Sufentanil Citrate Injection is indicated for intravenous administration in adults and pediatric patients:

{ "type": "p", "children": [], "text": "Sufentanil Citrate Injection is indicated for intravenous administration in adults and pediatric patients:\n" }

{ "type": "ul", "children": [ "as an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated.\n", "as a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, in patients who are intubated and ventilated, such as cardiovascular surgery or neurosurgical procedures in the sitting position, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated.\n" ], "text": "" }

Sufentanil Citrate Injection is indicated for epidural administration:

{ "type": "p", "children": [], "text": "Sufentanil Citrate Injection is indicated for epidural administration:\n" }

{ "type": "ul", "children": [ "as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine usually during labor and vaginal delivery.\n" ], "text": "" }

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

In patients administered high doses of Sufentanil Citrate Injection, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression.

For purposes of administering small volumes of Sufentanil Citrate Injection accurately, the use of a tuberculin syringe or equivalent is recommended.

As with other potent opioids, the respiratory depressant effect of sufentanil 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 Sufentanil 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 (5.5)].

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

Sufentanil Citrate may be administered intravenously by slow injection or infusion.

Adjunct to general anesthesia:

<div class="scrollingtable"><table> <caption> <span>Table 1: Adult Dosage Range Chart, Analgesic Component to General Anesthesia, Intravenous Use </span> </caption> <col width="49.55%"/> <col width="1px"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Total dosage</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Maintenance dosage</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Duration of anesthesia 1 to 2 hours</span></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 1 to 2 mcg/kg</span> </p> <p>Approximately 75% or more of total sufentanil dosage may be administered prior to intubation by either slow injection or infusion titrated to individual patient response.</p> <p>Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required. </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental: 10 to 25 mcg (0.2 to 0.5 mL)</span> may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to remaining operative time anticipated.</p> <p> <span class="Bold">Infusion:</span> Intermittent or continuous infusion as needed in response to signs of lightening of analgesia.</p> <p>In absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.</p> <p>Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Duration of anesthesia 2 to 8 hours</span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 2 to 8 mcg/kg</span> </p> <p>Approximately 75% or less of the total calculated sufentanil dosage may be administered by slow injection or infusion prior to intubation, titrated to individual patient response.</p> <p>Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures in which endotracheal intubation and mechanical ventilation are required.<br/>At dosages in this range, sufentanil has been shown to provide some attenuation of sympathetic reflex activity in response to surgical stimuli, provide hemodynamic stability, and provide relatively rapid recovery. </p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental: 10 to 50 mcg (0.2 to 1 mL)</span> may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated.</p> <p> <span class="Bold">Infusion:</span> Intermittent or continuous infusion as needed in response to signs of lightening of analgesia.</p> <p>In the absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.</p> <p>Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. </p> </td> </tr> </tbody> </table></div>

Induction and Maintenance of Anesthesia

<div class="scrollingtable"><table> <caption> <span>Table 2: Dosage Range Chart, Induction and Maintenance of Anesthesia, Intravenous Use </span> </caption> <col width="49.55%"/> <col width="1px"/> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 8 to 30 mcg/kg</span> <br/>Generally administered as a slow injection, as an infusion, or as an injection followed by an infusion.</p> <p>Sufentanil with 100% oxygen and a muscle relaxant has been found to produce sleep at dosages ≥8 mcg/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents. The addition of N<span class="Sub">2</span>O to these dosages will reduce systolic blood pressure. At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated.</p> <p>Dosages of 25 to 30 mcg/kg have been shown to block sympathetic response including catecholamine release.</p> <p>High doses are indicated in patients undergoing major surgical procedures, in which endotracheal intubation and mechanical ventilation are required, such as cardiovascular surgery and neurosurgery in the sitting position with maintenance of favorable myocardial and cerebral oxygen balance.</p> <p>Postoperative observation is essential and postoperative mechanical ventilation may be required at the higher dosage range due to extended postoperative respiratory depression. </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Incremental:</span> Depending on the initial dose, maintenance doses of 0.5 to 10 mcg/kg may be administered by slow injection in anticipation of surgical stress such as incision, sternotomy or cardiopulmonary bypass.</p> <p> <span class="Bold">Infusion:</span> Sufentanil citrate may be administered by continuous or intermittent infusion as needed in response to signs of lightening of anesthesia.</p> <p>In the absence of lightening of anesthesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.</p> <p>The maintenance infusion rate for sufentanil should be based upon the induction dose so that the total dose for the procedure does not exceed 30 mcg/kg. </p> </td> </tr> </tbody> </table></div>

Proper placement of the needle or catheter in the epidural space should be verified before sufentanil citrate is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil, bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery.

Dosage for Labor and Delivery

Sufentanil Citrate Injection, USP 50 mcg/mL (equivalent to 50 mcg/mL sufentanil base).

{ "type": "p", "children": [], "text": "Sufentanil Citrate Injection, USP 50 mcg/mL (equivalent to 50 mcg/mL sufentanil base).\n" }

Sufentanil Citrate Injection is contraindicated in patients with:

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

{ "type": "ul", "children": [ "Hypersensitivity to sufentanil (e.g., anaphylaxis) [see Adverse Reactions (6.2)]\n" ], "text": "" }

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

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling Sufentanil 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. Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Sufentanil 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.

As with other potent opioids, the respiratory depressant effect of Sufentanil 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 epidural anesthetics, can alter respiration by blocking intercostal nerves [see Clinical Pharmacology (12.2)]. Sufentanil Citrate Injection can also alter respiration. Therefore, when Sufentanil 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 Sufentanil 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 Sufentanil Citrate Injection and when Sufentanil Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Sufentanil Citrate Injection are essential [see Dosage and Administration (2.1)].

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

Concomitant use of Sufentanil Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could result in lower than expected sufentanil plasma concentrations, and decrease efficacy. When using Sufentanil Citrate Injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the Sufentanil Citrate Injection dosage [see Dosage and Administration (2.1), Drug Interactions (7)].

Intravenous administration or unintentional intravascular injection during epidural administration of Sufentanil 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. Administration of sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. 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 Sufentanil Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

The incidence of skeletal muscle rigidity 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 sufentanil at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of sufentanil and a full paralyzing dose of a neuromuscular blocking agent when sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg).

The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. The hemodynamic effects and degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. High doses of pancuronium may produce increases in heart rate during sufentanil-oxygen anesthesia. Bradycardia and hypotension have been reported with other muscle relaxants during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of calcium channel and/or beta-blockers. Muscle relaxants with no clinically significant effect on heart rate (at recommended doses) would not counteract the vagotonic effect of sufentanil, therefore a lower heart rate would be expected. Rare reports of bradycardia associated with the concomitant use of succinylcholine and sufentanil have been reported.

When benzodiazepines or other CNS depressants are used with Sufentanil 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 Sufentanil Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Sufentanil 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 Sufentanil Citrate Injection with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).

If the decision is made to manage postoperative pain with Sufentanil Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Follow 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)].

Sufentanil 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, Sufentanil 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 Sufentanil Citrate Injection.

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Sufentanil Citrate Injection 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), 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 Sufentanil Citrate Injection if serotonin syndrome is suspected.

Proper placement of the needle or catheter in the epidural space should be verified before sufentanil is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil/ bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Sufentanil should be administered epidurally by slow injection.

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), Sufentanil 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.

Sufentanil 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.

Sufentanil 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 Sufentanil Citrate Injection therapy.

Sufentanil Citrate Injection 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 after Sufentanil Citrate Injection administration.

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.

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself.

Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes.

There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g. after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

The following adverse reactions have been identified during post approval use of sufentanil. 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 Sufentanil Citrate Injection.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Table 3 includes clinically significant drug interactions with Sufentanil Citrate Injection.

{ "type": "p", "children": [], "text": "Table 3 includes clinically significant drug interactions with Sufentanil Citrate Injection.\n" }

<div class="scrollingtable"><table> <caption> <span>Table 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection </span> </caption> <col/> <col/> <thead> <tr class="First Last"> <th class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Inhibitors of CYP3A4</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved <span class="Italics">[see Warnings and Precautions (<a href="#LINK_9141df29-8caf-4c77-be42-00c57474df39">5.4</a>)].</span> <br/>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.<br/>If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Rrule" valign="top">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" valign="top"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a">12.3</a>)],</span> resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class="Italics">[see Warnings and Precautions (<a href="#LINK_9141df29-8caf-4c77-be42-00c57474df39">5.4</a>)].</span> <br/>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class="Italics">[see Clinical Pharmacology (<a href="#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a">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 align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Rrule" valign="top">Rifampin, carbamazepine, phenytoin </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">The concomitant use of Sufentanil 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 Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">As postoperative analgesia, start with a lower dose of Sufentanil 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="#LINK_26e282a4-ab42-4dc5-83f7-a34e1806c8ce">5.5</a>)].</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="justify" class="Botrule Rrule" valign="top">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" valign="top"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">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_26e282a4-ab42-4dc5-83f7-a34e1806c8ce">5.5</a>].</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Rrule" valign="top">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), 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" valign="top"><span class="Bold">Monoamine Oxidase Inhibitors</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (<a href="#LINK_af7ece1e-6c2d-4d1e-86fe-c080eeff4752">5.2</a>)].</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Rrule" valign="top">Phenelzine, tranylcypromine, linezolid </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">Avoid concomitant use. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Rrule" valign="top">Butorphanol, nalbuphine, pentazocine, buprenorphine </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary. </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Diuretics</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">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" colspan="2" valign="top"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">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="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs. </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Nitrous oxide</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Rrule" valign="top">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection. </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Rrule" valign="top">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<caption>\n<span>Table 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection\n</span>\n</caption>\n<col/>\n<col/>\n<thead>\n<tr class=\"First Last\">\n<th class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Inhibitors of CYP3A4</span></th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"First\">\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_9141df29-8caf-4c77-be42-00c57474df39\">5.4</a>)].</span>\n<br/>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a\">12.3</a>)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.<br/>If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a\">12.3</a>)],</span> resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_9141df29-8caf-4c77-be42-00c57474df39\">5.4</a>)].</span>\n<br/>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#LINK_2e4ccae8-1588-4d33-aeeb-b8a75f66ad1a\">12.3</a>)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Rifampin, carbamazepine, phenytoin\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">The concomitant use of Sufentanil 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 Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">As postoperative analgesia, start with a lower dose of Sufentanil 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=\"#LINK_26e282a4-ab42-4dc5-83f7-a34e1806c8ce\">5.5</a>)].</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"justify\" class=\"Botrule Rrule\" valign=\"top\">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\" valign=\"top\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">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_26e282a4-ab42-4dc5-83f7-a34e1806c8ce\">5.5</a>].</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Rrule\" valign=\"top\">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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Monoamine Oxidase Inhibitors</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_af7ece1e-6c2d-4d1e-86fe-c080eeff4752\">5.2</a>)].</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Phenelzine, tranylcypromine, linezolid\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Avoid concomitant use.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Butorphanol, nalbuphine, pentazocine, buprenorphine\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs.\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Nitrous oxide</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection.\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Sufentanil Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose. No malformations were observed in either rats or rabbits at doses below the human procedural dose [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 to 4% and 15 to 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 (5.3)].

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. Sufentanil 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 Sufentanil 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.

The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume).

Data

Animal Data

Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group).

Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or 0.9 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group).

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54 times the human procedural dose of 30 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps.

Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/day based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sufentanil Citrate Injection and any potential adverse effects on the breastfed infant from Sufentanil Citrate Injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Sufentanil Citrate Injection through breast milk should be monitored 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

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 (6.2)].

The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug.

Elderly patients (aged 65 years or older) may have increased sensitivity to sufentanil. 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 Sufentanil Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Sufentanil 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.

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

Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance.

Sufentanil Citrate Injection contains sufentanil, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Sufentanil Citrate Injection can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

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.

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

Risks Specific to Abuse of Sufentanil Citrate Injection

Abuse of Sufentanil Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Sufentanil Citrate Injection with alcohol and other central nervous system 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 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 (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Clinical Presentation

Acute overdose with Sufentanil Citrate Injection 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, 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 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 sufentanil overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to sufentanil overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in Sufentanil Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. 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.

Sufentanil Citrate Injection, is an opioid agonist, available as a solution containing 50 mcg/mL eq. of sufentanil base, adjusted to pH 3.5 to 6.0. The chemical name is N-[4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide: 2-hydroxy-1,2,3-propanetricarboxylate (1:1). The molecular weight is 578.68. It has the following chemical structure.

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Sufentanil Citrate Injection, is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or epidural injection.

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Sufentanil is an opioid agonist. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl.

Effects on the Central Nervous System

Sufentanil 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.

Sufentanil 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

Sufentanil 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

Sufentanil 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. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)].

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 minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids [see Dosage and Administration (2.1, 2.2)]. The minimum effective analgesic concentration of sufentanil 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 sufentanil 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, 2.2, 2.3)].

Sufentanil Citrate Injection is administered by the intravenous or epidural route. The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model.

Absorption

After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants.

Distribution

Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes.

Elimination

The elimination half-life is 164 minutes in adults. The elimination half-life of sufentanil is shorter (e.g. 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g. 434 +/- 160 minutes) compared to that of adolescents and adults.

Metabolism

The liver and small intestine are the major sites of biotransformation.

Excretion

Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

Carcinogenesis

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

Mutagenesis

Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay.

Impairment of Fertility

Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rates were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself.

Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes.

There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g. after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

Sufentanil Citrate Injection, USP is a sterile aqueous, preservative-free solution, containing 50 mcg/mL eq. of sufentanil base, for intravenous and epidural use, supplied as:

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   1 mL (50 mcg) ampuls packaged in 10s (NDC 0641-6110-10)

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   2 mL (100 mcg) ampuls packaged in 10s (NDC 0641-6111-10)

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   5 mL (250 mcg) ampuls packaged in 10s (NDC 0641-6112-10)

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Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.

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Manufactured by:

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WEST-WARD

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A HIKMA COMPANY

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Eatontown, NJ 07724 USA

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Revised August 2018

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462-303-02

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NDC 0641-6110-01 Sufentanil Citrate Inj., USP      CII50 mcg/mL      Rx only(0.05 mg/mL) sufentanil 1 mL Ampul FOR IV AND EPIDURAL USEPROTECT FROM LIGHT.

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NDC 0641-6110-10

{ "type": "p", "children": [], "text": "NDC 0641-6110-10\n" }

NDC 0641-6111-01   Rx only Sufentanil Citrate Injection, USP      CII100 mcg/2 mL     PRESERVATIVE-FREE50 mcg/mL (0.05 mg/mL) sufentanil 2 mL Ampul FOR IV AND EPIDURAL USEPROTECT FROM LIGHT.

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NDC 0641-6111-10

{ "type": "p", "children": [], "text": "NDC 0641-6111-10" }

NDC 0641-6112-01 Sufentanil Citrate Injection, USP      CII250 mcg/5 mL      Rx only50 mcg/mL (0.05 mg/mL) sufentanil 5 mL Ampul FOR IV AND EPIDURAL USE PRESERVATIVE-FREE PROTECT FROM LIGHT.

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NDC 0641-6112-10

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Sufentanil Citrate Injection is indicated for intravenous administration in adults and pediatric patients:

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Sufentanil Citrate Injection is indicated for epidural administration:

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

In patients administered high doses of Sufentanil Citrate Injection, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression.

For purposes of administering small volumes of Sufentanil Citrate Injection accurately, the use of a tuberculin syringe or equivalent is recommended.

As with other potent opioids, the respiratory depressant effect of sufentanil 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 Sufentanil 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.

Sufentanil Citrate may be administered intravenously by slow injection or infusion.

Adjunct to general anesthesia:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Adult Dosage Range Chart, Analgesic Component To General Anesthesia, Intravenous Use</span> </caption> <col width="50%"/> <col width="50%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Total dosage</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Maintenance dosage</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Duration of anesthesia 1 to 2 hours</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 1 to 2 mcg/kg</span> <br/>Approximately 75% or more of total sufentanil dosage may be administered prior to intubation by either slow injection or infusion titrated to individual patient response.<br/> <br/>Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental: 10 to 25 mcg (0.2 to 0.5 mL) </span>may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to remaining operative time anticipated.<br/> <br/> <span class="Bold">Infusion: </span>Intermittent or continuous infusion as needed in response to signs of lightening of analgesia.<br/> <br/>In absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.<br/> <br/>Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Duration of anesthesia 2 to 8 hours</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 2 to 8 mcg/kg</span> <br/>Approximately 75% or less of the total calculated sufentanil dosage may be administered by slow injection or infusion prior to intubation, titrated to individual patient response.<br/> <br/>Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures in which endotracheal intubation and mechanical ventilation are required.<br/> <br/>At dosages in this range, sufentanil has been shown to provide some attenuation of sympathetic reflex activity in response to surgical stimuli, provide hemodynamic stability, and provide relatively rapid recovery.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Incremental: 10 to 50 mcg (0.2 to 1 mL) </span>may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated.<br/> <br/> <span class="Bold">Infusion: </span>Intermittent or continuous infusion as needed in response to signs of lightening of analgesia.<br/> <br/>In the absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.<br/> <br/>Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time.</p> </td> </tr> </tbody> </table></div>

Induction And Maintenance Of Anesthesia

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Dosage Range Chart, Induction and Maintenance of Anesthesia, Intravenous Use</span> </caption> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Incremental or Infusion: 8 to 30 mcg/kg</span> <br/>Generally administered as a slow injection, as an infusion, or as an injection followed by an infusion.<br/> <br/>Sufentanil with 100% oxygen and a muscle relaxant has been found to produce sleep at dosages ≥8 mcg/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents. The addition of N<span class="Sub">2</span>O to these dosages will reduce systolic blood pressure. At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated.<br/> <br/>Dosages of 25 to 30 mcg/kg have been shown to block sympathetic response including catecholamine release.<br/> <br/>High doses are indicated in patients undergoing major surgical procedures, in which endotracheal intubation and mechanical ventilation are required, such as cardiovascular surgery and neurosurgery in the sitting position with maintenance of favorable myocardial and cerebral oxygen balance.<br/> <br/>Postoperative observation is essential and postoperative mechanical ventilation may be required at the higher dosage range due to extended postoperative respiratory depression.</p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Incremental: </span>Depending on the initial dose, maintenance doses of 0.5 to 10 mcg/kg may be administered by slow injection in anticipation of surgical stress such as incision, sternotomy or cardiopulmonary bypass.<br/> <br/> <span class="Bold">Infusion: </span>Sufentanil citrate may be administered by continuous or intermittent infusion as needed in response to signs of lightening of anesthesia.<br/> <br/>In the absence of lightening of anesthesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation.<br/> <br/>The maintenance infusion rate for sufentanil should be based upon the induction dose so that the total dose for the procedure does not exceed 30 mcg/kg.</p> </td> </tr> </tbody> </table></div>

Proper placement of the needle or catheter in the epidural space should be verified before sufentanil citrate is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil, bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery.

Dosage for Labor and Delivery

Sufentanil Citrate Injection, USP 50 mcg/mL (equivalent to 50 mcg/mL sufentanil base).

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Sufentanil Citrate Injection is contraindicated in patients with:

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Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance. As an opioid, Sufentanil 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 Sufentanil 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. Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Sufentanil 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.

As with other potent opioids, the respiratory depressant effect of Sufentanil 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 epidural anesthetics, can alter respiration by blocking intercostal nerves [see Clinical Pharmacology (12.2)]. Sufentanil Citrate Injection can also alter respiration. Therefore, when Sufentanil 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 Sufentanil 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 Sufentanil Citrate Injection and when Sufentanil Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Sufentanil 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 Sufentanil 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 Sufentanil Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Sufentanil 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 Sufentanil 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 Sufentanil 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 Sufentanil 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 sufentanil and prolong opioid adverse reactions, which may exacerbate fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Sufentanil Citrate Injection-treated patients may increase sufentanil plasma concentrations and prolong opioid adverse reactions. When using Sufentanil Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Sufentanil Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Sufentanil Citrate Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

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

Intravenous administration or unintentional intravascular injection during epidural administration of Sufentanil 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. Administration of sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. 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 Sufentanil Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

The incidence of skeletal muscle rigidity 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 sufentanil at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of sufentanil and a full paralyzing dose of a neuromuscular blocking agent when sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg).

The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. The hemodynamic effects and degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. High doses of pancuronium may produce increases in heart rate during sufentanil-oxygen anesthesia. Bradycardia and hypotension have been reported with other muscle relaxants during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of calcium channel and/or beta-blockers. Muscle relaxants with no clinically significant effect on heart rate (at recommended doses) would not counteract the vagotonic effect of sufentanil, therefore a lower heart rate would be expected. Rare reports of bradycardia associated with the concomitant use of succinylcholine and sufentanil have been reported.

Sufentanil 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, Sufentanil 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 Sufentanil 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 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), Warnings and Precautions (5.2)].‎

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of sufentanil 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 Sufentanil Citrate Injection if serotonin syndrome is suspected.

Proper placement of the needle or catheter in the epidural space should be verified before sufentanil is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil/bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Sufentanil should be administered epidurally by slow injection.

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), Sufentanil Citrate Injection 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 Sufentanil Citrate Injection. Opioids may also obscure the clinical course in a patient with a head injury.

Sufentanil 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.

Sufentanil 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 Sufentanil Citrate Injection therapy.

Sufentanil Citrate Injection 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 Sufentanil Citrate Injection and know how they will react to the medication.

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.

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself.

Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes.

There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g., after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

The following adverse reactions have been identified during post approval use of sufentanil. 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 Sufentanil 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: 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 Sufentanil Citrate Injection.

{ "type": "p", "children": [], "text": "Table 3 includes clinically significant drug interactions with Sufentanil Citrate Injection." }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection</span> </caption> <col width="30%"/> <col width="70%"/> <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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.4)</a>]</span>.<br/> <br/>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients at frequent intervals for respiratory depression and sedation.<br/> <br/>If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Examples:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.4)</a>]</span>.<br/> <br/>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Examples:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of Sufentanil Citrate Injection with CNS depressants my 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 Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2</a>, <a href="#ID_6ba564bf-915e-4370-a8fa-52b7dec44b36">5.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">As postoperative analgesia, start with a lower dose of Sufentanil 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 </span><span class="Italics"><a href="#ID_6ba564bf-915e-4370-a8fa-52b7dec44b36">Warnings and Precautions (5.3)</a></span><span class="Italics">]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Examples:</span></span> </p> </td><td class="Botrule Rrule" 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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></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 </span><span class="Italics"><a href="#S5.7">Warnings and Precautions (5.8)</a></span><span class="Italics">].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></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 Sufentanil Citrate Injection if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Examples:</span></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 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="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see <a href="#S5.2">Warnings and Precautions (5.2)</a>].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The use of Sufentanil Citrate Injection 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="Bold"><span class="Italics">Examples:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Examples:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></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 Sufentanil 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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></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 class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil 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">Nitrous oxide</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Clinical Impact:</span></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 Sufentanil Citrate Injection.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Intervention:</span></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 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection</span>\n</caption>\n<col width=\"30%\"/>\n<col width=\"70%\"/>\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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved <span class=\"Italics\">[see <a href=\"#S5.3\">Warnings and Precautions (5.4)</a>]</span>.<br/>\n<br/>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients at frequent intervals for respiratory depression and sedation.<br/>\n<br/>If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (12.3)</a>]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class=\"Italics\">[see <a href=\"#S5.3\">Warnings and Precautions (5.4)</a>]</span>.<br/>\n<br/>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of Sufentanil Citrate Injection with CNS depressants my 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 Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class=\"Italics\">[see <a href=\"#S5.2\">Warnings and Precautions (5.2</a>, <a href=\"#ID_6ba564bf-915e-4370-a8fa-52b7dec44b36\">5.3</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">As postoperative analgesia, start with a lower dose of Sufentanil 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 </span><span class=\"Italics\"><a href=\"#ID_6ba564bf-915e-4370-a8fa-52b7dec44b36\">Warnings and Precautions (5.3)</a></span><span class=\"Italics\">]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" 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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></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 </span><span class=\"Italics\"><a href=\"#S5.7\">Warnings and Precautions (5.8)</a></span><span class=\"Italics\">].</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\"><span class=\"Italics\">Intervention:</span></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 Sufentanil Citrate Injection if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></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 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=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see <a href=\"#S5.2\">Warnings and Precautions (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=\"Bold\"><span class=\"Italics\">Intervention:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">The use of Sufentanil 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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Examples:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></span>\n</p>\n</td><td class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">Sufentanil 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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></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 Sufentanil 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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Clinical Impact:</span></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 class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></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 Sufentanil 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\">Nitrous oxide</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\"><span class=\"Italics\">Clinical Impact:</span></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 Sufentanil Citrate Injection.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\"><span class=\"Italics\">Intervention:</span></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 Sufentanil Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose. No malformations were observed in either rats or rabbits at doses below the human procedural dose [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 [see Warnings and Precautions (5.4)].

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. Sufentanil 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 Sufentanil 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.

The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume).

Data

Animal Data

Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group).

Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or 0.9 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group).

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54 times the human procedural dose of 30 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps.

Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/day based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sufentanil Citrate Injection and any potential adverse effects on the breastfed infant from Sufentanil Citrate Injection or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to Sufentanil Citrate Injection 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)].

The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug.

Elderly patients (aged 65 years or older) may have increased sensitivity to sufentanil. 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 Sufentanil Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Sufentanil 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.

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

Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance.

Sufentanil Citrate Injection contains sufentanil, 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 Sufentanil 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 Sufentanil 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 Sufentanil Citrate Injection abuse include those ‎with a history of prolonged use of any opioid, including products containing sufentanil, those ‎with a history of drug or alcohol abuse, or those who use Sufentanil ‎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.‎

Sufentanil 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 that help to limit abuse of opioid drugs.‎

Risks Specific to Abuse of Sufentanil Citrate Injection

Abuse of Sufentanil Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Sufentanil 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 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.

Sufentanil Citrate Injection should not be abruptly discontinued in a ‎physically-dependent patient. If Sufentanil 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 sufentanil 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 sufentanil overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in Sufentanil Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. 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.

Sufentanil Citrate Injection, USP is a sterile, nonpyrogenic solution of sufentanil citrate in water for injection. Sufentanil Citrate is a potent opioid analgesic which is administered either epidurally or by intravenous injection.

{ "type": "p", "children": [], "text": "Sufentanil Citrate Injection, USP is a sterile, nonpyrogenic solution of sufentanil citrate in water for injection. Sufentanil Citrate is a potent opioid analgesic which is administered either epidurally or by intravenous injection." }

Each mL contains sufentanil citrate equivalent to 50 mcg of sufentanil. May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 4.2 (3.5 to 6.0).

{ "type": "p", "children": [], "text": "Each mL contains sufentanil citrate equivalent to 50 mcg of sufentanil. May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 4.2 (3.5 to 6.0)." }

The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-use injection. When smaller doses are required, the unused portion should be discarded in an appropriate manner.

{ "type": "p", "children": [], "text": "The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-use injection. When smaller doses are required, the unused portion should be discarded in an appropriate manner." }

Sufentanil Citrate, USP, occurs as a white crystalline powder and is chemically designated as N-[-4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1).

{ "type": "p", "children": [], "text": "Sufentanil Citrate, USP, occurs as a white crystalline powder and is chemically designated as N-[-4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1)." }

The molecular formula of sufentanil citrate is C22H30N2O2S∙C6H8O7 and the molecular weight is 578.69. Sufentanil Citrate has the following structural formula:

{ "type": "p", "children": [], "text": "The molecular formula of sufentanil citrate is C22H30N2O2S∙C6H8O7 and the molecular weight is 578.69. Sufentanil Citrate has the following structural formula:" }

Sufentanil is an opioid agonist. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl.

Effects on the Central Nervous System

Sufentanil 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.

Sufentanil 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

Sufentanil 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

Sufentanil 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. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)].

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 minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists [see Dosage and Administration (2.1, 2.2)]. The minimum effective analgesic concentration of sufentanil 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 sufentanil 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, 2.2, 2.3)].

Sufentanil Citrate Injection is administered by the intravenous or epidural route. The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model.

Absorption

After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants.

Distribution

Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes.

Elimination

The elimination half-life is 164 minutes in adults. The elimination half-life of sufentanil is shorter (e.g., 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g., 434 +/- 160 minutes) compared to that of adolescents and adults.

Metabolism

The liver and small intestine are the major sites of biotransformation.

Excretion

Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

Carcinogenesis

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

Mutagenesis

Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay.

Impairment of Fertility

Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rated were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself.

Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes.

There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g., after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

Protect from light. Retain in carton until time of use.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Addiction, Abuse, and Misuse

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

Inform patients that the use of Sufentanil 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 Sufentanil 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 Sufentanil 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 Sufentanil 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 (5.8), 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 (5.8), 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 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)]." }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

LAB-1124-11.0

{ "type": "p", "children": [], "text": "LAB-1124-11.0" }

1 mL Single-doseNDC 0409-3382-11Preservative-FreeRx only

{ "type": "p", "children": [], "text": "1 mL Single-doseNDC 0409-3382-11Preservative-FreeRx only" }

SUFENTANIL CITRATEInjection, USP

{ "type": "p", "children": [], "text": "SUFENTANIL CITRATEInjection, USP" }

50 mcg/mL

{ "type": "p", "children": [], "text": "50 mcg/mL" }

CII

{ "type": "p", "children": [], "text": "CII" }

For Intravenous and Epidural Use.

{ "type": "p", "children": [], "text": "For Intravenous and Epidural Use." }

Distributed by Hospira, Inc.,Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc.,Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

1 mL10 Single-dose Fliptop VialsPreservative-Free

{ "type": "p", "children": [], "text": "1 mL10 Single-dose Fliptop VialsPreservative-Free" }

Rx onlyNDC 0409-3382-21Contains 10 of NDC 0409-3382-11

{ "type": "p", "children": [], "text": "Rx onlyNDC 0409-3382-21Contains 10 of NDC 0409-3382-11" }

Protect from light.Retain in cartonuntil time of use.

{ "type": "p", "children": [], "text": "Protect from light.Retain in cartonuntil time of use." }

CII

{ "type": "p", "children": [], "text": "CII" }

SUFENTANIL CITRATE Inj., USP50 mcg/mL*

{ "type": "p", "children": [], "text": "SUFENTANIL CITRATE Inj., USP50 mcg/mL*" }

For Intravenous and Epidural Use.

{ "type": "p", "children": [], "text": "For Intravenous and Epidural Use." }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

2 mL Single-doseNDC 0409-3382-12

{ "type": "p", "children": [], "text": "2 mL Single-doseNDC 0409-3382-12" }

Preservative-FreeRx only

{ "type": "p", "children": [], "text": "Preservative-FreeRx only" }

SUFENTANILCITRATE Inj., USP

{ "type": "p", "children": [], "text": "SUFENTANILCITRATE Inj., USP" }

CII

{ "type": "p", "children": [], "text": "CII" }

100 mcg/2 mL (50 mcg/mL)

{ "type": "p", "children": [], "text": "100 mcg/2 mL (50 mcg/mL)" }

For Intravenous and Epidural Use.

{ "type": "p", "children": [], "text": "For Intravenous and Epidural Use." }

Distributed by Hospira, Inc.,Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc.,Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

2 mL 10 Single-doseFliptop VialsPreservative-Free

{ "type": "p", "children": [], "text": "2 mL 10 Single-doseFliptop VialsPreservative-Free" }

Rx onlyNDC 0409-3382-22Contains 10 of NDC 0409-3382-12

{ "type": "p", "children": [], "text": "Rx onlyNDC 0409-3382-22Contains 10 of NDC 0409-3382-12" }

Protect from light. Retain in carton until time of use.

{ "type": "p", "children": [], "text": "Protect from light. Retain in carton until time of use." }

CII

{ "type": "p", "children": [], "text": "CII" }

SUFENTANIL CITRATE Inj., USP100 mcg/2 mL (50 mcg/mL)*

{ "type": "p", "children": [], "text": "SUFENTANIL CITRATE Inj., USP100 mcg/2 mL (50 mcg/mL)*" }

For Intravenous and Epidural Use.

{ "type": "p", "children": [], "text": "For Intravenous and Epidural Use." }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

5 mL Single-dosePreservative-FreeNDC 0409-3382-15

{ "type": "p", "children": [], "text": "5 mL Single-dosePreservative-FreeNDC 0409-3382-15" }

SUFENTANIL CITRATEInjection, USP

{ "type": "p", "children": [], "text": "SUFENTANIL CITRATEInjection, USP" }

CII

{ "type": "p", "children": [], "text": "CII" }

250 mcg/5 mL(50 mcg/mL)

{ "type": "p", "children": [], "text": "250 mcg/5 mL(50 mcg/mL)" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

For Intravenousand EpiduralUse. Protectfrom light.Retain incarton untiltime of use.

{ "type": "p", "children": [], "text": "For Intravenousand EpiduralUse. Protectfrom light.Retain incarton untiltime of use." }

Distributed byHospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed byHospira, Inc., Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

5 mL 10 Single-dose Fliptop VialsPreservative-Free

{ "type": "p", "children": [], "text": "5 mL 10 Single-dose Fliptop VialsPreservative-Free" }

Rx onlyNDC 0409-3382-25Contains 10 of NDC 0409-3382-15

{ "type": "p", "children": [], "text": "Rx onlyNDC 0409-3382-25Contains 10 of NDC 0409-3382-15" }

SUFENTANIL CITRATE Inj., USPCII250 mcg/5 mL (50 mcg/mL)*

{ "type": "p", "children": [], "text": "SUFENTANIL CITRATE Inj., USPCII250 mcg/5 mL (50 mcg/mL)*" }

Protect from light. Retain in carton until time of use.For Intravenous and Epidural Use.

{ "type": "p", "children": [], "text": "Protect from light. Retain in carton until time of use.For Intravenous and Epidural Use." }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

Hospira

{ "type": "p", "children": [], "text": "Hospira" }

DSUVIA is indicated for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

{ "type": "p", "children": [], "text": "DSUVIA is indicated for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate." }

Limitations of Use:

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

{ "type": "ul", "children": [ "Not for home use or for use in children. Discontinue treatment with DSUVIA before patients leave the certified medically supervised healthcare setting. ", "Not for use for more than 72 hours. The use of DSUVIA beyond 72 hours has not been studied.", "Only to be administered by a healthcare provider.", "\nBecause of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.3)], reserve DSUVIA for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):\n" ], "text": "" }

- Have not been tolerated, or are not expected to be tolerated,

{ "type": "p", "children": [], "text": "- Have not been tolerated, or are not expected to be tolerated," }

- Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

{ "type": "p", "children": [], "text": "- Have not provided adequate analgesia, or are not expected to provide adequate analgesia." }

DSUVIA is only to be administered by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

DSUVIA is only to be used in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments.

DSUVIA treatment must be discontinued prior to the patient leaving the certified medically supervised setting.

The recommended dosage of DSUVIA is 30 mcg sublingually as needed with a minimum of 1 hour between doses. Do not exceed 12 tablets in 24 hours.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve the use of additional doses of DSUVIA for patients in whom a single dose is insufficiently effective and in whom the expected benefits of using additional doses of an opioid clearly outweigh the substantial risks.

The maximum cumulative daily dose of sufentanil is 360 mcg or 12 tablets (12 tablets x 30 mcg/dose).

Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addition, abuse, and misuse [see Warnings and Precautions (5.1)].

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following additional doses of DSUVIA. Consider this risk when initiating dosing and when making dose adjustments [see Warnings and Precautions (5)].

• Single-use product / Do not reuse. • Do not use if pouch seal is broken. • Do not use if the Single-Dose Applicator (SDA) is damaged. • Wear gloves when administering DSUVIA. • Instruct the patient to not chew or swallow the tablet. • Instruct the patient to not eat or drink and minimize talking for 10 minutes after receiving the tablet. If a patient experiences excessive dry mouth, ice chips should be provided prior to administration of DSUVIA. Administration Instructions

Sublingual tablets: DSUVIA is a single 30 mcg sufentanil tablet housed in a disposable, single-dose applicator (SDA). The tablet is blue-colored, flat-faced with rounded edges and is 3 mm in diameter.

{ "type": "p", "children": [], "text": "Sublingual tablets: DSUVIA is a single 30 mcg sufentanil tablet housed in a disposable, single-dose applicator (SDA). The tablet is blue-colored, flat-faced with rounded edges and is 3 mm in diameter." }

Use of DSUVIA is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.4)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)] • Known hypersensitivity to sufentanil or components of DSUVIA [see Adverse Reactions (6.1, 6.2)].

{ "type": "p", "children": [], "text": "Use of DSUVIA is contraindicated in patients with: \n• Significant respiratory depression [see Warnings and Precautions (5.4)]\n\n• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)]\n\n• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]\n\n• Known hypersensitivity to sufentanil or components of DSUVIA [see Adverse Reactions (6.1, 6.2)].\n" }

Accidental ingestion or exposure to even one dose of DSUVIA, especially in children, can result in respiratory depression and death due to an overdose of sufentanil.

DSUVIA is for use in adult patients only in a certified medically supervised healthcare setting. Use of DSUVIA outside of this setting can increase the risk of accidental exposure in others for whom it is not prescribed, causing fatal respiratory depression. Discontinue use of DSUVIA prior to discharge or transfer from the certified medically supervised healthcare setting. DSUVIA is not for home or pediatric use.

Following accidental ingestion of DSUVIA, monitor patients for opioid-related adverse events, such as respiratory depression.

Because of the potential for life-threatening respiratory depression due to accidental exposure, DSUVIA is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the DSUVIA REMS Program.

The goal of the DSUVIA REMS is to mitigate the risk of respiratory depression resulting from accidental exposure by: • Ensuring that DSUVIA is dispensed only to patients in certified medically supervised healthcare settings. 

The requirements of the DSUVIA REMS are as follows:

• Healthcare settings that dispense DSUVIA must:         - Be able to manage an acute opioid overdose including respiratory depression         - Train all relevant staff that DSUVIA must not be dispensed for use outside of the certified healthcare setting         - Train all relevant staff involved in administration of DSUVIA to refer to the Directions for Use prior to administration         - Establish processes and procedures to verify that DSUVIA is not dispensed for use outside of the certified healthcare setting.

• Wholesalers that distribute DSUVIA must:         - Establish processes and procedures to ensure that DSUVIA is distributed only to certified medically supervised healthcare settings.            - Distribute only to certified medically supervised healthcare settings.

Further information about the DSUVIA REMS Program is available at www.DSUVIAREMS.com, or by calling 1-855-925-8476.

DSUVIA contains sufentanil, a Schedule II controlled substance. As an opioid, DSUVIA 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 DSUVIA. 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 DSUVIA, and monitor all patients receiving DSUVIA 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 DSUVIA but use in such patients necessitates intensive counseling about the risks and proper use of DSUVIA along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing DSUVIA. 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. 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 DSUVIA, the risk is greatest during the initiation of therapy. Monitor patients closely for respiratory depression while on treatment with DSUVIA.

Accidental exposure to or ingestion of even one dose of DSUVIA, especially in children, can result in respiratory depression and death due to an overdose of sufentanil.

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 minimizing the use of DSUVIA and carefully monitor the patient for signs of respiratory depression [see Dosage and Administration (2.2)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DSUVIA with benzodiazepines 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. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

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.

Concomitant use of DSUVIA 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 sufentanil and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.4)], particularly when an inhibitor is added after a stable dose of DSUVIA is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DSUVIA-treated patients may increase sufentanil plasma concentrations and prolong opioid adverse reactions. When using DSUVIA with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DSUVIA-treated patients, monitor patients closely at frequent intervals for respiratory depression and sedation [see Drug Interactions (7)].

Concomitant use of DSUVIA with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease sufentanil plasma concentrations, decrease opioid efficacy or, possibly lead to a withdrawal syndrome in a patient who had developed physical dependence to sufentanil. When using DSUVIA with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals for adequate analgesia and for symptoms of opioid withdrawal [see Drug Interactions (7)].

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).

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of sufentanil, the active opioid ingredient of DSUVIA, 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 (e.g., 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 at the recommended dosage.

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 DSUVIA if serotonin syndrome is suspected.

The use of DSUVIA 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: DSUVIA-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 the recommended dosage of DSUVIA [see Warnings and Precautions (5.4)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely; particularly when initiating DSUVIA and when DSUVIA is used concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.4)]. 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 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.

DSUVIA 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)]. Monitor these patients for signs of hypotension after initiating DSUVIA. In patients with circulatory shock, DSUVIA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DSUVIA 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), DSUVIA 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 DSUVIA.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DSUVIA in patients with impaired consciousness or coma. DSUVIA is not suitable for use in patients who are not alert and able to follow directions.

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

The sufentanil in DSUVIA 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 sufentanil in DSUVIA 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 DSUVIA therapy.

DSUVIA may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with DSUVIA.

Use of opioids 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)].

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. In controlled and uncontrolled studies, the safety of DSUVIA was evaluated in a total of 646 patients with moderate-to-severe acute postoperative pain or pain due to trauma which required opioid analgesia. The most frequently reported adverse reactions ≥ 2% that were probably or possibly related to study treatment in the one pivotal, placebo-controlled trial (Study SAP301) are presented in Table 1. Discontinuation of study drug due to adverse events occurred in 0.9% of DSUVIA-treated patients (1 out of 107 patients) and 3.7% of placebo-treated patients (2 out of 54 placebo treated patients). The most common reasons for discontinuation of study drug due to adverse reactions in SAP301 were oxygen saturation decreased (0.9% in the DSUVIA group), and dizziness, hemiparesis, somnolence and syncope in the placebo group (1.9% each).    Table 1: Adverse Reactions Occurring in ≥ 2% of Patients and for Which Rate is Higher in DSUVIA than Placebo Group: Placebo-Controlled Study SAP301

<div class="scrollingtable"><table> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> <br/> <span class="Bold">Possibly or Probably Related <br/> Adverse Reactions </span></span> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> <br/> <span class="Bold">DSUVIA <br/> n=107 </span></span> <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold"> <br/> <span class="Bold">Placebo * <br/> n=54 </span></span> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Nausea  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule">29.0%  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 22.2% <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Headache  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 12.1% <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule">11.1%  <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Vomiting  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 5.6% <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule">1.9%  <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> Dizziness <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 5.6% <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule"> 3.7% <br/> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule">Hypotension  <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule">4.7% <br/> </td><td align="center" class="Botrule Lrule Rrule Toprule">3.7% <br/> </td> </tr> </tbody> </table></div>

*Morphine 1 mg IV was permitted as rescue medication

Other Reported Adverse Reactions Additional treatment related adverse drug reactions which occurred in at least 0.1% of the patients exposed to 30 mcg or higher of sublingual sufentanil are described below. Cardiac Disorders: sinus tachycardia, bradycardia. Gastrointestinal Disorders: constipation, dyspepsia, flatulence, diarrhea, dry mouth, eructation, retching, abdominal discomfort, abdominal distension, abdominal pain upper, gastritis, postoperative ileus, hypoesthesia oral. Investigations: oxygen saturation decreased, respiratory rate decreased, urine output decreased, aspartate aminotransferase increased, electrocardiogram abnormal, hepatic enzyme increased. Musculoskeletal and Connective Tissue Disorders: muscle spasms. Nervous System Disorders: somnolence, sedation, presyncope, lethargy, memory impairment. Psychiatric Disorders: insomnia, confusional state, anxiety, agitation, disorientation, euphoric mood, hallucination, mental status changes. Renal and Urinary Disorders: urinary retention, urinary hesitation, oliguria, renal failure. Respiratory, Thoracic and Mediastinal Disorders: hypoxia, bradypnea, hiccups, apnea, atelectasis, hypoventilation, respiratory distress, respiratory failure. Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, rash. Vascular Disorders: hypotension, hypertension, orthostatic hypotension, flushing.

The following adverse reactions have been identified during post-approval use of sufentanil. 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 DSUVIA.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time.

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

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 2 includes clinically significant drug interactions with DSUVIA.    Table 2: Clinically Significant Drug Interactions with DSUVIA

{ "type": "p", "children": [], "text": "\nTable 2 includes clinically significant drug interactions with DSUVIA. \n \nTable 2: Clinically Significant Drug Interactions with DSUVIA \n\n" }

<div class="scrollingtable"><table> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Inhibitors of CYP3A4</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact: </span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">The concomitant use of DSUVIA and CYP3A4 inhibitors can increase the plasma concentration of  sufentanil, resulting in increased or prolonged opioid effects. <br/> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease<span class="Italics"> [see Clinical Pharmacology (</span><span class="Italics"><span class="Bold"><span class="Italics"><span class="Bold"><a href="#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92">12.3</a></span></span></span></span><span class="Italics">)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention: </span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor patients for respiratory depression and sedation at frequent intervals. <br/> If a CYP3A4 inhibitor is discontinued, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples: </span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole),  protease inhibitors (e.g., ritonavir) <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">CYP3A4 Inducers</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">The concomitant use of DSUVIA and CYP3A4 inducers can decrease the plasma concentration of sufentanil<span class="Italics"> [see </span><span class="Italics">Clinical Pharmacology (</span><span class="Italics"><span class="Bold"><span class="Italics"><span class="Bold"><a href="#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92">12.3</a></span></span></span></span><span class="Italics">)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class="Italics">[see </span><span class="Italics">Warnings and Precautions (<span class="Bold"><a href="#LINK_d7f2e2de-0ced-4e9c-a5e2-bd9dcd2a7451">5.6</a></span></span><span class="Italics">)]</span>. <br/> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class="Italics">[see </span><span class="Italics">Clinical Pharmacology (</span><span class="Italics"><span class="Bold"><span class="Italics"><span class="Bold"><a href="#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92">12.3</a></span></span></span></span><span class="Italics">)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention: </span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider less frequent dosing of DSUVIA and monitor for signs of respiratory depression. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples: </span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Rifampin, carbamazepine, phenytoin <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Benzodiazepines and other Central Nervous System (CNS) Depressants <span class="Italics"> <br/> </span></span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics"> Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see </span><span class="Italics">Warnings and Precautions (<span class="Bold"><a href="#LINK_b5ffeaf6-fac9-4942-a993-d318b33564bf">5.5</a></span></span><span class="Italics">)]</span>. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">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">.</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids. <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Serotonergic Drugs <span class="Italics"> <br/> </span></span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics"> Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">The concomitant use of opioids with other drugs that affect the serotonergic <br/> neurotransmitter system has resulted in serotonin syndrome<span class="Italics"> [see </span><span class="Italics">Warnings and Precautions (</span><span class="Italics"><span class="Bold"><span class="Italics"><span class="Bold"><a href="#LINK_4136cad9-cf23-4d05-90b2-99392564cefe">5.8</a></span></span></span></span><span class="Italics">)]</span>. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DSUVIA if serotonin syndrome is suspected. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">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 (e.g., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs) </span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see </span><span class="Italics">Warnings and Precautions (<span class="Bold"><a href="#LINK_7a4edc11-08c7-412a-aedb-3f011b98e81d">5.4</a></span></span><span class="Italics">)].</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">The use of DSUVIA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">phenelzine, tranylcypromine, linezolid <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics <span class="Italics"> <br/> </span></span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics"> Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">May reduce the analgesic effect of DSUVIA and/or precipitate withdrawal symptoms. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Avoid concomitant use. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Butorphanol, nalbuphine, pentazocine, buprenorphine <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Muscle Relaxants</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Because respiratory depression may be greater than otherwise expected, decrease the dosage of the muscle relaxant as necessary or consider discontinuing use of DSUVIA.  <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Diuretics</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Anticholinergic Drugs</span> <br/> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. <br/> </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span> <br/> </td><td class="Botrule Lrule Rrule Toprule" valign="top">Monitor patients for signs of urinary retention or reduced gastric motility when DSUVIA is used concomitantly with anticholinergic drugs. <br/> </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\" valign=\"top\"><span class=\"Bold\">Inhibitors of CYP3A4</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact: </span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The concomitant use of DSUVIA and CYP3A4 inhibitors can increase the plasma concentration of  sufentanil, resulting in increased or prolonged opioid effects. <br/>\n After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease<span class=\"Italics\"> [see Clinical Pharmacology (</span><span class=\"Italics\"><span class=\"Bold\"><span class=\"Italics\"><span class=\"Bold\"><a href=\"#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92\">12.3</a></span></span></span></span><span class=\"Italics\">)]</span>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention: </span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor patients for respiratory depression and sedation at frequent intervals. <br/>\n If a CYP3A4 inhibitor is discontinued, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples: </span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole),  protease inhibitors (e.g., ritonavir) <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">CYP3A4 Inducers</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The concomitant use of DSUVIA and CYP3A4 inducers can decrease the plasma concentration of sufentanil<span class=\"Italics\"> [see </span><span class=\"Italics\">Clinical Pharmacology (</span><span class=\"Italics\"><span class=\"Bold\"><span class=\"Italics\"><span class=\"Bold\"><a href=\"#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92\">12.3</a></span></span></span></span><span class=\"Italics\">)]</span>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil <span class=\"Italics\">[see </span><span class=\"Italics\">Warnings and Precautions (<span class=\"Bold\"><a href=\"#LINK_d7f2e2de-0ced-4e9c-a5e2-bd9dcd2a7451\">5.6</a></span></span><span class=\"Italics\">)]</span>. <br/>\n After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase <span class=\"Italics\">[see </span><span class=\"Italics\">Clinical Pharmacology (</span><span class=\"Italics\"><span class=\"Bold\"><span class=\"Italics\"><span class=\"Bold\"><a href=\"#LINK_ad5be186-618a-4f9f-a8d2-9e73dc730b92\">12.3</a></span></span></span></span><span class=\"Italics\">)]</span>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention: </span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">If concomitant use is necessary, consider an alternate medication that permits dose titration. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider less frequent dosing of DSUVIA and monitor for signs of respiratory depression. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples: </span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Rifampin, carbamazepine, phenytoin <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Benzodiazepines and other Central Nervous System (CNS) Depressants <span class=\"Italics\">\n<br/>\n</span></span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\"> Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class=\"Italics\">[see </span><span class=\"Italics\">Warnings and Precautions (<span class=\"Bold\"><a href=\"#LINK_b5ffeaf6-fac9-4942-a993-d318b33564bf\">5.5</a></span></span><span class=\"Italics\">)]</span>. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">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\">.</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids. <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Serotonergic Drugs <span class=\"Italics\">\n<br/>\n</span></span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\"> Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The concomitant use of opioids with other drugs that affect the serotonergic <br/>\n neurotransmitter system has resulted in serotonin syndrome<span class=\"Italics\"> [see </span><span class=\"Italics\">Warnings and Precautions (</span><span class=\"Italics\"><span class=\"Bold\"><span class=\"Italics\"><span class=\"Bold\"><a href=\"#LINK_4136cad9-cf23-4d05-90b2-99392564cefe\">5.8</a></span></span></span></span><span class=\"Italics\">)]</span>. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DSUVIA if serotonin syndrome is suspected. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">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 (e.g., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs) </span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see </span><span class=\"Italics\">Warnings and Precautions (<span class=\"Bold\"><a href=\"#LINK_7a4edc11-08c7-412a-aedb-3f011b98e81d\">5.4</a></span></span><span class=\"Italics\">)].</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The use of DSUVIA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">phenelzine, tranylcypromine, linezolid <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics <span class=\"Italics\">\n<br/>\n</span></span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\"> Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">May reduce the analgesic effect of DSUVIA and/or precipitate withdrawal symptoms. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Avoid concomitant use. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Butorphanol, nalbuphine, pentazocine, buprenorphine <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Muscle Relaxants</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of the muscle relaxant as necessary or consider discontinuing use of DSUVIA.  <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Diuretics</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. <br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Anticholinergic Drugs</span>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. <br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span>\n<br/>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Monitor patients for signs of urinary retention or reduced gastric motility when DSUVIA is used concomitantly with anticholinergic drugs. <br/>\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 (5.16)]. There are no available data with sufentanil in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 4.4 times the maximum human daily dose of 360 mcg/60 kg/day, based on a body surface area comparison during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human daily dose of 360 mcg. No malformations were observed in either rats or rabbits at doses below the human daily dose of 360 mcg [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 non-medical 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 (5.16)].

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. DSUVIA is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including DSUVIA, 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

Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group).

Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.2, 1.0, or 4.4 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group).

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.2, 1.4, or 2.8 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps.

Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.14, 0.6, or 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DSUVIA and any potential adverse effects on the breastfed infant from DSUVIA or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to DSUVIA 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. DSUVIA is not intended for chronic use [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

The safety and efficacy of the use of DSUVIA in pediatric patients has not been established. The ability of pediatric patients to comply with the sublingual dosing instructions for DSUVIA has not been evaluated.  Use of DSUVIA in younger children is not recommended as younger children may not be able to comply with the sublingual dosing instructions for DSUVIA and could swallow the tablet or spit it out, which could impact the efficacy and safety of DSUVIA.

No special population studies were performed using DSUVIA in elderly patients.

Of the 646 patients exposed to 30 mcg sufentanil or higher in the first hour of treatment, approximately 11% (72) of patients were ≥ 75 years of age and approximately 20% (126) patients were 65 to 75 years of age. The overall rate of adverse events and most common adverse events, such as nausea, tended to increase with age in patients who received sublingual sufentanil, although vomiting was less common in patients aged ≥ 75 years than in younger 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. As the dose of DSUVIA cannot be titrated, monitor geriatric patients closely for signs of central nervous system and respiratory depression or consider an alternate medication that can be titrated [see Warnings and Precautions (5.4)].

Because sufentanil is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Sufentanil and its metabolites are known to be excreted by the kidney. No significant changes have been observed in subjects with mild or moderate renal impairment.  Monitor closely for adverse events such as respiratory depression, sedation, and hypotension in patients with severe renal impairment [seeClinical Pharmacology (12.3)].

DSUVIA contains sufentanil citrate, a Schedule II controlled opioid agonist that can be abused and may produce drug dependence.

DSUVIA contains sufentanil, 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 (5.3)].

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 DSUVIA 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 DSUVIA 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 DSUVIA abuse include those with a history of prolonged use of any opioid, including products containing sufentanil, those with a history of drug or alcohol abuse, or those who use DSUVIA 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 health care 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.

DSUVIA, 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.

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 sufentanil 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 sufentanil 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 sufentanil 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 sufentanil overdose, administer an opioid antagonist. " }

Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in DSUVIA, 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 sufentanil in DSUVIA, 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." }

DSUVIA contains one 30 mcg sufentanil tablet housed in a disposable single-dose applicator (SDA). The DSUVIA tablet is an immediate release formulation intended for sublingual administration. Each tablet is blue, flat-faced with a diameter of 3 mm. The IUPAC chemical name for sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide citrate. Sufentanil citrate has a molecular weight of 578.4 (molecular weight of free sufentanil base is 386.55), its empirical formula is C 28H 38N 2O 9S ● C 6H 8N 2O 7, and its chemical structure is shown below:

{ "type": "p", "children": [], "text": "DSUVIA contains one 30 mcg sufentanil tablet housed in a disposable single-dose applicator (SDA). The DSUVIA tablet is an immediate release formulation intended for sublingual administration. Each tablet is blue, flat-faced with a diameter of 3 mm. \n The IUPAC chemical name for sufentanil is N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide citrate. Sufentanil citrate has a molecular weight of 578.4 (molecular weight of free sufentanil base is 386.55), its empirical formula is C 28H 38N 2O 9S ● C 6H 8N 2O 7, and its chemical structure is shown below: " }

DSUVIA tablets inactive ingredients are: mannitol; dicalcium phosphate anhydrous; hypromellose; croscarmellose sodium; FD&C Blue #2; stearic acid and magnesium stearate.

{ "type": "p", "children": [], "text": " DSUVIA tablets inactive ingredients are: mannitol; dicalcium phosphate anhydrous; hypromellose; croscarmellose sodium; FD&C Blue #2; stearic acid and magnesium stearate." }

Sufentanil is an opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principle therapeutic action of sufentanil is analgesia and sedation, thought to be mediated through opioid-specific receptors throughout the CNS.  Like all full opioid agonists, there is no ceiling effect to analgesia.

Effects on the Central Nervous System Sufentanil 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. Sufentanil 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 Sufentanil 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 Sufentanil 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.  They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. 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.

Effects on the Respiratory System All opioid mu-receptor agonists, including DSUVIA, 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. Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with DSUVIA in the clinical trial, sufentanil given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration [see Warnings and Precautions (5.4)].

Absorption A single sublingual administration of DSUVIA has a bioavailability of approximately 53% relative to a one-minute IV sufentanil infusion of 30 mcg. Compared to IV administration, sublingual Cmax values were 17-fold lower. The sublingual route of administration of sufentanil avoids intestinal and hepatic first-pass effects, both which severely limit bioavailability of swallowed (oral) sufentanil sublingual tablet (9%). Following a single dose of DSUVIA, the mean AUC0-inf is 278 h*pg/mL, the average Cmax of 63.1 pg/mL occurs at a median Tmax of 1.00 hour. After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC0-60min) and Cmax values were increased by 3.7-fold and 2.3-fold greater compared to single-dose administration, respectively. Steady-state plasma concentrations were achieved after 7 doses (Figure 1).    Figure 1: Sufentanil Concentration-Time Values: Single vs. Consecutive Repeat Doses (12 DSUVIA Doses)

Distribution Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates.

Elimination Following a single dose of DSUVIA, the mean terminal half-life is 13.4 hours, and the mean apparent plasma clearance is 108 L/hour.  Metabolism: The liver and small intestine are the major sites of biotransformation  Excretion: Approximately 80% of the IV administered dose of sufentanil is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Specific Populations Clearance is not significantly affected by race, sex, mild or moderate renal impairment based on the population pharmacokinetics. Drug Interaction Study Co-administration of a single dose of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC0-inf and Cmax values of sufentanil, respectively, compared to its administration alone.

Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis: Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micro-nucleus assay. Impairment of Fertility Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rates were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.6 and 2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (2.2 times the maximum human daily dose of 360 mcg/60 kg, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

The efficacy and safety of DSUVIA were evaluated in one randomized, double-blind, placebo-controlled trial which enrolled 161 patients (age 18 to 69 years) with acute postoperative pain (pain intensity of ≥ 4 on a 0-10 Numeric Rating Scale [NRS]) after abdominal surgery (studied up to 48 hours) (Study SAP301, NCT# 02356588).  Patients were dosed with DSUVIA 30 mcg or placebo as needed with a minimum of 60 minutes between doses.  Morphine sulfate 1 mg IV was available as rescue medication. The primary efficacy endpoint was the time-weighted summed pain intensity difference over 12 hours (SPID12). Patients using DSUVIA had a statistically significantly higher SPID12 than patients using placebo.  Least squares means of pain intensity difference from baseline over 24 hours for the abdominal surgery study are shown in Figure 2. Median time to onset of meaningful pain relief (measured using the double stopwatch method) was 54 minutes for the DSUVIA group and 84 minutes for the placebo group. Approximately 22% of patients in the DSUVIA group and 65% of patients in the placebo group took rescue medication within the first 12 hours of the treatment phase.     Figure 2: Least Squares Mean of Pain Intensity Difference by Evaluation Time Point over the 24-Hour Study Period: Abdominal Surgery ITT Population

{ "type": "p", "children": [], "text": "The efficacy and safety of DSUVIA were evaluated in one randomized, double-blind, placebo-controlled trial which enrolled 161 patients (age 18 to 69 years) with acute postoperative pain (pain intensity of ≥ 4 on a 0-10 Numeric Rating Scale [NRS]) after abdominal surgery (studied up to 48 hours) (Study SAP301, NCT# 02356588).  Patients were dosed with DSUVIA 30 mcg or placebo as needed with a minimum of 60 minutes between doses.  Morphine sulfate 1 mg IV was available as rescue medication. \n\nThe primary efficacy endpoint was the time-weighted summed pain intensity difference over 12 hours (SPID12). Patients using DSUVIA had a statistically significantly higher SPID12 than patients using placebo.  Least squares means of pain intensity difference from baseline over 24 hours for the abdominal surgery study are shown in Figure 2. Median time to onset of meaningful pain relief (measured using the double stopwatch method) was 54 minutes for the DSUVIA group and 84 minutes for the placebo group. Approximately 22% of patients in the DSUVIA group and 65% of patients in the placebo group took rescue medication within the first 12 hours of the treatment phase.   \n\n Figure 2: Least Squares Mean of Pain Intensity Difference by Evaluation Time Point over the 24-Hour Study Period: Abdominal Surgery ITT Population \n\n" }

PID = pain intensity difference; ITT = intent-to-treat; LS = least squares; SEM = standard error of the mean

{ "type": "p", "children": [], "text": "PID = pain intensity difference; ITT = intent-to-treat; LS = least squares; SEM = standard error of the mean" }

Each DSUVIA tablet 30 mcg is housed in a single-dose applicator (SDA) and packaged within a tamper-evident laminate foil pouch. For distribution there is one presentation: • NDC 61621-430-11 (10 pouches per carton) The SDA should be disposed in biohazard waste after administration of DSUVIA. Instruct the healthcare provider to take steps to store DSUVIA securely and to dispose of any dropped or misplaced DSUVIA tablets according to institutional CII procedures.

Store DSUVIA at room temperature 20-25 ºC, excursions allowed 15-30 ºC in a secure, limited access location, in accordance with institutional procedures for CII products.

Increased Risk of Overdose and Death in Children Due to Accidental Exposure

{ "type": "p", "children": [], "text": "\nIncreased Risk of Overdose and Death in Children Due to Accidental Exposure\n" }

Inform patients that accidental exposure, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients that accidental exposure, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.1)]." }

Addiction, Abuse, and Misuse

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

Inform patients that the use of DSUVIA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.4)]. Instruct patients not to share DSUVIA with others and to take steps to protect DSUVIA from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of DSUVIA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.4)]. Instruct patients not to share DSUVIA with others and to take steps to protect DSUVIA 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 DSUVIA [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting DSUVIA [see Warnings and Precautions (5.4)]. " }

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), and Adverse Reactions (6.2)].

{ "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), and Adverse Reactions (6.2)]." }

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 physicians if they are taking, or plan to take serotonergic medications. [see Warnings and Precautions (5.8), and 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 physicians if they are taking, or plan to take serotonergic medications. [see Warnings and Precautions (5.8), and Drug Interactions (7)]." }

Important Administration Instructions

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions\n" }

Advise patients to allow DSUVIA to dissolve under the tongue and not to chew or swallow the tablet. Advise patients not to eat or drink and to minimize talking for 10 minutes after each dose of DSUVIA.

{ "type": "p", "children": [], "text": "Advise patients to allow DSUVIA to dissolve under the tongue and not to chew or swallow the tablet. Advise patients not to eat or drink and to minimize talking for 10 minutes after each dose of DSUVIA." }

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 (5.10)].

{ "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 (5.10)]." }

Hypotension

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

Inform patients that DSUVIA 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 Contraindications (4), and Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Inform patients that DSUVIA 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 Contraindications (4), and Warnings and Precautions (5.11)]." }

Anaphylaxis

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

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

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

Pregnancy

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

Embryo-Fetal Toxicity

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

Inform female patients of reproductive potential that DSUVIA can (or may) cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential that DSUVIA can (or may) cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.3)]." }

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)]." }

Marketed By: AcelRx Pharmaceuticals, Inc., Hayward, CA

{ "type": "p", "children": [], "text": "\nMarketed By: AcelRx Pharmaceuticals, Inc., Hayward, CA" }

PL-6410 Rev E

{ "type": "p", "children": [], "text": "PL-6410 Rev E" }

SUFENTANIL CARTON

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

SUFENTANIL CONTAINER POUCH BACK FOLDOUT

{ "type": "p", "children": [], "text": "\nSUFENTANIL CONTAINER POUCH BACK FOLDOUT \n\n" }

SUFENTANIL CONTAINER POUCH BACK BASE PANEL SUFENTANIL CONTAINER POUCH FRONT

{ "type": "p", "children": [], "text": "\n SUFENTANIL CONTAINER POUCH BACK BASE PANEL \n\n\n\nSUFENTANIL CONTAINER POUCH FRONT \n\n\n" }