p> <span class="Bold">(N=34)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> <p> <span class="Bold">(N=53)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">600 mcg</span> </p> <p> <span class="Bold">(N=56)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> <p> <span class="Bold">(N=113)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total</span> </p> <p> <span class="Bold">(N=304)*</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10 (19)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13 (23)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50 (17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (17)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12 (23)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18 (32)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21 (19)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">58 (19)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (12)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20 (7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (14)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26 (9)</p> </td> </tr> </tbody> </table></div>

*Three hundred and two (302) patients were included in the safety analysis.

Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.

<div class="scrollingtable"><table> <caption> <span>Table 3. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of ≥5%</span> </caption> <col width="19%"/> <col width="11%"/> <col width="12%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">System Organ Class MeDRA preferred term,</span> </p> <p> <span class="Bold">n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">100 mcg</span> </p> <p> <span class="Bold">(N=19)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> <p> <span class="Bold">(N=31)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> <p> <span class="Bold">(N=44)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">600 mcg</span> </p> <p> <span class="Bold">(N=48)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> <p> <span class="Bold">(N=58)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total</span> </p> <p> <span class="Bold">(N=200)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (32)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (10)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Neutropenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (42)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14 (32)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13 (27)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17 (31)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">57 (29)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (37)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (20)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (17)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11 (20)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">40 (20)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (26)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24 (12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Edema peripheral</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (32)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (10)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23 (12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (10)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (20)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (19)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">32 (16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Pneumonia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Weight decreased</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dehydration</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (21)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">21 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Hypokalemia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Back pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Arthralgia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">11 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Neoplasms benign, malignant, and unspecified (including cysts and polyps)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cancer pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10 (5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (26)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (10)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (13)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (10)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20 (10)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Confusional state</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (16)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">14 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Depression</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (6)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (11)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (4)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic, and mediastinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Cough</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (8)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5 (9)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13 (7)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1 (5)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6 (19)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7 (15)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4 (7)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18 (9)</p> </td> </tr> </tbody> </table></div>

In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of FENTORA. There was no evidence of excess toxicity in this subset of patients.

Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesia to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited, and only resulted in treatment discontinuation for 2% of patients.

The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving FENTORA. Events are classified by system organ class.

Adverse Events (≥1%)

Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration

General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess

Injury, Poisoning, and Procedural Complications: Fall, Spinal Compression Fracture

Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic, and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat

Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders:

- Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

- Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Endocrine Disorders:

- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

- Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Immune System Disorders:

- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in FENTORA.

General Disorders and Administration Site Conditions:

- Drug withdrawal syndrome

Metabolic and Nutritional Disorders:

- Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 4 includes clinically significant drug interactions with FENTORA.

{ "type": "p", "children": [], "text": "Table 4 includes clinically significant drug interactions with FENTORA." }

<div class="scrollingtable"><table> <caption> <span>Table 4. Clinically Significant Drug Interactions with FENTORA</span> </caption> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Inhibitors of CYP3A4</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of FENTORA and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of FENTORA is achieved <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_d5543b26-23cd-4a96-b077-0a99a80585e4">5.6</a>)]</span>.</p> <p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is necessary, consider dosage reduction of FENTORA until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the FENTORA dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">CYP3A4 Inducers</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of FENTORA and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_d5543b26-23cd-4a96-b077-0a99a80585e4">5.6</a>)]</span>.</p> <p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is necessary, consider increasing the FENTORA dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider FENTORA dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rifampin, carbamazepine, phenytoin</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_dbe513dc-858b-4099-aa95-8abc1d533e3f">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_5b30a97c-81b2-4e43-8f82-e487f61eae4a">5.1</a>, <a href="#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113">5.2</a>, <a href="#www.splportal.comLINK_9d2bf110-3755-460c-9ecb-e7d4a48509e6">5.4</a>)]</span>.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#LINK_c945de19-72ec-4d7d-a0e6-d850fe229120">5.10</a>)]</span>.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue FENTORA if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#LINK_c945de19-72ec-4d7d-a0e6-d850fe229120">5.10</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113">5.2</a>)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The use of FENTORA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Phenelzine, tranylcypromine, linezolid</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">May reduce the analgesic effect of FENTORA and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Butorphanol, nalbuphine, pentazocine, buprenorphine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Because respiratory depression may be greater than otherwise expected, decrease the dosage of FENTORA and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_dbe513dc-858b-4099-aa95-8abc1d533e3f">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113">5.2</a>, <a href="#www.splportal.comLINK_9d2bf110-3755-460c-9ecb-e7d4a48509e6">5.4</a>)].</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cyclobenzaprine, metaxalone</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p> </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Evaluate patients for signs of urinary retention or reduced gastric motility when FENTORA is used concomitantly with anticholinergic drugs.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<caption>\n<span>Table 4. Clinically Significant Drug Interactions with FENTORA</span>\n</caption>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inhibitors of CYP3A4</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of FENTORA and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of FENTORA is achieved <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_d5543b26-23cd-4a96-b077-0a99a80585e4\">5.6</a>)]</span>.</p>\n<p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43\">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of FENTORA until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the FENTORA dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">CYP3A4 Inducers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of FENTORA and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43\">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_d5543b26-23cd-4a96-b077-0a99a80585e4\">5.6</a>)]</span>.</p>\n<p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_d9565e43-90f0-499a-93a7-fbb721b6fd43\">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider increasing the FENTORA dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider FENTORA dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Rifampin, carbamazepine, phenytoin</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_dbe513dc-858b-4099-aa95-8abc1d533e3f\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_5b30a97c-81b2-4e43-8f82-e487f61eae4a\">5.1</a>, <a href=\"#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113\">5.2</a>, <a href=\"#www.splportal.comLINK_9d2bf110-3755-460c-9ecb-e7d4a48509e6\">5.4</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_c945de19-72ec-4d7d-a0e6-d850fe229120\">5.10</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue FENTORA if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_c945de19-72ec-4d7d-a0e6-d850fe229120\">5.10</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113\">5.2</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The use of FENTORA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Phenelzine, tranylcypromine, linezolid</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">May reduce the analgesic effect of FENTORA and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Butorphanol, nalbuphine, pentazocine, buprenorphine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of FENTORA and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_dbe513dc-858b-4099-aa95-8abc1d533e3f\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_ff2971aa-6616-497b-8759-5e9041703113\">5.2</a>, <a href=\"#www.splportal.comLINK_9d2bf110-3755-460c-9ecb-e7d4a48509e6\">5.4</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Cyclobenzaprine, metaxalone</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Evaluate patients for signs of urinary retention or reduced gastric motility when FENTORA is used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8)]. Available data with FENTORA in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of FENTORA for an extended period of time during pregnancy (see Clinical Considerations).

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. FENTORA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including FENTORA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

Fentanyl (25, 50, or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison).

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of FENTORA on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of FENTORA based on a mg/m2 basis). No evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg FENTORA per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of FENTORA in humans.

In a postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with FENTORA.

Clinical Considerations

Monitor infants exposed to FENTORA through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

The safety and efficacy of FENTORA have not been established in pediatric patients below the age of 18 years.

Of the 304 patients with cancer in clinical studies of FENTORA, 69 (23%) were 65 years of age and older. Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating FENTORA in elderly patients to provide adequate efficacy while minimizing risk.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of FENTORA slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

Insufficient information exists to make recommendations regarding the use of FENTORA in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

The pharmacokinetic effects of race with the use of FENTORA have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.

FENTORA contains fentanyl, a Schedule II controlled substance.

FENTORA contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of FENTORA increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of FENTORA with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of FENTORA abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use FENTORA in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

FENTORA, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of FENTORA

Abuse of FENTORA poses a risk of overdose and death. The risk is increased with concurrent use of FENTORA with alcohol and/or other CNS depressants.

FENTORA is approved for oral transmucosal use only.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]." }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

{ "type": "p", "children": [], "text": "In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures." }

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

{ "type": "p", "children": [], "text": "Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. " }

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in FENTORA, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in FENTORA, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information." }

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist." }

FENTORA (fentanyl buccal tablet) is an opioid agonist, intended for buccal mucosal administration.

{ "type": "p", "children": [], "text": "FENTORA (fentanyl buccal tablet) is an opioid agonist, intended for buccal mucosal administration." }

FENTORA is designed to be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet and absorption of fentanyl across the oral mucosa.

{ "type": "p", "children": [], "text": "FENTORA is designed to be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet and absorption of fentanyl across the oral mucosa." }

FENTORA employs the OraVescent® drug delivery technology, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient pH changes accompanying the reaction may optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) of fentanyl through the buccal mucosa.

{ "type": "p", "children": [], "text": "FENTORA employs the OraVescent® drug delivery technology, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient pH changes accompanying the reaction may optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) of fentanyl through the buccal mucosa." }

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:

{ "type": "p", "children": [], "text": "\nActive Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:" }

All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl free base. Inactive Ingredients: Mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

{ "type": "p", "children": [], "text": "All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl free base. Inactive Ingredients: Mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate." }

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Effects on the Central Nervous System

The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and to electrical stimulation.

Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals [see Dosage and Administration (2.1)].

The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.5)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.4, 2.5)].

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see Warnings and Precautions (5), Overdosage (10)].

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.

Absorption

Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of FENTORA is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract.

In a study that compared the absolute and relative bioavailability of FENTORA and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with FENTORA) (Table 5).

<div class="scrollingtable"><table> <caption> <span>Table 5. Pharmacokinetic Parameters* in Adult Subjects Receiving FENTORA or ACTIQ</span> </caption> <col width="38%"/> <col width="29%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Pharmacokinetic</span> </p> <p> <span class="Bold">Parameter (mean)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">FENTORA 400 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">ACTIQ 400 mcg</span> </p> <p> <span class="Bold">(adjusted dose)***        </span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Absolute Bioavailability</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">65% ± 20%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">47% ± 10.5%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Fraction Absorbed Transmucosally</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">48% ± 31.8%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22% ± 17.3%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">T<span class="Sub">max</span> (minute)</span><span class="Bold">**</span><span class="Bold">    </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">46.8 (20-240)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">90.8 (35-240)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">max</span> (ng/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.02 ± 0.42</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.63 ± 0.21</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-tmax</span> (ng•hr/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.40 ± 0.18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.14 ± 0.05</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-inf</span> (ng•hr/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.48 ± 2.98</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.79 ± 1.96</p> </td> </tr> </tbody> </table></div>

* Based on venous blood samples.

** Data for Tmax presented as median (range).

***ACTIQ data was dose adjusted (800 mcg to 400 mcg).

Similarly, in another bioavailability study exposure following administration of FENTORA was also greater (approximately 50%) compared to ACTIQ.

Due to differences in drug delivery, measures of exposure (Cmax, AUC0-tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with FENTORA compared to ACTIQ (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see Dosage and Administration (2.3), Warnings and Precautions (5.5)]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for FENTORA.

Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of FENTORA and ACTIQ in Healthy Subjects

ACTIQ data was dose adjusted (800 mcg to 400 mcg).

Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2.

<div class="scrollingtable"><table> <caption> <span>Table 6. Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in Healthy Subjects</span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Pharmacokinetic Parameter (mean±SD)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">100 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> <p> <span class="Bold">(ng/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.25 ± 0.14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.40 ± 0.18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.97 ± 0.53</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.59 ± 0.90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> <p class="First"> <span class="Bold">T<span class="Sub">max</span>, minute</span><span class="Bold">**</span> </p> <p> <span class="Bold">(range)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">45.0</p> <p>(25.0 - 181.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40.0</p> <p>(20.0 - 180.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35.0</p> <p>(20.0 - 180.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40.0</p> <p>(25.0 - 180.0)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-inf</span></span> </p> <p> <span class="Bold">(ng•hr/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.98 ± 0.37</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.11 ± 1.13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.72 ± 1.95</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9.05 ± 3.72</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-tmax</span></span> </p> <p> <span class="Bold">(ng•hr/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.09 ± 0.06</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.13 ± 0.09</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.34 ± 0.23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.52 ± 0.38</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">T<span class="Sub">1/2</span>, hr</span><span class="Bold">**</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.63</p> <p>(1.47 - 13.57)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.43</p> <p>(1.85 - 20.76)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11.09</p> <p>(4.63 - 20.59)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11.70</p> <p>(4.63 - 28.63)</p> </td> </tr> </tbody> </table></div>

* Based on venous sampling.

** Data for Tmax presented as median (range).

Figure 2. Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in Healthy Subjects

Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.

The effect of mucositis (Grade 1) on the pharmacokinetic profile of FENTORA was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected tmax where range was used) are presented in Table 7.

<div class="scrollingtable"><table> <caption> <span>Table 7. Pharmacokinetic Parameters in Patients with Mucositis</span> </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Patient status</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> <p> <span class="Bold">(ng/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">t<span class="Sub">max</span> (min)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-tmax</span></span> </p> <p> <span class="Bold">(ng•hr/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-8</span></span> </p> <p> <span class="Bold">(ng•hr/mL)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Mucositis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.25 ± 0.78</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25.0 (15 - 45)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.21 ± 0.16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.33 ± 0.93</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No mucositis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.24 ± 0.77</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22.5 (10 - 121)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.25 ± 0.24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.86 ± 0.86</p> </td> </tr> </tbody> </table></div>

Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.

Distribution

Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.

Elimination

Metabolism

The metabolic pathways following buccal administration of FENTORA have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active [see Drug Interactions (7)].

Excretion

Disposition of fentanyl following buccal administration of FENTORA has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.

The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Sex

Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.

Race

In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects (mean Cmax and AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).

Carcinogenesis

Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 2.3- and 3.4-times the exposure of a single human dose of 800 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

Mutagenesis

Fentanyl citrate was not mutagenic in the Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility

In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 8.6 times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 5.7- times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for FENTORA.

The efficacy of FENTORA was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid-tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.

{ "type": "p", "children": [], "text": "The efficacy of FENTORA was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid-tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer." }

In this trial, patients were titrated in an open-label manner to a successful dose of FENTORA. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects. Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of FENTORA and 3 being placebo. Patients used one tablet of study drug (either FENTORA or placebo) per breakthrough pain episode.

{ "type": "p", "children": [], "text": "In this trial, patients were titrated in an open-label manner to a successful dose of FENTORA. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects. Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of FENTORA and 3 being placebo. Patients used one tablet of study drug (either FENTORA or placebo) per breakthrough pain episode." }

Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45, and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.

{ "type": "p", "children": [], "text": "Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45, and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure." }

Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg.

{ "type": "p", "children": [], "text": "Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg." }

<div class="scrollingtable"><table> <caption> <span>Table 8. Successful Dose of FENTORA Following Initial Titration</span> </caption> <col width="37%"/> <col width="37%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">FENTORA Dose</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">n (%)</span> </p> <p> <span class="Bold">(N=80)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13 (16)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (14)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">400 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21 (26)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">600 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (13)</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">800 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25 (31)</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<caption>\n<span>Table 8. Successful Dose of FENTORA Following Initial Titration</span>\n</caption>\n<col width=\"37%\"/>\n<col width=\"37%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">FENTORA Dose</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">n (%)</span>\n</p>\n<p>\n<span class=\"Bold\">(N=80)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">100 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">13 (16)</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">200 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">11 (14)</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">400 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">21 (26)</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">600 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">10 (13)</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">800 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">25 (31)</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

The LS mean (SE) SPID30 for FENTORA-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).

{ "type": "p", "children": [], "text": "The LS mean (SE) SPID30 for FENTORA-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18)." }

Figure 3. Mean Pain Intensity Differences (PID) at Each Time Point During the Double-Blind Treatment Period

{ "type": "p", "children": [], "text": "\nFigure 3. Mean Pain Intensity Differences (PID) at Each Time Point During the Double-Blind Treatment Period\n" }

PID=pain intensity difference; SEM=standard error of the mean

{ "type": "p", "children": [], "text": "PID=pain intensity difference; SEM=standard error of the mean" }

FENTORA is supplied in individually sealed, child-resistant blister packages. Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with , and the other side of each dosage strength is uniquely identified by the debossing on the tablet as described in the table below. In addition, the dosage strength is indicated on the blister package and the carton. See blister package and carton for product information.

{ "type": "p", "children": [], "text": "FENTORA is supplied in individually sealed, child-resistant blister packages. Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with , and the other side of each dosage strength is uniquely identified by the debossing on the tablet as described in the table below. In addition, the dosage strength is indicated on the blister package and the carton. See blister package and carton for product information." }

<div class="scrollingtable"><table> <col width="12%"/> <col width="13%"/> <col width="18%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dosage</span> </p> <p> <span class="Bold">Strength</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Debossing</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Carton/Blister</span> </p> <p> <span class="Bold">Package Color</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC Number</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Blue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63459-541-28</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Orange</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63459-542-28</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">400 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sage green</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63459-544-28</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">600 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Magenta (pink)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63459-546-28</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">800 mcg</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Yellow</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NDC 63459-548-28</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"12%\"/>\n<col width=\"13%\"/>\n<col width=\"18%\"/>\n<col width=\"22%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Dosage</span>\n</p>\n<p>\n<span class=\"Bold\">Strength</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Debossing</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Carton/Blister</span>\n</p>\n<p>\n<span class=\"Bold\">Package Color</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC Number</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">100 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Blue</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 63459-541-28</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">200 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Orange</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 63459-542-28</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">400 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Sage green</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 63459-544-28</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">600 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">6</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Magenta (pink)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 63459-546-28</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">800 mcg</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Yellow</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">NDC 63459-548-28</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

{ "type": "p", "children": [], "text": "\nNote: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing." }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.)

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.)" }

Protect FENTORA from freezing and moisture. Do not use if the blister package has been tampered with.

{ "type": "p", "children": [], "text": "Protect FENTORA from freezing and moisture. Do not use if the blister package has been tampered with." }

Store FENTORA securely and dispose of properly.

{ "type": "p", "children": [], "text": "Store FENTORA securely and dispose of properly.\n" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide).\n" }

Storage and Disposal of Unused and Used FENTORA [see Medication Guide / Instructions for Use].

{ "type": "p", "children": [], "text": "\nStorage and Disposal of Unused and Used FENTORA [see Medication Guide / Instructions for Use].\n" }

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store FENTORA securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving FENTORA unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. 

{ "type": "p", "children": [], "text": "Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store FENTORA securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving FENTORA unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. " }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused FENTORA should be disposed of by removing FENTORA from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). Do not flush the FENTORA blister packages or cartons down the toilet. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused FENTORA should be disposed of by removing FENTORA from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). Do not flush the FENTORA blister packages or cartons down the toilet. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines." }

Disposal of Unopened FENTORA Blister Packages When No Longer Needed:

{ "type": "p", "children": [], "text": "Disposal of Unopened FENTORA Blister Packages When No Longer Needed:" }

{ "type": "ul", "children": [ "Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Instruct patients to read this information in its entirety and provide an opportunity to have their questions answered.", "In the event that a caregiver requires additional assistance in disposing of excess unusable tablets that remain in the home after a patient has expired, instruct them to call the Teva Pharmaceuticals toll-free number (1-888-483-8279) or seek assistance from their local DEA office." ], "text": "" }

Addiction, Abuse, and Misuse

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse\n" }

Inform patients that the use of FENTORA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share FENTORA with others and to take steps to protect FENTORA from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of FENTORA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share FENTORA with others and to take steps to protect FENTORA from theft or misuse." }

Life-Threatening Respiratory Depression

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n" }

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting FENTORA or when the dosage is increased, and that it can occur even at recommended dosages.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting FENTORA or when the dosage is increased, and that it can occur even at recommended dosages." }

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)]." }

Accidental Ingestion

{ "type": "p", "children": [], "text": "\nAccidental Ingestion\n" }

{ "type": "ul", "children": [ "Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure [see Warnings and Precautions (5.3)].", "Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].", "Instruct patients to take steps to store FENTORA securely and to dispose of unused FENTORA [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.7)].\n", "Instruct patients and caregivers to keep both used and unused FENTORA out of the reach of children [see Warnings and Precautions (5.3)]." ], "text": "" }

Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)

{ "type": "p", "children": [], "text": "\nInteractions with Benzodiazepines and Other CNS Depressants (including Alcohol)\n" }

Inform patients that potentially fatal additive effects may occur if FENTORA is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients that potentially fatal additive effects may occur if FENTORA is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)]." }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

{ "type": "p", "children": [], "text": "\nPatient Access to Naloxone for the Emergency Treatment of Opioid Overdose\n" }

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with FENTORA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with FENTORA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].\n" }

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize the signs and symptoms of an overdose." }

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

{ "type": "p", "children": [], "text": "Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)]." }

If naloxone is prescribed, also advise patients and caregivers:

{ "type": "p", "children": [], "text": "If naloxone is prescribed, also advise patients and caregivers:" }

{ "type": "ul", "children": [ "How to treat with naloxone in the event of an opioid overdose", "To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency", "To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do." ], "text": "" }

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

{ "type": "p", "children": [], "text": "\nTransmucosal Immediate-Release Fentanyl (TIRF) REMS\n" }

FENTORA is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:

{ "type": "p", "children": [], "text": "FENTORA is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:" }

{ "type": "ul", "children": [ "Outpatients must be enrolled in the REMS program", "Patients must be opioid-tolerant to receive FENTORA" ], "text": "" }

FENTORA is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

{ "type": "p", "children": [], "text": "FENTORA is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product." }

Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require FENTORA while hospitalized [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require FENTORA while hospitalized [see Warnings and Precautions (5.7)].\n" }

Hyperalgesia and Allodynia

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia\n" }

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].\n" }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)]." }

MAOI Interaction

{ "type": "p", "children": [], "text": "\nMAOI Interaction\n" }

Inform patients to avoid taking FENTORA while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FENTORA [see Warnings and Precautions (5.10), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients to avoid taking FENTORA while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FENTORA [see Warnings and Precautions (5.10), Drug Interactions (7)].\n" }

Important Administration Instructions [see Dosage and Administration (2)]

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions [see Dosage and Administration (2)]\n" }

{ "type": "ul", "children": [ "Instruct patients not to take FENTORA for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.", "Instruct patients on the meaning of opioid tolerance and that FENTORA is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.", "Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take FENTORA.", "Instruct patients that the titration phase is the only period in which they may take more than ONE tablet to achieve a desired dose (e.g., two 100 mcg tablets for a 200 mcg dose).", "Instruct patients that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF FENTORA USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of FENTORA for any breakthrough pain episode.", "Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA.", "Instruct patients NOT to share FENTORA and that sharing FENTORA with anyone else could result in the other individual’s death due to overdose.", "Make patients aware that FENTORA contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.", "Instruct patients not to open the blister until ready to use FENTORA and not to store the tablet in a temporary container such as a pill box, once it has been removed from the blister package.", "Instruct patients that FENTORA tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. Tablets are to be placed between the cheek and gum above a molar tooth or under the tongue and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.", "Caution patients to talk to their healthcare provider if breakthrough pain is not alleviated or worsens after taking FENTORA.", "Instruct patients to use FENTORA exactly as prescribed by their healthcare provider and not to take FENTORA more often than prescribed.", "Provide patients and their caregivers with a Medication Guide each time FENTORA is dispensed because new information may be available." ], "text": "" }

Driving or Operating Heavy Machinery

{ "type": "p", "children": [], "text": "\nDriving or Operating Heavy Machinery\n" }

Inform patients that FENTORA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].

{ "type": "p", "children": [], "text": "Inform patients that FENTORA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].\n" }

Constipation

{ "type": "p", "children": [], "text": "\nConstipation\n" }

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)]." }

Adrenal Insufficiency

{ "type": "p", "children": [], "text": "\nAdrenal Insufficiency\n" }

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)]." }

Hypotension

{ "type": "p", "children": [], "text": "\nHypotension\n" }

Inform patients that FENTORA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Inform patients that FENTORA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].\n" }

Anaphylaxis

{ "type": "p", "children": [], "text": "\nAnaphylaxis\n" }

Inform patients that anaphylaxis has been reported with ingredients contained in FENTORA. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Inform patients that anaphylaxis has been reported with ingredients contained in FENTORA. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].\n" }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Neonatal Opioid Withdrawal Syndrome

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome\n" }

Inform patients that use of FENTORA for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform patients that use of FENTORA for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)]." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Inform female patients of reproductive potential that FENTORA can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential that FENTORA can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)]." }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].\n" }

Dispense with Medication Guide available at: www.tevausa.com/medguides

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: www.tevausa.com/medguides" }

FENT-013

{ "type": "p", "children": [], "text": "FENT-013" }

Distributed By: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Distributed By:\nTeva Pharmaceuticals USA, Inc.\nParsippany, NJ 07054" }

©2023 Cephalon, LLC.

{ "type": "p", "children": [], "text": "©2023 Cephalon, LLC." }

Dispense with Medication Guide available at: www.tevausa.com/medguides

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: www.tevausa.com/medguides" }

<div class="scrollingtable"><table> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Medication Guide</span> </p> <p> <span class="Bold">FENTORA<span class="Sup">®</span> (fen-tor-a)</span> </p> <p> <span class="Bold">(fentanyl) buccal tablet, CII</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">IMPORTANT:</span> </p> <p> <span class="Bold">Do not use FENTORA unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.</span> </p> <p> <span class="Bold">Keep FENTORA in a safe place away from children. </span> </p> <p> <span class="Bold">Get emergency medical help right away if:</span> </p> <ul class="Disk"> <li> <span class="Bold">a child takes FENTORA. FENTORA can cause an overdose and death in any child who takes it.</span> </li> <li> <span class="Bold">an adult who has not been prescribed FENTORA uses it.</span> </li> <li> <span class="Bold">an adult who is not already taking opioids around-the-clock, uses FENTORA.</span> </li> </ul> <p> <span class="Bold">These are medical emergencies that can cause death. If possible, try to remove FENTORA from the mouth.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">FENTORA is:</span> </p> <ul class="Disk"> <li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. FENTORA is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use FENTORA if you are not opioid tolerant.</li> <li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Important information about FENTORA:</span> </p> <ul class="Disk"> <li> <span class="Bold">Get emergency help or call 911 right away if you take too much FENTORA (overdose).</span> When you first start taking FENTORA, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li> <li>Taking FENTORA with other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.</li> <li>Never give anyone else your FENTORA. They could die from taking it. Selling or giving away FENTORA is against the law. </li> <li>Store FENTORA securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li> <li>If you stop taking your around-the-clock opioid pain medicine for your cancer pain, <span class="Bold">you must stop</span> using FENTORA. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.</li> <li>FENTORA is available only through a program called the <span class="Bold">T</span>ransmucosal <span class="Bold">I</span>mmediate <span class="Bold">R</span>elease <span class="Bold">F</span>entanyl (TIRF) <span class="Bold">R</span>isk <span class="Bold">E</span>valuation and <span class="Bold">M</span>itigation <span class="Bold">S</span>trategy (REMS). To receive FENTORA, you must: <ul class="Circle"> <li>talk to your healthcare provider</li> <li>understand the benefits and risks of FENTORA</li> <li>agree to all of the instructions</li> <li>sign the Patient Enrollment Form</li> </ul> </li> </ul> <ul class="Disk"> <li>FENTORA is only available at pharmacies that are part of the TIRF REMS. Your healthcare provider can help you locate a pharmacy closest to your home where you can have your FENTORA prescription filled.</li> </ul> <ul class="Disk"> <li>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Do not take FENTORA if:</span> </p> <ul class="Disk"> <li>You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines.</li> <li>You have severe asthma, trouble breathing, or other lung problems.</li> <li>You have a bowel blockage or have narrowing of the stomach or intestines.</li> <li>You are allergic to any of the ingredients in FENTORA<span class="Italics">.</span> See the end of this Medication Guide for a complete list of ingredients in FENTORA.</li> <li>You have short-term pain that you would expect to go away in a few days, such as: <ul class="Circle"> <li>pain after surgery </li> <li>headache or migraine</li> <li>dental pain</li> </ul> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before taking FENTORA, tell your healthcare provider if you have a history of:</span> </p> <ul class="Disk"> <li>troubled breathing or lung problems such as asthma, wheezing, or shortness of breath</li> <li>head injury, seizures</li> <li>slow heart rate or other heart problems</li> <li>low blood pressure</li> <li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems </li> <li>mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)]</li> <li>problems urinating</li> <li>liver, kidney, thyroid problems</li> <li>pancreas or gallbladder problems</li> </ul> <p> <span class="Bold">Tell your healthcare provider if you are:</span> </p> <ul class="Disk"> <li> <span class="Bold">noticing <span class="Bold">your pain getting worse. </span></span>If your pain gets worse after you take FENTORA, do not take more FENTORA without first talking to your healthcare provider. Talk to your healthcare provider if the pain you have increases, if your feel more sensitive to pain, or if you have new pain after taking FENTORA.</li> <li> <span class="Bold">pregnant or planning to become pregnant.</span> Use of FENTORA for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</li> <li> <span class="Bold">breastfeeding.</span> FENTORA passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</li> <li>living in a household where there are small children or someone who has abused street or prescription drugs.</li> <li>taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking FENTORA with certain other medicines can cause serious side effects that could lead to death.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">When taking FENTORA:</span> </p> <ul class="Disk"> <li>Do not change your dose. Take FENTORA exactly as prescribed by your healthcare provider.</li> <li>Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you. </li> <li> <span class="Bold">See the detailed Instructions for Use at the end of this Medication Guide for information about how to use FENTORA. </span> </li> <li> <span class="Bold">Use FENTORA tablets whole.</span> </li> <li> <span class="Bold">Do not crush, split, suck, or chew FENTORA tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.</span> </li> <li>Wait 30 minutes after using FENTORA. If there is any of the FENTORA tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine.</li> <li>You must not use more than 2 doses of FENTORA for each episode of breakthrough cancer pain.</li> <li>Use <span class="Bold">1</span> dose of FENTORA for an episode of breakthrough cancer pain. </li> <li>If your breakthrough cancer pain does not get better 30 minutes after taking the first dose of FENTORA, you can use <span class="Bold">only 1</span> more dose of FENTORA as instructed by your healthcare provider.</li> <li>If your breakthrough pain does not get better after the second dose of FENTORA, call your healthcare provider for instructions. <span class="Bold">Do not use another dose of FENTORA at this time.</span> </li> <li>Wait at least <span class="Bold">4</span> hours before treating a new episode of breakthrough cancer pain with FENTORA. </li> <li>If you only need to take 1 dose of FENTORA for an episode of breakthrough pain, you must wait 4 hours from the time of that dose to take a dose of FENTORA for a <span class="Bold">new</span> episode of breakthrough pain.</li> <li>If you need to use 2 doses of FENTORA for an episode of breakthrough pain, you must wait 4 hours after the second dose to take a dose of FENTORA for a <span class="Bold">new</span> episode of breakthrough pain.</li> <li>It is important for you to keep taking your around-the-clock opioid pain medicine while using FENTORA.</li> <li>Talk to your healthcare provider if your dose of FENTORA does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of FENTORA needs to be changed.</li> <li>Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted.</li> <li>If you begin to feel dizzy, sick to your stomach, or very sleepy before the tablet is completely dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or toilet right away. Rinse the sink or flush the toilet to dispose of any remaining tablet pieces.</li> <li>Do not stop taking FENTORA without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.</li> <li>After you stop taking, or when FENTORA is no longer needed, see “<span class="Bold">How should I dispose of unused FENTORA tablets when they are no longer needed?</span>” for proper disposal of FENTORA.</li> <li>Dispose of expired, unwanted, or unused FENTORA by removing the product from the blister cards and promptly flushing down the toilet (if a drug take-back option is not readily available.) Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li> <li> <span class="Bold">DO NOT</span> Drive or operate heavy machinery until you know how FENTORA affects you. FENTORA can make you sleepy, dizzy, or lightheaded.</li> <li> <span class="Bold">DO NOT</span> Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with FENTORA may cause you to overdose and die.</li> <li> <span class="Bold">DO NOT Switch from FENTORA to other medicines that contain fentanyl without talking to your healthcare provider.</span> The amount of fentanyl in a dose of FENTORA is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of FENTORA that may be different than other fentanyl containing medicines you may have been taking.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">The possible side effects of FENTORA:</span> </p> <ul class="Disk"> <li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, low red blood cell count, swelling of the arms, hands, legs, and feet. Call your healthcare provider if you have any of these symptoms and they are severe.</li> <li>Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.</li> <li>Pain, irritation, or sores at the application site (on your gum, on the inside of your cheek, or under your tongue). Tell your healthcare provider if this is a problem for you.</li> </ul> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Get emergency medical help or call 911 right away if you have:</span> </p> <ul class="Disk"> <li>Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li> <li>These symptoms can be a sign that you have taken too much FENTORA or the dose is too high for you. <span class="Bold">These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not take any more FENTORA until you have talked to your healthcare provider.</span> </li> </ul> <p>These are not all the possible side effects of FENTORA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class="Bold">For more information go to dailymed.nlm.nih.gov</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Medication Guide</span>\n</p>\n<p>\n<span class=\"Bold\">FENTORA<span class=\"Sup\">®</span> (fen-tor-a)</span>\n</p>\n<p>\n<span class=\"Bold\">(fentanyl) buccal tablet, CII</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">IMPORTANT:</span>\n</p>\n<p>\n<span class=\"Bold\">Do not use FENTORA unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.</span>\n</p>\n<p>\n<span class=\"Bold\">Keep FENTORA in a safe place away from children. </span>\n</p>\n<p>\n<span class=\"Bold\">Get emergency medical help right away if:</span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">a child takes FENTORA. FENTORA can cause an overdose and death in any child who takes it.</span>\n</li>\n<li>\n<span class=\"Bold\">an adult who has not been prescribed FENTORA uses it.</span>\n</li>\n<li>\n<span class=\"Bold\">an adult who is not already taking opioids around-the-clock, uses FENTORA.</span>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">These are medical emergencies that can cause death. If possible, try to remove FENTORA from the mouth.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">FENTORA is:</span>\n</p>\n<ul class=\"Disk\">\n<li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. FENTORA is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use FENTORA if you are not opioid tolerant.</li>\n<li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Important information about FENTORA:</span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">Get emergency help or call 911 right away if you take too much FENTORA (overdose).</span> When you first start taking FENTORA, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li>\n<li>Taking FENTORA with other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.</li>\n<li>Never give anyone else your FENTORA. They could die from taking it. Selling or giving away FENTORA is against the law. </li>\n<li>Store FENTORA securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li>\n<li>If you stop taking your around-the-clock opioid pain medicine for your cancer pain, <span class=\"Bold\">you must stop</span> using FENTORA. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.</li>\n<li>FENTORA is available only through a program called the <span class=\"Bold\">T</span>ransmucosal <span class=\"Bold\">I</span>mmediate <span class=\"Bold\">R</span>elease <span class=\"Bold\">F</span>entanyl (TIRF) <span class=\"Bold\">R</span>isk <span class=\"Bold\">E</span>valuation and <span class=\"Bold\">M</span>itigation <span class=\"Bold\">S</span>trategy (REMS). To receive FENTORA, you must:\n <ul class=\"Circle\">\n<li>talk to your healthcare provider</li>\n<li>understand the benefits and risks of FENTORA</li>\n<li>agree to all of the instructions</li>\n<li>sign the Patient Enrollment Form</li>\n</ul>\n</li>\n</ul>\n<ul class=\"Disk\">\n<li>FENTORA is only available at pharmacies that are part of the TIRF REMS. Your healthcare provider can help you locate a pharmacy closest to your home where you can have your FENTORA prescription filled.</li>\n</ul>\n<ul class=\"Disk\">\n<li>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take FENTORA if:</span>\n</p>\n<ul class=\"Disk\">\n<li>You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines.</li>\n<li>You have severe asthma, trouble breathing, or other lung problems.</li>\n<li>You have a bowel blockage or have narrowing of the stomach or intestines.</li>\n<li>You are allergic to any of the ingredients in FENTORA<span class=\"Italics\">.</span> See the end of this Medication Guide for a complete list of ingredients in FENTORA.</li>\n<li>You have short-term pain that you would expect to go away in a few days, such as:\n <ul class=\"Circle\">\n<li>pain after surgery </li>\n<li>headache or migraine</li>\n<li>dental pain</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking FENTORA, tell your healthcare provider if you have a history of:</span>\n</p>\n<ul class=\"Disk\">\n<li>troubled breathing or lung problems such as asthma, wheezing, or shortness of breath</li>\n<li>head injury, seizures</li>\n<li>slow heart rate or other heart problems</li>\n<li>low blood pressure</li>\n<li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems </li>\n<li>mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)]</li>\n<li>problems urinating</li>\n<li>liver, kidney, thyroid problems</li>\n<li>pancreas or gallbladder problems</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">noticing <span class=\"Bold\">your pain getting worse. </span></span>If your pain gets worse after you take FENTORA, do not take more FENTORA without first talking to your healthcare provider. Talk to your healthcare provider if the pain you have increases, if your feel more sensitive to pain, or if you have new pain after taking FENTORA.</li>\n<li>\n<span class=\"Bold\">pregnant or planning to become pregnant.</span> Use of FENTORA for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</li>\n<li>\n<span class=\"Bold\">breastfeeding.</span> FENTORA passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</li>\n<li>living in a household where there are small children or someone who has abused street or prescription drugs.</li>\n<li>taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking FENTORA with certain other medicines can cause serious side effects that could lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">When taking FENTORA:</span>\n</p>\n<ul class=\"Disk\">\n<li>Do not change your dose. Take FENTORA exactly as prescribed by your healthcare provider.</li>\n<li>Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you. </li>\n<li>\n<span class=\"Bold\">See the detailed Instructions for Use at the end of this Medication Guide for information about how to use FENTORA. </span>\n</li>\n<li>\n<span class=\"Bold\">Use FENTORA tablets whole.</span>\n</li>\n<li>\n<span class=\"Bold\">Do not crush, split, suck, or chew FENTORA tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.</span>\n</li>\n<li>Wait 30 minutes after using FENTORA. If there is any of the FENTORA tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine.</li>\n<li>You must not use more than 2 doses of FENTORA for each episode of breakthrough cancer pain.</li>\n<li>Use <span class=\"Bold\">1</span> dose of FENTORA for an episode of breakthrough cancer pain. </li>\n<li>If your breakthrough cancer pain does not get better 30 minutes after taking the first dose of FENTORA, you can use <span class=\"Bold\">only 1</span> more dose of FENTORA as instructed by your healthcare provider.</li>\n<li>If your breakthrough pain does not get better after the second dose of FENTORA, call your healthcare provider for instructions. <span class=\"Bold\">Do not use another dose of FENTORA at this time.</span>\n</li>\n<li>Wait at least <span class=\"Bold\">4</span> hours before treating a new episode of breakthrough cancer pain with FENTORA. </li>\n<li>If you only need to take 1 dose of FENTORA for an episode of breakthrough pain, you must wait 4 hours from the time of that dose to take a dose of FENTORA for a <span class=\"Bold\">new</span> episode of breakthrough pain.</li>\n<li>If you need to use 2 doses of FENTORA for an episode of breakthrough pain, you must wait 4 hours after the second dose to take a dose of FENTORA for a <span class=\"Bold\">new</span> episode of breakthrough pain.</li>\n<li>It is important for you to keep taking your around-the-clock opioid pain medicine while using FENTORA.</li>\n<li>Talk to your healthcare provider if your dose of FENTORA does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of FENTORA needs to be changed.</li>\n<li>Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted.</li>\n<li>If you begin to feel dizzy, sick to your stomach, or very sleepy before the tablet is completely dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or toilet right away. Rinse the sink or flush the toilet to dispose of any remaining tablet pieces.</li>\n<li>Do not stop taking FENTORA without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.</li>\n<li>After you stop taking, or when FENTORA is no longer needed, see “<span class=\"Bold\">How should I dispose of unused FENTORA tablets when they are no longer needed?</span>” for proper disposal of FENTORA.</li>\n<li>Dispose of expired, unwanted, or unused FENTORA by removing the product from the blister cards and promptly flushing down the toilet (if a drug take-back option is not readily available.) Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li>\n<li>\n<span class=\"Bold\">DO NOT</span> Drive or operate heavy machinery until you know how FENTORA affects you. FENTORA can make you sleepy, dizzy, or lightheaded.</li>\n<li>\n<span class=\"Bold\">DO NOT</span> Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with FENTORA may cause you to overdose and die.</li>\n<li>\n<span class=\"Bold\">DO NOT Switch from FENTORA to other medicines that contain fentanyl without talking to your healthcare provider.</span> The amount of fentanyl in a dose of FENTORA is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of FENTORA that may be different than other fentanyl containing medicines you may have been taking.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The possible side effects of FENTORA:</span>\n</p>\n<ul class=\"Disk\">\n<li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, low red blood cell count, swelling of the arms, hands, legs, and feet. Call your healthcare provider if you have any of these symptoms and they are severe.</li>\n<li>Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.</li>\n<li>Pain, irritation, or sores at the application site (on your gum, on the inside of your cheek, or under your tongue). Tell your healthcare provider if this is a problem for you.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Get emergency medical help or call 911 right away if you have:</span>\n</p>\n<ul class=\"Disk\">\n<li>Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li>\n<li>These symptoms can be a sign that you have taken too much FENTORA or the dose is too high for you. <span class=\"Bold\">These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not take any more FENTORA until you have talked to your healthcare provider.</span>\n</li>\n</ul>\n<p>These are not all the possible side effects of FENTORA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class=\"Bold\">For more information go to dailymed.nlm.nih.gov</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

How should I store FENTORA?

{ "type": "p", "children": [], "text": "\nHow should I store FENTORA?\n" }

{ "type": "ul", "children": [ "\nAlways keep FENTORA in a safe place away from children and from anyone for whom it has not been prescribed. Protect FENTORA from theft.\n", "\nStore FENTORA at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use. Do not freeze FENTORA.\n", "\nKeep FENTORA in the original blister unit. Do not remove FENTORA from its blister packaging for storage in a temporary container, such as a pill box. \n", "\nKeep FENTORA dry.\n" ], "text": "" }

How should I dispose of unused FENTORA tablets when they are no longer needed?

{ "type": "p", "children": [], "text": "\nHow should I dispose of unused FENTORA tablets when they are no longer needed?\n" }

{ "type": "ul", "children": [ "\nDispose of any unused FENTORA tablets remaining from a prescription as soon as they are no longer needed.\n\n\n Remove the tablets from blister packages and flush them down the toilet.\n\n\n" ], "text": "" }

{ "type": "ul", "children": [ "\nDo not flush the FENTORA packaging (card, blister units, or cartons) down the toilet.\n", "\nIf you need help with disposal of FENTORA, call Teva Pharmaceuticals at 1-888-483-8279 or call your local Drug Enforcement Agency (DEA) office.\n" ], "text": "" }

General information about FENTORA

{ "type": "p", "children": [], "text": "\nGeneral information about FENTORA\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use FENTORA only for the purpose for which it was prescribed. Do not give FENTORA to other people, even if they have the same symptoms you have. FENTORA can harm other people and even cause death. Sharing FENTORA is against the law.

{ "type": "p", "children": [], "text": "\nMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use FENTORA only for the purpose for which it was prescribed. Do not give FENTORA to other people, even if they have the same symptoms you have. FENTORA can harm other people and even cause death. Sharing FENTORA is against the law.\n" }

This Medication Guide summarizes the most important information about FENTORA. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about FENTORA that is written for health professionals.

{ "type": "p", "children": [], "text": "\nThis Medication Guide summarizes the most important information about FENTORA. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about FENTORA that is written for health professionals. \n" }

For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.

{ "type": "p", "children": [], "text": "\nFor more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.\n" }

What are the ingredients in FENTORA?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in FENTORA?\n" }

Active Ingredient: fentanyl citrate

{ "type": "p", "children": [], "text": "\nActive Ingredient: fentanyl citrate\n" }

Inactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

{ "type": "p", "children": [], "text": "\nInactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.\n" }

Before you use FENTORA, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use FENTORA the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use FENTORA.

{ "type": "p", "children": [], "text": "\nBefore you use FENTORA, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use FENTORA the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use FENTORA.\n" }

When you get an episode of breakthrough cancer pain, use the dose of FENTORA prescribed by your healthcare provider as follows:

{ "type": "p", "children": [], "text": "\nWhen you get an episode of breakthrough cancer pain, use the dose of FENTORA prescribed by your healthcare provider as follows:\n" }

{ "type": "ul", "children": [ "\nFENTORA comes packaged as a blister card containing 4 blister units. Each blister unit contains 1 FENTORA tablet. Do not open a blister until ready to use. \n", "\nSeparate one of the blister units from the blister card by tearing apart at the perforations. Bend the blister unit along the line where indicated. The product strength of your FENTORA tablets will be printed in the boxed area shown as \n\n\n (See Figure 1).\n" ], "text": "" }

Figure 1

{ "type": "p", "children": [], "text": "\nFigure 1\n" }

{ "type": "ul", "children": [ "\nPeel back foil on blister unit to expose tablet (See Figure 2).\n" ], "text": "" }

Figure 2

{ "type": "p", "children": [], "text": "\nFigure 2\n" }

{ "type": "ul", "children": [ "\nDo not push the tablet through the foil on the blister unit because this could damage the tablet.\n", "\nWhen removed from the blister unit, FENTORA tablet must be used right away.\n", "\nUse FENTORA tablets whole.\n", "\nDo not crush, split, suck, or chew FENTORA tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.\n", "\nYou can place a FENTORA tablet:\n\n\nin your mouth above a rear molar tooth between the upper cheek and gum (See Figure 3). Switch (alternate) sides of your mouth for each dose.\n\n\n" ], "text": "" }

Figure 3

{ "type": "p", "children": [], "text": "\nFigure 3\n" }

OR,

{ "type": "p", "children": [], "text": "\nOR, \n" }

{ "type": "ul", "children": [ "\non the floor of your mouth, under your tongue (See Figures 4a, 4b, 4c, 4d).\n" ], "text": "" }

{ "type": "ul", "children": [ "\n When placing the tablet under your tongue, first lift your tongue (4b), then place the tablet under your tongue (4c), and lower your tongue over the tablet (4d).\n" ], "text": "" }

Figure 4a

{ "type": "p", "children": [], "text": "\nFigure 4a\n" }

Figure 4b

{ "type": "p", "children": [], "text": "\nFigure 4b\n" }

Figure 4c

{ "type": "p", "children": [], "text": "\nFigure 4c\n" }

Figure 4d

{ "type": "p", "children": [], "text": "\nFigure 4d \n" }

{ "type": "ul", "children": [ "\nLeave the tablet in place until it dissolves. A FENTORA tablet generally takes between 14 to 25 minutes to dissolve.\n", "\nAfter 30 minutes, if there is any FENTORA left in your mouth, you may drink a glass of water to help you swallow the left over medicine. \n", "\nIf you cannot use FENTORA in this manner, tell your healthcare provider. Your healthcare provider will tell you what to do.\n" ], "text": "" }

<div class="scrollingtable"><table> <col width="41%"/> <col/> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="bottom"> <p class="First"> Distributed by:<br/>  Teva Pharmaceuticals USA, Inc.                 call 1-888-483-8279<br/>  Parsippany, NJ 07054<br/> <br/>  FENTMG-012<br/>  ©2023 Cephalon, LLC.<br/>  Printed in USA</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"41%\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"bottom\">\n<p class=\"First\"> Distributed by:<br/>\n  Teva Pharmaceuticals USA, Inc.                 call 1-888-483-8279<br/>\n  Parsippany, NJ 07054<br/>\n<br/>\n  FENTMG-012<br/>\n  ©2023 Cephalon, LLC.<br/>\n  Printed in USA</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                      Revised: 12/2023

{ "type": "p", "children": [], "text": "\nThis Medication Guide has been approved by the U.S. Food and Drug Administration.                                                      Revised: 12/2023\n" }

28 Buccal Tablets (4 tablets X 7 cards)

{ "type": "p", "children": [], "text": "\n28 Buccal Tablets (4 tablets X 7 cards)" }

NDC 63459-541-28

{ "type": "p", "children": [], "text": "\nNDC 63459-541-28\n\n" }

FENTORA®   CII

{ "type": "p", "children": [], "text": "\nFENTORA®   CII\n" }

(fentanyl buccal tablet)

{ "type": "p", "children": [], "text": "(fentanyl buccal tablet)" }

equivalent to 100 mcg fentanyl base

{ "type": "p", "children": [], "text": "equivalent to 100 mcg fentanyl base" }

Information for Pharmacist:

{ "type": "p", "children": [], "text": "\nInformation for Pharmacist:\n" }

{ "type": "ul", "children": [ "Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode", "Instruct patients to read the enclosed FENTORA Medication Guide", "FENTORA must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com." ], "text": "" }

WARNING: Keep out of the reach of children

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS\n" }

FENTORA can be harmful or fatal if given to someone for whom it was not prescribed

{ "type": "p", "children": [], "text": "FENTORA can be harmful or fatal if given to someone for whom it was not prescribed" }

For Buccal or Sublingual Administration.

{ "type": "p", "children": [], "text": "\nFor Buccal or Sublingual Administration.\n" }

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

{ "type": "p", "children": [], "text": "\nDo NOT Split, Crush, Suck, Chew, or Swallow Tablet.\n" }

28 Buccal Tablets (4 tablets X 7 cards)

{ "type": "p", "children": [], "text": "\n28 Buccal Tablets (4 tablets X 7 cards)" }

NDC 63459-542-28

{ "type": "p", "children": [], "text": "\nNDC 63459-542-28\n" }

FENTORA®  CII

{ "type": "p", "children": [], "text": "\nFENTORA®  CII\n" }

(fentanyl buccal tablet)

{ "type": "p", "children": [], "text": "(fentanyl buccal tablet)" }

equivalent to 200 mcg fentanyl base

{ "type": "p", "children": [], "text": "equivalent to 200 mcg fentanyl base" }

Information for Pharmacist:

{ "type": "p", "children": [], "text": "\nInformation for Pharmacist:\n" }

{ "type": "ul", "children": [ "Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode", "Instruct patients to read the enclosed FENTORA Medication Guide", "FENTORA must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com." ], "text": "" }

WARNING: Keep out of the reach of children

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS\n" }

FENTORA can be harmful or fatal if given to someone for whom it was not prescribed

{ "type": "p", "children": [], "text": "FENTORA can be harmful or fatal if given to someone for whom it was not prescribed" }

For Buccal or Sublingual Administration.

{ "type": "p", "children": [], "text": "\nFor Buccal or Sublingual Administration.\n" }

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

{ "type": "p", "children": [], "text": "\nDo NOT Split, Crush, Suck, Chew, or Swallow Tablet.\n" }

28 Buccal Tablets (4 tablets X 7 cards)

{ "type": "p", "children": [], "text": "\n28 Buccal Tablets (4 tablets X 7 cards)" }

NDC 63459-544-28

{ "type": "p", "children": [], "text": "\nNDC 63459-544-28\n" }

FENTORA®  CII

{ "type": "p", "children": [], "text": "\nFENTORA®  CII\n" }

(fentanyl buccal tablet)

{ "type": "p", "children": [], "text": "(fentanyl buccal tablet)" }

equivalent to 400 mcg fentanyl base

{ "type": "p", "children": [], "text": "equivalent to 400 mcg fentanyl base" }

Information for Pharmacist:

{ "type": "p", "children": [], "text": "\nInformation for Pharmacist:\n" }

{ "type": "ul", "children": [ "Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode", "Instruct patients to read the enclosed FENTORA Medication Guide", "FENTORA must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com." ], "text": "" }

WARNING: Keep out of the reach of children

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS\n" }

FENTORA can be harmful or fatal if given to someone for whom it was not prescribed

{ "type": "p", "children": [], "text": "FENTORA can be harmful or fatal if given to someone for whom it was not prescribed" }

For Buccal or Sublingual Administration.

{ "type": "p", "children": [], "text": "\nFor Buccal or Sublingual Administration.\n" }

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

{ "type": "p", "children": [], "text": "\nDo NOT Split, Crush, Suck, Chew, or Swallow Tablet.\n" }

28 Buccal Tablets (4 tablets X 7 cards)

{ "type": "p", "children": [], "text": "\n28 Buccal Tablets (4 tablets X 7 cards)" }

NDC 63459-546-28

{ "type": "p", "children": [], "text": "\nNDC 63459-546-28\n" }

FENTORA®  CII

{ "type": "p", "children": [], "text": "\nFENTORA®  CII\n" }

(fentanyl buccal tablet)

{ "type": "p", "children": [], "text": "(fentanyl buccal tablet)" }

equivalent to 600 mcg fentanyl base

{ "type": "p", "children": [], "text": "equivalent to 600 mcg fentanyl base" }

Information for Pharmacist:

{ "type": "p", "children": [], "text": "\nInformation for Pharmacist:\n" }

{ "type": "ul", "children": [ "Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode", "Instruct patients to read the enclosed FENTORA Medication Guide", "FENTORA must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com." ], "text": "" }

WARNING: Keep out of the reach of children

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS\n" }

FENTORA can be harmful or fatal if given to someone for whom it was not prescribed

{ "type": "p", "children": [], "text": "FENTORA can be harmful or fatal if given to someone for whom it was not prescribed" }

For Buccal or Sublingual Administration.

{ "type": "p", "children": [], "text": "\nFor Buccal or Sublingual Administration.\n" }

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

{ "type": "p", "children": [], "text": "\nDo NOT Split, Crush, Suck, Chew, or Swallow Tablet.\n" }

28 Buccal Tablets (4 tablets X 7 cards)

{ "type": "p", "children": [], "text": "\n28 Buccal Tablets (4 tablets X 7 cards)" }

NDC 63459-548-28

{ "type": "p", "children": [], "text": "\nNDC 63459-548-28\n" }

FENTORA®  CII

{ "type": "p", "children": [], "text": "\nFENTORA®  CII\n" }

(fentanyl buccal tablet)

{ "type": "p", "children": [], "text": "(fentanyl buccal tablet)" }

equivalent to 800 mcg fentanyl base

{ "type": "p", "children": [], "text": "equivalent to 800 mcg fentanyl base" }

Information for Pharmacist:

{ "type": "p", "children": [], "text": "\nInformation for Pharmacist:\n" }

{ "type": "ul", "children": [ "Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode", "Instruct patients to read the enclosed FENTORA Medication Guide", "FENTORA must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com." ], "text": "" }

WARNING: Keep out of the reach of children

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE FENTORA FOR OTHER FENTANYL PRODUCTS\n" }

FENTORA can be harmful or fatal if given to someone for whom it was not prescribed

{ "type": "p", "children": [], "text": "FENTORA can be harmful or fatal if given to someone for whom it was not prescribed" }

For Buccal or Sublingual Administration.

{ "type": "p", "children": [], "text": "\nFor Buccal or Sublingual Administration.\n" }

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.

{ "type": "p", "children": [], "text": "\nDo NOT Split, Crush, Suck, Chew, or Swallow Tablet.\n" }

Oral Transmucosal Fentanyl Citrate (OTFC) is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

{ "type": "p", "children": [], "text": "Oral Transmucosal Fentanyl Citrate (OTFC) is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. " }

Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids when taking OTFC.

{ "type": "p", "children": [], "text": "Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids when taking OTFC. " }

Limitations of Use:

{ "type": "p", "children": [], "text": "\nLimitations of Use:\n" }

{ "type": "ul", "children": [ "Not for use in opioid non-tolerant patients.", "Not for use in the management of acute or postoperative pain, including headache/migraine and dental pain [see Contraindications (4)].", "As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. For inpatient administration of OTFC, patient and prescriber enrollment are not required. " ], "text": "" }

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with OTFC [see Warnings and Precautions (5.2)]. 

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). 

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.4)]. 

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 

Individually titrate OTFC to a dose that provides adequate analgesia and minimizes side effects. The initial dose of OTFC to treat episodes of breakthrough cancer pain is always 200 mcg. The OTFC unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg OTFC units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose.

Repeat Dosing

From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single OTFC dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of OTFC over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted.

In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of OTFC for any breakthrough pain episode.

Patients must wait at least 4 hours before treating another episode of breakthrough pain with OTFC. To reduce the risk of overdosing during titration, patients should have only one strength of OTFC available at any one time.

Open the blister package with scissors immediately prior to product use. The patient should place the OTFC unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The OTFC unit should be sucked, not chewed. A unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology (12.3)].

The OTFC unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in OTFC clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses.

When opioid therapy is no longer required, consider discontinuing OTFC along with a gradual downward tapering (titration) of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, OTFC therapy can usually be discontinued immediately [see Drug Abuse and Dependence (9.3)].

After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children.

If the temporary storage bottle provided as part of the OTFC Child Safety Kit is available, partially consumed units may be stored in the specially provided child-resistant container out of the reach of children until proper disposal is possible.

Unopened units remaining from a prescription must be properly disposed as soon as they are no longer needed.

To dispose of the unused OTFC units:

Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it.

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office.

Solid oral transmucosal lozenge: Each dosage unit has white to off-white color and is a solid drug matrix on a handle. Each strength is marked on the individual solid drug matrix and the handle tag. Oral Transmucosal Fentanyl Citrate (OTFC) is available in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg strengths [see How Supplied/Storage and Handling (16)].

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Oral Transmucosal Fentanyl Citrate (OTFC) is contraindicated in:

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{ "type": "ul", "children": [ "Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1), Warnings and Precautions (5.2)].\n", "Significant respiratory depression [see Warnings and Precautions (5.2)].\n", "Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see Indications and Usage (1)].", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.11)].\n", "Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.15)].\n", "Known hypersensitivity to fentanyl or components of OTFC (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions (6.2)].\n" ], "text": "" }

Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance. As an opioid, OTFC exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OTFC. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OTFC, and reassess all patients receiving OTFC for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OTFC, but use in such patients necessitates intensive counseling about the risks and proper use of OTFC along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OTFC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OTFC, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of OTFC are essential [see Dosage and Administration (2)]. Overestimating the OTFC dosage can result in a fatal overdose with the first dose. The substitution of OTFC for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion of even one dose of OTFC, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions (5.3)].

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.7)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with OTFC. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.4), Overdosage (10)].

Death has been reported in children who have accidentally ingested OTFC.

Patients and their caregivers must be informed that OTFC contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible.

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OTFC with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when OTFC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

When prescribing, do not convert a patient to OTFC from any other fentanyl product on a mcg per mcg basis as OTFC and other fentanyl products are not equivalent on a microgram per microgram basis.

OTFC is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an OTFC prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and OTFC are not equivalent. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of OTFC for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of OTFC should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.4)].

Concomitant use of OTFC with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of OTFC is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OTFC-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using OTFC with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OTFC-treated patients, evaluate patients at frequent intervals and consider dosage reduction of OTFC until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of OTFC with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using OTFC with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)], OTFC is available only through a restricted program called the TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to outpatients, the outpatients themselves, and pharmacies are required to enroll in the program. 

Notable requirements of the TIRF REMS are:

Further information, including a list of certified pharmacies and enrolled distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Use of OTFC for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.7)].

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of OTFC with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue OTFC if serotonin syndrome is suspected.

The use of OTFC in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: OTFC-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OTFC [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Regularly evaluate patients, particularly when initiating and titrating OTFC and when OTFC is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

OTFC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of OTFC. In patients with circulatory shock, OTFC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OTFC in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OTFC may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OTFC.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OTFC in patients with impaired consciousness or coma.

OTFC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in OTFC may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

The fentanyl in OTFC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during OTFC therapy.

OTFC may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OTFC and know how they will react to the medication.

Intravenous fentanyl may produce bradycardia. Therefore, use OTFC with caution in patients with bradyarrhythmias.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Oral Transmucosal Fentanyl Citrate (OTFC) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days.

The most serious adverse reactions associated with OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock.

Because the clinical trials of OTFC were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received OTFC for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of OTFC therapy, or cancer-related symptoms.

Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system.

<div class="scrollingtable"><table> <caption> <span>Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients)</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Dose Group</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Event</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200-</span> </p> <p> <span class="Bold">600 mcg</span> </p> <p> <span class="Bold">(n=230)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800-</span> </p> <p> <span class="Bold">1400 mcg (n=138)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1600 </span> </p> <p> <span class="Bold">mcg </span> </p> <p> <span class="Bold">(n=54)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">&gt;1600 </span> </p> <p> <span class="Bold">mcg </span> </p> <p> <span class="Bold">(n=41)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any </span> </p> <p> <span class="Bold">Dose</span><span class="Bold"><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> </p> <p> <span class="Bold">(n=254) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Body As A Whole</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Accidental Injury</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Digestive</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nervous</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Confusion</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Abnormal Gait</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dry Mouth</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Nervousness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vasodilatation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Hallucinations</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Thinking Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vertigo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Respiratory</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Skin</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Sweating</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Special Senses</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Abnormal Vision</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection

Digestive: Diarrhea, dyspepsia, flatulence

Metabolic and Nutritional: Peripheral edema, dehydration

Nervous: Hypesthesia, migraine

Respiratory: Pharyngitis, cough increased

The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system.

Body as a Whole: Bone pain

Cardiovascular: Deep thrombophlebitis, hypertension, hypotension

Digestive: Anorexia, eructation, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis

Hemic and Lymphatic: Anemia, leukopenia

Metabolic and Nutritional: Edema, hypercalcemia, weight loss

Musculoskeletal: Myalgia, pathological fracture, myasthenia

Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder

Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased

Skin and Appendages: Alopecia, exfoliative dermatitis

Special Senses: Taste perversion

Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection

A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study. Adverse reactions are listed in descending order of frequency within each body system.

<div class="scrollingtable"><table> <caption> <span>Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients)</span> </caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Dose Group</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Event</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200-</span> </p> <p> <span class="Bold">600 mcg</span> </p> <p> <span class="Bold">(n=98)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800-</span> </p> <p> <span class="Bold">1400 mcg</span> </p> <p> <span class="Bold">(n=83)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1600 </span> </p> <p> <span class="Bold">mcg </span> </p> <p> <span class="Bold">(n=53)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">&gt;1600 </span> </p> <p> <span class="Bold">mcg </span> </p> <p> <span class="Bold">(n=27)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Any </span> </p> <p> <span class="Bold">Dose<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></span> </p> <p> <span class="Bold">(n=152) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Body As A Whole</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">38</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Accidental Injury</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Hypertonia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Digestive</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">36</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">45</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">31</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Intestinal Obstruction</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cardiovascular</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nervous</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Confusion</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Depression</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Abnormal Gait</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dry Mouth</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Nervousness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Stupor</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vasodilatation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Thinking Abnormal</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Abnormal Dreams</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Convulsion</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Myoclonus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Vertigo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Respiratory</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Skin</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Sweating</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Special Senses</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Abnormal Vision</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Urogenital</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Toprule" valign="top"></td><td class="Botrule Rrule Toprule" valign="top"> <p class="First">Urinary Retention</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain

Cardiovascular: Deep thrombophlebitis, palpitation, vascular disorder

Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage

Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia

Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia

Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder

Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine

Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased

Skin and Appendages: Skin ulcer, alopecia

Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion

Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis

The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, mucous membrane disorder, neck rigidity

Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia

Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder

Hemic and Lymphatic: Bleeding time increased

Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst

Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder

Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma

Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration

Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash

Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness

Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis

The following adverse reactions have been identified during post approval use of OTFC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Digestive:

- Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion.

Nervous System Disorders:

- Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

- Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Endocrine Disorders:

- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

- Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Immune System Disorders:

- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in OTFC.

General Disorders and Administration Site Conditions:

- Application site reactions including irritation, pain, ulcer, and drug withdrawal syndrome.

Metabolic and Nutritional Disorders:

- Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 3 includes clinically significant drug interactions with Oral Transmucosal Fentanyl Citrate (OTFC).

{ "type": "p", "children": [], "text": "Table 3 includes clinically significant drug interactions with Oral Transmucosal Fentanyl Citrate (OTFC)." }

<div class="scrollingtable"><table> <caption> <span>Table 3: Clinically Significant Drug Interactions with OTFC</span> </caption> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Inhibitors of CYP3A4</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of OTFC and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of OTFC is achieved <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_2fbf6251-151d-4bfa-a38a-c560e750b5fb">5.6</a>)]</span>.</p> <p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is necessary, consider dosage reduction of OTFC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">CYP3A4 Inducers</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of OTFC and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_2fbf6251-151d-4bfa-a38a-c560e750b5fb">5.6</a>)]</span>.</p> <p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is necessary, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rifampin, carbamazepine, phenytoin</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_a5b82c92-7a8e-4385-8858-0a7dcc5d3549">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_4fe3da6a-75c0-4dff-a95c-1475e58e43c2">5.1</a>, <a href="#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c">5.2</a>, <a href="#www.splportal.comLINK_d8264329-2702-441f-a916-31547dd9f384">5.4</a>)]</span>.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#LINK_0511dab6-88ef-4742-a758-bcb46f1c615e">5.10</a>)]</span>.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#LINK_0511dab6-88ef-4742-a758-bcb46f1c615e">5.10</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (<a href="#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c">5.2</a>)].</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The use of OTFC is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Phenelzine, tranylcypromine, linezolid</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">May reduce the analgesic effect of OTFC and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Butorphanol, nalbuphine, pentazocine, buprenorphine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Because respiratory depression may be greater than otherwise expected, decrease the dosage of OTFC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_a5b82c92-7a8e-4385-8858-0a7dcc5d3549">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c">5.2</a>, <a href="#www.splportal.comLINK_d8264329-2702-441f-a916-31547dd9f384">5.4</a>)].</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Cyclobenzaprine, metaxalone</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical </span> </p> <p> <span class="Italics">Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p> </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Evaluate patients for signs of urinary retention or reduced gastric motility when OTFC is used concomitantly with anticholinergic drugs.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<caption>\n<span>Table 3: Clinically Significant Drug Interactions with OTFC</span>\n</caption>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inhibitors of CYP3A4</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of OTFC and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of OTFC is achieved <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_2fbf6251-151d-4bfa-a38a-c560e750b5fb\">5.6</a>)]</span>.</p>\n<p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09\">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of OTFC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">CYP3A4 Inducers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of OTFC and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09\">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_2fbf6251-151d-4bfa-a38a-c560e750b5fb\">5.6</a>)]</span>.</p>\n<p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_8ce97e60-7588-4890-8e4c-114bfb786c09\">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Rifampin, carbamazepine, phenytoin</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_a5b82c92-7a8e-4385-8858-0a7dcc5d3549\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_4fe3da6a-75c0-4dff-a95c-1475e58e43c2\">5.1</a>, <a href=\"#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c\">5.2</a>, <a href=\"#www.splportal.comLINK_d8264329-2702-441f-a916-31547dd9f384\">5.4</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_0511dab6-88ef-4742-a758-bcb46f1c615e\">5.10</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_0511dab6-88ef-4742-a758-bcb46f1c615e\">5.10</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c\">5.2</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The use of OTFC is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> Phenelzine, tranylcypromine, linezolid</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">May reduce the analgesic effect of OTFC and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Butorphanol, nalbuphine, pentazocine, buprenorphine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of OTFC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_a5b82c92-7a8e-4385-8858-0a7dcc5d3549\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_06242957-0525-4792-a17a-049b1ce9971c\">5.2</a>, <a href=\"#www.splportal.comLINK_d8264329-2702-441f-a916-31547dd9f384\">5.4</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Cyclobenzaprine, metaxalone</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical </span>\n</p>\n<p>\n<span class=\"Italics\">Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Evaluate patients for signs of urinary retention or reduced gastric motility when OTFC is used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8)]. Available data with Oral Transmucosal Fentanyl Citrate (OTFC) in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of OTFC for an extended period of time during pregnancy (see Clinical Considerations).

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. OTFC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including OTFC, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

Fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison).

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of OTFC on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of OTFC based on a mg/m2 basis). No evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 3 times the human dose of 1600 mcg OTFC per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean Cmax observed following administration of 1600 mcg dose of OTFC in humans.

In a postnatal development study, pregnant rats were treated from GD 6 through Lactation Day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with OTFC.

Clinical Considerations

Monitor infants exposed to OTFC through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

Safety and effectiveness in pediatric patients below 16 years of age have not been established.

In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with OTFC. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received OTFC at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) Cmax and AUC0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng.h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9).

Of the 257 patients in clinical studies of OTFC in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in OTFC clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating OTFC in elderly patients to provide adequate efficacy while minimizing risk.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OTFC slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.11)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

Insufficient information exists to make recommendations regarding the use of OTFC in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Both male and female opioid-tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

Oral Transmucosal Fentanyl Citrate (OTFC) contains fentanyl, a Schedule II controlled substance.

OTFC contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of OTFC increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of OTFC with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of OTFC abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use OTFC in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

OTFC, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of OTFC

Abuse of OTFC poses a risk of overdose and death. The risk is increased with concurrent use of OTFC with alcohol and/or other CNS depressants.

OTFC is approved for oral transmucosal use only.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]." }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

In case of overdose, priorities are: removal of the OTFC unit, if still in the mouth, the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

{ "type": "p", "children": [], "text": "In case of overdose, priorities are: removal of the OTFC unit, if still in the mouth, the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures." }

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

{ "type": "p", "children": [], "text": "Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist." }

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in OTFC, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in OTFC, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information." }

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist." }

Oral Transmucosal Fentanyl Citrate (OTFC) (fentanyl citrate) oral transmucosal lozenge is a solid formulation of fentanyl, an opioid agonist, intended for oral transmucosal administration. OTFC is formulated as a white to off-white solid drug matrix on a handle that is fracture resistant (ABS plastic) under normal conditions when used as directed.

{ "type": "p", "children": [], "text": "Oral Transmucosal Fentanyl Citrate (OTFC) (fentanyl citrate) oral transmucosal lozenge is a solid formulation of fentanyl, an opioid agonist, intended for oral transmucosal administration. OTFC is formulated as a white to off-white solid drug matrix on a handle that is fracture resistant (ABS plastic) under normal conditions when used as directed." }

OTFC is designed to be dissolved slowly in the mouth to facilitate transmucosal absorption. The handle allows the OTFC unit to be removed from the mouth if signs of excessive opioid effects appear during administration.

{ "type": "p", "children": [], "text": "OTFC is designed to be dissolved slowly in the mouth to facilitate transmucosal absorption. The handle allows the OTFC unit to be removed from the mouth if signs of excessive opioid effects appear during administration." }

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:

{ "type": "p", "children": [], "text": "\nActive Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:" }

Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar).

{ "type": "p", "children": [], "text": "\nInactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar)." }

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Effects on the Central Nervous System

The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu-opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and electrical stimulation.

Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals.

The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

Concentration-Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.4, 2.5)].

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of Oral Transmucosal Fentanyl Citrate (OTFC). Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see Warnings and Precautions (5), Overdosage (10)].

Absorption

The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed.

Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in 12 adult males was 50% compared to intravenous fentanyl.

Normally, approximately 25% of the total dose of OTFC is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the generally observed 50% bioavailability of OTFC is divided equally between rapid transmucosal and slower GI absorption. Therefore, a unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed.

Dose proportionality among four of the available strengths of OTFC (200, 400, 800, and 1600 mcg) has been demonstrated in a balanced crossover design in adult subjects (n=11). Mean serum fentanyl levels following these four doses of OTFC are shown in Figure 1. The curves for each dose level are similar in shape with increasing dose levels producing increasing serum fentanyl levels. Cmax and AUC0→∞ increased in a dose-dependent manner that is approximately proportional to the OTFC administered.

Figure 1. Mean Serum Fentanyl Concentration (ng/mL) in Adult Subjects Comparing 4 Doses of OTFC

The pharmacokinetic parameters of the four strengths of OTFC tested in the dose-proportionality study are shown in Table 4. The mean Cmax ranged from 0.39 - 2.51 ng/mL. The median time of maximum plasma concentration (Tmax) across these four doses of OTFC varied from 20 - 40 minutes (range of 20 – 480 minutes) as measured after the start of administration.

<div class="scrollingtable"><table> <caption> <span>Table 4. Pharmacokinetic Parameters* in Adult Subjects Receiving 200, 400, 800, and 1600 mcg Units of OTFC</span> </caption> <col width="19%"/> <col width="19%"/> <col width="20%"/> <col width="20%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Pharmacokinetic</span> <br/> <span class="Bold">Parameter</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1600 mcg</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">T<span class="Sub">max</span>, minute</span> <br/> <span class="Bold">median (range)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">40</span> <br/> <span class="Bold">(20-120)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">25</span> <br/> <span class="Bold">(20-240)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">25</span> <br/> <span class="Bold"> (20-120)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">20</span> <br/> <span class="Bold">(20-480)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">max</span>, ng/mL</span> <br/> <span class="Bold">mean (%CV)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">0.39 (23)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">0.75 (33)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1.55 (30)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">2.51 (23)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-1440</span>,</span> <br/> <span class="Bold"> ng/mL minute </span> </p> <p> <span class="Bold">mean (%CV)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">102 (65)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">243 (67)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">573 (64)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1026 (67)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">t<span class="Sub">1/2</span>, minute</span> </p> <p> <span class="Bold">mean (%CV)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">193 (48)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">386 (115)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">381 (55)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">358 (45)</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule" colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Underline">* Based on arterial blood samples.</span></span> </p> </td> </tr> </tbody> </table></div>

Distribution

Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Elimination

The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3 – 0.7 L/hr/kg). The terminal elimination half-life after OTFC administration is about 7 hours.

Metabolism

Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions (7)].

Excretion

Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.

Carcinogenesis

Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 1.13 and 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.

Mutagenesis

Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility

In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 4.0-times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for OTFC.

Oral Transmucosal Fentanyl Citrate (OTFC) was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.

{ "type": "p", "children": [], "text": "Oral Transmucosal Fentanyl Citrate (OTFC) was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer." }

In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of OTFC to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200, and 1600 mcg). A “successful” dose was defined as a dose where one unit of OTFC could be used consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable side effects. In these studies 11% of patients withdrew due to adverse reactions and 14% withdrew due to other reasons.

{ "type": "p", "children": [], "text": "In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of OTFC to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200, and 1600 mcg). A “successful” dose was defined as a dose where one unit of OTFC could be used consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable side effects. In these studies 11% of patients withdrew due to adverse reactions and 14% withdrew due to other reasons." }

The successful dose of OTFC for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by dose titration.

{ "type": "p", "children": [], "text": "The successful dose of OTFC for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by dose titration." }

A double-blind placebo controlled crossover study was performed in cancer patients to evaluate the effectiveness of OTFC for the treatment of breakthrough cancer pain. Of 130 patients who entered the study 92 patients (71%) achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 5.

{ "type": "p", "children": [], "text": "A double-blind placebo controlled crossover study was performed in cancer patients to evaluate the effectiveness of OTFC for the treatment of breakthrough cancer pain. Of 130 patients who entered the study 92 patients (71%) achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 5." }

<div class="scrollingtable"><table> <caption> <span>Table 5. Successful Dose of OTFC Following Initial Titration</span> </caption> <col width="28%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">OTFC Dose</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total No. (%)</span> </p> <p> <span class="Bold">(N=92)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">13 (14)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">19 (21)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">600 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">14 (15)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">18 (20)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">1200 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">13 (14)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">1600 mcg</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">15 (16)</span> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Mean +/- SD</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">789 +/- 468 mcg</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<caption>\n<span>Table 5. Successful Dose of OTFC Following Initial Titration</span>\n</caption>\n<col width=\"28%\"/>\n<col width=\"28%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">OTFC Dose</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Total No. (%)</span>\n</p>\n<p>\n<span class=\"Bold\">(N=92)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">200 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">13 (14)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">400 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">19 (21)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">600 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">14 (15)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">800 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">18 (20)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">1200 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">13 (14)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">1600 mcg</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">15 (16)</span>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Mean +/- SD</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">789 +/- 468 mcg</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the mean dose to which younger adult patients were titrated.

{ "type": "p", "children": [], "text": "On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the mean dose to which younger adult patients were titrated." }

OTFC was administered beginning at Time 0 minutes and produced more pain relief compared with placebo at 15, 30, 45, and 60 minutes as measured after the start of administration (see Figure 2). The differences were statistically significant.

{ "type": "p", "children": [], "text": "OTFC was administered beginning at Time 0 minutes and produced more pain relief compared with placebo at 15, 30, 45, and 60 minutes as measured after the start of administration (see Figure 2). The differences were statistically significant." }

Figure 2. Pain Relief (PR) Scores (Mean±SD) During the Double-Blind Phase – All Patients with Evaluable Episodes on Both OTFC and Placebo (N=86) 

{ "type": "p", "children": [], "text": "\nFigure 2. Pain Relief (PR) Scores (Mean±SD) During the Double-Blind Phase – All Patients with Evaluable Episodes on Both OTFC and Placebo (N=86) \n" }

1 0 minutes = Start of administration of OTFC

{ "type": "p", "children": [], "text": "\n1 0 minutes = Start of administration of OTFC" }

2 15 minutes = First time to measure pain relief

{ "type": "p", "children": [], "text": "\n2 15 minutes = First time to measure pain relief" }

Oral Transmucosal Fentanyl Citrate (OTFC) is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose.

{ "type": "p", "children": [], "text": "Oral Transmucosal Fentanyl Citrate (OTFC) is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose." }

Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with “FENTANYL” and the strength of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”). The dosage strength is also marked on the handle tag, the blister package and the carton. See blister package and carton for product information.

{ "type": "p", "children": [], "text": "Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with “FENTANYL” and the strength of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”). The dosage strength is also marked on the handle tag, the blister package and the carton. See blister package and carton for product information." }

<div class="scrollingtable"><table> <col width="18%"/> <col width="17%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dosage Strength</span> </p> <p> <span class="Bold">(fentanyl base)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Carton/Blister</span> </p> <p> <span class="Bold">Package Color</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC Number</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">200 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Gray</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7865-65</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">400 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Blue</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7866-65</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">600 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Orange</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7867-65</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">800 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Purple</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7868-65</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">1200 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Green</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7869-65</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">1600 mcg</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Burgundy</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0093-7870-65</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"18%\"/>\n<col width=\"17%\"/>\n<col width=\"21%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Dosage Strength</span>\n</p>\n<p>\n<span class=\"Bold\">(fentanyl base)</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Carton/Blister</span>\n</p>\n<p>\n<span class=\"Bold\">Package Color</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC Number</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">200 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Gray</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7865-65</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">400 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Blue</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7866-65</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">600 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Orange</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7867-65</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">800 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Purple</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7868-65</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">1200 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Green</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7869-65</span>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">1600 mcg</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Burgundy</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC 0093-7870-65</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

{ "type": "p", "children": [], "text": "Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing." }

Store at 20ºC to 25ºC (68ºF to 77ºF) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect OTFC from freezing and moisture. Do not use if the blister package has been opened.

{ "type": "p", "children": [], "text": "Store at 20ºC to 25ºC (68ºF to 77ºF) with excursions permitted between 15°C and 30°C (59°F to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect OTFC from freezing and moisture. Do not use if the blister package has been opened." }

Store OTFC securely and dispose of properly.

{ "type": "p", "children": [], "text": "Store OTFC securely and dispose of properly.\n" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide)." }

Storage and Disposal of Unused and Used OTFC [see Medication Guide / Instructions for Use].

{ "type": "p", "children": [], "text": "\nStorage and Disposal of Unused and Used OTFC [see Medication Guide / Instructions for Use].\n" }

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store OTFC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving OTFC unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].

{ "type": "p", "children": [], "text": "Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store OTFC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving OTFC unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. " }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines." }

Disposal of Used OTFC Units: Instruct patients on proper disposal of completely used and partially used OTFC units as follows:

{ "type": "p", "children": [], "text": "Disposal of Used OTFC Units:\nInstruct patients on proper disposal of completely used and partially used OTFC units as follows:" }

{ "type": "", "children": [], "text": "" }

If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the OTFC unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible.

{ "type": "p", "children": [], "text": "If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the OTFC unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible." }

Disposal of Unopened OTFC Units When No Longer Needed: Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed.

{ "type": "p", "children": [], "text": "Disposal of Unopened OTFC Units When No Longer Needed:\nPatients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed." }

To dispose of the unused OTFC units:

{ "type": "p", "children": [], "text": "To dispose of the unused OTFC units:" }

{ "type": "ul", "children": [ "Remove the OTFC unit from its blister package using scissors, and hold the OTFC by its handle over the toilet bowl.", "Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet.", "Dispose of the handle in a place that is out of the reach of children.", "Repeat steps 1, 2, and 3 for each OTFC unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet." ], "text": "" }

Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it.

{ "type": "p", "children": [], "text": "Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it. " }

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

{ "type": "p", "children": [], "text": "Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered." }

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office.

{ "type": "p", "children": [], "text": "In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office." }

Addiction, Abuse, and Misuse

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse\n" }

Inform patients that the use of OTFC, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share OTFC with others and to take steps to protect OTFC from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of OTFC, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share OTFC with others and to take steps to protect OTFC from theft or misuse." }

Life-Threatening Respiratory Depression

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n" }

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oral Transmucosal Fentanyl Citrate (OTFC) or when the dosage is increased, and that it can occur even at recommended dosages.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oral Transmucosal Fentanyl Citrate (OTFC) or when the dosage is increased, and that it can occur even at recommended dosages." }

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)]. 

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)]. " }

Accidental Ingestion

{ "type": "p", "children": [], "text": "\nAccidental Ingestion \n" }

{ "type": "ul", "children": [ "Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure [see Warnings and Precautions (5.3)]. ", "Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].\n", "Instruct patients to take steps to store OTFC securely and to dispose of unused OTFC [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.7)].", "Instruct patients and caregivers to keep both used and unused OTFC out of the reach of children [see Warnings and Precautions (5.3)].\n", "Inform patients and their caregivers that, in the event that a unit is not completely consumed, it must be properly disposed as soon as possible [see Warnings and Precautions (5.3)].\n" ], "text": "" }

OTFC Child Safety Kit Provide patients and their caregivers who have children in the home or visiting with an OTFC Child Safety Kit, which contains educational materials and safe interim storage containers to help patients store OTFC and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call 1-888-534-3119.

{ "type": "p", "children": [], "text": "\nOTFC Child Safety Kit\nProvide patients and their caregivers who have children in the home or visiting with an OTFC Child Safety Kit, which contains educational materials and safe interim storage containers to help patients store OTFC and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call 1-888-534-3119. " }

Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol)

{ "type": "p", "children": [], "text": "\nInteractions with Benzodiazepines and Other CNS Depressants (including Alcohol) \n" }

Inform patients and caregivers that potentially fatal additive effects may occur if OTFC is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers that potentially fatal additive effects may occur if OTFC is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)]." }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

{ "type": "p", "children": [], "text": "\nPatient Access to Naloxone for the Emergency Treatment of Opioid Overdose\n" }

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with OTFC. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with OTFC. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].\n" }

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize the signs and symptoms of an overdose." }

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

{ "type": "p", "children": [], "text": "Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)]." }

If naloxone is prescribed, also advise patients and caregivers:

{ "type": "p", "children": [], "text": "If naloxone is prescribed, also advise patients and caregivers:" }

{ "type": "ul", "children": [ "How to treat with naloxone in the event of an opioid overdose", "To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency", "To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do." ], "text": "" }

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

{ "type": "p", "children": [], "text": "\nTransmucosal Immediate-Release Fentanyl (TIRF) REMS\n" }

OTFC is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:

{ "type": "p", "children": [], "text": "OTFC is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7)]. Inform the patient of the following notable requirements:" }

{ "type": "ul", "children": [ "Outpatients must be enrolled in the REMS program", "Patients must be opioid-tolerant to receive OTFC" ], "text": "" }

OTFC is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

{ "type": "p", "children": [], "text": "OTFC is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product. " }

Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require OTFC while hospitalized [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require OTFC while hospitalized [see Warnings and Precautions (5.7)].\n" }

Hyperalgesia and Allodynia

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia\n" }

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].\n" }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10), Drug Interactions (7)]." }

MAOI Interaction

{ "type": "p", "children": [], "text": "\nMAOI Interaction\n" }

Inform patients to avoid taking OTFC while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking OTFC [see Warnings and Precautions (5.10), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients to avoid taking OTFC while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking OTFC [see Warnings and Precautions (5.10), Drug Interactions (7)].\n" }

Important Administration Instructions [see Dosage and Administration (2)]

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions [see Dosage and Administration (2)]\n" }

{ "type": "ul", "children": [ "Instruct patients not to take OTFC for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.", "Instruct patients on the meaning of opioid tolerance and that OTFC is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes. ", "Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take OTFC.", "Instruct patients that, if the breakthrough pain episode is not relieved 15 minutes after finishing the OTFC unit, they may take only one additional unit of OTFC using the same strength for that episode. Thus, patients should take no more than two units of OTFC for any breakthrough pain episode. \n", "Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with OTFC.", "Instruct patients NOT to share OTFC and that sharing OTFC with anyone else could result in the other individual’s death due to overdose.", "Make patients aware that OTFC contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.", "Caution patients to talk to their healthcare provider if breakthrough pain is not alleviated or worsens after taking OTFC.", "Instruct patients to use OTFC exactly as prescribed by their healthcare provider and not to take OTFC more often than prescribed." ], "text": "" }

Driving or Operating Heavy Machinery

{ "type": "p", "children": [], "text": "\nDriving or Operating Heavy Machinery\n" }

Inform patients that OTFC may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].

{ "type": "p", "children": [], "text": "Inform patients that OTFC may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17)].\n" }

Constipation

{ "type": "p", "children": [], "text": "\nConstipation\n" }

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)]." }

Dental Decay

{ "type": "p", "children": [], "text": "\nDental Decay\n" }

Because each OTFC unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk.

{ "type": "p", "children": [], "text": "Because each OTFC unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk. " }

Post-marketing reports of dental decay have been received in patients taking OTFC [see Adverse Reactions (6.2)]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using OTFC should consult their dentist to ensure appropriate oral hygiene.

{ "type": "p", "children": [], "text": "Post-marketing reports of dental decay have been received in patients taking OTFC [see Adverse Reactions (6.2)]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using OTFC should consult their dentist to ensure appropriate oral hygiene." }

Adrenal Insufficiency

{ "type": "p", "children": [], "text": "\nAdrenal Insufficiency\n" }

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)]. " }

Hypotension

{ "type": "p", "children": [], "text": "\nHypotension\n" }

Inform patients that OTFC may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Inform patients that OTFC may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.13)].\n" }

Anaphylaxis

{ "type": "p", "children": [], "text": "\nAnaphylaxis\n" }

Inform patients that anaphylaxis has been reported with ingredients contained in OTFC. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Inform patients that anaphylaxis has been reported with ingredients contained in OTFC. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].\n" }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Neonatal Opioid Withdrawal Syndrome Inform patients that use of OTFC for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome\nInform patients that use of OTFC for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].\n\n" }

Embryo-Fetal Toxicity Inform female patients of reproductive potential that OTFC can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\nInform female patients of reproductive potential that OTFC can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)]." }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].\n" }

Diabetic Patients

{ "type": "p", "children": [], "text": "\nDiabetic Patients\n" }

Advise diabetic patients that OTFC contains approximately 2 grams of sugar per unit.

{ "type": "p", "children": [], "text": "Advise diabetic patients that OTFC contains approximately 2 grams of sugar per unit." }

Dispense with Medication Guide available at: www.tevausa.com/medguides

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: www.tevausa.com/medguides" }

OTF-017

{ "type": "p", "children": [], "text": "OTF-017" }

Distributed By: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Distributed By:\nTeva Pharmaceuticals USA, Inc.\nParsippany, NJ 07054" }

©2024 Cephalon, LLC.

{ "type": "p", "children": [], "text": "©2024 Cephalon, LLC." }

Dispense with Medication Guide available at: www.tevausa.com/medguides

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: www.tevausa.com/medguides" }

Medication Guide

{ "type": "p", "children": [], "text": "Medication Guide" }

<div class="scrollingtable"><table> <col width="100%"/> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Oral Transmucosal Fentanyl Citrate (OTFC)</span> </p> <p> <span class="Bold">(fentanyl citrate) oral transmucosal lozenge, CII</span> </p> <p> <span class="Bold">IMPORTANT:</span> </p> <p> <span class="Bold">Do not use Oral Transmucosal Fentanyl Citrate (OTFC) unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.</span> </p> <p> <span class="Bold">Keep OTFC in a safe place away from children.</span> </p> <p> <span class="Bold">Get emergency medical help right away if: </span> </p> <ul class="Disk"> <li> <span class="Bold">a child takes OTFC. OTFC can cause an overdose and death in any child who takes it.</span> </li> <li> <span class="Bold">an adult who has not been prescribed OTFC uses it.</span> </li> <li> <span class="Bold">an adult who is not already taking opioids around-the-clock, uses OTFC. </span> </li> </ul> <p> <span class="Bold">These are medical emergencies that can cause death. If possible, remove OTFC from the mouth.</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Oral Transmucosal Fentanyl Citrate (OTFC)</span>\n</p>\n<p>\n<span class=\"Bold\">(fentanyl citrate) oral transmucosal lozenge, CII</span>\n</p>\n<p>\n<span class=\"Bold\">IMPORTANT:</span>\n</p>\n<p>\n<span class=\"Bold\">Do not use Oral Transmucosal Fentanyl Citrate (OTFC) unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.</span>\n</p>\n<p>\n<span class=\"Bold\">Keep OTFC in a safe place away from children.</span>\n</p>\n<p>\n<span class=\"Bold\">Get emergency medical help right away if: </span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">a child takes OTFC. OTFC can cause an overdose and death in any child who takes it.</span>\n</li>\n<li>\n<span class=\"Bold\">an adult who has not been prescribed OTFC uses it.</span>\n</li>\n<li>\n<span class=\"Bold\">an adult who is not already taking opioids around-the-clock, uses OTFC. </span>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">These are medical emergencies that can cause death. If possible, remove OTFC from the mouth.</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Oral Transmucosal Fentanyl Citrate (OTFC) is:

{ "type": "p", "children": [], "text": "\nOral Transmucosal Fentanyl Citrate (OTFC) is:\n" }

{ "type": "ul", "children": [ "A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (16 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. OTFC is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use OTFC if you are not opioid tolerant.", "An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.\n\n\n" ], "text": "" }

Important information about Oral Transmucosal Fentanyl Citrate (OTFC):

{ "type": "p", "children": [], "text": "\nImportant information about Oral Transmucosal Fentanyl Citrate (OTFC):\n" }

{ "type": "ul", "children": [ "\nGet emergency help or call 911 right away if you take too much OTFC (overdose). When you first start taking OTFC, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.", "Taking OTFC with other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.", "Never give anyone else your OTFC. They could die from taking it. Selling or giving away OTFC is against the law.", "Store OTFC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.", "If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using OTFC. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.", "OTFC is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS). To receive OTFC, you must:\n \ntalk to your healthcare provider\nunderstand the benefits and risks of OTFC\nagree to all of the instructions\nsign the Patient Enrollment Form\n\n", "OTFC is only available at pharmacies that are part of the TIRF REMS. Your healthcare provider can help you locate a pharmacy closest to your home where you can have your OTFC prescription filled.", "Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine." ], "text": "" }

Do not take Oral Transmucosal Fentanyl Citrate (OTFC) if:

{ "type": "p", "children": [], "text": "\nDo not take Oral Transmucosal Fentanyl Citrate (OTFC) if:\n" }

{ "type": "ul", "children": [ "You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines.", "You have severe asthma, trouble breathing, or other lung problems.", "You have a bowel blockage or have narrowing of the stomach or intestines.", "You are allergic to any of the ingredients in OTFC. See the end of this Medication Guide for a complete list of ingredients in OTFC.", "You have short-term pain that you would expect to go away in a few days, such as:\n \npain after surgery \nheadache or migraine\ndental pain\n\n" ], "text": "" }

Before taking Oral Transmucosal Fentanyl Citrate (OTFC), tell your healthcare provider if you have a history of:

{ "type": "p", "children": [], "text": "\nBefore taking Oral Transmucosal Fentanyl Citrate (OTFC), tell your healthcare provider if you have a history of:\n" }

{ "type": "ul", "children": [ "troubled breathing or lung problems such as asthma, wheezing, or shortness of breath", "head injury, seizures", "slow heart rate or other heart problems", "low blood pressure", "mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)]", "problems urinating", "liver, kidney, thyroid problems", "pancreas or gallbladder problems", "abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems", "diabetes. Each OTFC unit contains about 1/2 teaspoon (2 grams) of sugar." ], "text": "" }

Tell your healthcare provider if you are:

{ "type": "p", "children": [], "text": "\nTell your healthcare provider if you are:\n" }

{ "type": "ul", "children": [ "\nnoticing your pain getting worse. If your pain gets worse after you take OTFC, do not take more OTFC without first talking to your healthcare provider. Talk to your healthcare provider if the pain you have increases, if your feel more sensitive to pain, or if you have new pain after taking OTFC.", "\npregnant or planning to become pregnant. Use of OTFC for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.", "\nbreastfeeding. OTFC passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.", "living in a household where there are small children or someone who has abused street or prescription drugs.", "taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking OTFC with certain other medicines can cause serious side effects that could lead to death." ], "text": "" }

When taking Oral Transmucosal Fentanyl Citrate (OTFC):

{ "type": "p", "children": [], "text": "\nWhen taking Oral Transmucosal Fentanyl Citrate (OTFC):\n" }

{ "type": "ul", "children": [ "Do not change your dose. Take OTFC exactly as prescribed by your healthcare provider.", "Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you.", "\nSee the detailed Patient Instructions for Use at the end of this Medication Guide for information about how to use OTFC.\n", "Finish the unit completely in 15 minutes to get the most relief. If you finish OTFC too quickly, you will swallow more of the medicine and get less relief.", "\nDo not bite or chew. You will get less relief for your breakthrough cancer pain.\n", "You may drink some water before using OTFC but you should not drink or eat anything while using OTFC.", "You must not use more than 2 units of OTFC during each episode of breakthrough cancer pain:\n \nUse 1 unit for an episode of breakthrough cancer pain. Finish the unit over 15 minutes.\nIf your breakthrough cancer pain is not relieved 15 minutes after you finished the OTFC unit, use only 1 more unit of OTFC at this time.\nIf your breakthrough pain does not get better after the second unit of OTFC, call your healthcare provider for instructions. Do not use another unit of OTFC at this time.\n\n\n", "Wait at least 4 hours before treating a new episode of breakthrough cancer pain with OTFC.", "It is important for you to keep taking your around-the-clock opioid pain medicine.", "Talk to your healthcare provider if your dose of OTFC does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of OTFC needs to be changed.", "Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted.", "If you begin to feel dizzy, sick to your stomach, or very sleepy before OTFC is completely dissolved, remove OTFC from your mouth. ", "Do not stop taking OTFC without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.", "After you stop taking, or when OTFC is no longer needed, see “How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?” for proper disposal of OTFC.", "Dispose of expired, unwanted, or unused OTFC by following the “How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?” sections of this Medication Guide below. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.", "\n DO NOT Drive or operate heavy machinery until you know how OTFC affects you. OTFC can make you sleepy, dizzy, or lightheaded.", "\nDO NOT Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with OTFC may cause you to overdose and die.", "\nDO NOT Switch from OTFC to other medicines that contain fentanyl without talking to your healthcare provider. The amount of fentanyl in a dose of OTFC is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of OTFC that may be different than other fentanyl containing medicines you may have been taking." ], "text": "" }

The possible side effects of Oral Transmucosal Fentanyl Citrate (OTFC):

{ "type": "p", "children": [], "text": "\nThe possible side effects of Oral Transmucosal Fentanyl Citrate (OTFC):\n" }

{ "type": "ul", "children": [ "constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping. Call your healthcare provider if you have any of these symptoms and they are severe.", "Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.", "OTFC contains sugar. Cavities and tooth decay can happen in people taking OTFC. When taking OTFC, you should talk to your dentist about proper care of your teeth." ], "text": "" }

Get emergency medical help or call 911 right away if you have:

{ "type": "p", "children": [], "text": "\nGet emergency medical help or call 911 right away if you have:\n" }

{ "type": "ul", "children": [ "trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.", "These symptoms can be a sign that you have used too much OTFC or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not use any more OTFC until you have talked to your healthcare provider.\n" ], "text": "" }

These are not all the possible side effects of OTFC. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

{ "type": "p", "children": [], "text": "These are not all the possible side effects of OTFC. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov\n" }

How should I store Oral Transmucosal Fentanyl Citrate (OTFC)?

{ "type": "p", "children": [], "text": "\nHow should I store Oral Transmucosal Fentanyl Citrate (OTFC)? \n" }

{ "type": "ul", "children": [ "\nAlways keep OTFC in a safe place away from children and from anyone for whom it has not been prescribed. Protect OTFC from theft.\n \nYou can use the OTFC Child Safety Kit to help you store OTFC and your other medicines out of the reach of children. It is very important that you use the items in the OTFC Child Safety Kit to help protect the children in your home or visiting your home.\nIf you were not offered a Child Safety Kit when you received your medicine, call 888-534-3119.\n\n" ], "text": "" }

The OTFC Child Safety Kit contains important information on the safe storage and handling of OTFC.

{ "type": "p", "children": [], "text": "The OTFC Child Safety Kit contains important information on the safe storage and handling of OTFC. " }

The Child Safety Kit includes:

{ "type": "p", "children": [], "text": "The Child Safety Kit includes: " }

{ "type": "ul", "children": [ "\nA child-resistant lock that you use to secure the storage space where you keep OTFC (See Figure 1). " ], "text": "" }

Figure 1

{ "type": "p", "children": [], "text": "\nFigure 1\n" }

{ "type": "ul", "children": [ "\nA portable locking pouch for you to keep a small supply of OTFC nearby. The rest of your OTFC must be kept in a locked storage space.\n \nKeep this pouch secured with its lock and keep it out of the reach and sight of children (See Figure 2).\n\n" ], "text": "" }

Figure 2

{ "type": "p", "children": [], "text": "\nFigure 2\n" }

{ "type": "ul", "children": [ "\nA child-resistant temporary storage bottle (See Figure 3). " ], "text": "" }

Figure 3

{ "type": "p", "children": [], "text": "\nFigure 3\n" }

{ "type": "ul", "children": [ "Store OTFC at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use.", "Do not freeze OTFC.", "\nKeep OTFC in the original sealed child-resistant blister package. Do not open the blister package until you are ready to use OTFC.\n", "Keep OTFC dry." ], "text": "" }

How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?

{ "type": "p", "children": [], "text": "\nHow should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?\n" }

Disposing of OTFC units after use:

{ "type": "p", "children": [], "text": "\nDisposing of OTFC units after use:\n" }

Partially used OTFC units may contain enough medicine to be harmful or fatal to a child or other adults who have not been prescribed OTFC. You must properly dispose of the OTFC handle right away after use even if there is little or no medicine left on it.

{ "type": "p", "children": [], "text": "Partially used OTFC units may contain enough medicine to be harmful or fatal to a child or other adults who have not been prescribed OTFC. You must properly dispose of the OTFC handle right away after use even if there is little or no medicine left on it. \n" }

After you have finished the OTFC unit and the medicine is totally gone, throw the handle away in a place that is out of the reach of children.

{ "type": "p", "children": [], "text": "After you have finished the OTFC unit and the medicine is totally gone, throw the handle away in a place that is out of the reach of children." }

If any medicine remains on the used OTFC unit after you have finished:

{ "type": "p", "children": [], "text": "If any medicine remains on the used OTFC unit after you have finished: " }

{ "type": "ul", "children": [ "Place the used OTFC unit under hot running water until the medicine is gone, and then throw the handle away out of the reach of children and pets (See Figure 4)." ], "text": "" }

Figure 4

{ "type": "p", "children": [], "text": "\nFigure 4\n" }

Temporary Storage of Used OTFC Units:

{ "type": "p", "children": [], "text": "\nTemporary Storage of Used OTFC Units:\n" }

{ "type": "ul", "children": [ "If you did not finish the entire OTFC unit and you cannot dissolve the medicine under hot running water right away, put the used OTFC unit in the temporary storage bottle that you received in the OTFC Child Safety Kit. Push the used OTFC unit into the opening on the top until it falls completely into the bottle. Never leave unused or partially used OTFC units where children or pets can get to them (See Figure 5)." ], "text": "" }

Figure 5

{ "type": "p", "children": [], "text": "\nFigure 5\n" }

Disposing of Used OTFC Units from the Temporary Storage Bottle:

{ "type": "p", "children": [], "text": "\nDisposing of Used OTFC Units from the Temporary Storage Bottle:\n" }

You must dispose of all used OTFC units in the temporary storage bottle at least one time each day, as follows:

{ "type": "p", "children": [], "text": "\nYou must dispose of all used OTFC units in the temporary storage bottle at least one time each day, as follows: " }

1. To open the temporary storage bottle, push down on the cap until you are able to twist the cap to the left to remove it (See Figure 6).

{ "type": "p", "children": [], "text": "1. To open the temporary storage bottle, push down on the cap until you are able to twist the cap to the left to remove it (See Figure 6)." }

Figure 6

{ "type": "p", "children": [], "text": "\nFigure 6\n" }

2. Remove one OTFC unit from the temporary storage bottle. Hold the OTFC by its handle over the toilet bowl. 3. Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet. 4. Throw the handle away in a place that is out of the reach of children. 5. Repeat these 3 steps for each OTFC handle that is in the storage bottle. There should not be more than 4 handles in the temporary storage bottle for 1 day. 6. Flush the toilet twice.

{ "type": "p", "children": [], "text": "2. Remove one OTFC unit from the temporary storage bottle. Hold the OTFC by its handle over the toilet bowl.\n3. Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet.\n4. Throw the handle away in a place that is out of the reach of children.\n5. Repeat these 3 steps for each OTFC handle that is in the storage bottle. There should not be more than 4 handles in the temporary storage bottle for 1 day.\n6. Flush the toilet twice." }

Do not flush entire unused OTFC units, OTFC handles, or blister packages down the toilet.

{ "type": "p", "children": [], "text": "Do not flush entire unused OTFC units, OTFC handles, or blister packages down the toilet." }

Disposing of unopened OTFC units: Dispose of any unopened OTFC units remaining from a prescription as soon as they are no longer needed, as follows:

{ "type": "p", "children": [], "text": "\nDisposing of unopened OTFC units: Dispose of any unopened OTFC units remaining from a prescription as soon as they are no longer needed, as follows:" }

1. Remove all OTFC from the locked storage space (See Figure 7).

{ "type": "p", "children": [], "text": "1. Remove all OTFC from the locked storage space (See Figure 7). " }

Figure 7

{ "type": "p", "children": [], "text": "\nFigure 7\n" }

2. Remove one OTFC unit from its blister package by using scissors to cut off the marked end and then peel back the blister backing (See Figures 8A and 8B).

{ "type": "p", "children": [], "text": "2. Remove one OTFC unit from its blister package by using scissors to cut off the marked end and then peel back the blister backing (See Figures 8A and 8B)." }

Figure 8A Figure 8B 3. Hold OTFC by its handle over the toilet bowl. Use wire-cutting pliers to cut the medicine end off so that it falls into the toilet (See Figures 9A and 9B).

{ "type": "p", "children": [], "text": "\nFigure 8A\tFigure 8B\n3. Hold OTFC by its handle over the toilet bowl. Use wire-cutting pliers to cut the medicine end off so that it falls into the toilet (See Figures 9A and 9B)." }

Figure 9A Figure 9B 4. Throw the handle away in a place that is out of the reach of children (See Figure 10).

{ "type": "p", "children": [], "text": "\nFigure 9A Figure 9B\n4. Throw the handle away in a place that is out of the reach of children (See Figure 10)." }

Figure 10

{ "type": "p", "children": [], "text": "\nFigure 10\n" }

5. Repeat steps 1 through 4 for each OTFC unit. 6. Flush the toilet twice after the medicine ends from 5 OTFC units have been cut off (See Figure 11). Do not flush more than 5 OTFC units at a time.

{ "type": "p", "children": [], "text": "5. Repeat steps 1 through 4 for each OTFC unit.\n6. Flush the toilet twice after the medicine ends from 5 OTFC units have been cut off (See Figure 11). Do not flush more than 5 OTFC units at a time." }

Figure 11

{ "type": "p", "children": [], "text": "\nFigure 11\n" }

{ "type": "ul", "children": [ "Do not flush entire unused OTFC units, OTFC handles, or blister packages down the toilet." ], "text": "" }

If you need help with disposal of OTFC, call Teva Pharmaceuticals at 1-888-483-8279, or call your local Drug Enforcement Agency (DEA) office.

{ "type": "p", "children": [], "text": "If you need help with disposal of OTFC, call Teva Pharmaceuticals at 1-888-483-8279, or call your local Drug Enforcement Agency (DEA) office." }

General information about Oral Transmucosal Fentanyl Citrate (OTFC)

{ "type": "p", "children": [], "text": "\nGeneral information about Oral Transmucosal Fentanyl Citrate (OTFC)\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use OTFC only for the purpose for which it was prescribed. Do not give OTFC to other people, even if they have the same symptoms you have. OTFC can harm other people and even cause death. Sharing OTFC is against the law.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use OTFC only for the purpose for which it was prescribed. Do not give OTFC to other people, even if they have the same symptoms you have. OTFC can harm other people and even cause death. Sharing OTFC is against the law." }

This Medication Guide summarizes the most important information about OTFC. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about OTFC that is written for healthcare professionals.

{ "type": "p", "children": [], "text": "This Medication Guide summarizes the most important information about OTFC. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about OTFC that is written for healthcare professionals. " }

For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.

{ "type": "p", "children": [], "text": "For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483." }

What are the ingredients of Oral Transmucosal Fentanyl Citrate (OTFC)?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients of Oral Transmucosal Fentanyl Citrate (OTFC)?\n" }

Active Ingredient: fentanyl citrate

{ "type": "p", "children": [], "text": "\nActive Ingredient: fentanyl citrate" }

Inactive Ingredients: sugar, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch and confectioner’s sugar.

{ "type": "p", "children": [], "text": "\nInactive Ingredients: sugar, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch and confectioner’s sugar." }

Patient Instructions for Use

{ "type": "p", "children": [], "text": "\nPatient Instructions for Use\n" }

Before you use OTFC, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use OTFC the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use OTFC.

{ "type": "p", "children": [], "text": "Before you use OTFC, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use OTFC the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use OTFC." }

When you get an episode of breakthrough cancer pain, use the dose of OTFC prescribed by your healthcare provider as follows:

{ "type": "p", "children": [], "text": "\nWhen you get an episode of breakthrough cancer pain, use the dose of OTFC prescribed by your healthcare provider as follows:\n" }

{ "type": "ul", "children": [ "You may drink some water before using OTFC but you should not drink or eat anything while using OTFC.", "Each unit of OTFC is sealed in its own blister package (See Figure 12). Do not open the blister package until you are ready to use OTFC.\n" ], "text": "" }

Figure 12

{ "type": "p", "children": [], "text": "\nFigure 12\n" }

{ "type": "ul", "children": [ "When you are ready to use OTFC, cut open the package using scissors. Peel back the blister backing, and remove the OTFC unit (See Figures 13A and 13B). The end of the unit printed with “FENTANYL” and the strength number of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”) is the medicine end that is to be placed in your mouth. Hold the OTFC unit by the handle (See Figure 14). " ], "text": "" }

Figure 13A Figure 13B

{ "type": "p", "children": [], "text": "\nFigure 13A\tFigure 13B\n" }

Figure 14

{ "type": "p", "children": [], "text": "\nFigure 14\n" }

1. Place the medicine end of the OTFC unit in your mouth between your cheeks and gums and actively suck on the medicine. 2. Move the medicine end of the OTFC unit around in your mouth, especially along the inside of your cheeks (See Figure 15).

{ "type": "p", "children": [], "text": "1. Place the medicine end of the OTFC unit in your mouth between your cheeks and gums and actively suck on the medicine.\n2. Move the medicine end of the OTFC unit around in your mouth, especially along the inside of your cheeks (See Figure 15)." }

Figure 15

{ "type": "p", "children": [], "text": "\nFigure 15\n" }

3. Twirl the handle often. 4. Finish the OTFC unit completely over 15 minutes to get the most relief. If you finish OTFC too quickly, you will swallow more of the medicine and get less relief. 5. Do not bite or chew OTFC. You will get less relief for your breakthrough cancer pain.

{ "type": "p", "children": [], "text": "3. Twirl the handle often.\n4. Finish the OTFC unit completely over 15 minutes to get the most relief. If you finish OTFC too quickly, you will swallow more of the medicine and get less relief.\n5. Do not bite or chew OTFC. You will get less relief for your breakthrough cancer pain.\n" }

{ "type": "ul", "children": [ "If you cannot finish all of the medicine on the OTFC unit and cannot dissolve the medicine under hot tap water right away, immediately put the OTFC unit in the temporary storage bottle for safe keeping (See Figure 16).\n \nPush the OTFC unit into the opening on the top until it falls completely into the bottle. You must properly dispose of the OTFC unit as soon as you can.\n\n" ], "text": "" }

Figure 16

{ "type": "p", "children": [], "text": "\nFigure 16\n" }

See “How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?” for proper disposal of OTFC.

{ "type": "p", "children": [], "text": "See “How should I dispose of Oral Transmucosal Fentanyl Citrate (OTFC) units when they are no longer needed?” for proper disposal of OTFC." }

<div class="scrollingtable"><table> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Distributed by: </p> <p>Teva Pharmaceuticals USA, Inc.                                      call 1-888-483-8279<br/> Parsippany, NJ 07054</p> <p>OTFMG-017<br/> ©2024 Cephalon, LLC.</p> <p>Printed in USA</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First"> <span class="Bold">This Medication Guide has been approved by the U.S. Food and Drug Administration.                                           Revised: 1/2024</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Distributed by: </p>\n<p>Teva Pharmaceuticals USA, Inc.                                      call 1-888-483-8279<br/>\n Parsippany, NJ 07054</p>\n<p>OTFMG-017<br/>\n ©2024 Cephalon, LLC.</p>\n<p>Printed in USA</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">This Medication Guide has been approved by the U.S. Food and Drug Administration.                                           Revised: 1/2024</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 0093-7865-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 200 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7865-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 200 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n\n" }

 PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\n PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n" ], "text": "" }

 Rx only 30 Units TEVA

{ "type": "p", "children": [], "text": "\n Rx only\n30 Units\nTEVA\n" }

NDC 0093-7866-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 400 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7866-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 400 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n\nRx only\n\n\n30 Units\n\n\nTEVA\n\n" ], "text": "" }

NDC 0093-7867-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 600 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7867-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 600 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\n" }

DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n\nRx only\n\n\n30 Units\n\n" ], "text": "" }

TEVA

{ "type": "p", "children": [], "text": "\nTEVA\n" }

NDC 0093-7868-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 800 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7868-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 800 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n\nRx only\n\n\n30 Units\n\n\nTEVA\n\n" ], "text": "" }

NDC 0093-7869-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 1200 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7869-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 1200 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n\nRx only\n\n\n30 Units\n\n\nTEVA\n\n" ], "text": "" }

NDC 0093-7870-65 Oral Transmucosal Fentanyl Citrate (OTFC) CII equivalent to 1600 mcg fentanyl base

{ "type": "p", "children": [], "text": "\nNDC 0093-7870-65\nOral Transmucosal Fentanyl Citrate (OTFC) CII\nequivalent to 1600 mcg fentanyl base" }

Only for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.

{ "type": "p", "children": [], "text": "\nOnly for patients already taking around-the-clock opioids (narcotics) such as fentanyl or morphine.\n" }

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS

{ "type": "p", "children": [], "text": "\nPATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY\nDO NOT SUBSTITUTE OTFC FOR OTHER FENTANYL PRODUCTS\n" }

WARNING: Keep out of the reach of children.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of the reach of children.\n" }

{ "type": "ul", "children": [ "\nAccidental ingestion of this medicine by a child could be harmful or fatal.\n", "\nPartially consumed OTFC must be disposed of properly.\n", "\nRead enclosed OTFC Medication Guide and consult your physician for important warnings and directions.\n", "\nCall 1-888-534-3119 for a free OTFC Child Safety Kit with important additional information about safe use, storage, and disposal of this medicine.\n\nRx only\n\n\n30 Units\n\n\nTEVA\n\n" ], "text": "" }

Fentanyl Citrate Injection is indicated for:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is indicated for: " }

{ "type": "", "children": [], "text": "" }

Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

If Fentanyl Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product's duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available [see Warnings and Precautions (5.3)].

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Premedication in Adults

50 mcg to 100 mcg may be administered intramuscularly 30 to 60 minutes prior to surgery.

Adjunct to General Anesthesia

See Dosage Range Charts below.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Dosage Range Chart </span> </caption> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total Dosage</span> (expressed as fentanyl base)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Low Dose-</span>2 mcg/kg<br/>For use in minor, but painful, surgical procedures.<br/>May also provide some pain relief in the immediate postoperative period. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Moderate Dose-</span>2 mcg/kg to 20 mcg/kg<br/>For use in more major surgical procedures, in addition to adequate analgesia, may abolish some of the stress response.<br/> <br/>Expect respiratory depression requiring artificial ventilation during anesthesia and careful observation of ventilation postoperatively is essential. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">High dose-</span>20 mcg/kg to 50 mcg/kg<br/>For open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and the stress response to surgery would be detrimental to the well-being of the patient.<br/> <br/>In conjunction with nitrous oxide/oxygen has been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin.<br/> <br/>Expect the need of postoperative ventilation and observation due to extended post-operative respiratory depression. </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Maintenance Dose</span> (expressed as fentanyl base)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Low Dose-</span>2 mcg/kg Additional dosages infrequently needed in these minor procedures. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Moderate Dose-</span>2 mcg/kg to 20 mcg/kg<br/>25 mcg to 100 mcg<br/>Administer intravenously or intramuscularly as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">High Dose-</span>20 mcg/kg to 50 mcg/kg<br/>Maintenance dosage [ranging from 25 mcg to one half the initial loading dose] as needed based on vital signs indicative of stress and lightening of analgesia.<br/>Individualize the dosage especially if the anticipated remaining operative time is short. </p> </td> </tr> </tbody> </table></div>

Adjunct to Regional Anesthesia

50 mcg to 100 mcg may be administered intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is required.

Postoperatively (recovery room)

50 mcg to 100 mcg may be administered intramuscularly for the control of pain, tachypnea and emergence delirium. The dose may be repeated in one to two hours as needed.

For Induction and Maintenance in Children 2 to 12 Years of Age

A reduced dose as low as 2 mcg/kg to 3 mcg/kg is recommended.

As a General Anesthetic

As a technique to attenuate the responses to surgical stress without the use of additional anesthetic agents, doses of 50 mcg/kg to 100 mcg/kg may be administered with oxygen and a muscle relaxant. In certain cases, doses up to 150 mcg/kg may be necessary to produce this anesthetic effect. It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures.

Needle Usage

Use caution when penetrating vial stopper with a needle exceeding 1 inch in length.

Single-Dose Vials:

{ "type": "p", "children": [], "text": "Single-Dose Vials: " }

Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 1 mL, 2 mL, 5 mL, 20 mL, 50 mL single-dose glass vials.

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 1 mL, 2 mL, 5 mL, 20 mL, 50 mL single-dose glass vials. " }

Fentanyl Citrate Injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is contraindicated in patients with: " }

{ "type": "", "children": [], "text": "" }

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential. As with other potent opioids, the respiratory depressant effect of Fentanyl Citrate Injection may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms [see Clinical Pharmacology (12.2)] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved and be prepared to manage them in the patients selected for these forms of anesthesia.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentanyl Citrate Injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.

Monitor such patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration (2.1)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.1)].

When benzodiazepines or other CNS depressants are used with Fentanyl Citrate Injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Fentanyl Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Fentanyl Citrate Injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentanyl Citrate Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to manage postoperative pain with Fentanyl Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate Injection-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentanyl Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentanyl Citrate Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations, decreased efficacy, or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using Fentanyl Citrate Injection with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider increasing the Fentanyl Citrate Injection dosage [see Dosage and Administration (2.1), Drug Interactions (7)].

Fentanyl Citrate Injection may cause muscle rigidity, particularly involving the muscles of respiration. The incidence and severity of muscle rigidity is dose related. These effects are related to the dose and speed of injection. Skeletal muscle rigidity also has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck, and external eye have been reported during induction of anesthesia with Fentanyl Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

These effects are related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Fentanyl Citrate Injection; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when Fentanyl Citrate Injection is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of Fentanyl Citrate Injection and a full paralyzing dose of a neuromuscular blocking agent when Fentanyl Citrate Injection is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient's cardiovascular status.

Fentanyl Citrate Injection may cause severe bradycardia, severe hypotension including orthostatic hypotension, and syncope. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. In patients with circulatory shock, Fentanyl Citrate Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Fentanyl Citrate Injection.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biological plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2)].

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Fentanyl Citrate Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of increasing intracranial pressure. Monitor such patients closely, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7).]

Opioids may also obscure the clinical course in a patient with a head injury.

Fentanyl may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Fentanyl may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Fentanyl Citrate Injection therapy.

Fentanyl Citrate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery after Fentanyl Citrate Injection administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Fentanyl Citrate Injection and know how they will react to the medication.

Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. Administer neuroleptic agents with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI's), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

When Fentanyl Citrate Injection is used with a neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern may return to normal slowly.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Fentanyl Citrate Injection

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7)].

Hypoglycemia: Causes of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 2 includes clinically significant drug interactions with Fentanyl Citrate Injection.

{ "type": "p", "children": [], "text": "\nTable 2 includes clinically significant drug interactions with Fentanyl Citrate Injection. " }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Clinically Significant Drug Interactions with Fentanyl Citrate Injection </span> </caption> <col width="20%"/> <col width="80%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Inhibitors of CYP3A4</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved <span class="Italics">[see Warnings and Precautions (<a href="#s23">5.4</a>)]</span>.<br/> <br/> </p> <p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology (<a href="#s74">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved <span class="Italics">[see Dosage and Administration (<a href="#s8">2.1</a>)]</span>. Monitor patients at frequent intervals for respiratory depression and sedation.<br/> <br/> </p> <p>If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">CYP3A4 Inducers</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see Clinical Pharmacology (<a href="#s74">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see Warnings and Precautions (<a href="#s23">5.4</a>)].<br/> <br/> </span> </p> <p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see Clinical Pharmacology (<a href="#s74">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Rifampin, carbamazepine, phenytoin </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Fentanyl Citrate Injection with CNS depressants may result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available <span class="Italics">[see Warnings and Precautions (<a href="#s22">5.3</a>)]</span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#s27">5.8</a>)]</span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see Warnings and Precautions (<a href="#s27">5.8</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (<a href="#s21">5.2</a>)].</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Phenelzine, tranylcypromine, linezolid </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Avoid concomitant use. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Butorphanol, nalbuphine, pentazocine, buprenorphine. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Fentanyl Citrate Injection and/or the muscle relaxant as necessary. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Neuroleptics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic <span class="Italics">[see Warnings and Precautions (<a href="#ID_46510abd-f894-43c2-b8d3-849be7e92e74">5.13</a>)]</span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nitrous oxide</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection. </p> </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 2: Clinically Significant Drug Interactions with Fentanyl Citrate Injection </span>\n</caption>\n<col width=\"20%\"/>\n<col width=\"80%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inhibitors of CYP3A4</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s23\">5.4</a>)]</span>.<br/>\n<br/>\n</p>\n<p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#s74\">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved <span class=\"Italics\">[see Dosage and Administration (<a href=\"#s8\">2.1</a>)]</span>. Monitor patients at frequent intervals for respiratory depression and sedation.<br/>\n<br/>\n</p>\n<p>If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">CYP3A4 Inducers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#s74\">12.3</a>)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s23\">5.4</a>)].<br/>\n<br/>\n</span>\n</p>\n<p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#s74\">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Rifampin, carbamazepine, phenytoin </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Fentanyl Citrate Injection with CNS depressants may result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s22\">5.3</a>)]</span>. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s27\">5.8</a>)]</span>. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s27\">5.8</a>)]</span> or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#s21\">5.2</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Phenelzine, tranylcypromine, linezolid </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Avoid concomitant use. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Butorphanol, nalbuphine, pentazocine, buprenorphine. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Fentanyl Citrate Injection and/or the muscle relaxant as necessary. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Neuroleptics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#ID_46510abd-f894-43c2-b8d3-849be7e92e74\">5.13</a>)]</span>. </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Nitrous oxide</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection. </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Fentanyl Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

There are insufficient data to support the use of fentanyl in labor or delivery. Therefore, such use is not recommended. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl Citrate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Fentanyl Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Animal Data

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m2 basis). There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m2 basis.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.38%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Fentanyl Citrate Injection and any potential adverse effects on the breastfed infant from Fentanyl Citrate Injection or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

The safety and efficacy of Fentanyl Citrate Injection in pediatric patients under two years of age has not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Fentanyl Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

Fentanyl Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of Fentanyl Citrate Injection and its metabolites. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled drug substance.

Fentanyl Citrate Injection contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Fentanyl Citrate Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Fentanyl Citrate Injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Fentanyl Citrate Injection abuse include those with a history of prolonged use of any opioid, including products containing fentanyl, those with a history of drug or alcohol abuse, or those who use Fentanyl Citrate Injection in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Fentanyl Citrate Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures to limit abuse of opioid drugs.

Risks Specific to Abuse of Fentanyl Citrate Injection

Abuse of Fentanyl Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Fentanyl Citrate Injection with alcohol and/or other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Both tolerance and physical dependence can develop during chronic opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of physiological adaptation in a response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dosage reduction of a drug.

Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Fentanyl Citrate Injection should not be abruptly discontinued in a physically-dependent patient. If Fentanyl Citrate Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Fentanyl Citrate Injection is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration. Fentanyl citrate is chemically identified as N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1) with the following structural formula:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration. Fentanyl citrate is chemically identified as N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1) with the following structural formula: " }

C22H28N2O • C6H8O7          Molecular Weight is 528.59

{ "type": "p", "children": [], "text": "C22H28N2O • C6H8O7          Molecular Weight is 528.59 " }

Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection. Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. The pH range is 4.0 to 7.5. Contains no preservative.

{ "type": "p", "children": [], "text": "Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection. Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. The pH range is 4.0 to 7.5. Contains no preservative. " }

Fentanyl Citrate Injection is an opioid agonist, whose principal actions of therapeutic value are analgesia and sedation.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration – Efficacy Relationships

A dose of 100 mcg of Fentanyl Citrate Injection is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1)].

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal analgesic effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg. Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours.

Concentration – Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1)].

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal respiratory depressant effect may not be noted for several minutes. As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of fentanyl may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of fentanyl citrate:

Fentanyl Citrate Injection is administered by the intravenous or intramuscular route. The pharmacokinetics of fentanyl can be described as a three-compartment model.

Distribution

Fentanyl plasma protein binding capacity increases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat and is released slowly into the blood. The volume of distribution for fentanyl is 4 L/kg. It has a distribution time of 1.7 minutes and redistribution time of 13 minutes.

Elimination

The terminal elimination half-life is 219 minutes.

Fentanyl, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of fentanyl citrate have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of fentanyl citrate have been conducted.

Impairment of Fertility

Decreased pregnancy rates occurred in a multigenerational study in which pregnant rats were treated subcutaneously during the first 21 days of pregnancy with 160 mcg/kg to 1250 mcg/kg fentanyl (0.26 times to 2.0 times a human dose of 100 mcg/kg based on body surface area).

Studies in animals to characterize the effect of fentanyl on male fertility have not been conducted.

Fentanyl Citrate Injection is supplied as a sterile, clear, and colorless solution.

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection is supplied as a sterile, clear, and colorless solution. " }

Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows:

{ "type": "p", "children": [], "text": "Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows: " }

<div class="scrollingtable"><table width="100%"> <col width="14%"/> <col width="29%"/> <col width="28%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Product Code</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Unit of Sale</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Each</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">806101 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-01<br/>Unit of 25 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">50 mcg in 1 mL<br/>(50 mcg per mL) </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-11<br/>1 mL fill in a 2 mL single-dose vial </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">806102 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-02<br/>Unit of 25 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">100 mcg in 2 mL<br/>(50 mcg per mL) </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-12<br/>2 mL single-dose vial </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">806105 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-05<br/>Unit of 25 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">250 mcg in 5 mL<br/>(50 mcg per mL) </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-13<br/>5 mL single-dose vial </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"14%\"/>\n<col width=\"29%\"/>\n<col width=\"28%\"/>\n<col width=\"29%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Product Code</span>\n</p>\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Unit of Sale</span>\n</p>\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Strength</span>\n</p>\n</td><td class=\"Botrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Each</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">806101 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-01<br/>Unit of 25 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">50 mcg in 1 mL<br/>(50 mcg per mL) </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-11<br/>1 mL fill in a 2 mL single-dose vial </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">806102 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-02<br/>Unit of 25 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">100 mcg in 2 mL<br/>(50 mcg per mL) </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-12<br/>2 mL single-dose vial </p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">806105 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-05<br/>Unit of 25 </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">250 mcg in 5 mL<br/>(50 mcg per mL) </p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">NDC 63323-806-13<br/>5 mL single-dose vial </p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

For Intravenous Use by Hospital Personnel Specifically Trained in the Use of Narcotic Analgesics:

{ "type": "p", "children": [], "text": "For Intravenous Use by Hospital Personnel Specifically Trained in the Use of Narcotic Analgesics: " }

<div class="scrollingtable"><table width="100%"> <col width="14%"/> <col width="29%"/> <col width="28%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Product Code</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Unit of Sale</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Each</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">806120 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-20<br/>Unit of 25 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1,000 mcg in 20 mL<br/>(50 mcg per mL) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-14<br/>20 mL single-dose vial </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">806150 </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-50<br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2,500 mcg in 50 mL<br/>(50 mcg per mL) <br/> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">NDC 63323-806-50<br/>50 mL single-dose vial, packaged individually. </p> </td> </tr> </tbody> </table></div>

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PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20˚C to 25˚C (68˚F to 77˚F), excursions permitted to 15˚C to 30˚C (59˚F to 86˚F) [See USP Controlled Room Temperature]. Contains no preservative. DISCARD ANY UNUSED CONTENTS.

{ "type": "p", "children": [], "text": "PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20˚C to 25˚C (68˚F to 77˚F), excursions permitted to 15˚C to 30˚C (59˚F to 86˚F) [See USP Controlled Room Temperature]. Contains no preservative. DISCARD ANY UNUSED CONTENTS. " }

The container closure is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "The container closure is not made with natural rubber latex. " }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. " }

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. " }

Addiction, Abuse, and Misuse

Inform patients that the use of Fentanyl Citrate Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Fentanyl Citrate Injection or when the dosage is increased, and that it can occur even at recommended dosages.

Hyperalgesia and Allodynia

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7); Adverse Reactions (6)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.8), Drug Interactions (7)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Clinical Pharmacology (12.2)].

Lake Zurich, IL 60047

For Product Inquiry:1-800-551-7176 orwww.fresenius-kabi.com/us

451610E

NDC 63323-806-11          806101

{ "type": "p", "children": [], "text": "NDC 63323-806-11          806101 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

50 mcg per 1 mL

{ "type": "p", "children": [], "text": "\n50 mcg per 1 mL\n" }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

1 mL Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "\n1 mL Single-Dose Vial           Rx only " }

NDC 63323-806-01          806101

{ "type": "p", "children": [], "text": "NDC 63323-806-01          806101 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

50 mcg per 1 mL

{ "type": "p", "children": [], "text": "\n50 mcg per 1 mL\n" }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

25 x 1 mL

{ "type": "p", "children": [], "text": "\n25 x 1 mL\n" }

Single-Dose Vials           Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vials           Rx only " }

NDC 63323-806-12          806102

{ "type": "p", "children": [], "text": "NDC 63323-806-12          806102 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

100 mcg per 2 mL

{ "type": "p", "children": [], "text": "\n100 mcg per 2 mL\n" }

(50 mcg per mL)

{ "type": "p", "children": [], "text": "(50 mcg per mL) " }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

2 mL Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "\n2 mL Single-Dose Vial           Rx only " }

NDC 63323-806-02          806102

{ "type": "p", "children": [], "text": "NDC 63323-806-02          806102 " }

Fentanyl               CII

{ "type": "p", "children": [], "text": "\nFentanyl               CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

100 mcg per 2 mL

{ "type": "p", "children": [], "text": "\n100 mcg per 2 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

25 x 2 mL

{ "type": "p", "children": [], "text": "\n25 x 2 mL\n" }

Single-Dose Vials           Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vials           Rx only " }

NDC 63323-806-13          806105

{ "type": "p", "children": [], "text": "NDC 63323-806-13          806105 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

250 mcg per 5 mL

{ "type": "p", "children": [], "text": "\n250 mcg per 5 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

5 mL

{ "type": "p", "children": [], "text": "\n5 mL\n" }

Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vial           Rx only " }

NDC 63323-806-05          806105

{ "type": "p", "children": [], "text": "NDC 63323-806-05          806105 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

250 mcg per 5 mL

{ "type": "p", "children": [], "text": "\n250 mcg per 5 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR INTRAVENOUS OR INTRAMUSCULAR USE

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS OR \n\nINTRAMUSCULAR USE\n" }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

25 x 5 mL

{ "type": "p", "children": [], "text": "\n25 x 5 mL\n" }

Single-Dose Vials          Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vials          Rx only " }

NDC 63323-806-14          806120

{ "type": "p", "children": [], "text": "NDC 63323-806-14          806120 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

1,000 mcg per 20 mL

{ "type": "p", "children": [], "text": "\n1,000 mcg per 20 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR SLOW INTRAVENOUS USE

{ "type": "p", "children": [], "text": "\nFOR SLOW INTRAVENOUS USE\n" }

BY HOSPITAL PERSONNEL SPECIFICALLY

{ "type": "p", "children": [], "text": "BY HOSPITAL PERSONNEL SPECIFICALLY " }

TRAINED IN THE USE OF NARCOTIC ANALGESICS

{ "type": "p", "children": [], "text": "TRAINED IN THE USE OF NARCOTIC ANALGESICS " }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

20 mL

{ "type": "p", "children": [], "text": "\n20 mL\n" }

Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vial           Rx only " }

NDC 63323-806-20          806120

{ "type": "p", "children": [], "text": "NDC 63323-806-20          806120 " }

Fentanyl              CII

{ "type": "p", "children": [], "text": "\nFentanyl              CII\n" }

Citrate Injection, USP

{ "type": "p", "children": [], "text": "Citrate Injection, USP" }

1,000 mcg per 20 mL

{ "type": "p", "children": [], "text": "\n1,000 mcg per 20 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR SLOW INTRAVENOUS USE

{ "type": "p", "children": [], "text": "\nFOR SLOW INTRAVENOUS USE\n" }

BY HOSPITAL PERSONNEL

{ "type": "p", "children": [], "text": "BY HOSPITAL PERSONNEL " }

SPECIFICALLY TRAINED IN THE

{ "type": "p", "children": [], "text": "SPECIFICALLY TRAINED IN THE " }

USE OF NARCOTIC ANALGESICS

{ "type": "p", "children": [], "text": "USE OF NARCOTIC ANALGESICS " }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

25 x 20 mL

{ "type": "p", "children": [], "text": "\n25 x 20 mL\n" }

Single-Dose Vials           Rx only

{ "type": "p", "children": [], "text": "Single-Dose Vials           Rx only " }

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Fentanyl Citrate 2,500 mcg per 50 mL Vial Label

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Fentanyl Citrate 2,500 mcg per 50 mL Vial Label\n" }

NDC 63323-806-50       806150

{ "type": "p", "children": [], "text": "NDC 63323-806-50       806150 " }

Fentanyl              CII Citrate Injection, USP

{ "type": "p", "children": [], "text": "\nFentanyl              CII\nCitrate Injection, USP" }

2,500 mcg per 50 mL

{ "type": "p", "children": [], "text": "\n2,500 mcg per 50 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR SLOW INTRAVENOUS USE

{ "type": "p", "children": [], "text": "\nFOR SLOW INTRAVENOUS USE\n" }

BY HOSPITAL PERSONNEL SPECIFICALLY

{ "type": "p", "children": [], "text": "BY HOSPITAL PERSONNEL SPECIFICALLY " }

TRAINED IN THE USE OF NARCOTIC

{ "type": "p", "children": [], "text": "TRAINED IN THE USE OF NARCOTIC " }

ANALGESICS

{ "type": "p", "children": [], "text": "ANALGESICS " }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

50 mL Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "\n50 mL \nSingle-Dose Vial           Rx only " }

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Fentanyl Citrate 2,500 mcg per 50 mL Carton

{ "type": "p", "children": [], "text": "\nPACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Fentanyl Citrate 2,500 mcg per 50 mL Carton\n" }

NDC 63323-806-50        806150

{ "type": "p", "children": [], "text": "NDC 63323-806-50        806150 " }

Fentanyl              CII Citrate Injection, USP

{ "type": "p", "children": [], "text": "\nFentanyl              CII\nCitrate Injection, USP " }

2,500 mcg per 50 mL

{ "type": "p", "children": [], "text": "\n2,500 mcg per 50 mL\n" }

(50 mcg per mL)*

{ "type": "p", "children": [], "text": "(50 mcg per mL)* " }

FOR SLOW INTRAVENOUS USE

{ "type": "p", "children": [], "text": "\nFOR SLOW INTRAVENOUS USE\n" }

BY HOSPITAL PERSONNELSPECIFICALLY TRAINED IN THEUSE OF NARCOTIC ANALGESICS

{ "type": "p", "children": [], "text": "BY HOSPITAL PERSONNELSPECIFICALLY TRAINED IN THEUSE OF NARCOTIC ANALGESICS " }

Preservative-free

{ "type": "p", "children": [], "text": "Preservative-free " }

50 mL Single-Dose Vial           Rx only

{ "type": "p", "children": [], "text": "\n50 mL \nSingle-Dose Vial           Rx only " }

Fentanyl transdermal system is indicated for the management of severe and persistent pain in opioid-tolerant patients, that requires an extended treatment period with a daily opioid analgesic in opioid-tolerant patients, and for which alternative treatment options are inadequate.

{ "type": "p", "children": [], "text": "Fentanyl transdermal system is indicated for the management of severe and persistent pain in opioid-tolerant patients, that requires an extended treatment period with a daily opioid analgesic in opioid-tolerant patients, and for which alternative treatment options are inadequate." }

Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60　mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

{ "type": "p", "children": [], "text": "Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60　mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid." }

Limitations of Use

{ "type": "p", "children": [], "text": "\nLimitations of Use\n" }

{ "type": "ul", "children": [ "Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n , reserve fentanyl transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.\n \n ", "Fentanyl transdermal system is not indicated as an as-needed (prn) analgesic." ], "text": "" }

Fentanyl transdermal system should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid [see Indications and Usage ( 1)] .

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system  [see Warnings and Precautions ( 5.2), Patient Counseling Information ( 17)] . 

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).  

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1, 5.2, 5.4)] .   

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.

Conversion from other opioids to fentanyl transdermal system

Do not initiate treatment with fentanyl transdermal system in opioid nontolerant patients [see Contraindications ( 4)] .

The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose.

When fentanyl transdermal system therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour fentanyl requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which could result in adverse reactions. In a fentanyl transdermal system clinical trial, patients were converted from their prior opioid to fentanyl transdermal system using Table 1 as a guide for the initial fentanyl transdermal system dose.

Each fentanyl transdermal system is worn continuously for up to 72 hours [see Dosage and Administration ( 2.7)] . 

When converting patients from oral or parenteral opioids to fentanyl, use Table 1 (alternatively use Table 2 for adult and pediatric patients taking opioids or doses not listed in Table 1) and consider the following:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1 <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>: Dose Conversion from Other Opioids to Fentanyl Transdermal System </span> </caption> <col width="30%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.9)]. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Current Analgesic</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Daily Dosage (mg/day)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral morphine</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">60‒134</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">135‒224</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">225‒314</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">315‒404</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intramuscular or Intravenous morphine</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10‒22</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">23‒37</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38‒52</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">53‒67</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral oxycodone</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">30‒67</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">67.5‒112</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">112.5‒157</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">157.5‒202</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral codeine</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">150‒447</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral hydromorphone</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8‒17</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17.1‒28</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">28.1‒39</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">39.1‒51</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intravenous hydromorphone</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.5‒3.4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3.5‒5.6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5.7‒7.9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8‒10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Intramuscular meperidine</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75‒165</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">166‒278</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">279‒390</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">391‒503</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oral methadone</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">20‒44</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">45‒74</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75‒104</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">105‒134</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">⇓</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">⇓</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">⇓</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">⇓</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Recommended Fentanyl Transdermal System Dose</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25 mcg/hour</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50 mcg/hour</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75 mcg/hour</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100 mcg/hour</p> </td> </tr> </tbody> </table></div>

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology when converting patients from oral or parenteral opioids to fentanyl:

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.

3. Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24‑hour morphine dose and the corresponding recommended initial fentanyl transdermal system dose.

4. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained. A 37.5 mcg/hour dose may also be used. For patients that require more than 100 mcg/hour, several transdermal systems may be used.

5. Do not use Table 2 to convert from fentanyl transdermal system to other therapiesbecause this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2 <a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a>: Recommended Initial Fentanyl Transdermal System Dose based upon Daily Oral Morphine Dose </span> </caption> <col width="50%"/> <col width="50%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"><span class="Bold">NOTE:</span>In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system. </td> </tr> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.9)]. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Oral 24-hour</span> </p> <p> <span class="Bold">Morphine</span> </p> <p> <span class="Bold">(mg/day)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fentanyl Transdermal System</span> </p> <p> <span class="Bold">Dose</span> </p> <p> <span class="Bold">(mcg/hour)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">60‒134</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">135‒224</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">225‒314</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">315‒404</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">100</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">405‒494</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">125</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">495‒584</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">150</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">585‒674</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">175</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">675‒764</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">200</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">765‒854</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">225</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">855‒944</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">250</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">945‒1034</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">275</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1035‒1124</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">300</p> </td> </tr> </tbody> </table></div>

An additional intermediate strength 37.5 mcg/hour fentanyl transdermal system is available and may be considered during conversion from prior opioids or dose titration. For example, the 37.5 mcg/hour system could be used before converting or titrating to a 50 mcg/hour system. 

The additional 37.5 mcg/hour system was not used in the clinical studies.

For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Individually titrate fentanyl transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal system to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reaction, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1, 5.21)] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of fentanyl transdermal system, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the fentanyl transdermal system dosage.

The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl transdermal system dose for the first time until at least 3 days after the initial application. Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.

It may take up to 6　days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology ( 12.3)] . Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.

Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24　hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system dose.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5)] . Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

A small proportion of adult patients may not achieve adequate analgesia using a 72-hour dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen.

Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions ( 5.17), Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)].

Avoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions ( 5.18), Use in Specific Populations ( 8.7), and Clinical Pharmacology ( 12.3)].

FENTANYL TRANSDERMAL SYSTEM PATCHES ARE FOR TRANSDERMAL USE ONLY.

Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions ( 5.3)].

Application and Handling Instructions

Avoidance of Heat

Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions ( 5.8)] .

Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures and deaths, including deaths of children [see Warnings and Precautions ( 5.3)] .

Instruct patients to dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet.

Instruct patients to remove unused patches from their pouches, remove the release liners, fold the patches so that the adhesive side of the patch adheres to itself, and to immediately flush the patches down the toilet.

Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed.

Do not abruptly discontinue fentanyl transdermal system in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrollable pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking fentanyl transdermal system, there are a variety of factors that should be considered, including the total daily dose of opioid (including fentanyl transdermal system) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. 

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on fentanyl transdermal system who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.21) , Drug Abuse and Dependence ( 9.3) ].

Transdermal system:

{ "type": "p", "children": [], "text": "Transdermal system:" }

{ "type": "ul", "children": [ "Fentanyl Transdermal System 12 mcg/hour* (system size 5.35 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 25 mcg/hour (system size 10.7 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 37.5 mcg/hour (system size 16.05 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 50 mcg/hour (system size 21.4 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 62.5 mcg/hour (system size 26.75 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 75 mcg/hour (system size 32.1 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 87.5 mcg/hour (system size 37.45 cm\n \n 2)\n \n ", "Fentanyl Transdermal System 100 mcg/hour (system size 42.8 cm\n \n 2)\n \n " ], "text": "" }

*This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.

{ "type": "p", "children": [], "text": "\n*This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.\n\n " }

Fentanyl transdermal system is contraindicated in:

{ "type": "p", "children": [], "text": "Fentanyl transdermal system is contraindicated in:" }

{ "type": "ul", "children": [ "patients who are not opioid-tolerant.", "the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time.", "the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies).", "the management of mild pain.", "patients with significant respiratory depression\n \n [see Warnings and Precautions (\n \n 5.12)]\n \n .\n \n ", "in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment\n \n [see Warnings and Precautions (\n \n 5.12)]\n \n .\n \n ", "in patients with known or suspected gastrointestinal obstruction, including paralytic ileus\n \n [see Warnings and Precautions (\n \n 5.19)]\n \n .\n \n ", "in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system\n \n [see Adverse Reactions (\n \n 6.2)]\n \n .\n \n " ], "text": "" }

Fentanyl transdermal system contains fentanyl, an opioid agonist and a Schedule II controlled substance. As an opioid, fentanyl transdermal system exposes users to the risks of addiction, abuse, and misuse. Because modified-release products such as fentanyl transdermal system deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of fentanyl present [see Drug Abuse and Dependence ( 9)] .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed fentanyl transdermal system. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing fentanyl transdermal system, and reassess all patients receiving fentanyl transdermal system for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as fentanyl transdermal system, but use in such patients necessitates intensive counseling about the risks and proper use of fentanyl transdermal system along with frequent re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.2)].

Abuse or misuse of fentanyl transdermal system by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death [see Overdosage ( 10)] .

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing fentanyl transdermal system. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10)] . Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Fentanyl transdermal system is indicated only in opioid tolerant patients because of the risk for respiratory depression and death. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of fentanyl transdermal system, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal system are essential [see Dosage and Administration ( 2)] . Overestimating the fentanyl transdermal system dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental exposure to fentanyl transdermal system, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.9)] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions ( 5.1,  5.4), Patient Counseling Information ( 17)].

A considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression, and has resulted in deaths. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Improper disposal of fentanyl transdermal system in the trash has resulted in accidental exposures and deaths.

Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal system [see Dosage and Administration ( 2.7), ( 2.8)].  Exposure to fentanyl transdermal system patches discarded in the trash by children have been reported and have resulted in deaths. 

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl transdermal system with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7)] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.2)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when fentanyl transdermal system is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7), Patient Counseling Information ( 17)] .

Use of fentanyl transdermal system for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17)] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

Concomitant use of fentanyl transdermal system with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions ( 5.2)] , particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl transdermal system -treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl transdermal system with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl transdermal system-treated patients, evaluate patients at frequent intervals and consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved [see Dosage and Administration ( 2.4), Drug Interactions ( 7)] .

Concomitant use of Fentanyl transdermal system with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl transdermal system plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using fentanyl transdermal system with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions ( 7)] .

Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased fentanyl exposure [see Clinical Pharmacology ( 12.3)] .

Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources [see Dosage and Administration ( 2.7)] .

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing fentanyl transdermal systems who develop fever closely for sedation and respiratory depression and reduce the fentanyl transdermal system dose, if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl transdermal system to avoid the risk of potential overdose and death.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3)] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.  

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.1); Warnings and Precautions ( 5.10)] .

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl transdermal system with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7)] . This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue fentanyl transdermal system immediately if serotonin syndrome is suspected.

The use of fentanyl transdermal system in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

Fentanyl transdermal system-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of fentanyl transdermal system [see Warnings and Precautions ( 5.2)] .

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.2)] .

Regularly evaluate patients, particularly when initiating and titrating fentanyl transdermal system and when fentanyl transdermal system is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5), Drug Interactions ( 7)] . Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Fentanyl transdermal system may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of fentanyl transdermal system. In patients with circulatory shock, fentanyl transdermal system may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of fentanyl transdermal system in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO 2retention (e.g., those with evidence of increased intracranial pressure or brain tumors), fentanyl transdermal system may reduce respiratory drive, and the resultant CO 2retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal system.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of fentanyl transdermal system in patients with impaired consciousness or coma.

Fentanyl transdermal system may produce bradycardia. Regularly evaluate patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal system.

A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as fentanyl transdermal system and hepatic metabolism of fentanyl, avoid use of fentanyl transdermal system in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal system. Regularly evaluate for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration ( 2.5), Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)] .

A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because of the long half-life of fentanyl when administered as fentanyl transdermal system, avoid the use of fentanyl transdermal system in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal system. Regularly evaluate for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration ( 2.6), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)] .

Fentanyl transdermal system is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in fentanyl transdermal system may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

The fentanyl in fentanyl transdermal system may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during fentanyl transdermal system therapy.

Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids. When discontinuing fentanyl transdermal system in a physically dependent patient, gradually taper the dosage. Rapid tapering of fentanyl transdermal system in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.9), Drug Abuse and Dependence ( 9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including fentanyl transdermal system. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions ( 7)] .

Fentanyl transdermal system may impair the mental or physical abilities required for the performance of potentially dangerous activities, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the fentanyl transdermal system and know how they will react to the medication [see Patient Counseling Information ( 17)] .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of fentanyl transdermal system was evaluated in 216　patients who took at least one dose of fentanyl transdermal system in a multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal system. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.

The most common adverse reactions (≥5%) in a double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (≥5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for ≥1% of fentanyl transdermal system-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3.

The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in ≥1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal System</span> </caption> <col width="56%"/> <col width="28%"/> <col width="16%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">System/Organ Class</span> <br/> Adverse Reaction </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Fentanyl Transdermal System</span> <br/> <span class="Bold">%</span> <br/> <span class="Bold">(N = 216)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Placebo</span> <br/> <span class="Bold">%</span> <br/> <span class="Bold">(N = 200)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Palpitations</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Ear and labyrinth disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vertigo</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">41</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">26</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain upper</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dry mouth</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Feeling cold</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Malaise</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema peripheral</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Muscle spasms</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Depression</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperhidrosis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

Adverse reactions not reported in Table 3 that were reported by ≥1% of fentanyl transdermal system-treated adult and pediatric patients (N=1854) in 11　controlled and uncontrolled clinical trials of fentanyl transdermal system used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Patients in 11 Clinical Trials of Fentanyl Transdermal System</span> </caption> <col width="59%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">System/Organ Class</span> <br/> Adverse Reaction </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Fentanyl Transdermal System</span> <br/> <span class="Bold">%</span> <br/> <span class="Bold">(N = 1854)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypersensitivity</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Paresthesia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Confusional state</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hallucination</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary retention</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Erythema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

The following adverse reactions occurred in adult and pediatric patients with an overall frequency of <1% and are listed in descending frequency within each System/Organ Class:

Cardiac disorders:cyanosis

Eye disorders:miosis

Gastrointestinal disorders:subileus

General disorders and administration site conditions:application site reaction, influenza-like illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis

Musculoskeletal and connective tissue disorders:muscle twitching

Nervous system disorders:hypoesthesia

Psychiatric disorders:disorientation, euphoric mood

Reproductive system and breast disorders:erectile dysfunction, sexual dysfunction

Respiratory, thoracic and mediastinal disorders:respiratory depression

Skin and subcutaneous tissue disorders:eczema, dermatitis allergic, dermatitis contact

Pediatrics The safety of fentanyl transdermal system was evaluated in three open-label trials in 289　pediatric patients with chronic pain, 2　years of age through 18　years of age. Adverse reactions reported by ≥1% of fentanyl transdermal system-treated pediatric patients are shown in Table　5.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Adverse Reactions Reported by ≥ 1% of Fentanyl Transdermal System-treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal System</span> </caption> <col width="62%"/> <col width="38%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">System/Organ Class</span> <br/> Adverse Reaction </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fentanyl Transdermal System</span> <br/> <span class="Bold">%</span> <br/> <span class="Bold">(N = 289)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">34</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">24</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain upper</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dry mouth</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Edema peripheral</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Application site reaction</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Immune system disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypersensitivity</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and nutrition disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Muscle spasms</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">16</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoesthesia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Depression</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hallucination</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary retention</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Respiratory depression</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperhidrosis</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Erythema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of fentanyl transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders:tachycardia, bradycardia

Eye Disorders:vision blurred

Gastrointestinal Disorders:ileus, dyspepsia

General Disorders and Administration Site Conditions:pyrexia, application site erosion and application site ulcer

I nvestigations: weight decreased

Nervous System Disorders:convulsions (including clonic convulsions and grand mal convulsion), amnesia, depressed level of consciousness, loss of consciousness

Psychiatric Disorders:agitation

Respiratory, Thoracic, and Mediastinal Disorders:respiratory distress, apnea, bradypnea, hypoventilation, dyspnea

Vascular Disorders: hypotension, hypertension

Serotonin syndrome:Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency:Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis:Anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system.

Androgen deficiency:Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2)] .

Hyperalgesia and Allodynia:Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.10)]

Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 6 includes clinically significant drug interactions with fentanyl transdermal system.

{ "type": "p", "children": [], "text": "Table 6 includes clinically significant drug interactions with fentanyl transdermal system." }

<div class="scrollingtable"><table> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal System</span></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Inhibitors of CYP3A4</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved <span class="Italics">[see Warnings and Precautions ( <a href="#_ad6fac97-1198-db99-c820-0ce1edb8fe28">5.7</a>)]. </span> <br/> <br/> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology ( <a href="#PHARMACOKINETICS">12.3</a>)] </span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. </td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention</span>: </td><td class="Botrule Lrule Rrule">If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples</span></td><td class="Botrule Lrule Rrule">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see Clinical Pharmacology ( <a href="#PHARMACOKINETICS">12.3</a>)] </span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see Warnings and Precautions ( <a href="#_ad6fac97-1198-db99-c820-0ce1edb8fe28">5.7</a>)] </span>. <br/> <br/> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see Clinical Pharmacology ( <a href="#PHARMACOKINETICS">12.3</a>)] </span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. </td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and evaluate patient at frequent intervals for signs of respiratory depression and sedation.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule">Rifampin, carbamazepine, phenytoin</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#_a42a4fee-8ba9-3f0b-ab6a-19b769206e63">2.2</a>), Warnings and Precautions ( <a href="#_3ae2cd8f-75af-04ca-86a3-924bbbf2741d">5.1</a>, <a href="#_d454b36d-6d57-43e8-f2f1-265cb67de441">5.2</a>, <a href="#_0ad27ca0-cbcc-1e69-7ce6-a062b4994997">5.4</a>)]. </span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see Warnings and Precautions <a href="#_5442f599-bddf-ba2f-8514-0232ecaa47f9">(5.11)</a>] </span>. </td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see Warnings and Precautions ( <a href="#_5442f599-bddf-ba2f-8514-0232ecaa47f9">5.11</a>)] </span>or opioid toxicity (e.g., respiratory depression, coma). </td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule">phenelzine, tranylcypromine, linezolid</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">Avoid concomitant use.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule">butorphanol, nalbuphine, pentazocine, buprenorphine</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule">Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">Because respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#_a42a4fee-8ba9-3f0b-ab6a-19b769206e63">2.2</a>), Warnings and Precautions ( <a href="#_d454b36d-6d57-43e8-f2f1-265cb67de441">5.2</a>, <a href="#_0ad27ca0-cbcc-1e69-7ce6-a062b4994997">5.4</a>)]. </span></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Diuretics</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact</span>: </td><td class="Botrule Lrule Rrule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr> <td class="Botrule Lrule Rrule"><span class="Italics">Clinical Impact</span>: </td><td class="Botrule Lrule Rrule">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule">Evaluate patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal System</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#_ad6fac97-1198-db99-c820-0ce1edb8fe28\">5.7</a>)].\n \n </span>\n<br/>\n<br/> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#PHARMACOKINETICS\">12.3</a>)]\n \n </span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.\n \n </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention</span>:\n \n </td><td class=\"Botrule Lrule Rrule\">If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples</span></td><td class=\"Botrule Lrule Rrule\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#PHARMACOKINETICS\">12.3</a>)]\n \n </span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#_ad6fac97-1198-db99-c820-0ce1edb8fe28\">5.7</a>)]\n \n </span>. \n <br/>\n<br/> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#PHARMACOKINETICS\">12.3</a>)]\n \n </span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.\n \n </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and evaluate patient at frequent intervals for signs of respiratory depression and sedation.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule\">Rifampin, carbamazepine, phenytoin</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#_a42a4fee-8ba9-3f0b-ab6a-19b769206e63\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#_3ae2cd8f-75af-04ca-86a3-924bbbf2741d\">5.1</a>,\n \n <a href=\"#_d454b36d-6d57-43e8-f2f1-265cb67de441\">5.2</a>,\n \n <a href=\"#_0ad27ca0-cbcc-1e69-7ce6-a062b4994997\">5.4</a>)].\n \n </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome\n \n <span class=\"Italics\">[see Warnings and Precautions\n \n <a href=\"#_5442f599-bddf-ba2f-8514-0232ecaa47f9\">(5.11)</a>]\n \n </span>.\n \n </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">MAOI interactions with opioids may manifest as serotonin syndrome\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#_5442f599-bddf-ba2f-8514-0232ecaa47f9\">5.11</a>)]\n \n </span>or opioid toxicity (e.g., respiratory depression, coma).\n \n </td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule\">phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">Avoid concomitant use.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule\">butorphanol, nalbuphine, pentazocine, buprenorphine</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule\">Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#_a42a4fee-8ba9-3f0b-ab6a-19b769206e63\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#_d454b36d-6d57-43e8-f2f1-265cb67de441\">5.2</a>,\n \n <a href=\"#_0ad27ca0-cbcc-1e69-7ce6-a062b4994997\">5.4</a>)].\n \n </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact</span>:\n \n </td><td class=\"Botrule Lrule Rrule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Clinical Impact</span>:\n \n </td><td class=\"Botrule Lrule Rrule\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule\">Evaluate patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5)] . Available data with fentanyl transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5)] .

Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl transdermal system is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl transdermal system, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 2 times the daily human dose administered by a 100 mcg/h patch on a mg/m 2basis).

In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03　mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03　mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m 2basis). There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0,　0.025,　0.1, 0.4　mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4　mg/kg (approximately 3 times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2basis).

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4　mg/kg/day fentanyl via intravenous infusion from Day 6 of pregnancy through 3　weeks of lactation. Fentanyl treatment (0.4　mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Day　28 which recovered by Day 50). The mid-dose and the high-dose are 0.4 and 1.6　times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2basis.

Risk Summary

Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for use in nursing women because of the possibility of effects in their infants. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system.

Clinical Considerations

Monitor infants exposed to fentanyl transdermal system through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)].

The safety of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25　mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45　mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60　mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials.

The safety and effectiveness of fentanyl transdermal system in children under 2 years of age have not been established.

To guard against excessive exposure to fentanyl transdermal system by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal system application and disposal instructions [see Dosage and Administration ( 2.7), ( 2.8) and Warnings and Precautions ( 5.3)] .

Clinical studies of fentanyl transdermal system did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34　hours [see Clinical Pharmacology ( 12.3)] .

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl transdermal system slowly in geriatric patients and frequently re-evaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12)] .

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in-vitroand in-vivoevidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.16) and Clinical Pharmacology 12.3)] .

The effect of renal impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because there is in-vivoevidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration ( 2.6), Warnings and Precautions ( 5.18) and Clinical Pharmacology ( 12.3)].

Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance.

Fentanyl transdermal system contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1)] . 

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug  use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of fentanyl transdermal system increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent use of fentanyl transdermal system with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.  

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl transdermal system abuse include those with a history of prolonged use of any opioid including, products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl transdermal system in combination with other abused drugs.  

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.  

Fentanyl transdermal system, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.  

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to the Abuse of Fentanyl transdermal system

Fentanyl transdermal system is intended for transdermal use only. Abuse of fentanyl transdermal system poses a risk of overdose and death. This risk is increased with concurrent use of fentanyl transdermal system with alcohol and/or other CNS depressants [see Warnings and Precautions ( 5.4) and Drug Interactions ( 7)] . Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1)] . Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose.

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids. Rapid tapering of fentanyl transdermal system in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing fentanyl transdermal system, gradually taper the dosage using a patient-specific plan that considers the following: the dose of fentanyl transdermal system the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.9), and Warnings and Precautions ( 5.21) ].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)] .

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2)] .

{ "type": "p", "children": [], "text": "Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations\n \n [see Clinical Pharmacology (\n \n 12.2)]\n \n .\n\n " }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Once stable, examine the patient and ensure that all fentanyl transdermal systems have been removed. 

{ "type": "p", "children": [], "text": "Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Once stable, examine the patient and ensure that all fentanyl transdermal systems have been removed. " }

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.

{ "type": "p", "children": [], "text": "Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist." }

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl transdermal system, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 27　hours. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl transdermal system, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 27　hours. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose." }

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist." }

Fentanyl transdermal system contains fentanyl, an opioid agonist, for transdermal administration. The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per 10.5 cm 2). The composition per unit area of all transdermal system sizes is identical.

{ "type": "p", "children": [], "text": "Fentanyl transdermal system contains fentanyl, an opioid agonist, for transdermal administration. The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per 10.5 cm\n \n 2). The composition per unit area of all transdermal system sizes is identical.\n\n " }

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Nominal delivery rate per hour</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Nominal delivery rate is 12.5 mcg/hour</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength <a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> <br/> (mcg/hour) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Size <br/> (cm <span class="Sup">2</span>) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Fentanyl Content <br/> (mg) </span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">12 <a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.35</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.38</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.76</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">37.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16.05</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.14</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">50</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.52</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">62.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26.75</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.90</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">75</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">32.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.28</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">87.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37.45</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9.66</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">42.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11.04</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"33%\"/>\n<col width=\"33%\"/>\n<col width=\"33%\"/>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"3\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-3\" name=\"footnote-3\">*</a>\n</dt>\n<dd>Nominal delivery rate per hour</dd>\n<dt>\n<a href=\"#footnote-reference-4\" name=\"footnote-4\">†</a>\n</dt>\n<dd>Nominal delivery rate is 12.5 mcg/hour</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Strength\n \n <a class=\"Sup\" href=\"#footnote-3\" name=\"footnote-reference-3\">*</a>\n<br/> (mcg/hour)\n \n </span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Size \n <br/> (cm\n \n <span class=\"Sup\">2</span>)\n \n </span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Fentanyl Content \n <br/> (mg)\n </span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">12\n \n <a class=\"Sup\" href=\"#footnote-4\" name=\"footnote-reference-4\">†</a>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">5.35</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.38</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">25</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">10.7</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.76</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">37.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">16.05</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4.14</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">50</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">21.4</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">5.52</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">62.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">26.75</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">6.90</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">75</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">32.1</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">8.28</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">87.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">37.45</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">9.66</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">100</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">42.8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">11.04</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

The molecular weight of fentanyl base is 336.5 g/mol, and the empirical formula is C 22H 28N 2O. The n-octanol: water partition coefficient is 860:1. The pKa is 8.4.

{ "type": "p", "children": [], "text": "The molecular weight of fentanyl base is 336.5 g/mol, and the empirical formula is C\n \n 22H\n \n 28N\n \n 2O. The n-octanol: water partition coefficient is 860:1. The pKa is 8.4.\n\n " }

The chemical name is N-phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:

{ "type": "p", "children": [], "text": "The chemical name is N-phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:" }

Fentanyl transdermal system is a rectangular transparent unit comprising a release liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:

{ "type": "p", "children": [], "text": "Fentanyl transdermal system is a rectangular transparent unit comprising a release liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:" }

1) a backing layer of polyethylene terephalate film; 2) a drug-in-adhesive layer. Before use, a release liner covering the drug-in-adhesive layer is removed and discarded.

{ "type": "p", "children": [], "text": "1) a backing layer of polyethylene terephalate film; 2) a drug-in-adhesive layer. Before use, a release liner covering the drug-in-adhesive layer is removed and discarded." }

Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8　breaths/minute or a pCO 2greater than 55　mm　Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63　kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50　mcg/kg.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in-vitroand animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1, 2.4)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1, 2.3, 2.4)].

Absorption

Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin, drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.

Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 6). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 1). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3 to 12) hours.

A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.

<div class="scrollingtable"><table> <caption> <span>Table 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of Fentanyl Transdermal System</span> </caption> <tbody align="center" class="Headless" valign="middle"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule">Mean (SD) Time to Maximal Concentration <br/> T <span class="Sub">max</span>(h) </td><td class="Botrule Lrule Rrule Toprule">Mean (SD) Maximal Concentration <br/> C <span class="Sub">max</span>(ng/mL) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System 12 mcg/hour</td><td class="Botrule Lrule Rrule Toprule">28.8 (13.7)</td><td class="Botrule Lrule Rrule Toprule">0.38 (0.13)*</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System 25 mcg/hour</td><td class="Botrule Lrule Rrule Toprule">31.7 (16.5)</td><td class="Botrule Lrule Rrule Toprule">0.85 (0.26)**</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System 50 mcg/hour</td><td class="Botrule Lrule Rrule Toprule">32.8 (15.6)</td><td class="Botrule Lrule Rrule Toprule">1.72 (0.53)**</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System 75 mcg/hour</td><td class="Botrule Lrule Rrule Toprule">35.8 (14.1)</td><td class="Botrule Lrule Rrule Toprule">2.32 (0.86)**</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System 100 mcg/hour</td><td class="Botrule Lrule Rrule Toprule">29.9 (13.3)</td><td class="Botrule Lrule Rrule Toprule">3.36 (1.28)**</td> </tr> </tbody> </table></div>

* C maxvalues dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers

** C maxvalues: Study C-2002-048 dose proportionality study in healthy volunteers NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20 to 27 hours.

Figure 1 Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/h

Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl In Patients

<div class="scrollingtable"><table> <tbody align="center" class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Clearance (L/h) Range  [70 kg]</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Volume of Distribution V <span class="Sub">SS</span> <br/> (L/kg) Range </span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Half-Life t <span class="Sub">1/2</span>(h) Range </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Surgical Patients</td><td class="Botrule Lrule Rrule Toprule">27 - 75</td><td class="Botrule Lrule Rrule Toprule">3 - 8</td><td class="Botrule Lrule Rrule Toprule">3 - 12</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Hepatically Impaired Patients</td><td class="Botrule Lrule Rrule Toprule">3 - 80+</td><td class="Botrule Lrule Rrule Toprule">0.8 - 8+</td><td class="Botrule Lrule Rrule Toprule">4 - 12+</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule">Renally Impaired Patients</td><td class="Botrule Lrule Rrule Toprule">30 - 78</td><td class="Botrule Lrule Rrule Toprule">–</td><td class="Botrule Lrule Rrule Toprule">–</td> </tr> </tbody> </table></div>

+Estimated

NOTE:Information on volume of distribution and half-life not available for renally impaired patients.

Distribution

Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8; N=8).

Elimination

Metabolism

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. 

Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Excretion

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Specific Populations

Age: Geriatric Population

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34　hours. In this study, a single fentanyl transdermal system　100　mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65　years old (n=21, mean age 71　years) and worn for 72　hours. The mean C maxand AUC ∞values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45　years old. Inter-subject variability in AUC ∞was higher in elderly subjects than in healthy adult subjects 18 to 45　years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65　years old than in subjects 18　to 45　years old (34.4　hours versus 23.5　hours) [see Warnings and Precautions ( 5.11) and Use in Specific Populations ( 8.5)] . 

Age: Pediatric Population

In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration ( 2.3)].

Hepatic Impairment

Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C maxand AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.

Because there is in-vitroand in-vivoevidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration ( 2.5), Warnings and Precautions ( 5.17), and Use in Specific Populations ( 8.6)] .

Renal Impairment

Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found.

Because there is in-vivoevidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosing and Administration ( 2.6), Warnings and Precautions ( 5.18) and Use in Specific Populations ( 8.7)].

Drug Interaction Studies

CYP3A4 Inhibitors

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CYP3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3　days. The ritonavir dose was 200　mg　 three times a day on Day　1 and 300　mg three times a day on Day　2 followed by one morning dose of 300　mg on Day　3. On Day　2, fentanyl was given as a single IV dose at 5　mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to 420%) increase in fentanyl AUC 0-∞. The concomitant use of transdermal fentanyl with all CYP3A4　inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warningand Warnings and Precautions ( 5.6), and Drug Interactions ( 7)].

CYP3A4 Inducers

Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.

Carcinogenesis

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC 0-24hcomparison).

Mutagenesis

There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitroassays.

Impairment of Fertility

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.

Fentanyl transdermal system as therapy for pain due to cancer has been studied in 153 patients. In this patient population, fentanyl transdermal system has been administered in doses of 25 mcg/h to 600 mcg/h. Individual patients have used fentanyl transdermal system continuously for up to 866 days. At one month after initiation of fentanyl transdermal system therapy, patients generally reported lower pain intensity scores as compared to a pre-study analgesic regimen of oral morphine.

{ "type": "p", "children": [], "text": "Fentanyl transdermal system as therapy for pain due to cancer has been studied in 153 patients. In this patient population, fentanyl transdermal system has been administered in doses of 25 mcg/h to 600 mcg/h. Individual patients have used fentanyl transdermal system continuously for up to 866 days. At one month after initiation of fentanyl transdermal system therapy, patients generally reported lower pain intensity scores as compared to a pre-study analgesic regimen of oral morphine." }

The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year.

{ "type": "p", "children": [], "text": "The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year." }

In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 289 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.

{ "type": "p", "children": [], "text": "In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 289 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months." }

Fentanyl transdermal system is supplied in cartons containing 5 individual child-resistant packaged systems. See chart for information regarding individual systems.

{ "type": "p", "children": [], "text": "Fentanyl transdermal system is supplied in cartons containing 5 individual child-resistant packaged systems. See chart for information regarding individual systems." }

<div class="scrollingtable"><table> <tbody align="center" class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System Dose (mcg/hour)</td><td class="Botrule Lrule Rrule Toprule">System Size (cm <span class="Sup">2</span>) </td><td class="Botrule Lrule Rrule Toprule">Fentanyl Content (mg)</td><td class="Botrule Lrule Rrule Toprule">NDC Number for Blister Containing Individual System</td><td class="Botrule Lrule Rrule Toprule">NDC Number for Carton Containing 5 Systems</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-12*</td><td class="Botrule Lrule Rrule Toprule">5.35</td><td class="Botrule Lrule Rrule Toprule">1.38</td><td class="Botrule Lrule Rrule Toprule">50742-549-01</td><td class="Botrule Lrule Rrule Toprule">50742-549-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-25</td><td class="Botrule Lrule Rrule Toprule">10.7</td><td class="Botrule Lrule Rrule Toprule">2.76</td><td class="Botrule Lrule Rrule Toprule">50742-550-01</td><td class="Botrule Lrule Rrule Toprule">50742-550-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-37.5</td><td class="Botrule Lrule Rrule Toprule">16.05</td><td class="Botrule Lrule Rrule Toprule">4.14</td><td class="Botrule Lrule Rrule Toprule">50742-551-01</td><td class="Botrule Lrule Rrule Toprule">50742-551-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-50</td><td class="Botrule Lrule Rrule Toprule">21.4</td><td class="Botrule Lrule Rrule Toprule">5.52</td><td class="Botrule Lrule Rrule Toprule">50742-552-01</td><td class="Botrule Lrule Rrule Toprule">50742-552-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-62.5</td><td class="Botrule Lrule Rrule Toprule">26.75</td><td class="Botrule Lrule Rrule Toprule">6.90</td><td class="Botrule Lrule Rrule Toprule">50742-553-01</td><td class="Botrule Lrule Rrule Toprule">50742-553-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-75</td><td class="Botrule Lrule Rrule Toprule">32.1</td><td class="Botrule Lrule Rrule Toprule">8.28</td><td class="Botrule Lrule Rrule Toprule">50742-554-01</td><td class="Botrule Lrule Rrule Toprule">50742-554-05</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-87.5</td><td class="Botrule Lrule Rrule Toprule">37.45</td><td class="Botrule Lrule Rrule Toprule">9.66</td><td class="Botrule Lrule Rrule Toprule">50742-555-01</td><td class="Botrule Lrule Rrule Toprule">50742-555-05</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl Transdermal System-100</td><td class="Botrule Lrule Rrule Toprule">42.8</td><td class="Botrule Lrule Rrule Toprule">11.04</td><td class="Botrule Lrule Rrule Toprule">50742-556-01</td><td class="Botrule Lrule Rrule Toprule">50742-556-05</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<tbody align=\"center\" class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System Dose (mcg/hour)</td><td class=\"Botrule Lrule Rrule Toprule\">System Size (cm\n \n <span class=\"Sup\">2</span>)\n \n </td><td class=\"Botrule Lrule Rrule Toprule\">Fentanyl Content (mg)</td><td class=\"Botrule Lrule Rrule Toprule\">NDC Number for Blister Containing Individual System</td><td class=\"Botrule Lrule Rrule Toprule\">NDC Number for Carton Containing 5 Systems</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-12*</td><td class=\"Botrule Lrule Rrule Toprule\">5.35</td><td class=\"Botrule Lrule Rrule Toprule\">1.38</td><td class=\"Botrule Lrule Rrule Toprule\">50742-549-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-549-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-25</td><td class=\"Botrule Lrule Rrule Toprule\">10.7</td><td class=\"Botrule Lrule Rrule Toprule\">2.76</td><td class=\"Botrule Lrule Rrule Toprule\">50742-550-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-550-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-37.5</td><td class=\"Botrule Lrule Rrule Toprule\">16.05</td><td class=\"Botrule Lrule Rrule Toprule\">4.14</td><td class=\"Botrule Lrule Rrule Toprule\">50742-551-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-551-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-50</td><td class=\"Botrule Lrule Rrule Toprule\">21.4</td><td class=\"Botrule Lrule Rrule Toprule\">5.52</td><td class=\"Botrule Lrule Rrule Toprule\">50742-552-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-552-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-62.5</td><td class=\"Botrule Lrule Rrule Toprule\">26.75</td><td class=\"Botrule Lrule Rrule Toprule\">6.90</td><td class=\"Botrule Lrule Rrule Toprule\">50742-553-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-553-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-75</td><td class=\"Botrule Lrule Rrule Toprule\">32.1</td><td class=\"Botrule Lrule Rrule Toprule\">8.28</td><td class=\"Botrule Lrule Rrule Toprule\">50742-554-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-554-05</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-87.5</td><td class=\"Botrule Lrule Rrule Toprule\">37.45</td><td class=\"Botrule Lrule Rrule Toprule\">9.66</td><td class=\"Botrule Lrule Rrule Toprule\">50742-555-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-555-05</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl Transdermal System-100</td><td class=\"Botrule Lrule Rrule Toprule\">42.8</td><td class=\"Botrule Lrule Rrule Toprule\">11.04</td><td class=\"Botrule Lrule Rrule Toprule\">50742-556-01</td><td class=\"Botrule Lrule Rrule Toprule\">50742-556-05</td>\n</tr>\n</tbody>\n</table></div>" }

* This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from 125 mcg/hour strength that could be prescribed by using multiple transdermal systems.

{ "type": "p", "children": [], "text": "* This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from 125 mcg/hour strength that could be prescribed by using multiple transdermal systems." }

Store in original unopened blister. Store up to 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).

{ "type": "p", "children": [], "text": "Store in original unopened blister. Store up to 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F)." }

Store fentanyl transdermal system securely and dispose of properly [see Patient Counseling Information ( 17) ].

{ "type": "p", "children": [], "text": "Store fentanyl transdermal system securely and dispose of properly\n \n [see Patient Counseling Information (\n \n 17)\n \n ].\n" }

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Storage and Disposal

{ "type": "p", "children": [], "text": "\nStorage and Disposal\n" }

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.1, 5.3), Drug Abuse and Dependence ( 9.2)] . Inform patients that leaving fentanyl transdermal system unsecured can pose a deadly risk to others in the home.

{ "type": "p", "children": [], "text": "Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home\n \n [see Warnings and Precautions (\n \n 5.1,\n \n 5.3), Drug Abuse and Dependence (\n \n 9.2)]\n \n . Inform patients that leaving fentanyl transdermal system unsecured can pose a deadly risk to others in the home.\n\n " }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl transdermal system should be disposed of by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [ see Instructions for Use]. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl transdermal system should be disposed of by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [\n \n see Instructions for Use]. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.\n\n " }

Addiction, Abuse, and Misuse

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse\n" }

Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1)] . Instruct patients not to share fentanyl transdermal system with others and to take steps to protect fentanyl transdermal system from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n . Instruct patients not to share fentanyl transdermal system with others and to take steps to protect fentanyl transdermal system from theft or misuse.\n\n " }

Life-Threatening Respiratory Depression

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n" }

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl transdermal system or when the dosage is increased, and that it can occur even at recommended dosages.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl transdermal system or when the dosage is increased, and that it can occur even at recommended dosages." }

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.2)]. 

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose\n \n [see Warnings and Precautions (\n \n 5.2)]. \n \n \n" }

Accidental Exposure

{ "type": "p", "children": [], "text": "\nAccidental Exposure\n" }

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3)] .

{ "type": "p", "children": [], "text": "Inform patients that accidental exposure, especially in children, may result in respiratory depression or death\n \n [see Warnings and Precautions (\n \n 5.3)]\n \n .\n\n " }

Fentanyl transdermal system can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children.

{ "type": "p", "children": [], "text": "Fentanyl transdermal system can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children." }

Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems.

{ "type": "p", "children": [], "text": "Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems." }

Interactions with Benzodiazepines and Other CNS Depressants

{ "type": "p", "children": [], "text": "\nInteractions with Benzodiazepines and Other CNS Depressants\n" }

Inform patients and caregivers that potentially fatal additive effects may occur if fentanyl transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4), Drug Interactions ( 7)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers that potentially fatal additive effects may occur if fentanyl transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider\n \n [see Warnings and Precautions (\n \n 5.4), Drug Interactions (\n \n 7)].\n \n \n" }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

{ "type": "p", "children": [], "text": "Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose" }

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.3)] .

{ "type": "p", "children": [], "text": "Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program)\n \n [see Dosage and Administration (\n \n 2.2), Warnings and Precautions (\n \n 5.3)]\n \n .\n\n " }

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.  

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.  " }

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage ( 10)] .  

{ "type": "p", "children": [], "text": "Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered\n \n [see Overdosage (\n \n 10)]\n \n .  \n\n " }

If naloxone is prescribed, also advise patients and caregivers:

{ "type": "p", "children": [], "text": "If naloxone is prescribed, also advise patients and caregivers:" }

{ "type": "ul", "children": [ "How to treat with naloxone, in the event of an opioid overdose", "To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency", "To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do." ], "text": "" }

Hyperalgesia and Allodynia

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia\n" }

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.10); Adverse Reactions ( 6.2)] .

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain\n \n [see Warnings and Precautions (\n \n 5.10); Adverse Reactions (\n \n 6.2)]\n \n .\n\n " }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warningsand Precautions( 5.11) and Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications\n \n [see Warningsand\n \n Precautions(\n \n 5.11) and Drug Interactions (\n \n 7)]\n \n .\n\n " }

MAOI Interaction

{ "type": "p", "children": [], "text": "\nMAOI Interaction\n" }

Inform patients to avoid taking fentanyl transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl transdermal system [see Drug Interactions ( 7)].

{ "type": "p", "children": [], "text": "Inform patients to avoid taking fentanyl transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl transdermal system\n \n [see Drug Interactions (\n \n 7)].\n \n \n" }

Important Administration Instructions

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions\n" }

Advise patients never to change the dose of fentanyl transdermal system or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.  

{ "type": "p", "children": [], "text": "Advise patients never to change the dose of fentanyl transdermal system or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.  " }

Warnings About Heat

{ "type": "p", "children": [], "text": "\nWarnings About Heat\n" }

Warn patients of the potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl. Instruct patients to contact their healthcare provider if they develop a high fever. Instruct patients to:

{ "type": "p", "children": [], "text": "Warn patients of the potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl. Instruct patients to contact their healthcare provider if they develop a high fever. Instruct patients to:" }

{ "type": "ul", "children": [ "avoid strenuous exertion that can increase body temperature while wearing the patch", "avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources including heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds." ], "text": "" }

Important Discontinuation Instructions

{ "type": "p", "children": [], "text": "\nImportant Discontinuation Instructions\n" }

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber [ see Dosage and Administration ( 2.9) ].

{ "type": "p", "children": [], "text": "In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber [\n \n see Dosage and Administration (\n \n 2.9)\n \n ].\n\n " }

Driving or Operating Heavy Machinery

{ "type": "p", "children": [], "text": "\nDriving or Operating Heavy Machinery\n" }

Inform patients that fentanyl transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.21)] .

{ "type": "p", "children": [], "text": "Inform patients that fentanyl transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication\n \n [see Warnings and Precautions (\n \n 5.21)]\n \n .\n\n " }

Constipation

{ "type": "p", "children": [], "text": "\nConstipation\n" }

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6), Clinical Pharmacology ( 12.2)] .

{ "type": "p", "children": [], "text": "Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention\n \n [see Adverse Reactions (\n \n 6), Clinical Pharmacology (\n \n 12.2)]\n \n .\n\n " }

Adrenal Insufficiency

{ "type": "p", "children": [], "text": "\nAdrenal Insufficiency\n" }

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.13)] .

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms\n \n [see Warnings and Precautions (\n \n 5.13)]\n \n .\n\n " }

Hypotension

{ "type": "p", "children": [], "text": "\nHypotension\n" }

Inform patients that fentanyl transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.14)].

{ "type": "p", "children": [], "text": "Inform patients that fentanyl transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position)\n \n [see Warnings and Precautions (\n \n 5.14)].\n \n \n" }

Anaphylaxis

{ "type": "p", "children": [], "text": "\nAnaphylaxis\n" }

Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4), Adverse Reactions ( 6)].

{ "type": "p", "children": [], "text": "Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention\n \n [see Contraindications (\n \n 4), Adverse Reactions (\n \n 6)].\n \n \n" }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of fentanyl transdermal system for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.5), Use in Specific Populations ( 8.1)] .

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome\n Inform female patients of reproductive potential that use of fentanyl transdermal system for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated\n \n [see Warnings and Precautions (\n \n 5.5), Use in Specific Populations (\n \n 8.1)]\n \n .\n\n " }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Inform female patients of reproductive potential that fentanyl transdermal system can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations ( 8.1)].

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential that fentanyl transdermal system can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy\n \n [see Use in Specific Populations (\n \n 8.1)].\n \n \n" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system [see Use in Specific Populations ( 8.2)] .

{ "type": "p", "children": [], "text": "Advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system\n \n [see Use in Specific Populations (\n \n 8.2)]\n \n .\n\n " }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3)].

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible\n \n [see Use in Specific Populations (\n \n 8.3)].\n \n \n" }

Manufactured by: Aveva Drug Delivery Systems, Inc. Miramar, FL 33025

{ "type": "p", "children": [], "text": "\nManufactured by:\n Aveva Drug Delivery Systems, Inc. \n Miramar, FL 33025\n\n " }

Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193

{ "type": "p", "children": [], "text": "\nManufactured for:\n Ingenus Pharmaceuticals, LLC \n Orlando, FL 32811-7193\n\n " }

                                                      Fentanyl Transdermal System, Cll

{ "type": "p", "children": [], "text": "\n                                                      Fentanyl Transdermal System, Cll\n" }

                                                                           (fen' ta nil)

{ "type": "p", "children": [], "text": "\n                                                                           (fen' ta nil)\n" }

Fentanyl transdermal system is:

{ "type": "p", "children": [], "text": "\nFentanyl transdermal system is:\n\n " }

{ "type": "ul", "children": [ "A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine, in people who are already regularly using opioid pain medicine, when other pain medicines do not treat your pain well enough or you cannot tolerate them.", "A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.", "Not to be used on an “as needed” basis." ], "text": "" }

Important information about fentanyl transdermal system:

{ "type": "p", "children": [], "text": "\nImportant information about fentanyl transdermal system:\n" }

{ "type": "ul", "children": [ "\nGet emergency help or call 911 right away if you use too much fentanyl transdermal system (overdose). When you first start taking fentanyl transdermal system, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.\n \n ", "Taking fentanyl transdermal system with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) may cause severe drowsiness, decreased awareness, breathing difficulties, with slow or shallow breathing, coma, and death.", "Never give anyone else your fentanyl transdermal system. They could die from taking it. Selling or giving away fentanyl transdermal system is against the law.", "Store fentanyl transdermal system, securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.", "If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems. ", "Dispose of expired, unwanted, or unused fentanyl transdermal system, by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [\n \n see Instructions for Use]. Visit\n \n www.fda.gov/drugdisposalfor additional information on disposal of unused medicines.\n \n " ], "text": "" }

Do not use fentanyl transdermal system if you have:

{ "type": "p", "children": [], "text": "\nDo not use fentanyl transdermal system if you have:\n" }

{ "type": "ul", "children": [ "severe asthma, trouble breathing, or other lung problems.", "a bowel blockage or have narrowing of the stomach or intestines." ], "text": "" }

Before applying fentanyl transdermal system, tell your healthcare provider if you have a history of:

{ "type": "p", "children": [], "text": "\nBefore applying fentanyl transdermal system, tell your healthcare provider if you have a history of:\n" }

{ "type": "ul", "children": [ "head injury, seizures", "problems urinating", "liver, kidney, thyroid problems", "pancreas or gallbladder problems", "abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems." ], "text": "" }

Tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "\nTell your healthcare provider if you:\n" }

{ "type": "ul", "children": [ "noticing your pain getting worse. If your pain gets worse after you use fentanyl transdermal system, do not use more of fentanyl transdermal system without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after using fentanyl transdermal system.", "have a fever", "\nAre pregnant or planning to become pregnant. Use of fentanyl transdermal system for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.\n \n ", "\nare breastfeeding.Not recommended during treatment with fentanyl transdermal system. It may harm your baby.\n \n ", "are living in a household where there are small children or someone who has abused street or prescription drugs.", "are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl with certain other medicines can cause serious side effects that could lead to death." ], "text": "" }

When using fentanyl transdermal system:

{ "type": "p", "children": [], "text": "\nWhen using fentanyl transdermal system:\n\n " }

{ "type": "ul", "children": [ "Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.", "See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system patch. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.", "Do not apply more than 1 patch at the same time unless your healthcare provider tells you to.", "You should wear the fentanyl transdermal patch continuously for 3 days, unless advised otherwise by your healthcare provider.", "Do not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die.", "\nCall your healthcare provider if the dose you are using does not control your pain.\n", "\nDo not stop using fentanyl transdermal system without talking to your healthcare provider.\n" ], "text": "" }

While using fentanyl transdermal system DO NOT:

{ "type": "p", "children": [], "text": "\nWhile using fentanyl transdermal system DO NOT:\n" }

{ "type": "ul", "children": [ "Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated waterbeds, or tanning lamps, or engage in exercise that increases your body temperature. These can cause an overdose that can lead to death.    ", "Drive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you sleepy, dizzy, or lightheaded.    ", "Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with fentanyl transdermal system may cause you to overdose and die." ], "text": "" }

The possible side effects of fentanyl transdermal system are:

{ "type": "p", "children": [], "text": "\nThe possible side effects of fentanyl transdermal system are:\n" }

{ "type": "ul", "children": [ "constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, itching, redness, or rash where the patch is applied. Call your healthcare provider if you have any of these symptoms and they are severe." ], "text": "" }

Get emergency medical help or call 911 right away if you have:

{ "type": "p", "children": [], "text": "\nGet emergency medical help or call 911 right away if you have:\n" }

{ "type": "ul", "children": [ "trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion." ], "text": "" }

These are not all the possible side effects of fentanyl transdermal system. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of fentanyl transdermal system. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n \n For more information go to dailymed.nlm.nih.gov.\n" }

Manufactured by: Aveva Drug Delivery Systems, Inc., Miramar, FL 33025

{ "type": "p", "children": [], "text": "\nManufactured by:\n Aveva Drug Delivery Systems, Inc., \n Miramar, FL 33025\n\n " }

Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193

{ "type": "p", "children": [], "text": "\nManufactured for:\n Ingenus Pharmaceuticals, LLC \n Orlando, FL 32811-7193\n\n " }

medinfo@ingenus.com or call 1-877-748-1970, 9 A.M. to 5 P.M., Eastern Time, Monday through Friday.

{ "type": "p", "children": [], "text": "medinfo@ingenus.com or call 1-877-748-1970, 9 A.M. to 5 P.M., Eastern Time, Monday through Friday." }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Revised: February 2024

{ "type": "p", "children": [], "text": "Revised: February 2024" }

                                                                  Instructions for Use

{ "type": "p", "children": [], "text": "\n                                                                  Instructions for Use\n" }

                                                    Fentanyl Transdermal System, CII

{ "type": "p", "children": [], "text": "\n                                                    Fentanyl Transdermal System, CII\n" }

                                                                       (fen' ta nil)

{ "type": "p", "children": [], "text": "\n                                                                       (fen' ta nil)\n" }

                                                                           Rx only

{ "type": "p", "children": [], "text": "\n                                                                           Rx only\n" }

Be sure that you read, understand, and follow these Instructions for Use before you apply fentanyl transdermal system (patch). Talk to your healthcare provider or pharmacist if you have any questions.

{ "type": "p", "children": [], "text": "\nBe sure that you read, understand, and follow these Instructions for Use before you apply fentanyl transdermal system (patch). Talk to your healthcare provider or pharmacist if you have any questions.\n" }

Important information about the fentanyl transdermal system (patch) appearance:

{ "type": "p", "children": [], "text": "\nImportant information about the fentanyl transdermal system (patch) appearance:\n" }

{ "type": "ul", "children": [ "\nFentanyl transdermal system is a rectangular unit with round corners.\n", "\nFentanyl transdermal system comes in 8 different dosage strengths and sizes:\n\n\n12 mcg/hour\n\n\n25 mcg/hour\n\n\n37.5 mcg/hour\n\n\n50 mcg/hour\n\n\n62.5 mcg/hour\n\n\n75 mcg/hour\n\n\n87.5 mcg/hour\n\n\n100 mcg/hour\n\n\n", "\nThe product name, “Fentanyl” and dosage strength are printed in green on overall clear backing material.\n" ], "text": "" }

Parts of Fentanyl Transdermal System Patch:

{ "type": "p", "children": [], "text": "\nParts of Fentanyl Transdermal System Patch:\n" }

Before applying Fentanyl Transdermal System

{ "type": "p", "children": [], "text": "\nBefore applying Fentanyl Transdermal System\n" }

{ "type": "ul", "children": [ "\nEach fentanyl transdermal system patch is sealed in its own protective blister. Do not remove a fentanyl transdermal system patch from the blister until you are ready to use it.\n", "\nDo not use a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged or changed in any way.\n", "\nFentanyl transdermal system patches are available in 8 different dosage strengths and patch sizes. Make sure you have the right dose patch or patches that have been prescribed for you.\n" ], "text": "" }

Applying a Fentanyl Transdermal System Patch

{ "type": "p", "children": [], "text": "\nApplying a Fentanyl Transdermal System Patch\n" }

1.Skin areas where the fentanyl transdermal system patch may be applied:

{ "type": "p", "children": [], "text": "\n1.Skin areas where the fentanyl transdermal system patch may be applied:\n" }

For adults:

{ "type": "p", "children": [], "text": "\nFor adults:\n" }

{ "type": "ul", "children": [ "Put the patch on the chest, back, flank (sides of the waist), or upper arm in a place where there is no hair (see Figures A to D)." ], "text": "" }

For children (and adults with mental impairment):

{ "type": "p", "children": [], "text": "\nFor children (and adults with mental impairment):\n" }

{ "type": "ul", "children": [ "\nPut the patch on the upper back(see Figure B)\n \n .This will lower the chances that the child will remove the patch and put it in their mouth.\n \n " ], "text": "" }

For adults and children

{ "type": "p", "children": [], "text": "\nFor adults and children\n" }

{ "type": "ul", "children": [ "\nDo notput a fentanyl transdermal system patch on skin that is very oily, burned, broken out, cut, irritated, or damaged in any way.\n \n ", "Avoid sensitive areas or those that move around a lot. If there is hair,\n \n do not shave (shaving irritates the skin).Instead, clip hair as close to the skin as possible (see Figure E).\n \n " ], "text": "" }

{ "type": "ul", "children": [ "\nTalk to your healthcare provider if you have questions about skin application sites.\n" ], "text": "" }

2. Prepare to apply a fentanyl transdermal system patch:

{ "type": "p", "children": [], "text": "\n2. Prepare to apply a fentanyl transdermal system patch:\n" }

{ "type": "ul", "children": [ "Choose the time of day that is best for you to apply the fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider.", "Do not wear more than one fentanyl transdermal system patch at a time unless your healthcare provider tells you to do so. Before applying a new fentanyl transdermal system patch, remove the patch you have been wearing.", "Clean the skin area with clear water\n \n only. Pat skin completely dry. Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied.\n \n " ], "text": "" }

3. Open the blister:Fold and tear at slit, or cut at slit taking care not to cut the patch. Remove the fentanyl transdermal system patch. Each fentanyl transdermal system patch is sealed in its own protective blister. Do not remove the fentanyl transdermal system patch from the blister until you are ready to use it (see Figure F).

{ "type": "p", "children": [], "text": "\n3. Open the blister:Fold and tear at slit, or cut at slit taking care not to cut the patch. Remove the fentanyl transdermal system patch. Each fentanyl transdermal system patch is sealed in its own protective blister. Do not remove the fentanyl transdermal system patch from the blister until you are ready to use it (see Figure F).\n\n " }

4. Peel:Peel off both parts of the release liner from the patch. Each fentanyl transdermal system patch has a clear plastic release liner that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this release liner off and throw the pieces away. Touch the sticky side of the fentanyl transdermal system patch as little as possible(see Figure G) .

{ "type": "p", "children": [], "text": "\n4. Peel:Peel off both parts of the release liner from the patch. Each fentanyl transdermal system patch has a clear plastic release liner that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this release liner off and throw the pieces away.\n \n Touch the sticky side of the fentanyl transdermal system patch as little as possible(see Figure G)\n \n .\n" }

5. Press:Press the patch onto the chosen skin site with the palm of your hand and hold there for at least 30 seconds(see Figure H) .Make sure it sticks well, especially at the edges.

{ "type": "p", "children": [], "text": "\n5. Press:Press the patch onto the chosen skin site\n \n with the palm of your hand and hold there for at least 30 seconds(see Figure H)\n \n .Make sure it sticks well, especially at the edges.\n\n " }

{ "type": "ul", "children": [ "Fentanyl transdermal system may not stick to all people. You need to check the patch often to make sure that it is sticking well to the skin.", "If the patch falls off right away after applying, throw it away and put a new one on at a different skin site. See the section below called “Disposing of a fentanyl transdermal system patch”.", "If you have a problem with the patch not sticking\n \n \nApply first aid tape only to the edges of the patch.\nIf you continue to have problems with the patch not sticking, you may cover the patch with a transparent adhesive film dressing such as Bioclusive™ or Tegaderm™. These are special see-through adhesive dressings.\n \n Never cover a fentanyl transdermal system patch with any other bandage or tape.Remove the backing from the Bioclusive™ or Tegaderm™ dressing and place it carefully over the fentanyl transdermal system patch, smoothing it over the patch and your skin.\n \n \n\n", "\nIf your patch falls off before 3 days (72 hours) of use, dispose of (throw away) properly. See the section below “Disposing of a Fentanyl Transdermal System Patch”. Apply a new fentanyl transdermal system patch on at a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider).\n" ], "text": "" }

6.Wash your hands when you have finished applying a fentanyl transdermal system patch.

{ "type": "p", "children": [], "text": "\n6.Wash your hands when you have finished applying a fentanyl transdermal system patch.\n\n " }

7.Remove a fentanyl transdermal system patch after wearing it for 3 days (72 hours). Dispose of the used patch right away. See the section below “Disposing of a Fentanyl Transdermal System Patch”.Choose a differentskin site to apply a new fentanyl transdermal system patch. Repeat Steps 2 through 6 above when applying a new fentanyl transdermal system patch.

{ "type": "p", "children": [], "text": "\n7.Remove a fentanyl transdermal system patch after wearing it for 3 days (72 hours).\n \n Dispose of the used patch right away. See the section below “Disposing of a Fentanyl Transdermal System Patch”.Choose a\n \n differentskin site to apply a new fentanyl transdermal system patch. Repeat Steps 2 through 6 above when applying a new fentanyl transdermal system patch.\n\n " }

Do not apply the new patch to the same place as the last one.

{ "type": "p", "children": [], "text": "\nDo not apply the new patch to the same place as the last one.\n" }

Water and Fentanyl Transdermal System

{ "type": "p", "children": [], "text": "\nWater and Fentanyl Transdermal System\n" }

{ "type": "ul", "children": [ "You can bathe, swim or shower while you are wearing a fentanyl transdermal system patch. If the patch falls off before 3 days (72 hours) after application, dispose of properly. See the section below “Disposing of a Fentanyl Transdermal System Patch”. Apply a new fentanyl transdermal system patch on at a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider)." ], "text": "" }

Disposing of a Fentanyl Transdermal System Patch

{ "type": "p", "children": [], "text": "\nDisposing of a Fentanyl Transdermal System Patch\n" }

{ "type": "ul", "children": [ "Fold the used fentanyl transdermal system patch in half so that the sticky side sticks to itself (see Figure I)\n \n . Flush the used fentanyl transdermal system down the toilet right away(see Figure J)\n \n . A used fentanyl transdermal system patch can be very dangerous for or lead to death in babies, children, pets, and adults who have not been prescribed fentanyl transdermal system.\n" ], "text": "" }

{ "type": "ul", "children": [ "Throw away any fentanyl transdermal system patches that are left over from your prescription as soon as they are no longer needed. Remove the leftover patches from their protective blister and remove the release liner.\n \n Fold the patches in half with the sticky sides together, and flush the patches down the toilet.Do not flush the blister or the release liner down the toilet. These items can be thrown away in a trash can.\n \n " ], "text": "" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.All registered trademarks in this document are the property of their respective owners.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration.All registered trademarks in this document are the property of their respective owners." }

Manufactured by: Aveva Drug Delivery Systems, Inc. Miramar, FL 33025

{ "type": "p", "children": [], "text": "\nManufactured by:\n Aveva Drug Delivery Systems, Inc. \n Miramar, FL 33025\n\n " }

Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193

{ "type": "p", "children": [], "text": "\nManufactured for:\n Ingenus Pharmaceuticals, LLC \n Orlando, FL 32811-7193\n\n " }

Revised: February 2024

{ "type": "p", "children": [], "text": "Revised: February 2024" }

NDC 50742-549-05

{ "type": "p", "children": [], "text": "\nNDC 50742-549-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

12 mcg/h

{ "type": "p", "children": [], "text": "\n12 mcg/h\n" }

NDC 50742-550-05

{ "type": "p", "children": [], "text": "\nNDC 50742-550-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

25 mcg/h

{ "type": "p", "children": [], "text": "\n25 mcg/h\n" }

NDC 50742-551-05

{ "type": "p", "children": [], "text": "\nNDC 50742-551-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

37.5 mcg/h

{ "type": "p", "children": [], "text": "\n37.5 mcg/h\n" }

NDC 50742-552-05

{ "type": "p", "children": [], "text": "\nNDC 50742-552-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

50 mcg/h

{ "type": "p", "children": [], "text": "\n50 mcg/h\n" }

NDC 50742-553-05

{ "type": "p", "children": [], "text": "\nNDC 50742-553-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

62.5 mcg/h

{ "type": "p", "children": [], "text": "\n62.5 mcg/h\n" }

NDC 50742-554-05

{ "type": "p", "children": [], "text": "\nNDC 50742-554-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

75 mcg/h

{ "type": "p", "children": [], "text": "\n75 mcg/h\n" }

NDC 50742-555-05

{ "type": "p", "children": [], "text": "\nNDC 50742-555-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

87.5 mcg/h

{ "type": "p", "children": [], "text": "\n87.5 mcg/h\n" }

NDC 50742-556-05

{ "type": "p", "children": [], "text": "\nNDC 50742-556-05\n" }

Fentanyl Transdermal System CII

{ "type": "p", "children": [], "text": "\nFentanyl Transdermal System CII\n" }

100 mcg/h

{ "type": "p", "children": [], "text": "\n100 mcg/h\n" }

SUBSYS is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

{ "type": "p", "children": [], "text": "SUBSYS is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain." }

Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking SUBSYS.

{ "type": "p", "children": [], "text": "Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking SUBSYS." }

Limitations of Use:

{ "type": "p", "children": [], "text": "\nLimitations of Use:\n" }

{ "type": "ul", "children": [ "Not for use in opioid non-tolerant patients.", "Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency room \n [see Contraindications ( \n 4)]. \n \n", "As part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS Program, SUBSYS may be dispensed only to outpatients enrolled in the program. \n [see Warnings and Precautions ( \n 5.7)] \n . For inpatient administration of SUBSYS, patient enrollment is not required.\n " ], "text": "" }

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SUBSYS [see Warnings and Precautions ( 5.1), Patient Counseling Information ( 17)] .

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1, 5.4, 5.6)] .

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

Initiate treatment with SUBSYS for all patients (including those switching from another fentanyl product) using ONE 100 mcg spray sublingually.

Prescribe an initial titration supply of 100 mcg SUBSYS units, which limits the number of units in the home during titration.

Avoid prescribing a higher dose until patients have used up all units to prevent confusion and possible overdose.

Conversion from Actiq to SUBSYS

The initial dose of SUBSYS is always 100 mcg with the only exception of patients already using Actiq.

In cancer patients with mucositis, exposure to SUBSYS was greater than in patients without mucositis. For patients with Grade 1 mucositis, the increased maximum serum concentration and overall exposure requires closer monitoring for respiratory depression and central nervous system depression, particularly during initiation of therapy with SUBSYS. For patients with Grade 2 mucositis or higher, avoid use of SUBSYS unless the benefits outweigh the potential risk of respiratory depression from increased exposure. [see Clinical Pharmacology ( 12.3)]

Individually titrate SUBSYS to a dose that provides adequate analgesia and minimizes adverse reactions.

<div class="scrollingtable"><table class="Noautorules" width="500"> <caption> <span>Table 2. Titration Steps</span> </caption> <colgroup> <col align="left" width="50%"/> <col align="left" width="50%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">SUBSYS DOSE</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Using</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">100 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 100 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 200 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">400 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 400 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 600 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">800 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 800 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">1200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">2 × 600 mcg unit</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">1600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">2 × 800 mcg unit</td> </tr> </tbody> </table></div>

SUBSYS Titration Process

Once titrated to a dose that provides adequate pain relief and tolerable side effects, patients should generally use ONLY ONE SUBSYS dose of the appropriate strength per breakthrough pain episode.

On those occasions when the breakthrough pain episode is not relieved within 30 minutes after administration of the SUBSYS dose, the patient may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS. Once a successful dose has been found, patients should limit consumption to four or fewer doses per day.

Dosage adjustment of SUBSYS may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

If signs of excessive opioid effects appear following administration of a single SUBSYS dose, subsequent doses should be decreased.

Generally, only increase the SUBSYS dose when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated. In addition, if pain worsens, re-evaluate the patient for changes in the underlying pain condition.

For patients no longer requiring opioid therapy, consider discontinuing SUBSYS along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, SUBSYS therapy can usually be discontinued immediately. [ see Drug Abuse and Dependence ( 9.3) ].

Patients and caregivers must be advised to dispose of used unit dose systems immediately after use and any unneeded unit dose systems remaining from a prescription as soon as they are no longer needed. Consumed units represent a special risk because they are no longer protected by the child resistant blister package, yet may contain enough medicine to be fatal to a child. [see Patient Counseling Information ( 17)].

Charcoal-lined disposal pouches are provided with every carton dispensed. A charcoal-lined disposal pouch is to be used by patients or their caregivers to dispose of the contents of any unneeded unit dose systems when they are no longer needed. Instructions for usage of the charcoal-lined disposal pouch are included in the Medication Guide and Instructions for Use.

SUBSYS is a sublingual spray available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, and 1600 mcg strengths. SUBSYS is supplied as spray units consisting of a white actuator attached to a light purple vial holder [see How Supplied/Storage and Handling ( 16)] . 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg doses are delivered as a single unit (spray). To administer 1200 mcg and 1600 mcg doses, two units (sprays) must be used.

{ "type": "p", "children": [], "text": "SUBSYS is a sublingual spray available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, and 1600 mcg strengths. SUBSYS is supplied as spray units consisting of a white actuator attached to a light purple vial holder \n \n \n [see How Supplied/Storage and Handling (\n \n \n 16)]\n \n \n . 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg doses are delivered as a single unit (spray). To administer 1200 mcg and 1600 mcg doses, two units (sprays) must be used. \n \n\n " }

Each dosage strength is differentiated by the color of the blister package, and carton as described below in Table 3. The strength of the spray unit is indicated on the actuator.

{ "type": "p", "children": [], "text": "Each dosage strength is differentiated by the color of the blister package, and carton as described below in Table 3. The strength of the spray unit is indicated on the actuator." }

<div class="scrollingtable"><table class="Noautorules" width="600"> <caption> <span>Table 3. Subsys Strengths</span> </caption> <col align="left" width="20%"/> <col align="left" width="50%"/> <col align="left" width="30%"/> <tbody class="Headless"> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Dosage Strength (fentanyl base)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Using</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Carton/Blister Package Color</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">100 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 100 mcg unit packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Blue</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 200 mcg unit packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Green</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">400 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 400 mcg unit packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Magenta (Pink)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 600 mcg unit packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Purple</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">800 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">1 × 800 mcg unit packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Orange</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">1200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">2 × 600 mcg units packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Brown</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">1600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule">2 × 800 mcg units packaged in a single blister</td><td align="left" class="Botrule Lrule Rrule Toprule">Red</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"600\">\n<caption>\n<span>Table 3. Subsys Strengths</span>\n</caption>\n<col align=\"left\" width=\"20%\"/>\n<col align=\"left\" width=\"50%\"/>\n<col align=\"left\" width=\"30%\"/>\n<tbody class=\"Headless\">\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Dosage Strength (fentanyl base)</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Using</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Carton/Blister Package Color</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">100 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1 × 100 mcg unit packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Blue</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">200 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1 × 200 mcg unit packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Green</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">400 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1 × 400 mcg unit packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Magenta (Pink)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">600 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1 × 600 mcg unit packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Purple</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">800 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1 × 800 mcg unit packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Orange</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1200 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">2 × 600 mcg units packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Brown</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">1600 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">2 × 800 mcg units packaged in a single blister</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Red</td>\n</tr>\n</tbody>\n</table></div>" }

SUBSYS is contraindicated in:

{ "type": "p", "children": [], "text": "SUBSYS is contraindicated in:" }

{ "type": "ul", "children": [ "Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients \n \n \n [see Indications and Usage (\n \n \n 1); Warnings and Precautions (\n \n \n 5.1)]\n \n \n .\n \n \n ", "Acute or postoperative pain including headache/migraine and dental pain, or in the emergency department \n \n \n [see Indications and Usage (\n \n \n 1)]\n \n \n . \n \n \n ", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment \n \n \n [see Warnings and Precautions (\n \n \n 5.9)].\n \n \n \n", "Known or suspected gastrointestinal obstruction, including paralytic ileus \n \n \n [see Warnings and Precautions (\n \n \n 5.14)].\n \n \n \n", "Known hypersensitivity (e.g., anaphylaxis) to fentanyl or components of SUBSYS \n \n \n [see Adverse Reactions (\n \n \n 6.2)]\n \n \n .\n \n \n " ], "text": "" }

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10)] . Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of SUBSYS, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of SUBSYS.

To reduce the risk of respiratory depression, proper dosing and titration of SUBSYS are essential [see Dosage and Administration ( 2.5)] . Overestimating the SUBSYS dosage can result in a fatal overdose with the first dose. The substitution of SUBSYS for any other fentanyl product may result in fatal overdose [see Warnings and Precautions ( 5.5)].

SUBSYS could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion or exposure to even one dose of SUBSYS, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SUBSYS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.4, 5.6), Patient Counseling Information (17)].

Death has been reported in children who have accidentally ingested transmucosal immediate–release fentanyl products.

Patients and their caregivers must be informed that SUBSYS contains a medicine in an amount which can be fatal to a child. Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [ see Patient Counseling Information ( 17) ].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of SUBSYS are provided in the SUBSYS Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

Concomitant use of SUBSYS with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [ see Warnings and Precautions ( 5.9) ], particularly when an inhibitor is added after a stable dose of SUBSYS is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in SUBSYS-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using SUBSYS with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in SUBSYS-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of SUBSYS until stable drug effects are achieved [see Drug Interactions ( 7)] .

Concomitant use of SUBSYS with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using SUBSYS with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [ see Drug Interactions ( 7)] .

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SUBSYS with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7)] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when SUBSYS is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7) and Patient Counseling Information ( 17)].

When prescribing, DO NOT convert a patient to SUBSYS from any other fentanyl product on a mcg per mcg basis as SUBSYS and other fentanyl products are not equivalent on a microgram per microgram basis.

SUBSYS is NOT a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, DO NOT substitute a SUBSYS prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and SUBSYS are not equivalent. Substantial differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of SUBSYS for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Dosage and Administration ( 2.1)] . Therefore, for opioid tolerant patients, the initial dose of SUBSYS should always be ONE 100 mcg spray. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration ( 2.4)] .

SUBSYS contains fentanyl, a Schedule II controlled substance. As an opioid, SUBSYS exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SUBSYS. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing SUBSYS, and monitor all patients receiving SUBSYS for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as SUBSYS, but use in such patients necessitates intensive counseling about the risks and proper use of SUBSYS along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing SUBSYS. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information ( 17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Because of the risk of accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.1)], SUBSYS is available only through a restricted program under a REMS called the TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to outpatients, the outpatients themselves, and pharmacies, are required to enroll in the program.

Notable requirements of the TIRF REMS are:

Prolonged use of SUBSYS during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17)].

The use of SUBSYS in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: SUBSYS treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of SUBSYS [see Warnings and Precautions ( 5.1)] .

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.1)] .

Monitor such patients closely, particularly when initiating and titrating SUBSYS and when SUBSYS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.9)] . Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of SUBSYS with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7)] . This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue SUBSYS if serotonin syndrome is suspected.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

SUBSYS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of SUBSYS. In patients with circulatory shock, SUBSYS may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SUBSYS in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SUBSYS may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SUBSYS.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SUBSYS in patients with impaired consciousness or coma.

SUBSYS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in SUBSYS may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

The fentanyl in SUBSYS may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during SUBSYS therapy.

SUBSYS may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SUBSYS and know how they will react to the medication.

Intravenous fentanyl may produce bradycardia. Therefore, use SUBSYS with caution in patients with bradyarrhythmias.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain. The duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study showed that the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy was 149 days. The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose.

The most serious adverse reactions associated with all opioids including SUBSYS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.

The most common adverse reaction leading to discontinuation of SUBSYS was nausea. There were also adverse reactions of abdominal distension, anorexia, confusional state, disorientation, somnolence, and constipation.

The clinical trials of SUBSYS were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received SUBSYS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain.

Table 4 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical trials. Adverse reactions are listed in descending order of frequency within each system organ class.

<div class="scrollingtable"><table class="Noautorules" width="650"> <caption> <span>Table 4. Percent of Patients with Specific Adverse Events During Titration in the Clinical Trials (Events in 5% or More of Patients)</span> </caption> <col align="left" width="70%"/> <col align="center" width="30%"/> <tbody class="Headless"> <tr valign="top"> <td align="left" class="Botrule"><span class="Bold">System Organ Class</span></td><td align="center" class="Botrule"><span class="Bold">Titration <br/> n=359 (%) </span></td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center"></td> </tr> <tr> <td align="left">Nausea</td><td align="center">47 (13.1%)</td> </tr> <tr> <td align="left">Vomiting</td><td align="center">37 (10.3%)</td> </tr> <tr> <td align="left">Constipation</td><td align="center">18 (5.0%)</td> </tr> <tr> <td align="left"><span class="Bold">Nervous System Disorders</span></td><td align="center"></td> </tr> <tr> <td align="left">Somnolence</td><td align="center">34 (9.5%)</td> </tr> <tr> <td align="left">Dizziness</td><td align="center">26 (7.2%)</td> </tr> <tr> <td align="left" colspan="2">A patient was counted only once within each category.</td><td></td> </tr> </tbody> </table></div>

The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth

General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral, fatigue, asthenia

Metabolism and Nutrition Disorders: Decreased appetite

Nervous System Disorders: Lethargy, sedation, tremor, headache

Psychiatric Disorders: Depression, confusional state, hallucination, insomnia

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Pruritus

The following reactions occurred during titration in the clinical trials with an overall frequency of less than 1% and are listed in descending order of frequency within each system organ class.

Eye Disorders: Vision blurred, dry eye

Gastrointestinal Disorders: Abdominal pain

Infections and Infestations: Oral candidiasis, cellulitis

Injury, Poisoning and Procedural Complications: Fall

Metabolism and Nutrition Disorders: Dehydration, anorexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling

Psychiatric Disorders: Anxiety, agitation

Renal and Urinary Disorders: Urinary retention

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia, pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Vascular Disorders: Hot flush

Table 5 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to titration during the clinical trials.

<div class="scrollingtable"><table class="Noautorules" width="700"> <caption> <span>Table 5. Adverse Reactions Subsequent to Titration in 5% or More of Patients</span> </caption> <col align="left" width="70%"/> <col align="center" width="30%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule"><span class="Bold">System Organ Class</span></td><td align="center" class="Botrule"><span class="Bold">Dosing <br/> n=269 </span></td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center"></td> </tr> <tr> <td align="left">Vomiting</td><td align="center">43 (16.0%)</td> </tr> <tr> <td align="left">Nausea</td><td align="center">28 (10.4%)</td> </tr> <tr> <td align="left">Constipation</td><td align="center">28 (10.4%)</td> </tr> <tr> <td align="left"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center"></td> </tr> <tr> <td align="left">Asthenia</td><td align="center">26 (9.7%)</td> </tr> <tr> <td align="left"><span class="Bold">Respiratory, Thoracic and Mediastinal Disorders</span></td><td align="center"></td> </tr> <tr> <td align="left">Dyspnea</td><td align="center">28 (10.4%)</td> </tr> <tr> <td align="left"><span class="Bold">Psychiatric Disorders </span></td><td align="center"></td> </tr> <tr> <td align="left">Anxiety</td><td align="center">16 (5.9%)</td> </tr> <tr> <td align="left" colspan="2">A patient was counted only once within each category.</td><td></td> </tr> </tbody> </table></div>

The following adverse reactions occurred during the dosing period of the clinical trial with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class.

Blood and Lymphatic System Disorders: Anemia, neutropenia, lymphadenopathy, thrombocytopenia, leukopenia

Cardiac Disorders: Tachycardia, sinus tachycardia

Gastrointestinal Disorders: Diarrhea, stomatitis, abdominal pain, abdominal distension, gastritis, dysphagia, dyspepsia, gastroesophageal reflux disease, ascites, hematemesis

General Disorders and Administration Site Conditions: Edema peripheral, fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability, malaise, application site irritation

Infections and Infestations: Oral candidiasis, pneumonia, urinary tract infection, oral herpes, gastroenteritis, laryngitis

Injury, Poisoning and Procedural Complications: Contusion

Investigations: Weight decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood glucose increased, blood lactate increased

Metabolism and Nutrition Disorders: Anorexia, dehydration, hypokalemia, decreased appetite, hyponatremia, hypocalcemia, hypoalbuminemia, cachexia

Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, muscular weakness

Nervous System Disorders: Hypoesthesia, lethargy, sedation, tremor, somnolence, headache, dizziness

Psychiatric Disorders: Depression, restlessness, agitation, confusional state, insomnia, hallucination, disorientation

Renal and Urinary Disorders: hypertension, hypotension

Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, wheezing, pharyngolaryngeal pain, hypoxia, dyspnea exertional

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus

In a single-dose mucositis study, a group of patients with Grade 1 or 2 oral mucositis (n=9) and without oral mucositis (n=9) were included in a clinical trial designed to support the safety of SUBSYS. Two of the nine subjects with mucositis (one with Grade 1 and one with Grade 2) reported a burning sensation in the oral mucosa after treatment. Both of these events were considered mild and probably related to treatment. There was no change in grade of mucositis after treatment for any subject.

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SUBSYS.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

Table 6 includes clinically significant drug interactions with SUBSYS.

{ "type": "p", "children": [], "text": "\nTable 6 includes clinically significant drug interactions with SUBSYS.\n " }

<div class="scrollingtable"><table class="Noautorules" width="775"> <caption> <span>Table 6. Clinically Significant Drug Interactions with SUBSYS</span> </caption> <colgroup> <col align="left" width="20%"/> <col align="left" width="80%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Inhibitors of CYP3A4</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule"> <p class="First">The concomitant use of SUBSYS and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBSYS is achieved <span class="Italics">[see Warnings and Precautions ( <a href="#SK0503">5.3</a>)] </span>. </p> <p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology ( <a href="#SK1203">12.3</a>)] </span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule"> <p class="First">If concomitant use is necessary, consider dosage reduction of SUBSYS until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.</p> <p>If a CYP3A4 inhibitor is discontinued, consider increasing the SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">CYP3A4 Inducers</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule"> <p class="First">The concomitant use of SUBSYS and CYP3A4 inducers can decrease the plasma concentration of fentanyl <span class="Italics">[see Clinical Pharmacology ( <a href="#SK1203">12.3</a>)] </span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl <span class="Italics">[see Warnings and Precautions ( <a href="#SK0503">5.3</a>)] </span>. </p> <p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase <span class="Italics">[see Clinical Pharmacology ( <a href="#SK1203">12.3</a>)] </span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">If concomitant use is necessary, consider increasing the SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBSYS dosage reduction and monitor for signs of respiratory depression.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Rifampin, carbamazepine, phenytoin</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Benzodiazepines and other Central Nervous System (CNS) Depressants</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation <span class="Italics">[see Warnings and Precautions ( <a href="#SK0501">5.1</a>)] </span>. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (2.2), Warnings and Precautions ( <a href="#SK0501">5.1</a>, <a href="#SK0504">5.4</a>, <a href="#SK0506">5.6</a>)] </span>. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Serotonergic Drugs </span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <span class="Italics">[see Warnings and Precautions ( <a href="#SK0510">5.10</a>)] </span>. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBSYS if serotonin syndrome is suspected.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">MAOI interactions with opioids may manifest as serotonin syndrome <span class="Italics">[see Warnings and Precautions ( <a href="#SK0510">5.10</a>)] </span> or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions ( <a href="#SK0502">5.2</a>)] </span>. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">The use of SUBSYS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">phenelzine, tranylcypromine, linezolid</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">May reduce the analgesic effect of SUBSYS and/or precipitate withdrawal symptoms.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Avoid concomitant use.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">butorphanol, nalbuphine, pentazocine, buprenorphine,</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Muscle Relaxants</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBSYS and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#id_link_c185b09e-a884-0993-e053-2995a90a8fc6">2.2</a>), Warnings and Precautions ( <a href="#SK0501">5.1</a>, <a href="#SK0504">5.4</a>)] </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="left" class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Diuretics</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Anticholinergic Drugs</span></td><td></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor patients for signs of urinary retention or reduced gastric motility when SUBSYS is used concomitantly with anticholinergic drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"775\">\n<caption>\n<span>Table 6. Clinically Significant Drug Interactions with SUBSYS</span>\n</caption>\n<colgroup>\n<col align=\"left\" width=\"20%\"/>\n<col align=\"left\" width=\"80%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The concomitant use of SUBSYS and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of SUBSYS is achieved \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0503\">5.3</a>)] \n </span>.\n </p>\n<p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease \n <span class=\"Italics\">[see Clinical Pharmacology ( \n <a href=\"#SK1203\">12.3</a>)] \n </span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.\n </p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of SUBSYS until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.</p>\n<p>If a CYP3A4 inhibitor is discontinued, consider increasing the SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">CYP3A4 Inducers</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The concomitant use of SUBSYS and CYP3A4 inducers can decrease the plasma concentration of fentanyl \n <span class=\"Italics\">[see Clinical Pharmacology ( \n <a href=\"#SK1203\">12.3</a>)] \n </span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0503\">5.3</a>)] \n </span>.\n </p>\n<p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase \n <span class=\"Italics\">[see Clinical Pharmacology ( \n <a href=\"#SK1203\">12.3</a>)] \n </span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.\n </p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">If concomitant use is necessary, consider increasing the SUBSYS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider SUBSYS dosage reduction and monitor for signs of respiratory depression.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Rifampin, carbamazepine, phenytoin</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Benzodiazepines and other Central Nervous System (CNS) Depressants</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0501\">5.1</a>)]\n </span>. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose \n <span class=\"Italics\">[see Dosage and Administration (2.2), Warnings and Precautions (\n <a href=\"#SK0501\">5.1</a>, \n <a href=\"#SK0504\">5.4</a>, \n <a href=\"#SK0506\">5.6</a>)]\n </span>.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Serotonergic Drugs </span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0510\">5.10</a>)] \n </span>.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue SUBSYS if serotonin syndrome is suspected.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">MAOI interactions with opioids may manifest as serotonin syndrome \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0510\">5.10</a>)] \n </span> or opioid toxicity (e.g., respiratory depression, coma) \n <span class=\"Italics\">[see Warnings and Precautions ( \n <a href=\"#SK0502\">5.2</a>)] \n </span>.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">The use of SUBSYS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">May reduce the analgesic effect of SUBSYS and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Avoid concomitant use.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">butorphanol, nalbuphine, pentazocine, buprenorphine,</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Muscle Relaxants</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of SUBSYS and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose \n <span class=\"Italics\">[see Dosage and Administration (\n <a href=\"#id_link_c185b09e-a884-0993-e053-2995a90a8fc6\">2.2</a>), Warnings and Precautions (\n <a href=\"#SK0501\">5.1</a>, \n <a href=\"#SK0504\">5.4</a>)]\n </span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Diuretics</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Anticholinergic Drugs</span></td><td></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">Monitor patients for signs of urinary retention or reduced gastric motility when SUBSYS is used concomitantly with anticholinergic drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.8)] . Available data with SUBSYS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [ see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.8)] .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. SUBSYS is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including SUBSYS, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Animal Data

Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of SUBSYS on a mg/m 2 basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of SUBSYS based on a mg/m 2 basis). There was no evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg SUBSYS per pain episode on a mg/m 2 basis and produced mean steady-state plasma levels that are 5.3 times higher than the mean C max observed following administration of 800 mcg dose of SUBSYS in humans.

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SUBSYS.

Clinical Considerations

Monitor infants exposed to SUBSYS through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)] .

Safety and efficacy in pediatric patients below the age of 18 years have not been established.

Of the 359 patients in clinical studies of SUBSYS in breakthrough cancer pain, 27% were 60 years of age and older, 17% were 65 years of age and older, and 3% were 75 years of age and older. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in SUBSYS clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, monitor patients for respiratory depression and CNS effects when titrating SUBSYS in elderly patients.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of SUBSYS slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [ see Warnings and Precautions ( 5.1)] .

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Insufficient information exists to make recommendations regarding the use of SUBSYS in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, monitor patients closely for signs of respiratory and central nervous system depression.

Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.

SUBSYS contains fentanyl a Schedule II controlled substance.

SUBSYS contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. SUBSYS can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions ( 5.6)] .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

SUBSYS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to the Abuse of SUBSYS

SUBSYS is for sublingual transmucosal use only. Abuse of SUBSYS poses a risk of overdose and death. The risk is increased with concurrent abuse of SUBSYS with alcohol and other central nervous system depressants.

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [ see Use in Specific Populations ( 8.1)] .

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdose with SUBSYS be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [ see Clinical Pharmacology ( 12.2)] .

{ "type": "p", "children": [], "text": "Acute overdose with SUBSYS be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [\n \n \n see Clinical Pharmacology (\n \n \n 12.2)]\n \n \n .\n \n\n " }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

{ "type": "p", "children": [], "text": "In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques." }

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

{ "type": "p", "children": [], "text": "The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose." }

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in SUBSYS, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in SUBSYS, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information." }

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist." }

SUBSYS (fentanyl sublingual spray) is an opioid agonist, available as a sublingual spray designed to deliver doses of 100, 200, 400, 600, 800, 1200 and 1600 mcg of fentanyl. The chemical name of fentanyl is N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide.

{ "type": "p", "children": [], "text": "SUBSYS (fentanyl sublingual spray) is an opioid agonist, available as a sublingual spray designed to deliver doses of 100, 200, 400, 600, 800, 1200 and 1600 mcg of fentanyl. The chemical name of fentanyl is N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide." }

Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 860:1) that is freely soluble in ethanol and methanol and practically insoluble in water (1:40). The molecular weight of the free base is 336.47. The pKa is 8.4.

{ "type": "p", "children": [], "text": "Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 860:1) that is freely soluble in ethanol and methanol and practically insoluble in water (1:40). The molecular weight of the free base is 336.47. The pKa is 8.4." }

The inactive ingredients in SUBSYS include: dehydrated alcohol 63.6% (V/V), purified water, propylene glycol, xylitol, and L-menthol.

{ "type": "p", "children": [], "text": "The inactive ingredients in SUBSYS include: dehydrated alcohol 63.6% (V/V), purified water, propylene glycol, xylitol, and L-menthol. " }

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2)] .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1, 2.3, 2.5)] .

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.

Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see Warnings and Precautions ( 5.1)].

Absorption

Following the single dose administration of SUBSYS, 400 mcg, the mean absolute bioavailability of fentanyl is 76% as measured by AUC 0-∞. Fentanyl pharmacokinetic profile and bioavailability depend on the fraction of the dose that is absorbed through the sublingual mucosa and the fraction swallowed from the gastrointestinal tract.

In a study that compared the relative bioavailability of SUBSYS and oral transmucosal fentanyl citrate [OTFC]) in 21 healthy adult subjects, the rate and extent of fentanyl absorption were considerably greater with SUBSYS [34% greater maximum plasma concentration (C max) and 38% greater systemic exposure (AUC inf)] ( Table 7 and Figure 1) [see Dosage and Administration ( 2.1, 2.3, 2.5) and Warnings and Precautions ( 5.5)] .

Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 4 hours.

<div class="scrollingtable"><table class="Noautorules" width="775"> <caption> <span>Table 7. Pharmacokinetic Parameters of Fentanyl in Healthy Adult Subjects Receiving a Single Dose of SUBSYS or OTFC</span> </caption> <colgroup> <col align="left" width="50%"/> <col align="left" width="30%"/> <col align="left" width="30%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="4"> <p class="First">* Data for T <span class="Sub">max</span> presented as median (range) </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Pharmacokinetic Parameter (Mean (CV%))</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">SUBSYS 400 mcg</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">OTFC 400 mcg</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">T <span class="Sub">max</span> (hour)* </span></td><td align="left" class="Botrule Lrule Rrule Toprule">1.5 (0.17, 2.00)</td><td align="left" class="Botrule Lrule Rrule Toprule">2.0 (0.5, 2.12)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">C <span class="Sub">max</span> (ng/mL) </span></td><td align="left" class="Botrule Lrule Rrule Toprule">0.813 (31.00)</td><td align="left" class="Botrule Lrule Rrule Toprule">0.607 (30.48)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC <span class="Sub">0-t</span> (ng/mL × hr) </span></td><td align="left" class="Botrule Lrule Rrule Toprule">4.863 (35.12)</td><td align="left" class="Botrule Lrule Rrule Toprule">3.677 (39.16)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC <span class="Sub">0-∞</span> (ng/mL × hr) </span></td><td align="left" class="Botrule Lrule Rrule Toprule">5.761 (33.26)</td><td align="left" class="Botrule Lrule Rrule Toprule">4.182 (39.93)</td> </tr> </tbody> </table></div>

Figure 1 Mean Fentanyl Plasma Concentration-Time Profiles Following Single Dose Administration of SUBSYS 400 mcg and OTFC 400 mcg in Healthy Adult Subjects

Neither peak fentanyl concentration nor total exposure was appreciably affected by the pretreatment of oral cavity with hot water or refrigerated iced water, low or high pH beverages when SUBSYS was administered under fasted condition.

Dose proportionality among the five available strengths of SUBSYS (100, 200, 400, 600, and 800 mcg) has been evaluated in a crossover study in healthy subjects. Mean plasma fentanyl levels following these five dose levels of SUBSYS are shown in Figure 2. The curves for each dose level are similar in shape with increasing dose levels producing increasing plasma fentanyl levels. The C max and AUC 0-∞ values increased in a dose-dependent manner that is approximately proportional to the SUBSYS doses administered.

Figure 2. Mean Fentanyl Plasma Concentration-Time Profiles (36 hours) after Administration of SUBSYS 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg in Healthy Subjects

The pharmacokinetic parameters of the five strengths of SUBSYS tested are shown in Table 8. The mean Cmax ranged from 0.202 – 1.610 ng/mL. The median time of maximum plasma concentration (T max) across these five doses of SUBSYS varied from 0.67 - 1.25 hours (range of 0.08 – 4.00 hours) as measured after the start of administration.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 8. Fentanyl Plasma Pharmacokinetic Parameters in Healthy Adult Subjects Receiving Single Doses of 100, 200, 400, 600, 800 mcg of SUBSYS</span> </caption> <colgroup> <col align="left" width="20%"/> <col align="left" width="16%"/> <col align="left" width="16%"/> <col align="left" width="16%"/> <col align="left" width="16%"/> <col align="left" width="16%"/> </colgroup> <thead> <tr class="Noautorules" valign="top"> <th align="left">Pharmacokinetic Parameter (Mean (%CV))</th><th align="left">100 mcg</th><th align="left">200 mcg</th><th align="left">400 mcg</th><th align="left">600 mcg</th><th align="left">800 mcg</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <p class="First">* Data for T <span class="Sub">max</span> presented as median (range) </p> </td> </tr> </tfoot> <tbody> <tr valign="top"> <td align="left" class="Bold">T <span class="Sub">max</span> (hr)* </td><td align="left">1.25 <br/> <br/> (0.17-2.05) </td><td align="left">1.25 <br/> <br/> (0.17-2.03) </td><td align="left">1.00 <br/> <br/> (0.17-2.03) </td><td align="left">0.67 <br/> <br/> (0.08-2.00) </td><td align="left">0.69 <br/> <br/> (0.17-4.00) </td> </tr> <tr valign="top"> <td align="left" class="Bold">C <span class="Sub">max</span> (ng/mL) </td><td align="left">0.202 <br/> <br/> (28.35) </td><td align="left">0.378 <br/> <br/> (29.69) </td><td align="left">0.800 <br/> <br/> (27.66) </td><td align="left">1.17 <br/> <br/> (32.48) </td><td align="left">1.610 <br/> <br/> (37.22) </td> </tr> <tr valign="top"> <td align="left" class="Bold">AUC <span class="Sub">last</span> (ng/mL × hr) </td><td align="left">0.9776 <br/> <br/> (49.82) </td><td align="left">1.985 <br/> <br/> (40.93) </td><td align="left">4.643 <br/> <br/> (44.53) </td><td align="left">6.682 <br/> <br/> (32.46) </td><td align="left">9.450 <br/> <br/> (36.62) </td> </tr> <tr valign="top"> <td align="left" class="Bold">AUC <span class="Sub">0-∞</span> (ng/mL × hr) </td><td align="left">1.245 <br/> <br/> (53.82) </td><td align="left">2.475 <br/> <br/> (46.48) </td><td align="left">5.342 <br/> <br/> (44.16) </td><td align="left">7.446 <br/> <br/> (81.54) </td><td align="left">10.38 <br/> <br/> (35.60) </td> </tr> <tr valign="top"> <td align="left" class="Bold">T <span class="Sub">½</span> (hr) </td><td align="left">5.25 <br/> <br/> (89.92) </td><td align="left">8.45 <br/> <br/> (77.94) </td><td align="left">11.03 <br/> <br/> (62.20) </td><td align="left">10.64 <br/> <br/> (41.73) </td><td align="left">11.99 <br/> <br/> (32.15) </td> </tr> </tbody> </table></div>

Distribution Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.

Elimination

Metabolism Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions ( 7)] .

Excretion Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important. The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3 - 0.7 L/hr/kg). The terminal half-life after SUBSYS administration is from 5 to 12 hours.

Specific Population

Patients with mucositis:

The effect of mucositis (Grades 1 and 2) on the pharmacokinetics of SUBSYS was studied in a group of cancer patients with mucositis (N = 7 for Grade 1 and N = 2 for Grade 2) and without mucositis (N = 8). A single 100 mcg dose was administered. Mean summary statistics (standard deviation in parentheses) for patients with Grade 1 mucositis and patients without mucositis are presented in Table 9. Cancer patients with Grade 1 mucositis exhibited 73% greater Cmax and 52% greater AUClast values in comparison to patients without mucositis. The two cancer patients with Grade 2 mucositis had 4- and 7-fold higher C max and ≥3- fold higher AUC last values compared to patients without mucositis.

Monitor patients with Grade 1 mucositis closely for signs of respiratory and central nervous system depression particularly during initiation of therapy with SUBSYS. As a result of the large and variable increase in exposure of fentanyl, use of SUBSYS should be avoided in patients with Grade 2 and more severe mucositis unless the benefits are expected to outweigh the risk of respiratory depression.

<div class="scrollingtable"><table class="Noautorules" width="600"> <caption> <span>Table 9. Mean (%CV) Pharmacokinetic Parameters in Patients with Mucositis</span> </caption> <colgroup> <col align="left" width="22%"/> <col align="left" width="8%"/> <col align="left" width="22%"/> <col align="left" width="22%"/> <col align="left" width="26%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="4"> <p class="First">* Data for T <span class="Sub">max</span> presented as median (range) </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Patient Status</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">N</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">C <span class="Sub">max</span> (ng/mL) </span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">T <span class="Sub">max</span> (hr)* </span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC <span class="Sub">0-last</span> (ng/mL × hr) </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Mucositis Grade 1</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">7</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">0.45 (95.56)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">0.25 (0.25, 2.00)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">1.38 (44.93)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">No Mucositis</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">8</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">0.26 (57.69)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">0.38 (0.25, 2.00)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">0.91 (14.29)</span></td> </tr> </tbody> </table></div>

Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of fentanyl have not been conducted

Mutagenesis Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg intravenously and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for SUBSYS.

The efficacy of SUBSYS was demonstrated in a double-blind, placebo-controlled, crossover study in opioid tolerant adult patients with cancer and breakthrough pain. The dose range studied was from 100 mcg per dose to 1600 mcg per dose. Patients entering the trial must have had on average 1-4 episodes of pain per day not controlled on stable, chronic maintenance doses of opioid medication of at least 60 mg/day of morphine, 25 mcg/hr of transdermal fentanyl, or an equianalgesic dose of another opioid for at least 7 days.

{ "type": "p", "children": [], "text": "The efficacy of SUBSYS was demonstrated in a double-blind, placebo-controlled, crossover study in opioid tolerant adult patients with cancer and breakthrough pain. The dose range studied was from 100 mcg per dose to 1600 mcg per dose. Patients entering the trial must have had on average 1-4 episodes of pain per day not controlled on stable, chronic maintenance doses of opioid medication of at least 60 mg/day of morphine, 25 mcg/hr of transdermal fentanyl, or an equianalgesic dose of another opioid for at least 7 days." }

The study began with an open-label dose titration period followed by a double-blind treatment period. The goal of titration was to find the dose of SUBSYS that provided adequate analgesia with acceptable side effects. Patients were titrated from a 100 mcg starting dose. Once a successful dose was established, patients were enrolled into the double-blind period and randomized to a sequence of 10 treatments; 7 with SUBSYS and 3 with placebo.

{ "type": "p", "children": [], "text": "The study began with an open-label dose titration period followed by a double-blind treatment period. The goal of titration was to find the dose of SUBSYS that provided adequate analgesia with acceptable side effects. Patients were titrated from a 100 mcg starting dose. Once a successful dose was established, patients were enrolled into the double-blind period and randomized to a sequence of 10 treatments; 7 with SUBSYS and 3 with placebo. " }

Patients assessed pain intensity on a 100 mm visual analog scale that rated the pain as 0=none to 100=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-100) was then measured at 5, 10, 15, 30, 45 and 60 minutes after the start of administration. The summed pain intensity difference from baseline to 30 minutes after dosing was the primary efficacy measure.

{ "type": "p", "children": [], "text": "Patients assessed pain intensity on a 100 mm visual analog scale that rated the pain as 0=none to 100=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-100) was then measured at 5, 10, 15, 30, 45 and 60 minutes after the start of administration. The summed pain intensity difference from baseline to 30 minutes after dosing was the primary efficacy measure." }

Out of 130 patients who entered the titration phase, 98 (75%) were able to titrate to a dose that adequately reduced pain with tolerable side effects and entered into the double-blind period.

{ "type": "p", "children": [], "text": "Out of 130 patients who entered the titration phase, 98 (75%) were able to titrate to a dose that adequately reduced pain with tolerable side effects and entered into the double-blind period." }

The breakdown of successful dose for the patients entering the double-blind period of the study is as follows:

{ "type": "p", "children": [], "text": "The breakdown of successful dose for the patients entering the double-blind period of the study is as follows:" }

<div class="scrollingtable"><table class="Noautorules" width="300"> <col align="left" width="50%"/> <col align="center" width="50%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule"><span class="Bold">SUBSYS Dose</span></td><td align="center" class="Botrule"><span class="Bold">Total No. (%) <br/>n=96 </span></td> </tr> <tr> <td align="left">100 mcg</td><td align="center">4 (4%)</td> </tr> <tr> <td align="left">200 mcg</td><td align="center">7 (7%)</td> </tr> <tr> <td align="left">400 mcg</td><td align="center">14 (15%)</td> </tr> <tr> <td align="left">600 mcg</td><td align="center">15 (16%)</td> </tr> <tr> <td align="left">800 mcg</td><td align="center">23 (24%)</td> </tr> <tr> <td align="left">1200 mcg (2 × 600 mcg)</td><td align="center">20 (21%)</td> </tr> <tr> <td align="left">1600 mcg (2 × 800 mcg)</td><td align="center">13 (14%)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"300\">\n<col align=\"left\" width=\"50%\"/>\n<col align=\"center\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" class=\"Botrule\"><span class=\"Bold\">SUBSYS Dose</span></td><td align=\"center\" class=\"Botrule\"><span class=\"Bold\">Total No. (%)\n \n \n <br/>n=96\n \n \n </span></td>\n</tr>\n<tr>\n<td align=\"left\">100 mcg</td><td align=\"center\">4 (4%)</td>\n</tr>\n<tr>\n<td align=\"left\">200 mcg</td><td align=\"center\">7 (7%)</td>\n</tr>\n<tr>\n<td align=\"left\">400 mcg</td><td align=\"center\">14 (15%)</td>\n</tr>\n<tr>\n<td align=\"left\">600 mcg</td><td align=\"center\">15 (16%)</td>\n</tr>\n<tr>\n<td align=\"left\">800 mcg</td><td align=\"center\">23 (24%)</td>\n</tr>\n<tr>\n<td align=\"left\">1200 mcg (2 × 600 mcg)</td><td align=\"center\">20 (21%)</td>\n</tr>\n<tr>\n<td align=\"left\">1600 mcg (2 × 800 mcg)</td><td align=\"center\">13 (14%)</td>\n</tr>\n</tbody>\n</table></div>" }

SUBSYS produced a statistically significantly greater reduction in pain intensity compared to placebo as measured by the Summed Pain Intensity Differences scale (SPID) at 30 minutes.

{ "type": "p", "children": [], "text": "SUBSYS produced a statistically significantly greater reduction in pain intensity compared to placebo as measured by the Summed Pain Intensity Differences scale (SPID) at 30 minutes. " }

The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for SUBSYS than for placebo. The difference in mean pain intensity based on a 100 mm visual analog scale is displayed in Figure 3.

{ "type": "p", "children": [], "text": "The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for SUBSYS than for placebo. The difference in mean pain intensity based on a 100 mm visual analog scale is displayed in \n \n \n Figure 3.\n \n\n " }

Figure 3. Pain Intensity Differences over Time

{ "type": "p", "children": [], "text": "\nFigure 3. Pain Intensity Differences over Time \n" }

SUBSYS (fentanyl sublingual spray) is supplied as spray units.

{ "type": "p", "children": [], "text": "SUBSYS (fentanyl sublingual spray) is supplied as spray units." }

Each SUBSYS carton contains individual blister packages containing spray units of SUBSYS, a supply of small white disposal bags for disposing of used SUBSYS units and charcoal-lined disposal pouches, a supply of charcoal-lined disposal pouches (wrapped in aluminum foil) for use when disposing of the contents of unused SUBSYS units, a Medication Guide and a Package Insert.

{ "type": "p", "children": [], "text": "Each SUBSYS carton contains individual blister packages containing spray units of SUBSYS, a supply of small white disposal bags for disposing of used SUBSYS units and charcoal-lined disposal pouches, a supply of charcoal-lined disposal pouches (wrapped in aluminum foil) for use when disposing of the contents of unused SUBSYS units, a Medication Guide and a Package Insert." }

SUBSYS is supplied in individually sealed, protective blister packages. These blister packages are packed into 10 and 30 per shelf cartons.

{ "type": "p", "children": [], "text": "SUBSYS is supplied in individually sealed, protective blister packages. These blister packages are packed into 10 and 30 per shelf cartons." }

Each unit dose system consists of a white actuator attached to a light purple vial holder. The dosage strength is marked on the label on the actuator, the blister package and the shelf carton. See the protective blister package and shelf carton for product information.

{ "type": "p", "children": [], "text": "Each unit dose system consists of a white actuator attached to a light purple vial holder. The dosage strength is marked on the label on the actuator, the blister package and the shelf carton. See the protective blister package and shelf carton for product information." }

<div class="scrollingtable"><table class="Noautorules" width="700"> <colgroup> <col align="left" width="40%"/> <col align="left" width="30%"/> <col align="left" width="30%"/> </colgroup> <tbody class="Headless"> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Dosage Strength (fentanyl base)</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Carton/Blister Package Color</span></td><td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">NDC Number</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">100 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">Blue</td><td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-001-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-001-10</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">Green</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-002-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-002-10</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">400 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">Magenta (Pink)</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-004-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-004-10</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">Purple</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-006-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-006-10</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">800 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2">Orange</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-008-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">20482-008-10</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="1" rowspan="2">1200 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" colspan="1" rowspan="2">Brown</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-012-01</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule">20482-012-15</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="1" rowspan="2" valign="top">1600 mcg</td><td align="left" class="Botrule Lrule Rrule Toprule" colspan="1" rowspan="2" valign="top">Red</td><td align="left" class="Botrule Lrule Rrule Toprule">20482-016-01</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">20482-016-15</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"700\">\n<colgroup>\n<col align=\"left\" width=\"40%\"/>\n<col align=\"left\" width=\"30%\"/>\n<col align=\"left\" width=\"30%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Dosage Strength (fentanyl base)</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Carton/Blister Package Color</span></td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">NDC Number</span></td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">100 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">Blue</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-001-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-001-10</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">200 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">Green</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-002-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-002-10</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">400 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">Magenta (Pink)</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-004-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-004-10</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">600 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">Purple</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-006-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-006-10</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">800 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\">Orange</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-008-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">20482-008-10</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"1\" rowspan=\"2\">1200 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"1\" rowspan=\"2\">Brown</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-012-01</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-012-15</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"1\" rowspan=\"2\" valign=\"top\">1600 mcg</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"1\" rowspan=\"2\" valign=\"top\">Red</td><td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-016-01</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\">20482-016-15</td>\n</tr>\n</tbody>\n</table></div>" }

Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

{ "type": "p", "children": [], "text": "\nNote: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.\n" }

Storage and Handling

{ "type": "p", "children": [], "text": "Storage and Handling" }

Store at 20-25ºC (68-77ºF) with excursions permitted between 15º and 30ºC (59º to 86ºF) until ready to use. [See USP Controlled Room Temperature.] Do not use if the blister package has been opened.

{ "type": "p", "children": [], "text": "Store at 20-25ºC (68-77ºF) with excursions permitted between 15º and 30ºC (59º to 86ºF) until ready to use. [See USP Controlled Room Temperature.] Do not use if the blister package has been opened." }

Store SUBSYS securely and dispose of properly [see Patient Counseling Information (17)].

{ "type": "p", "children": [], "text": "Store SUBSYS securely and dispose of properly \n [see Patient Counseling Information (17)].\n " }

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling \n ( Medication Guide).\n " }

Storage and Disposal of Unused and Used SUBSYS [see Instructions for Use].

{ "type": "p", "children": [], "text": "\nStorage and Disposal of Unused and Used SUBSYS \n [see Instructions for Use].\n \n" }

Because of risk associated with accidental ingestion, misuse, and abuse, advise patients to store SUBSYS securely, out of sight and reach of children and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Inform Patients that leaving SUBSYS unsecured can pose a deadly risk to others in the home.

{ "type": "p", "children": [], "text": "Because of risk associated with accidental ingestion, misuse, and abuse, advise patients to store SUBSYS securely, out of sight and reach of children and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Inform Patients that leaving SUBSYS unsecured can pose a deadly risk to others in the home." }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly." }

Disposal of Unopened SUBSYS Unit Dose Systems When No Longer Needed

{ "type": "p", "children": [], "text": "Disposal of Unopened SUBSYS Unit Dose Systems When No Longer Needed" }

Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed.

{ "type": "p", "children": [], "text": "Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed." }

To dispose of the unopened SUBSYS units:

{ "type": "p", "children": [], "text": "To dispose of the unopened SUBSYS units:" }

1. Using a pair of scissors, cut the blister package on the line marked by an image of a pair of scissors and the instruction “cut to open” printed on the blister. Peel back the blister material to remove the SUBSYS unit from the package.

{ "type": "p", "children": [], "text": "1. Using a pair of scissors, cut the blister package on the line marked by an image of a pair of scissors and the instruction “cut to open” printed on the blister. Peel back the blister material to remove the SUBSYS unit from the package." }

2. Remove a charcoal-lined disposal pouch from the aluminum foil package by tearing open the package at the notch.

{ "type": "p", "children": [], "text": "2. Remove a charcoal-lined disposal pouch from the aluminum foil package by tearing open the package at the notch." }

3. Hold the charcoal-lined disposal pouch with the opening facing up. Put the nozzle of the SUBSYS spray unit upside-down into the opening of the charcoal-lined disposal pouch.

{ "type": "p", "children": [], "text": "3. Hold the charcoal-lined disposal pouch with the opening facing up. Put the nozzle of the SUBSYS spray unit upside-down into the opening of the charcoal-lined disposal pouch." }

4. Squeeze your fingers and thumb together to spray SUBSYS into the charcoal-lined disposal pouch.

{ "type": "p", "children": [], "text": "4. Squeeze your fingers and thumb together to spray SUBSYS into the charcoal-lined disposal pouch." }

5. Dispose of the empty spray unit in a disposal bag.

{ "type": "p", "children": [], "text": "5. Dispose of the empty spray unit in a disposal bag." }

6. Repeat the above steps for each unused SUBSYS spray unit. The charcoal-lined disposal pouch may be used for disposing of the contents of up to 10 spray units. Make sure all unused spray units have been sprayed into a charcoal-lined disposal pouch.

{ "type": "p", "children": [], "text": "6. Repeat the above steps for each unused SUBSYS spray unit. The charcoal-lined disposal pouch may be used for disposing of the contents of up to 10 spray units. Make sure all unused spray units have been sprayed into a charcoal-lined disposal pouch." }

7. To seal a used charcoal-lined disposal pouch, remove the backing from the adhesive strip. Fold the flap down and press to seal the charcoal-lined disposal pouch.

{ "type": "p", "children": [], "text": "7. To seal a used charcoal-lined disposal pouch, remove the backing from the adhesive strip. Fold the flap down and press to seal the charcoal-lined disposal pouch." }

8. Place the sealed charcoal-lined disposal pouch into a disposal bag.

{ "type": "p", "children": [], "text": "8. Place the sealed charcoal-lined disposal pouch into a disposal bag." }

9. To seal the disposal bag, remove the backing from the adhesive strip. Fold the flap down and press to seal.

{ "type": "p", "children": [], "text": "9. To seal the disposal bag, remove the backing from the adhesive strip. Fold the flap down and press to seal." }

10. Discard the sealed disposal bag in the trash out of the reach of children.

{ "type": "p", "children": [], "text": "10. Discard the sealed disposal bag in the trash out of the reach of children." }

Disposal of Used SUBSYS Unit Dose Systems

{ "type": "p", "children": [], "text": "\nDisposal of Used SUBSYS Unit Dose Systems\n" }

Patients must be instructed to safely dispose of used SUBSYS units.

{ "type": "p", "children": [], "text": "Patients must be instructed to safely dispose of used SUBSYS units." }

1. After administration of SUBSYS, place the used spray unit into one of the disposable bags provided with your prescription.

{ "type": "p", "children": [], "text": "1. After administration of SUBSYS, place the used spray unit into one of the disposable bags provided with your prescription." }

2. Seal the bag and discard into a trash container out of the reach of children.

{ "type": "p", "children": [], "text": "2. Seal the bag and discard into a trash container out of the reach of children." }

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of SUBSYS are provided in the SUBSYS Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

{ "type": "p", "children": [], "text": "Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of SUBSYS are provided in the SUBSYS \n Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.\n " }

In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for West Therapeutic Development, LLC., 1-844-452-9263) or seek assistance from their local DEA office.

{ "type": "p", "children": [], "text": "In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for West Therapeutic Development, LLC., 1-844-452-9263) or seek assistance from their local DEA office." }

Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting SUBSYS or when the dosage is increased, and that it can occur even at recommended dosages.

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n\nInform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting SUBSYS or when the dosage is increased, and that it can occur even at recommended dosages.\n " }

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose \n [see Warnings and Precautions (\n 5.1)]\n .\n " }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

{ "type": "p", "children": [], "text": "\nPatient Access to Naloxone for the Emergency Treatment of Opioid Overdose\n" }

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBSYS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and

{ "type": "p", "children": [], "text": "Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBSYS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and" }

prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) \n [see Dosage and Administration (\n 2.2), Warnings and Precautions (\n 5.1)]\n .\n " }

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize the signs and symptoms of an overdose." }

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage ( 10)] .

{ "type": "p", "children": [], "text": "Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered \n [see Overdosage (\n 10)]\n .\n " }

If naloxone is prescribed, also advise patients and caregivers:

{ "type": "p", "children": [], "text": "If naloxone is prescribed, also advise patients and caregivers:" }

{ "type": "ul", "children": [ "How to treat with naloxone in the event of an opioid overdose", "To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency", "To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do." ], "text": "" }

Increased Risk of Overdose and Death in Children Due to Accidental Exposure [see Warnings and Precautions ( 5.2)]

{ "type": "p", "children": [], "text": "\nIncreased Risk of Overdose and Death in Children Due to Accidental Exposure \n [see Warnings and Precautions ( \n 5.2)] \n \n" }

{ "type": "ul", "children": [ "Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.", "Inform patients that accidental exposure, especially in children, may result in respiratory depression or death.", "Instruct patients to take steps to store SUBSYS securely and use the Child Safety Kit to store SUBSYS and other medicines out of the reach of children and to dispose of unused SUBYS by emptying all of the medicine into the charcoal-lined disposal pouch, seal the pouch, and dispose in the trash out of reach of children.", "Instruct patients and caregivers to keep both used and unused SUBSYS out of the reach of children." ], "text": "" }

SUBSYS Child Safety Kit Provide patients and their caregivers with a SUBSYS Child Safety Kit. The kit consists of a portable carrying case, a lock for the bag and contains a package of cabinet and drawer child safety latches for securing the storage space at home to help patients store SUBSYS and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call West Therapeutic Development, LLC., at 1-844-452-9263.

{ "type": "p", "children": [], "text": "\nSUBSYS Child Safety Kit \n\n\nProvide patients and their caregivers with a SUBSYS Child Safety Kit. The kit consists of a portable carrying case, a lock for the bag and contains a package of cabinet and drawer child safety latches for securing the storage space at home to help patients store SUBSYS and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call West Therapeutic Development, LLC., at 1-844-452-9263.\n " }

Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if SUBSYS is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4), Drug Interactions ( 7)].

{ "type": "p", "children": [], "text": "\nInteractions with Benzodiazepines and Other CNS Depressants\n\n\nInform patients and caregivers that potentially fatal additive effects may occur if SUBSYS is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider \n [see Warnings and Precautions ( \n 5.4), Drug Interactions ( \n 7)]. \n \n" }

Addiction, Abuse, and Misuse Inform patients that the use of SUBSYS, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.6)]. Instruct patients not to share SUBSYS with others and to take steps to protect SUBSYS from theft or misuse.

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse\n\n\nInform patients that the use of SUBSYS, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death \n [see Warnings and Precautions ( \n 5.6)]. \n Instruct patients not to share SUBSYS with others and to take steps to protect SUBSYS from theft or misuse.\n " }

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

{ "type": "p", "children": [], "text": "\nTransmucosal Immediate-Release Fentanyl (TIRF) REMS\n" }

SUBSYS is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions ( 5.7)] . Inform the patient of the following notable requirements:

{ "type": "p", "children": [], "text": "SUBSYS is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS \n [see Warnings and Precautions (\n 5.7)]\n . Inform the patient of the following notable requirements:\n " }

{ "type": "ul", "children": [ "Outpatients must be enrolled in the REMS program", "Patients must be opioid-tolerant to receive SUBSYS" ], "text": "" }

SUBSYS is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

{ "type": "p", "children": [], "text": "SUBSYS is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product." }

Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require SUBSYS while hospitalized​ [see Warnings and Precautions ( 5.7)].

{ "type": "p", "children": [], "text": "Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require SUBSYS while hospitalized​ \n [see Warnings and Precautions ( \n 5.7)]. \n \n" }

Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Warnings and Precautions ( 5.10), Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n\n\nInform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. \n [see Warnings and Precautions ( \n 5.10), Drug Interactions ( \n 7)] \n .\n " }

MAOI Interaction Inform patients to avoid taking SUBSYS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking SUBSYS [see Warnings and Precautions ( 5.1, 5.10); Drug Interactions ( 7)].

{ "type": "p", "children": [], "text": "\nMAOI Interaction\n\n\nInform patients to avoid taking SUBSYS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking SUBSYS \n [see Warnings and Precautions ( \n 5.1, \n 5.10); Drug Interactions ( \n 7)]. \n \n" }

Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.11)] .

{ "type": "p", "children": [], "text": "\nAdrenal Insufficiency \n\n\nInform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms \n [see Warnings and Precautions ( \n 5.11)] \n .\n " }

Important Administration Instructions [see Dosage and Administration ( 2)]

{ "type": "p", "children": [], "text": "Important Administration Instructions \n [see Dosage and Administration ( \n 2)] \n \n" }

{ "type": "ul", "children": [ "Instruct patients not to take SUBSYS for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.", "Instruct patients on the meaning of opioid tolerance and that SUBSYS is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.", "Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take SUBSYS.", "Instruct patients that, if the breakthrough pain episode is not relieved 30 minutes after administration, they may take \n only one additional dose of SUBSYS using the same strength for that episode. Thus, patients should take no more than two doses of SUBSYS for any breakthrough pain episode.\n ", "Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with SUBSYS.", "Instruct patients NOT to share SUBSYS and that sharing SUBSYS with anyone else could result in the other individual’s death due to overdose.", "Make patients aware that SUBSYS contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.", "Instruct patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking SUBSYS.", "Instruct patients to use SUBSYS exactly as prescribed by their doctor and not to take SUBSYS more often than prescribed.", "Provide patients and their caregivers with a \n Medication Guide each time SUBSYS is dispensed because new information may be available.\n " ], "text": "" }

Hypotension Inform patients that SUBSYS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.12)] .

{ "type": "p", "children": [], "text": "\nHypotension\n\n\nInform patients that SUBSYS may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) \n [see Warnings and Precautions ( \n 5.12)] \n .\n " }

Anaphylaxis Inform patients that anaphylaxis have been reported with ingredients contained in SUBSYS. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4), Adverse Reactions ( 6)].

{ "type": "p", "children": [], "text": "\nAnaphylaxis \n\n\nInform patients that anaphylaxis have been reported with ingredients contained in SUBSYS. Advise patients how to recognize such a reaction and when to seek medical attention \n [see Contraindications ( \n 4), Adverse Reactions ( \n 6)]. \n \n" }

Pregnancy

{ "type": "p", "children": [], "text": "Pregnancy" }

Neonatal Opioid Withdrawal Syndrome Inform patients that prolonged use of SUBSYS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [See Warnings and Precautions ( 5.8), Use in Specific Populations ( 8.1)] .

{ "type": "p", "children": [], "text": "Neonatal Opioid Withdrawal Syndrome\n \n\nInform patients that prolonged use of SUBSYS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated \n [See Warnings and Precautions ( \n 5.8), Use in Specific Populations ( \n 8.1)] \n .\n " }

Embryo-Fetal Toxicity Inform female patients of reproductive potential that SUBSYS can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1), Non-Clinical Toxicology ( 13.1)].

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n\n\nInform female patients of reproductive potential that SUBSYS can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy \n [see Use in Specific Populations ( \n 8.1), Non-Clinical Toxicology ( \n 13.1)]. \n \n" }

Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations ( 8.2)] .

{ "type": "p", "children": [], "text": "\nLactation \n\n\nAdvise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs \n [see Use in Specific Populations ( \n 8.2)] \n .\n " }

Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Use in Specific Populations ( 8.3)].

{ "type": "p", "children": [], "text": "\nInfertility\n\n\nInform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible \n [see Adverse Reactions ( \n 6.2), Use in Specific Populations ( \n 8.3)]. \n \n" }

Driving or Operating Heavy Machinery Inform patients that SUBSYS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.16)] .

{ "type": "p", "children": [], "text": "\nDriving or Operating Heavy Machinery\n\n\nInform patients that SUBSYS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication \n [see Warnings and Precautions ( \n 5.16)] \n .\n " }

Constipation Advise patients of the potential for severe constipation, including management instructions, and when to seek medical attention [see Adverse Reactions ( 6), Clinical Pharmacology ( 12.2)] .

{ "type": "p", "children": [], "text": "\nConstipation\n\n\nAdvise patients of the potential for severe constipation, including management instructions, and when to seek medical attention \n [see Adverse Reactions ( \n 6), Clinical Pharmacology ( \n 12.2)] \n .\n " }

Manufactured by: Renaissance Lakewood, LLC, Lakewood, NJ 08701

{ "type": "p", "children": [], "text": "\nManufactured by:\n\n\nRenaissance Lakewood, LLC, Lakewood, NJ 08701\n " }

Manufactured for and Distributed by: West Therapeutic Development, LLC., Northbrook, IL 60062

{ "type": "p", "children": [], "text": "\nManufactured for and Distributed by:\n\nWest Therapeutic Development, LLC., Northbrook, IL 60062\n " }

U.S. Patents: 8,486,972 B2 and 8,486,973 B2

{ "type": "p", "children": [], "text": "U.S. Patents: 8,486,972 B2 and 8,486,973 B2" }

2104221

{ "type": "p", "children": [], "text": "2104221" }

April 2021

{ "type": "p", "children": [], "text": "April 2021" }

SUBSYS ® is a registered trademark of West Therapeutic Development, LLC

{ "type": "p", "children": [], "text": "SUBSYS \n ® is a registered trademark of West Therapeutic Development, LLC\n " }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col width="82%"/> <col width="18%"/> </colgroup> <tfoot> <tr valign="top"> <td align="left"> <p class="First"> <span class="Bold">This Medication Guide has been approved by the U.S. Food and Drug Administration.</span> </p> </td><td align="right"> <p class="First">Issued: 02/2020</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Medication Guide <br/> <br/> SUBSYS <span class="Sup">®</span> (sub sis)) <br/> <br/> (fentanyl) sublingual spray , CII </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Important information about SUBSYS:</span> <br/> <br/> <span class="Bold">Do not use SUBSYS unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant. <br/> <br/> Keep SUBSYS in a safe place away from children. <br/> <br/> Get emergency help right away if: </span> <ul> <li> <span class="Bold">A child uses SUBSYS. SUBSYS can cause an overdose and death in any child who uses it.</span> </li> <li> <span class="Bold">An adult who has not been prescribed SUSBYS uses it</span> </li> <li> <span class="Bold">An adult who is not already taking opioids around-the-clock, uses SUBSYS</span> </li> </ul> <span class="Bold">These are medical emergencies that can cause death.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">SUBSYS is:</span> <ul class="Disc"> <li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (18 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. SUBSYS is started only after you have been taking other opioid pain medicines and your body has become used to them ( you are opioid tolerant). Do not use SUBSYS if you are not opioid tolerant.</li> <li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li> </ul> <p class="First"> <span class="Bold">Important information about SUBSYS:</span> </p> <ul class="Disc"> <li> <span class="Bold">Get emergency help right away if you take too much SUBSYS (overdose)</span> When you first start taking SUBSYS, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. </li> <li>Taking SUBSYS with other opioid medicines, that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.</li> <li>If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using SUBSYS. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain</li> <li>Never give anyone else your SUBSYS. They could die from taking it. Selling or giving away SUBSYS is against the law.</li> <li>Store SUBSYS securely, out of sight and reach of children, in a location not accessible by others, including visitors to the home.</li> <li>SUBSYS is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) <span class="Bold">R</span>isk <span class="Bold">E</span>valuation and <span class="Bold">M</span>itigation <span class="Bold">S</span>trategy (REMS) Access program. To receive SUBSYS, you must: <ul> <li>talk to your healthcare provider</li> <li>understand the benefits and risks of SUBSYS</li> <li>agree to all of the instructions</li> <li>sign the Patient-Prescriber Agreement form</li> </ul> </li> <li>SUBSYS is only available at pharmacies that are part of the TIRF REMS Access program. Your healthcare provider will let you know the pharmacy closest to your home where you can have your SUBSYS prescription filled.</li> <li>Be very careful about taking other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers.</li> <li>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Do not take SUBSYS if:</span> <ul class="Disc"> <li>You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for your cancer pain, and your body is used to these medicines.</li> <li>You have severe asthma, trouble breathing, or other lung problems.</li> <li>You have a bowel blockage or have narrowing of the stomach or intestines</li> <li>You have a short-term pain that you would expect to go away in a few days, such as: <ul> <li>pain after surgery</li> <li>headache or migraine</li> <li>dental pain</li> </ul> </li> <li>You have an allergy to any of the ingredients in SUBSYS: <ul> <li>Active ingredient: fentanyl</li> <li>Inactive ingredients: dehydrated alcohol 63.6%, purified water, propylene glycol, xylitol, and L-menthol.</li> </ul> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Before taking SUBSYS, tell your healthcare provider if you have a history of:</span> <ul class="Disc"> <li> <span class="Bold">Trouble breathing or lung problems such as asthma, wheezing, or shortness of breath</span> </li> <li>head injury, seizures</li> <li>liver, kidney, thyroid problems</li> <li>problems urinating</li> <li>pancreas or gallbladder problems</li> <li>abuse of street or prescription drugs, alcohol addiction</li> <li>mental problems including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)</li> <li>Slow heart rate or other heart problems</li> <li>Low blood pressure</li> </ul> <span class="Bold">Tell your healthcare provider if you are:</span> <ul class="Disc"> <li> <span class="Bold">Pregnant or planning to become pregnant.</span> Prolonged use of SUBSYS during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. </li> <li> <span class="Bold">Breastfeeding.</span> SUBSYS passes into breast milk and may harm your baby. </li> <li>Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking SUBSYS with certain other medicines can cause serious side effects that could lead to death.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">When taking SUBSYS:</span> <ul class="Disc"> <li>Do not change your dose. Take SUBSYS exactly as prescribed by your healthcare provider.</li> <li>See the detailed Instructions for Use for information about how to take SUBSYS.</li> <li>Use SUBSYS exactly as prescribed by your healthcare provider. Do not use more than 2 doses of SUBSYS for each episode of breakthrough cancer pain. You must wait four hours before treating a new episode of breakthrough pain with SUBSYS.</li> <li>Your healthcare provider will prescribe a starting dose of SUBSYS that may be different than other fentanyl containing medicines you may have been taking.</li> <li>Do not stop taking SUBSYS without talking to your healthcare provider.</li> <li>After you stop taking SUBSYS, see the “Instructions for Use” section at the end of this Medication Guide for information about the right way to dispose of SUBSYS when no longer needed.</li> <li>Dispose of expired, unwanted or unused SUBSYS by following the “Disposing of SUBSYS”directions in the Instructions for Use. Visit www.fda.gov/drugdisposal for additional information on disposalof unsed medicines.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <ul class="Disc"> <li> <span class="Bold">DO NOT</span> drive or operate heavy machinery, until you know how SUBSYS affects you. SUBSYS can make you sleepy, dizzy, or lightheaded. </li> <li> <span class="Bold">DO NOT</span> drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with SUBSYS may cause you to overdose and die. </li> <li> <span class="Bold">DO NOT</span> Switch from SUBSYS to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of SUBSYS is not the same as the amount of fentanyl in other medicines that contain fentanyl. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">The possible side effects of SUBSYS:</span> <ul class="Disc"> <li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping, low red blood cell count, swelling of the arms, hands, legs, and feet. Call your healthcare provider if you have any of these symptoms and they are severe.</li> <li>Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.</li> </ul> <span class="Bold">Get emergency medical help if you have:</span> <ul class="Disc"> <li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li> </ul> <p class="First">These are not all the possible side effects of SUBSYS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class="Bold">For more information go to dailymed.nlm.nih.gov.</span> </p> <p>Manufactured by: <span class="Bold">Renaissance Lakewood, LLC, Lakewood, NJ 08701</span> </p> <p>Distributed by: <span class="Bold">West Therapeutic Development, LLC, Northbrook, IL, 60062, (1-844-452-9263)</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col width=\"82%\"/>\n<col width=\"18%\"/>\n</colgroup>\n<tfoot>\n<tr valign=\"top\">\n<td align=\"left\">\n<p class=\"First\">\n<span class=\"Bold\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</span>\n</p>\n</td><td align=\"right\">\n<p class=\"First\">Issued: 02/2020</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Medication Guide\n <br/>\n<br/>\n\t\t\tSUBSYS \n <span class=\"Sup\">®</span> (sub sis))\n <br/>\n<br/>\n\t\t\t(fentanyl) sublingual spray , CII \n </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Important information about SUBSYS:</span>\n<br/>\n<br/>\n<span class=\"Bold\">Do not use SUBSYS unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.\n <br/>\n<br/>\n\t\t\tKeep SUBSYS in a safe place away from children.\n <br/>\n<br/>\n\t\t\tGet emergency help right away if: \n </span>\n<ul>\n<li>\n<span class=\"Bold\">A child uses SUBSYS. SUBSYS can cause an overdose and death in any child who uses it.</span>\n</li>\n<li>\n<span class=\"Bold\">An adult who has not been prescribed SUSBYS uses it</span>\n</li>\n<li>\n<span class=\"Bold\">An adult who is not already taking opioids around-the-clock, uses SUBSYS</span>\n</li>\n</ul>\n<span class=\"Bold\">These are medical emergencies that can cause death.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">SUBSYS is:</span>\n<ul class=\"Disc\">\n<li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (18 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. SUBSYS is started only after you have been taking other opioid pain medicines and your body has become used to them ( you are opioid tolerant). Do not use SUBSYS if you are not opioid tolerant.</li>\n<li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">Important information about SUBSYS:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Get emergency help right away if you take too much SUBSYS (overdose)</span> When you first start taking SUBSYS, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.\n </li>\n<li>Taking SUBSYS with other opioid medicines, that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.</li>\n<li>If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using SUBSYS. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain</li>\n<li>Never give anyone else your SUBSYS. They could die from taking it. Selling or giving away SUBSYS is against the law.</li>\n<li>Store SUBSYS securely, out of sight and reach of children, in a location not accessible by others, including visitors to the home.</li>\n<li>SUBSYS is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) \n <span class=\"Bold\">R</span>isk \n <span class=\"Bold\">E</span>valuation and \n <span class=\"Bold\">M</span>itigation \n <span class=\"Bold\">S</span>trategy (REMS) Access program. To receive SUBSYS, you must:\n\t\t\t\t\n <ul>\n<li>talk to your healthcare provider</li>\n<li>understand the benefits and risks of SUBSYS</li>\n<li>agree to all of the instructions</li>\n<li>sign the Patient-Prescriber Agreement form</li>\n</ul>\n</li>\n<li>SUBSYS is only available at pharmacies that are part of the TIRF REMS Access program. Your healthcare provider will let you know the pharmacy closest to your home where you can have your SUBSYS prescription filled.</li>\n<li>Be very careful about taking other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers.</li>\n<li>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Do not take SUBSYS if:</span>\n<ul class=\"Disc\">\n<li>You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for your cancer pain, and your body is used to these medicines.</li>\n<li>You have severe asthma, trouble breathing, or other lung problems.</li>\n<li>You have a bowel blockage or have narrowing of the stomach or intestines</li>\n<li>You have a short-term pain that you would expect to go away in a few days, such as:\n\t\t\t\t\n <ul>\n<li>pain after surgery</li>\n<li>headache or migraine</li>\n<li>dental pain</li>\n</ul>\n</li>\n<li>You have an allergy to any of the ingredients in SUBSYS:\n\t\t\t\t\n <ul>\n<li>Active ingredient: fentanyl</li>\n<li>Inactive ingredients: dehydrated alcohol 63.6%, purified water, propylene glycol, xylitol, and L-menthol.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Before taking SUBSYS, tell your healthcare provider if you have a history of:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Trouble breathing or lung problems such as asthma, wheezing, or shortness of breath</span>\n</li>\n<li>head injury, seizures</li>\n<li>liver, kidney, thyroid problems</li>\n<li>problems urinating</li>\n<li>pancreas or gallbladder problems</li>\n<li>abuse of street or prescription drugs, alcohol addiction</li>\n<li>mental problems including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)</li>\n<li>Slow heart rate or other heart problems</li>\n<li>Low blood pressure</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Pregnant or planning to become pregnant.</span> Prolonged use of SUBSYS during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.\n </li>\n<li>\n<span class=\"Bold\">Breastfeeding.</span> SUBSYS passes into breast milk and may harm your baby.\n </li>\n<li>Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking SUBSYS with certain other medicines can cause serious side effects that could lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">When taking SUBSYS:</span>\n<ul class=\"Disc\">\n<li>Do not change your dose. Take SUBSYS exactly as prescribed by your healthcare provider.</li>\n<li>See the detailed Instructions for Use for information about how to take SUBSYS.</li>\n<li>Use SUBSYS exactly as prescribed by your healthcare provider. Do not use more than 2 doses of SUBSYS for each episode of breakthrough cancer pain. You must wait four hours before treating a new episode of breakthrough pain with SUBSYS.</li>\n<li>Your healthcare provider will prescribe a starting dose of SUBSYS that may be different than other fentanyl containing medicines you may have been taking.</li>\n<li>Do not stop taking SUBSYS without talking to your healthcare provider.</li>\n<li>After you stop taking SUBSYS, see the “Instructions for Use” section at the end of this Medication Guide for information about the right way to dispose of SUBSYS when no longer needed.</li>\n<li>Dispose of expired, unwanted or unused SUBSYS by following the “Disposing of SUBSYS”directions in the Instructions for Use. Visit www.fda.gov/drugdisposal for additional information on disposalof unsed medicines.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">DO NOT</span> drive or operate heavy machinery, until you know how SUBSYS affects you. SUBSYS can make you sleepy, dizzy, or lightheaded.\n </li>\n<li>\n<span class=\"Bold\">DO NOT</span> drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with SUBSYS may cause you to overdose and die.\n </li>\n<li>\n<span class=\"Bold\">DO NOT</span> Switch from SUBSYS to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of SUBSYS is not the same as the amount of fentanyl in other medicines that contain fentanyl.\n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">The possible side effects of SUBSYS:</span>\n<ul class=\"Disc\">\n<li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping, low red blood cell count, swelling of the arms, hands, legs, and feet. Call your healthcare provider if you have any of these symptoms and they are severe.</li>\n<li>Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.</li>\n</ul>\n<span class=\"Bold\">Get emergency medical help if you have:</span>\n<ul class=\"Disc\">\n<li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li>\n</ul>\n<p class=\"First\">These are not all the possible side effects of SUBSYS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. \n <span class=\"Bold\">For more information go to dailymed.nlm.nih.gov.</span>\n</p>\n<p>Manufactured by: \n <span class=\"Bold\">Renaissance Lakewood, LLC, Lakewood, NJ 08701</span>\n</p>\n<p>Distributed by: \n <span class=\"Bold\">West Therapeutic Development, LLC, Northbrook, IL, 60062, (1-844-452-9263)</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Child Safety Kit

{ "type": "p", "children": [], "text": "\nChild Safety Kit\n" }

The SUBSYS Child Safety Kit contains important information on the storage and handling of SUBSYS.

{ "type": "p", "children": [], "text": "The SUBSYS Child Safety Kit contains important information on the storage and handling of SUBSYS." }

The SUBSYS Child Safety Kit includes:

{ "type": "p", "children": [], "text": "The SUBSYS Child Safety Kit includes:" }

{ "type": "ul", "children": [ "a \n portable pouch (FIGURE A) and lock (FIGURE B) for you to keep a small supply of SUBSYS. Keep the rest of your SUBSYS in the locked storage space.\n\n\t\n \n\n\nFigure A\n\n\n\n\nFigure B\n\n", "a \n package of cabinet and drawer child safety latches (FIGURE C) to secure the storage space where SUBSYS is kept at home.\n\t\n \n\n\nFigure C\n\n", "Keep the pouch locked and away from children. \n (See FIGURE C) \n" ], "text": "" }

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

Before you use SUBSYS, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use SUBSYS the right way. Ask your healthcare provider or pharmacist if you have questions about the right way to use SUBSYS.

{ "type": "p", "children": [], "text": "Before you use SUBSYS, it is important that you read the \n Medication Guide and these \n Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use SUBSYS the right way. Ask your healthcare provider or pharmacist if you have questions about the right way to use SUBSYS.\n " }

What will I find in the SUBSYS package? Each SUBSYS Carton contains (See Figure D) :

{ "type": "p", "children": [], "text": "\nWhat will I find in the SUBSYS package?\n\n\nEach SUBSYS Carton contains \n (See \n Figure D) \n :\n " }

{ "type": "ul", "children": [ "individual blister packages containing spray units of SUBSYS", "a supply of small white disposal bags for use when disposing of used SUBSYS units and charcoal-lined disposal pouches", "a supply of charcoal-lined disposal pouches (wrapped in aluminum foil) for use when disposing of the contents of unused SUBSYS units\n\t\n \n\nCall West Therapeutic Development, LLC at 1-844-452-9263 for additional supplies of disposal bags and charcoal-lined disposal pouches.\n\n\n", "a Medication Guide (not shown)", "a Package Insert (not shown)" ], "text": "" }

{ "type": "ul", "children": [ "\nWhen you get an episode of breakthrough cancer pain, take the dose prescribed by your healthcare provider as follows: SUBSYS comes in individual blister packages. Do not open the blister package until you are ready to use it.\n\n\t\n \n\n\nFigure D\n\n", "Remove the SUBSYS spray unit from the blister package by cutting the dashed line with a pair of scissors. \n (See \n Figure E.) \n \n\n\n\nFigure E\n\n", "To correctly use SUBSYS:\n\t\n \nSwallow any saliva in your mouth\nHold the SUBSYS spray unit \n upright using your index and middle fingers and thumb. \n (See \n Figure F.) \n \n\n\n\nFigure F\n\n\nPoint the nozzle \n into your mouth and \n under your tongue. \n (See \n Figures G and \n H) \n \n\n\n\nFigure G\n\n\n\n\nFigure H\n\n\nSqueeze your fingers and thumb together to spray SUBSYS under your tongue. \n (See \n Figure I) \n \n\nHold the medicine under your tongue for \n 30-60 seconds. Do not spit out any medicine. Do not rinse your mouth.\n\t\t\n \n\n\nFigure I\n\n\nThe SUBSYS spray unit will remain locked after use. \n (See \n Figure J) \n \n\n\n\nFigure J\n\n\n\n" ], "text": "" }

Disposing of SUBSYS:

{ "type": "p", "children": [], "text": "\nDisposing of SUBSYS:\n" }

After using SUBSYS, dispose of the spray unit as follows:

{ "type": "p", "children": [], "text": "\nAfter using SUBSYS, dispose of the spray unit as follows:\n " }

{ "type": "ul", "children": [ "Place the used SUBSYS spray unit into one of the disposal bags provided in the carton containing the spray units. \n (See \n Figure K) \n \n\n\n\nFigure K\n\n", "Remove the backing from the adhesive strip.", "Fold the flap to seal the bag. \n (See \n Figure L) \n \n\n\n\nFigure L\n\n", "Discard in the trash out of the reach of children. \n (See \n Figure M) \n \n\n\n\nFigure M\n\n" ], "text": "" }

Do not ingest the contents of the bag.

{ "type": "p", "children": [], "text": "Do not ingest the contents of the bag." }

Disposal of any unused SUBSYS when no longer needed:

{ "type": "p", "children": [], "text": "\nDisposal of any unused SUBSYS when no longer needed:\n" }

Before you throw away the SUBSYS spray units, you must empty all of the medicine into the charcoal-lined disposal pouch. This protects others, especially children from harm . Charcoal-lined disposal pouches are supplied wrapped in an aluminum foil package.

{ "type": "p", "children": [], "text": "Before you throw away the SUBSYS spray units, you must empty all of the medicine into the charcoal-lined disposal pouch. This protects others, especially children from harm \n . Charcoal-lined disposal pouches are supplied wrapped in an aluminum foil package.\n" }

{ "type": "ul", "children": [ "Remove a charcoal-lined disposal pouch from the aluminum foil package by tearing open the package at the notch. \n (See \n Figures N) \n \n\n\n\nFigure N\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Remove the SUBSYS spray unit from the blister package by cutting the dashed line with a pair of scissors. \n (See \n Figure O) \n \n\n\n\nFigure O\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Hold the charcoal-lined disposal pouch with the opening facing up. Put the nozzle of the SUBSYS spray unit upside-down into the opening of the charcoal-lined disposal pouch. \n (See \n Figure P) \n \n\n\n\nFigure P\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Squeeze your fingers and thumb together to spray SUBSYS into the charcoal-lined disposal pouch.", "Dispose of the spray unit in a disposal bag. \n (See \n Figures K and \n L) \n \n", "\nRepeat steps O and P for each unused SUBSYS spray unit. The charcoal-lined disposal pouch may be used for disposing of the contents of up to 10 spray units.\n", "Make sure all unused spray units have been sprayed into a charcoal-lined disposal pouch.\n \n\n\tTo seal a used charcoal-lined disposal pouch, remove the backing from the adhesive strip. \n (See \n Figure Q) \n Fold the flap down and press to seal the charcoal-lined disposal pouch.\n\t\n \n\n\nFigure Q\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Place the sealed charcoal-lined disposal pouch into a disposal bag. \n (See \n Figure R) \n \n\n\n\nFigure R\n\n" ], "text": "" }

{ "type": "ul", "children": [ "To seal the disposal bag, remove the backing from the adhesive strip. Fold the flap down and press to seal.", "Discard the sealed disposal bag in the trash out of the reach of children. \n (See \n Figure S) \n \n\n\n\nFigure S\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Do not ingest the contents of the bag." ], "text": "" }

If you need help with disposal of SUBSYS, call Insys Therapeutics, Inc. at 1-877-978-2797 or call your local Drug Enforcement Agency (DEA) office.

{ "type": "p", "children": [], "text": "If you need help with disposal of SUBSYS, call Insys Therapeutics, Inc. at 1-877-978-2797 or call your local Drug Enforcement Agency (DEA) office." }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

Manufactured by: Renaissance Lakewood, LLC, Lakewood, NJ 08701

{ "type": "p", "children": [], "text": "Manufactured by:\n \n\nRenaissance Lakewood, LLC, Lakewood, NJ 08701\n " }

for: West Therapeutic Development, LLC, Northbrook, IL 60062

{ "type": "p", "children": [], "text": "for:\n \nWest Therapeutic Development, LLC, Northbrook, IL 60062\n " }

Revised February 2020

{ "type": "p", "children": [], "text": "Revised February 2020" }

SUB-MKT-19-005(a) 022020

{ "type": "p", "children": [], "text": "SUB-MKT-19-005(a)\n \n022020\n " }