Morphine Sulfate Injection, is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

{ "type": "p", "children": [], "text": "Morphine Sulfate Injection, is indicated for the management of 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" }

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1)], reserve Morphine Sulfate Injection for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or opioid combination products):

{ "type": "p", "children": [], "text": "\nBecause of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.1)], reserve Morphine Sulfate Injection for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or opioid combination products):\n" }

{ "type": "ul", "children": [ "\nHave not been tolerated, or are not expected to be tolerated\n", "\nHave not provided adequate analgesia, or are not expected to provide adequate analgesia\n" ], "text": "" }

Morphine Sulfate Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

{ "type": "p", "children": [], "text": "\nMorphine Sulfate Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.\n" }

Direct Intravenous Injection

Use the lowest dose necessary to achieve adequate analgesia.

Adults: Initiate treatment in a dosing range of 0.1 mg to 0.2 mg per kg every 4 hours as needed to manage pain. Administer the injection slowly.

Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Injection. Individually titrate Morphine Sulfate Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1), (5.14)]. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed, (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

When a patient who has been taking Morphine Sulfate Injection regularly and may be physically dependent no longer requires therapy with Morphine Sulfate Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Morphine Sulfate Injection in a physically-dependent patient [see WARNINGS AND PRECAUTIONS (5.14), DRUG ABUSE AND DEPENDENCE (9.3)].

Single Dose 1 mL Syringes:

{ "type": "p", "children": [], "text": "\nSingle Dose 1 mL Syringes:\n" }

Morphine Sulfate Injection is available as 2 mg/mL, 4 mg/mL, sterile solution in single dose prefilled syringes for intravenous (IV) administration.

{ "type": "p", "children": [], "text": "Morphine Sulfate Injection is available as 2 mg/mL, 4 mg/mL, sterile solution in single dose prefilled syringes for intravenous (IV) administration." }

Morphine Sulfate Injection is contraindicated in patients with:

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

{ "type": "ul", "children": [ "Significant respiratory depression [see WARNINGS AND PRECAUTIONS (5.2)]\n", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS AND PRECAUTIONS (5.7)]\n", "Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see WARNINGS AND PRECAUTIONS (5.8)]\n", "Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS AND PRECAUTIONS (5.12)]\n", "Hypersensitivity to morphine (e.g., anaphylaxis) [see ADVERSE REACTIONS (6)]\n" ], "text": "" }

Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Injection 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 Morphine Sulfate Injection. 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 Morphine Sulfate Injection, and monitor all patients receiving morphine sulfate for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Morphine Sulfate Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Injection 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. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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 Morphine Sulfate Injection, the risk is greatest during the initiation of therapy or following a dosage increase. Because of a delay in the maximum CNS effect with intravenously administered Morphine Sulfate Injection (30 min), rapid administration may result in overdosing. The respiratory depression may be severe and could require intervention [see OVERDOSAGE (10)].

To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Injection are essential [see DOSAGE AND ADMINISTRATION (2.3)]. Overestimating the Morphine Sulfate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

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 (2.3)].

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

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

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

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

Use of Morphine Sulfate Injection 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 management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)]

While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines. Have naloxone injection and resuscitative equipment immediately available for use in case of life-threatening or intolerable side effects and whenever morphine therapy is being initiated.

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 (2.4); Warnings and Precautions (5.14)].

The use of Morphine Sulfate Injection 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:

Morphine Sulfate Injection-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Morphine Sulfate Injection [see WARNINGS AND PRECAUTIONS (5.2)].

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

Monitor such patients closely, particularly when initiating and titrating Morphine Sulfate Injection and when Morphine Sulfate Injection is given concomitantly with other drugs that depress respiration [see WARNINGS AND PRECAUTIONS (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

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

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

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

Morphine Sulfate Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in Morphine Sulfate Injection 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 morphine in Morphine Sulfate Injection 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 Morphine Sulfate Injection therapy.

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Sulfate Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Morphine Sulfate Injection in a physically-dependent patient, gradually taper the dosage [see DOSAGE AND ADMINISTRATION (2.4)]. Do not abruptly discontinue Morphine Sulfate Injection in these patients [see DRUG ABUSE AND DEPENDENCE (9.3)].

Morphine Sulfate 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 Morphine Sulfate Injection and know how they will react to the medication.

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

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

{ "type": "ul", "children": [ "Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS (5.1)]\n", "Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS (5.2)]\n", "Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS (5.3)]\n", "Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS (5.4)]", "Cardiovascular Instability [see WARNINGS AND PRECAUTIONS (5.5)]\n", "Opioid-Induced Hyperalgesia and Allodynia [see WARNINGS AND PRECAUTIONS (5.6)]\n", "Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS (5.9)]\n", "Severe Hypotension [see WARNINGS AND PRECAUTIONS (5.10)]\n", "Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS (5.12)]\n", "Seizures [see WARNINGS AND PRECAUTIONS (5.13)]\n", "Withdrawal [see WARNINGS AND PRECAUTIONS (5.14)]\n" ], "text": "" }

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

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

Serious adverse reactions associated with Morphine Sulfate Injection included respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously.

{ "type": "p", "children": [], "text": "Serious adverse reactions associated with Morphine Sulfate Injection included respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously." }

The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, constipation, and diaphoresis.

{ "type": "p", "children": [], "text": "The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, constipation, and diaphoresis." }

Other possible adverse reactions included:

{ "type": "p", "children": [], "text": "Other possible adverse reactions included:" }

Central Nervous System – Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations and disorientation.

{ "type": "p", "children": [], "text": "\nCentral Nervous System – Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations and disorientation." }

Gastrointestinal – Constipation, biliary tract spasm.

{ "type": "p", "children": [], "text": "\nGastrointestinal – Constipation, biliary tract spasm." }

Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, and orthostatic hypotension.

{ "type": "p", "children": [], "text": "\nCardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, and orthostatic hypotension." }

Genitourinary – Oliguria and urinary retention; an antidiuretic effect has been reported.

{ "type": "p", "children": [], "text": "\nGenitourinary – Oliguria and urinary retention; an antidiuretic effect has been reported." }

Allergic – Pruritus, urticaria, and skin rashes. Anaphylactoid reactions have been reported following intravenous administration.

{ "type": "p", "children": [], "text": "\nAllergic – Pruritus, urticaria, and skin rashes. Anaphylactoid reactions have been reported following intravenous administration." }

Other – Opioid-induced histamine release may be responsible for the flushing of the face, diaphoresis, and pruritus often seen with these drugs. Wheals and urticaria at the site of injection are probably related to histamine release. Local tissue irritation, pain and induration have been reported following repeated subcutaneous injection. Morphine may alter temperature regulation in susceptible individuals and will depress the cough reflex.

{ "type": "p", "children": [], "text": "\nOther – Opioid-induced histamine release may be responsible for the flushing of the face, diaphoresis, and pruritus often seen with these drugs. Wheals and urticaria at the site of injection are probably related to histamine release. Local tissue irritation, pain and induration have been reported following repeated subcutaneous injection. Morphine may alter temperature regulation in susceptible individuals and will depress the cough reflex." }

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

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

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

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Injection.

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

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

{ "type": "p", "children": [], "text": "\nAndrogen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY (12.2)].\n" }

 Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "\n Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)].\n" }

 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).

{ "type": "p", "children": [], "text": "\n 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 1 includes clinically significant drug interactions with Morphine Sulfate Injection.

{ "type": "p", "children": [], "text": "Table 1 includes clinically significant drug interactions with Morphine Sulfate Injection." }

Table 1:  Clinically Significant Drug Interactions with Morphine Sulfate Injection

{ "type": "p", "children": [], "text": "\nTable 1:  Clinically Significant Drug Interactions with Morphine Sulfate Injection\n" }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="490.5pt"> <col width="490.5pt"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see Warnings and Precautions (<a href="#LINK_d1d65c8f-9d12-4aae-9b7f-16ae08a2a210">5.3</a>)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <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 Toprule" colspan="2"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.  Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">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_c8b8d3fc-5227-484d-bd41-23b0d55f692b">5.2</a>, <a href="#LINK_9a40a87c-352b-4c5f-8ccd-543f1f82c2e6">5.8</a>)].</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of <span class="Underline">other</span> opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">phenelzine, tranylcypromine, linezolid</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">butorphanol, nalbuphine, pentazocine, buprenorphine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Morphine 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 Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Cimetidine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Concomitant administration of Morphine Sulfate Injection and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an</p> <p>isolated report.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <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 Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <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 Toprule" colspan="2"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <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 Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Oral P2Y<span class="Sub">12 </span>Inhibitors</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">The co-administration of oral P2Y<span class="Sub">12</span> inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y<span class="Sub">12</span> inhibitors and delay the onset of the antiplatelet effect.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">clopidogrel, prasugrel, ticagrelor</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"490.5pt\">\n<col width=\"490.5pt\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class=\"Italics\">[see Warnings and Precautions (<a href=\"#LINK_d1d65c8f-9d12-4aae-9b7f-16ae08a2a210\">5.3</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\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 Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.  Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\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 WARNINGS AND PRECAUTIONS (<a href=\"#LINK_c8b8d3fc-5227-484d-bd41-23b0d55f692b\">5.2</a>, <a href=\"#LINK_9a40a87c-352b-4c5f-8ccd-543f1f82c2e6\">5.8</a>)].</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of <span class=\"Underline\">other</span> opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">phenelzine, tranylcypromine, linezolid</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">butorphanol, nalbuphine, pentazocine, buprenorphine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Morphine 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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Cimetidine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Concomitant administration of Morphine Sulfate Injection and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an</p>\n<p>isolated report.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\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 Toprule\" colspan=\"2\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\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 Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Oral P2Y<span class=\"Sub\">12 </span>Inhibitors</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">The co-administration of oral P2Y<span class=\"Sub\">12</span> inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y<span class=\"Sub\">12</span> inhibitors and delay the onset of the antiplatelet effect.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">clopidogrel, prasugrel, ticagrelor</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS (5.4)]. There are no available data with Morphine Sulfate Injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal 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 signs 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. Morphine Sulfate Injection is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations.  However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions.  The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Injection, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

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

Clinical Considerations

Monitor infants exposed to Morphine Sulfate Injection, through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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 CLINICAL PHARMACOLOGY 12.2)].

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see NONCLINICAL TOXICOLOGY (13)].

The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established.

The pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial elderly patients (aged 65 years or older) may have increased sensitivity to morphine. 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 Morphine Sulfate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see WARNINGS AND PRECAUTIONS (5.7)].

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

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see CLINICAL PHARMACOLOGY (12.3)].

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see CLINICAL PHARMACOLOGY (12.3)].

Morphine Sulfate Injection contains morphine, a Schedule II controlled substance.

Morphine Sulfate Injection contains morphine, 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 to other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Morphine Sulfate 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 Morphine Sulfate 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 Morphine Sulfate Injection abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use Morphine Sulfate 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.

Morphine Sulfate 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 Morphine Sulfate Injection

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

Morphine Sulfate Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.4)]. If Morphine Sulfate 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

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Acute overdose with Morphine Sulfate 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)].

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Treatment of Overdose

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In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ 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.

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

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

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In an individual physically dependent on opioids, administration of the recommended 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 begin with care and by titration with smaller than usual doses of the antagonist.

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Morphine is a phenanthrene-derivative opiate agonist. It is the principal alkaloid of opium and is considered to be the prototype of the opiate agonists.

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Morphine sulfate occurs as white, feathery, silky crystals; cubical masses of crystals; or a white, crystalline powder.

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When exposed to air it gradually loses water of hydration, and darkens on prolonged exposure to light. It is soluble in water and ethanol at room temperature. The chemical name of morphine sulfate is 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula:

{ "type": "p", "children": [], "text": "When exposed to air it gradually loses water of hydration, and darkens on prolonged exposure to light. It is soluble in water and ethanol at room temperature. The chemical name of morphine sulfate is 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula:" }

 (C17H19NO3)2•H2SO4• 5H2O                     Molecular Weight is 758.83

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Morphine Sulfate Injection, USP is a sterile, nonpyrogenic solution, free of antioxidants and preservatives, intended for intravenous administration. Each milliliter of sterile solution contains 2 mg, 4 mg, morphine sulfate and the following inactive ingredients: 0.2 mg edetate disodium, 0.4 mg citric acid monohydrate for the 2 mg, 4 mg, Morphine Sulfate Injection, USP sodium chloride to adjust isotonicity and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. The pH range is 2.5 to 4.0.

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Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioidlike activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Effects on the Central Nervous System

Morphine sulfate produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine 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

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach 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 of the Cardiovascular System

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

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormones (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

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

Effects on the Immune System

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

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION (2.1, 2.2)].

 Concentration–Adverse Reaction Relationships

There is a relationship between increasing morphine sulfate 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, 2.4)].

Distribution

Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after parenteral administration. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS, plasma concentrations of morphine remain higher than the corresponding CSF morphine levels.

Elimination

Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h in postoperative patients, but shows considerable interindividual variation.

Metabolism

The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive.

Excretion

The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours.

Specific population

Sex

While evidence of greater postoperative Morphine Sulfate Injection USP consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of Morphine Sulfate Injection USP, including respiratory depression, in women compared to men.

Hepatic Impairment

Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Carcinogenesis

Longterm studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was also reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in these species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.

Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD). 

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

Morphine Sulfate Injection, USP is supplied as a sterile solution in single-dose 1 mL prefilled syringes for intravenous administration as follows: 

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2 mg/mL packaged in 10s (NDC 0641-6191-10)

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4 mg/mL packaged in 10s (NDC 0641-6192-10)

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Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature] until ready to use. PROTECT FROM LIGHT. DO NOT FREEZE. Contains no preservative or antioxidant. DISCARD ANY UNUSED PORTION. DO NOT HEAT-STERILIZE.

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Addiction, Abuse, and Misuse

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Inform patients that the use of Morphine Sulfate 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)]. Instruct patients not to share Morphine Sulfate Injection with others and to take steps to protect Morphine Sulfate Injection from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of Morphine Sulfate 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)]. Instruct patients not to share Morphine Sulfate Injection with others and to take steps to protect Morphine Sulfate Injection 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 Morphine Sulfate Injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Morphine Sulfate Injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)].\n" }

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 (5.6); 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 (5.6); Adverse Reactions (6)].\n" }

Serotonin Syndrome

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

Inform patients that opioids can 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 Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients that opioids can 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 Drug Interactions (7)].\n" }

Constipation

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

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

{ "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)].\n" }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate. CAUTION: Certain glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. This syringe has a larger internal syringe tip and an external collar (luer collar). The external collar must remain attached to the syringe. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe –NLAD connection before and during drug administration. Refer to Figure 1 for syringe diagram.

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate.\n\nCAUTION: Certain glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. This syringe has a larger internal syringe tip and an external collar (luer collar). The external collar must remain attached to the syringe. However, spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Visually inspect the glass syringe-needle or glass syringe –NLAD connection before and during drug administration. Refer to Figure 1 for syringe diagram. " }

Figure 1

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

1. Inspect the outer packaging (plastic tube) by verifying:  

{ "type": "p", "children": [], "text": "1. Inspect the outer packaging (plastic tube) by verifying:  " }

- plastic tube integrity  

{ "type": "p", "children": [], "text": "- plastic tube integrity  " }

- drug name  

{ "type": "p", "children": [], "text": "- drug name  " }

- drug strength  

{ "type": "p", "children": [], "text": "- drug strength  " }

- dose volume  

{ "type": "p", "children": [], "text": "- dose volume  " }

- route of administration  

{ "type": "p", "children": [], "text": "- route of administration  " }

- expiration date to be sure that the drug has not expired  

{ "type": "p", "children": [], "text": "- expiration date to be sure that the drug has not expired  " }

- sterile field applicability

{ "type": "p", "children": [], "text": "- sterile field applicability " }

Do not use if package has been damaged.

{ "type": "p", "children": [], "text": "Do not use if package has been damaged. " }

2. Remove the plastic tube cap of the outer packaging that displays the product information to access the syringe. 

{ "type": "p", "children": [], "text": "2. Remove the plastic tube cap of the outer packaging that displays the product information to access the syringe.  " }

3. Remove the syringe from the plastic tube.

{ "type": "p", "children": [], "text": "3. Remove the syringe from the plastic tube.\n" }

4. Perform visual inspection on the syringe by verifying:  

{ "type": "p", "children": [], "text": "4. Perform visual inspection on the syringe by verifying:  " }

- absence of syringe damage  

{ "type": "p", "children": [], "text": "- absence of syringe damage  " }

- absence of external particles  

{ "type": "p", "children": [], "text": "- absence of external particles  " }

- absence of internal particles  

{ "type": "p", "children": [], "text": "- absence of internal particles  " }

- proper drug color  

{ "type": "p", "children": [], "text": "- proper drug color  " }

- expiration date to be sure that the drug has not expired 

{ "type": "p", "children": [], "text": "- expiration date to be sure that the drug has not expired " }

- drug name  

{ "type": "p", "children": [], "text": "- drug name  " }

- drug strength  

{ "type": "p", "children": [], "text": "- drug strength  " }

- dose volume  

{ "type": "p", "children": [], "text": "- dose volume  " }

- route of administration  

{ "type": "p", "children": [], "text": "- route of administration  " }

- sterile field applicability

{ "type": "p", "children": [], "text": "- sterile field applicability " }

5. Push plunger rod slightly to break the stopper loose while tip cap is still on.

{ "type": "p", "children": [], "text": "5. Push plunger rod slightly to break the stopper loose while tip cap is still on. " }

6. Remove tip cap by twisting it off. (See Figure 2)

{ "type": "p", "children": [], "text": "6. Remove tip cap by twisting it off. (See Figure 2) " }

Figure 2

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

7. Discard the tip cap.

{ "type": "p", "children": [], "text": "7. Discard the tip cap. " }

8. Expel air bubble.

{ "type": "p", "children": [], "text": "8. Expel air bubble. " }

9. Adjust dose by expelling extra volume (where applicable) from the syringe into sterile material prior to administration.

{ "type": "p", "children": [], "text": "9. Adjust dose by expelling extra volume (where applicable) from the syringe into sterile material prior to administration." }

10. Connect the syringe to appropriate injection connection depending on route of administration. Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD).

{ "type": "p", "children": [], "text": "10. Connect the syringe to appropriate injection connection depending on route of administration. Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). " }

11. Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration.

{ "type": "p", "children": [], "text": "11. Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. " }

12. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. To prevent needle-stick injuries, needles should not be recapped.

{ "type": "p", "children": [], "text": "12. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. To prevent needle-stick injuries, needles should not be recapped. " }

NOTES:  

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

- All steps must be done sequentially  

{ "type": "p", "children": [], "text": "- All steps must be done sequentially  " }

- Do not autoclave syringe  

{ "type": "p", "children": [], "text": "\n- Do not autoclave syringe  \n" }

- Do not use this product on a sterile field  

{ "type": "p", "children": [], "text": "\n- Do not use this product on a sterile field  \n" }

- Do not introduce any other fluid into the syringe at any time  

{ "type": "p", "children": [], "text": "- Do not introduce any other fluid into the syringe at any time  " }

- This product is for single dose only

{ "type": "p", "children": [], "text": "- This product is for single dose only " }

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

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

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

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

Manufactured by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 USA Revised March 2024

{ "type": "p", "children": [], "text": "Manufactured by:\nHikma Pharmaceuticals USA Inc.\nBerkeley Heights, NJ 07922 USA\nRevised March 2024" }

462-054-00

{ "type": "p", "children": [], "text": "462-054-00" }

 NDC 0641-6191-01 Rx only

{ "type": "p", "children": [], "text": " NDC 0641-6191-01 Rx only " }

1 mL Single-Dose Prefilled Syringe   462-858-00

{ "type": "p", "children": [], "text": "\n1 mL Single-Dose Prefilled Syringe   462-858-00 " }

Morphine Sulfate

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

Injection, USP

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

2 mg/mL

{ "type": "p", "children": [], "text": "\n2 mg/mL \n" }

For IV use ONLY 

{ "type": "p", "children": [], "text": "\nFor IV use ONLY \n" }

NDC 0641-6191-10 Rx only

{ "type": "p", "children": [], "text": "NDC 0641-6191-10 Rx only " }

Morphine 

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

Sulfate Injection, USP

{ "type": "p", "children": [], "text": "\nSulfate Injection, USP \n" }

2 mg/mL

{ "type": "p", "children": [], "text": "\n2 mg/mL \n" }

For Intravenous use ONLY

{ "type": "p", "children": [], "text": "\nFor Intravenous use ONLY\n" }

No added preservative

{ "type": "p", "children": [], "text": "No added preservative " }

10 x 1 mL Single-Dose

{ "type": "p", "children": [], "text": "10 x 1 mL Single-Dose " }

Prefilled Syringes

{ "type": "p", "children": [], "text": "Prefilled Syringes " }

Discard unused portion.

{ "type": "p", "children": [], "text": "\nDiscard unused portion.\n" }

NDC 0641-6192-01   Rx only

{ "type": "p", "children": [], "text": "NDC 0641-6192-01   Rx only " }

1 mL Single-Dose Prefilled Syringe   462-860-00

{ "type": "p", "children": [], "text": "\n1 mL Single-Dose Prefilled Syringe   462-860-00 " }

Morphine Sulfate

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

Injection, USP

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

4 mg/mL

{ "type": "p", "children": [], "text": "\n4 mg/mL \n" }

For IV use ONLY

{ "type": "p", "children": [], "text": "\nFor IV use ONLY\n" }

NDC 0641-6192-10   Rx only

{ "type": "p", "children": [], "text": "NDC 0641-6192-10   Rx only " }

Morphine

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

Sulfate Injection, USP

{ "type": "p", "children": [], "text": "\nSulfate Injection, USP \n" }

4 mg/mL

{ "type": "p", "children": [], "text": "\n4 mg/mL \n" }

For Intravenous use ONLY

{ "type": "p", "children": [], "text": "\nFor Intravenous use ONLY\n" }

No added preservative

{ "type": "p", "children": [], "text": "No added preservative " }

10 x 1 mL Single-Dose

{ "type": "p", "children": [], "text": "10 x 1 mL Single-Dose " }

Prefilled Syringes

{ "type": "p", "children": [], "text": "Prefilled Syringes " }

Discard unused portion. 

{ "type": "p", "children": [], "text": "\nDiscard unused portion. \n" }

Morphine sulfate extended-release capsules are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules are indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate." }

Limitations of Use

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

{ "type": "ul", "children": [ "Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, [see Warnings and Precautions (5.1)], reserve morphine sulfate extended-release capsules for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.", "Morphine sulfate extended-release capsules are not indicated as an as-needed (prn) analgesic." ], "text": "" }

Morphine sulfate extended-release capsules should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Morphine sulfate extended-release 90 mg and 120 mg capsules are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

Morphine sulfate extended-release capsules are administered at a frequency of once daily (every 24 hours).

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

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

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.3)].

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

Use of Morphine Sulfate Extended-Release Capsules as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with morphine sulfate extended-release capsules with a 30 mg capsule orally every 24 hours. Adjust the dose of morphine sulfate extended-release capsules in increments not greater than 30 mg every 3 to 4 days.

Use of Morphine Sulfate Extended-Release Capsules in Patients who are not Opioid Tolerant (opioid non-tolerant patients)

The starting dose of morphine sulfate extended-release capsules for patients who are not opioid tolerant is 30 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Opioids to Morphine Sulfate Extended-Release Capsules

When morphine sulfate extended-release capsules therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios from other opioids to morphine sulfate extended-release capsules defined by clinical trials. Initiate dosing using morphine sulfate extended-release capsules 30 mg orally every 24 hours.

It is safer to underestimate a patient's 24-hour oral morphine dosage and provide rescue medication (e.g. immediate-release morphine) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and formulations.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to morphine sulfate extended-release capsules.

Conversion from Other Oral Morphine Formulations to Morphine Sulfate Extended-Release Capsules

Patients receiving other oral morphine formulations may be converted to morphine sulfate extended-release capsules by administering the patient's total daily oral morphine dose as morphine sulfate extended-release capsules once-daily. Monitor patients closely when initiating morphine sulfate extended-release capsule therapy and adjust the dosage of morphine sulfate extended-release capsules as needed. Morphine sulfate extended-release capsules should not be given more frequently than every 24 hours.

Conversion from Parenteral Morphine or Other Non-Morphine Opioids (Parenteral or Oral) to Morphine Sulfate Extended-Release Capsules

When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to morphine sulfate extended-release capsules, consider the following general points:

Parenteral to oral morphine ratio:

Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient.

Other parenteral or oral non-morphine opioids to oral morphine sulfate:

Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release morphine.

Conversion from Methadone to Morphine Sulfate Extended-Release Capsules

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

The first dose of morphine sulfate extended-release capsules may be taken with the last dose of any immediate-release opioid medication due to the extended-release characteristics of the morphine sulfate extended-release capsules formulation.

Individually titrate morphine sulfate extended-release capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate extended-release capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

Patients who experience breakthrough pain may require a dose increase of morphine sulfate extended-release capsules, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate extended-release capsules dosage. Because steady-state plasma concentrations are approximated within 2 to 3 days, morphine sulfate extended-release capsules dosage adjustments may be done every 3 to 4 days.

The daily dose of morphine sulfate extended-release capsules must be limited to a maximum of 1,600 mg/day. Morphine sulfate extended-release capsules doses of over 1,600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe, and which may result in serious renal toxicity.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Do not abruptly discontinue morphine sulfate extended-release capsules in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking morphine sulfate extended-release capsules, there are a variety of factors that should be considered, including the total daily dose of opioid (including morphine sulfate extended-release capsules) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on morphine sulfate extended-release capsules who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].

Morphine sulfate extended-release capsules must be taken whole. Crushing, chewing, or dissolving the pellets in morphine sulfate extended-release capsules will result in uncontrolled delivery of morphine and can lead to overdose or death [see Warnings and Precautions (5.1)].

Alternatively, the contents of the morphine sulfate extended-release capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:

Do not administer morphine sulfate extended-release capsules pellets through a nasogastric or gastric tubes.

Morphine sulfate extended-release capsules, USP (once daily) contain pellets of morphine sulfate and are available as follows: 30 mg capsule has a dark blue opaque cap and body, printed with and 3090 on both the cap and body in black ink. 45 mg capsule has a violet opaque cap and body, printed with and 3116 on both the cap and body in black ink. 60 mg capsule has a light green opaque cap and body, printed with and 3091 on both the cap and body in black ink. 75 mg capsule has a brown opaque cap and body, printed with and 3117 on both the cap and body in black ink. 90 mg capsule has a green opaque cap and body, printed with  and 3092 on both the cap and body in black ink. 120 mg capsule has a light blue opaque cap and body, printed with and 3093 on both the cap and body in black ink.

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules, USP (once daily) contain pellets of morphine sulfate and are available as follows:\n30 mg capsule has a dark blue opaque cap and body, printed with and 3090 on both the cap and body in black ink.\n45 mg capsule has a violet opaque cap and body, printed with and 3116 on both the cap and body in black ink.\n60 mg capsule has a light green opaque cap and body, printed with and 3091 on both the cap and body in black ink. \n75 mg capsule has a brown opaque cap and body, printed with and 3117 on both the cap and body in black ink.\n90 mg capsule has a green opaque cap and body, printed with  and 3092 on both the cap and body in black ink. \n120 mg capsule has a light blue opaque cap and body, printed with and 3093 on both the cap and body in black ink. " }

Morphine sulfate extended-release capsules are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules are contraindicated in patients with:" }

{ "type": "ul", "children": [ "Significant respiratory depression [see Warnings and Precautions (5.2)]\n", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]\n", "Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.8)].", "Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)]\n", "Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]\n" ], "text": "" }

Morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate extended-release capsules exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as morphine sulfate extended-release capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate extended-release capsules. Addiction can occur at recommended doses and if the drug is misused or abused.

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

Abuse or misuse of morphine sulfate extended-release capsules by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the morphine and can result in overdose and death [see Overdosage (10)].

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

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

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

To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate extended-release capsules are essential [see Dosage and Administration (2)]. Overestimating the morphine sulfate extended-release capsules dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of morphine sulfate extended-release capsules, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate extended-release capsules. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.1, 5.3), Overdosage (10), Patient Counseling Information (17)].

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on morphine sulfate extended-release capsules therapy. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine [see Clinical Pharmacology (12.3)].

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

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

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

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

Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate extended-release capsules is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

Use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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 (2.5); Warnings and Precautions (5.6)].

The use of morphine sulfate extended-release capsules 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: Morphine sulfate extended-release capsules-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of morphine sulfate extended-release capsules [see Warnings and Precautions (5.2)].

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

Regularly evaluate patients, particularly when initiating and titrating morphine sulfate extended-release capsules and when morphine sulfate extended-release capsules are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interaction (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine sulfate extended-release capsules should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

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

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of morphine sulfate extended-release capsules in patients with impaired consciousness or coma.

Morphine sulfate extended-release capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in morphine sulfate extended-release capsules may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

The morphine in morphine sulfate extended-release capsules may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during morphine sulfate extended-release capsules therapy.

Do not abruptly discontinue morphine sulfate extended-release capsules in a patient physically dependent on opioids. When discontinuing morphine sulfate extended-release capsules in a physically dependent patient, gradually taper the dosage. Rapid tapering of meperidine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.4), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including morphine sulfate extended-release capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

Morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules and know how they will react to the medication [see Patient Counseling Information (17)].

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

In controlled and open-label clinical studies, 560 patients with chronic malignant or non-malignant pain were treated with morphine sulfate extended-release capsules. The most common serious adverse events reported with administration of morphine sulfate extended-release capsules were vomiting, nausea, death, dehydration, dyspnea, and sepsis. (Deaths occurred in patients treated for pain due to underlying malignancy.) Serious adverse events caused by morphine include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

The most common adverse events (seen in greater than 10%) reported by patients treated with morphine sulfate extended-release capsules during the clinical trials at least once during therapy were constipation, nausea, somnolence, vomiting, and headache. Adverse events occurring in 5 to 10% of study patients were peripheral edema, diarrhea, abdominal pain, infection, urinary tract infection, accidental injury, flu syndrome, back pain, rash, sweating, fever, insomnia, depression, paresthesia, anorexia, dry mouth, asthenia and dyspnea. Other less common side effects expected from opioid analgesics, including morphine, or seen in fewer than 5% of patients taking morphine sulfate extended-release capsules in the clinical trials were:

Body as a Whole: malaise, withdrawal syndrome.

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia.

Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst.

Hemic and Lymphatic System: anemia, thrombocytopenia.

Metabolic and Nutritional Disorders: edema, weight loss.

Musculoskeletal: skeletal muscle rigidity.

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo.

Respiratory System: hiccup, hypoventilation, voice alteration.

Skin and Appendages: dry skin, urticaria.

Special Senses: amblyopia, eye pain, taste perversion.

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention.

Anaphylaxis has been reported with ingredients contained in morphine sulfate extended-release capsules. Advise patients how to recognize such a reaction and when to seek medical attention.

The following adverse reactions have been identified during post approval use of morphine. 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 morphine sulfate extended-release capsules.

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 (5.6)].

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 1 includes clinically significant drug interactions with morphine sulfate extended-release capsules.

{ "type": "p", "children": [], "text": "Table 1 includes clinically significant drug interactions with morphine sulfate extended-release capsules." }

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="90%"> <caption> <span>Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release Capsules </span> </caption> <col width="513pt"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule" colspan="2"></td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Alcohol</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Concomitant use of alcohol with morphine sulfate extended-release capsules can result in an increase of morphine plasma levels and potentially fatal overdose of morphine.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on morphine sulfate extended-release capsules therapy <span class="Italics">[see Clinical Pharmacology (<a href="#www.splportal.comLINK_6dbaf988-f7a4-43ad-a708-683445623a25">12.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepine or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_66b2b764-739c-4d5e-95c7-c0c475c8ee80">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_9a291fd4-4f4b-4af1-916e-35a42a0fa598">5.1</a>, <a href="#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1">5.2</a>, <a href="#www.splportal.comLINK_29598311-83ae-4ae8-a6d6-6cd82464a16a">5.3</a>)]</span>.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers and muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release capsules if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT<span class="Sub">3</span> receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">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="#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1">5.2</a>)]</span>.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Do not use morphine sulfate extended-release capsules in patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">May reduce the analgesic effect of morphine sulfate extended-release capsules and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Lrule Toprule"> <p class="First">butorphanol, nalbuphine, pentazocine, buprenorphine</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate extended-release capsules and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. <span class="Italics">[see Dosage and Administration (<a href="#www.splportal.comLINK_66b2b764-739c-4d5e-95c7-c0c475c8ee80">2.2</a>), Warnings and Precautions (<a href="#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1">5.2</a>, <a href="#www.splportal.comLINK_29598311-83ae-4ae8-a6d6-6cd82464a16a">5.3</a>)]</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Cimetidine</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release capsules and/or cimetidine as necessary.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <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="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Evaluate patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release capsules are used concomitantly with anticholinergic drugs.</p> </td> </tr> <tr> <td class="Toprule" colspan="2"> <p class="First"> <span class="Bold">P-Glycoprotein (PGP) Inhibitors</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Lrule Toprule"> <p class="First">The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr class="Last"> <td class="Toprule"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Lrule Toprule"> <p class="First">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release capsules and/or the PGP-inhibitor as necessary.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"90%\">\n<caption>\n<span>Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release Capsules\n </span>\n</caption>\n<col width=\"513pt\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"></td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Alcohol</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Concomitant use of alcohol with morphine sulfate extended-release capsules can result in an increase of morphine plasma levels and potentially fatal overdose of morphine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on morphine sulfate extended-release capsules therapy <span class=\"Italics\">[see Clinical Pharmacology (<a href=\"#www.splportal.comLINK_6dbaf988-f7a4-43ad-a708-683445623a25\">12.3</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\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=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepine or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_66b2b764-739c-4d5e-95c7-c0c475c8ee80\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_9a291fd4-4f4b-4af1-916e-35a42a0fa598\">5.1</a>, <a href=\"#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1\">5.2</a>, <a href=\"#www.splportal.comLINK_29598311-83ae-4ae8-a6d6-6cd82464a16a\">5.3</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers and muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release capsules if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT<span class=\"Sub\">3</span> receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\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 Warnings and Precautions (<a href=\"#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1\">5.2</a>)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Do not use morphine sulfate extended-release capsules in patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\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=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">May reduce the analgesic effect of morphine sulfate extended-release capsules and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">butorphanol, nalbuphine, pentazocine, buprenorphine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Morphine 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=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate extended-release capsules and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose. <span class=\"Italics\">[see Dosage and Administration (<a href=\"#www.splportal.comLINK_66b2b764-739c-4d5e-95c7-c0c475c8ee80\">2.2</a>), Warnings and Precautions (<a href=\"#www.splportal.comLINK_c8d0d2f0-6cec-4f91-8bd1-7b3217997da1\">5.2</a>, <a href=\"#www.splportal.comLINK_29598311-83ae-4ae8-a6d6-6cd82464a16a\">5.3</a>)]</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Cimetidine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release capsules and/or cimetidine as necessary.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\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=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\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=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Evaluate patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release capsules are used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">P-Glycoprotein (PGP) Inhibitors</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Lrule Toprule\">\n<p class=\"First\">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release capsules and/or the PGP-inhibitor as necessary.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with morphine sulfate extended-release capsules in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data].

In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse.

Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

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

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. Morphine sulfate extended-release capsules are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including morphine sulfate extended-release capsules, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extended–release morphine, including morphine sulfate extended-release capsules. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules.

Clinical Considerations

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

Infertility

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

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see  Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

The safety and effectiveness of morphine sulfate extended-release capsules in pediatric patients below the age of 18 have not been established. The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.

The pharmacokinetics of morphine sulfate extended-release capsules have not been studied in elderly patients. In clinical studies of morphine sulfate extended-release capsules, 100 patients who received morphine sulfate extended-release capsules were age 65 and over, including 37 patients were age 75 and over. No overall differences in safety were observed between these subjects and younger subjects [see Clinical Pharmacology (12.3)].

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. 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 morphine sulfate extended-release capsules slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

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

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than normal dosage of morphine sulfate extended-release capsules and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than normal dosage of morphine sulfate extended-release capsules and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine sulfate extended-release capsules contain morphine, a Schedule II controlled substance.

Morphine sulfate extended-release capsules contains morphine, 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 morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules with alcohol and 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 morphine sulfate extended-release capsules abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use morphine sulfate extended-release capsules 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.

Morphine sulfate extended-release capsules, 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 Morphine Sulfate Extended-Release Capsules

Abuse of morphine sulfate extended-release capsules poses a risk of overdose and death. The risk is increased with concurrent use of morphine sulfate extended-release capsules with alcohol and/or other CNS depressants.

Morphine sulfate extended-release capsules is approved for oral use only.

Inappropriate intravenous, intramuscular, or subcutaneous use of morphine sulfate extended-release capsules can result in death, local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, and embolism.

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.

Do not abruptly discontinue morphine sulfate extended-release capsules in a patient physically dependent on opioids. Rapid tapering of morphine sulfate extended-release capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing morphine sulfate extended-release capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate extended-release capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), and Warnings and Precautions (5.14)].

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 overdosage with morphine sulfate extended-release capsules 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 and complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

{ "type": "p", "children": [], "text": "Acute overdosage with morphine sulfate extended-release capsules 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 and complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations." }

Treatment of Overdose

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In cases of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, 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 cases of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, 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 morphine overdose, administer and 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 morphine overdose, administer and opioid antagonist. " }

Because the duration of reversal would be expected to be less than the duration of action of morphine in morphine sulfate extended-release capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. Morphine sulfate extended-release capsules will continue to release morphine and add to the morphine load for 36 to 48 hours or longer following ingestion necessitating prolonged monitoring. 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 reversal would be expected to be less than the duration of action of morphine in morphine sulfate extended-release capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. Morphine sulfate extended-release capsules will continue to release morphine and add to the morphine load for 36 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information." }

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

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

Morphine sulfate extended-release capsules, USP (once daily) are for oral use and contain pellets of morphine sulfate, an opioid agonist.

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules, USP (once daily) are for oral use and contain pellets of morphine sulfate, an opioid agonist." }

Each morphine sulfate extended-release capsule contains either 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, or 120 mg of morphine sulfate, USP and the following inactive ingredients: diethyl phthalate, ethylcellulose, gelatin, hydroxypropyl cellulose, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, and titanium dioxide. The 30 mg capsules also contain FD&C blue #1. The 45 mg capsules also contain FD&C blue #1 and FD&C red #3. The 60 mg capsules also contain D&C yellow #10 and FD&C green #3. The 75 mg capsules also contain black iron oxide, red iron oxide, and yellow iron oxide. The 90 mg capsules also contain D&C red #33, D&C yellow #10 and FD&C blue #1. The 120 mg capsules also contain FD&C blue #1. The ink ingredients are common for all strengths: Tek-Print SW-9008 or SW-9009 black contains: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution.

{ "type": "p", "children": [], "text": "Each morphine sulfate extended-release capsule contains either 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, or 120 mg of morphine sulfate, USP and the following inactive ingredients: diethyl phthalate, ethylcellulose, gelatin, hydroxypropyl cellulose, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, and titanium dioxide. The 30 mg capsules also contain FD&C blue #1. The 45 mg capsules also contain FD&C blue #1 and FD&C red #3. The 60 mg capsules also contain D&C yellow #10 and FD&C green #3. The 75 mg capsules also contain black iron oxide, red iron oxide, and yellow iron oxide. The 90 mg capsules also contain D&C red #33, D&C yellow #10 and FD&C blue #1. The 120 mg capsules also contain FD&C blue #1. The ink ingredients are common for all strengths: Tek-Print SW-9008 or SW-9009 black contains: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, and strong ammonia solution." }

The chemical name of morphine sulfate is 7,8-didehydro-4,5 alpha-epoxy-17-methylmorphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate with a molecular weight of 758.83. The molecular formula is (C17H19NO3)2•H2SO4•5H2O.

{ "type": "p", "children": [], "text": "The chemical name of morphine sulfate is 7,8-didehydro-4,5 alpha-epoxy-17-methylmorphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate with a molecular weight of 758.83. The molecular formula is (C17H19NO3)2•H2SO4•5H2O." }

Morphine sulfate is an odorless, white, crystalline powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Its structural formula is:

{ "type": "p", "children": [], "text": "Morphine sulfate is an odorless, white, crystalline powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Its structural formula is:" }

FDA approved dissolution test specifications differ from USP.

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Morphine is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when morphine sulfate extended-release capsules are used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation.

Morphine 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 with hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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

Morphine may also cause spasm of the sphincter of the urinary bladder.

Effects on the Cardiovascular System

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

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

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

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system. 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. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.2)].

Concentration–Adverse Reaction Relationships

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

Absorption

Morphine sulfate extended-release capsules consist of two components, an immediate-release component and an extended-release component.

The oral bioavailability of morphine is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Following single-dose oral administration of a 60 mg dose of morphine sulfate extended-release capsules under fasting conditions, morphine concentrations of approximately 3 to 6 ng/mL were achieved within 30 minutes after dosing and maintained for the 24-hour dosing interval. The pharmacokinetics of morphine sulfate extended-release capsules were shown to be dose-proportional over a single oral dose range of 30 to 120 mg in healthy volunteers and a multiple oral dose range of at least 30 to 180 mg in patients with chronic moderate to severe pain.

Food Effect: When a 60 mg dose of morphine sulfate extended-release capsules was administered immediately following a high fat meal, peak morphine concentrations and AUC values were similar to those observed when the dose of morphine sulfate extended-release capsules was administered in a fasting state, although achievement of initial concentrations was delayed by approximately 1 hour under fed conditions. Therefore, morphine sulfate extended-release capsules can be administered without regard to food. When the contents of morphine sulfate extended-release capsules were administered by sprinkling on applesauce, the rate and extent of morphine absorption were found to be bioequivalent to the same dose when administered as an intact capsule.

Steady State: Steady-state plasma concentrations of morphine are achieved 2 to 3 days after initiation of once-daily administration of morphine sulfate extended-release capsules.

Morphine sulfate extended-release 60 mg capsules (once-daily) and 10 mg morphine oral solution (6 times daily) were equally bioavailable.

Graph 1

Mean Steady-State Plasma Morphine Concentrations Following Once-Daily Administration of Morphine Sulfate Extended-Release Capsules or 6-Times Daily Administration of Morphine Solution

A once-daily dose of morphine sulfate extended-release capsules provided similar Cmax, Cmin, and AUC values and peak-trough fluctuations (% FL, Cmax-Cmin/Cav) compared to 6-times daily administration of the same total daily dose of morphine oral solution (Table 2).

<div class="scrollingtable"><table width="668px"> <caption> <span>Table 2 Pharmacokinetic Data Mean ± SD</span> </caption> <col width="1px"/> <col width="1px"/> <col width="1px"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule"> <span class="Bold">Parameter</span></td><td class="Toprule"><span class="Bold">Morphine Sulfate Extended Release Capsules Once-Daily</span></td><td class="Toprule"><span class="Bold">Morphine Oral Solution</span><span class="Bold"> <br/> 6-Times Daily</span></td> </tr> <tr> <td> AUC (ng/mL.h)</td><td> 273.25 ± 81.24</td><td> 279.11 ± 63.00</td> </tr> <tr> <td> C<span class="Sub">max</span> (ng/mL)</td><td> 18.65 ± 7.13</td><td> 19.96 ± 4.82</td> </tr> <tr> <td> C<span class="Sub">min</span> (ng/mL)</td><td> 6.98 ± 2.44</td><td> 6.61 ±2.15</td> </tr> <tr class="Last"> <td> % FL</td><td> 106.38 ± 78.14</td><td> 116.22 ± 26.67</td> </tr> </tbody> </table></div>

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine also crosses the placental membranes and has been found in breast milk [see Use in Specific Populations (8.1, 8.3)]. The volume of distribution of morphine is approximately 1 to 6 L/kg, and morphine is 20 to 35% reversibly bound to plasma proteins.

Elimination

Metabolism The major pathways of morphine metabolism include glucuronidation to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion Approximately 10% of a morphine dose is excreted unchanged in the urine. Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites M3G and M6G which are then renally excreted. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic recycling. Seven to 10% of administered morphine is excreted in the feces. The mean adult plasma clearance of morphine is about 20 to 30 mL/minute/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following single dose of morphine sulfate extended-release capsules administration is approximately 24 hrs.

 Specific Populations

Sex An analysis of pharmacokinetic data from healthy subjects taking morphine sulfate extended-release capsules indicated that morphine concentrations were similar in males and females.

Race/Ethnicity Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

Hepatic Impairment Morphine pharmacokinetics are altered in individuals with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted. 

Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted. 

Drug Interaction/Alcohol Interaction In in vitro studies of the dissolution of morphine sulfate extended-release capsules 30 mg mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the amount of morphine released increased in an alcohol concentration-dependent manner. While the relevance of in vitro lab tests regarding morphine sulfate extended-release capsules to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

Carcinogenesis

Long-term animal studies have not been completed to evaluate the carcinogenic potential of morphine.

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported. Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation, and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

Morphine sulfate extended-release capsules were studied in a double-blind, placebo-controlled, fixed-dose, parallel group trial in 295 patients with moderate to severe pain due to osteoarthritis. These patients had either a prior sub-optimal response to acetaminophen, NSAID therapy, or previously received intermittent opioid analgesic therapy. Thirty-milligrams morphine sulfate extended-release capsules administered once-daily, either in the morning or the evening, were more effective than placebo in reducing pain.

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules were studied in a double-blind, placebo-controlled, fixed-dose, parallel group trial in 295 patients with moderate to severe pain due to osteoarthritis. These patients had either a prior sub-optimal response to acetaminophen, NSAID therapy, or previously received intermittent opioid analgesic therapy. Thirty-milligrams morphine sulfate extended-release capsules administered once-daily, either in the morning or the evening, were more effective than placebo in reducing pain." }

<div class="scrollingtable"><table width="800px"> <caption> <span>Table 3 Change from Baseline in WOMAC OA Index Pain VAS Subscale Score</span> </caption> <col width="1px"/> <col width="1px"/> <col width="1px"/> <col width="1px"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Toprule"> Overall</td><td align="center" class="Toprule"> Placebo</td><td align="center" class="Toprule"> Morphine Sulfate<br/> Extended-Release <br/> Capsules QAM</td><td align="center" class="Toprule"> <p class="First">Morphine Sulfate<br/> Extended-Release <br/> Capsules QPM</p> </td> </tr> <tr> <td align="center"> LS Mean</td><td align="center"> -36.23</td><td align="center"> -75.26<span class="Sup">a</span></td><td align="center"> -75.39<span class="Sup">a</span></td> </tr> <tr> <td align="center"> Std. Error</td><td align="center"> 11.482</td><td align="center"> 11.305</td><td align="center"> 11.747</td> </tr> <tr class="Last"> <td class="Toprule" colspan="4"><span class="Sup"> a)</span> P&lt;0.05; REPEATED MEASURES ANALYSIS</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"800px\">\n<caption>\n<span>Table 3 Change from Baseline in WOMAC OA Index Pain VAS Subscale Score</span>\n</caption>\n<col width=\"1px\"/>\n<col width=\"1px\"/>\n<col width=\"1px\"/>\n<col width=\"1px\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Toprule\"> Overall</td><td align=\"center\" class=\"Toprule\"> Placebo</td><td align=\"center\" class=\"Toprule\"> Morphine Sulfate<br/>\n Extended-Release <br/>\n Capsules QAM</td><td align=\"center\" class=\"Toprule\">\n<p class=\"First\">Morphine Sulfate<br/>\n Extended-Release <br/>\n Capsules QPM</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\"> LS Mean</td><td align=\"center\"> -36.23</td><td align=\"center\"> -75.26<span class=\"Sup\">a</span></td><td align=\"center\"> -75.39<span class=\"Sup\">a</span></td>\n</tr>\n<tr>\n<td align=\"center\"> Std. Error</td><td align=\"center\"> 11.482</td><td align=\"center\"> 11.305</td><td align=\"center\"> 11.747</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Toprule\" colspan=\"4\"><span class=\"Sup\"> a)</span> P&lt;0.05; REPEATED MEASURES ANALYSIS</td>\n</tr>\n</tbody>\n</table></div>" }

This study was not designed to assess the effects of morphine sulfate extended-release capsules on the course of the osteoarthritis.

{ "type": "p", "children": [], "text": "This study was not designed to assess the effects of morphine sulfate extended-release capsules on the course of the osteoarthritis." }

Morphine sulfate extended-release capsules, USP (Once Daily) are available as follows:

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules, USP (Once Daily) are available as follows:" }

30 mg – Size 3 capsule with dark blue opaque cap and body, printed with and 3090 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3090-11).

{ "type": "p", "children": [], "text": "30 mg – Size 3 capsule with dark blue opaque cap and body, printed with and 3090 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3090-11)." }

45 mg – Size 3 capsule with violet opaque cap and body, printed with and 3116 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3116-11).

{ "type": "p", "children": [], "text": "45 mg – Size 3 capsule with violet opaque cap and body, printed with and 3116 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3116-11)." }

60 mg – Size 2 capsule with light green opaque cap and body, printed with and 3091 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3091-11).

{ "type": "p", "children": [], "text": "60 mg – Size 2 capsule with light green opaque cap and body, printed with and 3091 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3091-11)." }

75 mg – Size 1 capsule with brown opaque cap and body, printed with and 3117 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3117-11).

{ "type": "p", "children": [], "text": "75 mg – Size 1 capsule with brown opaque cap and body, printed with and 3117 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3117-11)." }

90 mg – Size 1 capsule with green opaque cap and body, printed with and 3092 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3092-11).

{ "type": "p", "children": [], "text": "90 mg – Size 1 capsule with green opaque cap and body, printed with and 3092 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3092-11)." }

120 mg – Size 0 capsule with light blue opaque cap and body, printed with and 3093 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3093-11).

{ "type": "p", "children": [], "text": "120 mg – Size 0 capsule with light blue opaque cap and body, printed with and 3093 on both the cap and body in black ink. Capsules are supplied in bottles of 100 (NDC 0228-3093-11)." }

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]." }

Protect from light and moisture.

{ "type": "p", "children": [], "text": "Protect from light and moisture." }

Dispense in a tight, light-resistant container as defined in USP.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in USP." }

Store morphine sulfate extended-release capsules securely and dispose of properly [see Patient Counseling Information (17)].

{ "type": "p", "children": [], "text": "Store morphine sulfate extended-release capsules securely and dispose of properly [see Patient Counseling Information (17)]." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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

Storage and Disposal

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

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store morphine sulfate extended-release capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving morphine sulfate extended-release capsules unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.5), Drug Abuse and Dependence (9.2)].

{ "type": "p", "children": [], "text": "Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store morphine sulfate extended-release capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving morphine sulfate extended-release capsules unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.5), Drug Abuse and Dependence (9.2)]." }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused morphine sulfate extended-release capsules should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

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

Addiction, Abuse, and Misuse

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

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

{ "type": "p", "children": [], "text": "Inform patients that the use of morphine sulfate extended-release capsules, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share morphine sulfate extended-release capsules with others and to take steps to protect morphine sulfate extended-release capsules 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 morphine sulfate extended-release capsules or when the dose is increased, and that it can occur even at recommended doses.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting morphine sulfate extended-release capsules or when the dose is increased, and that it can occur even at recommended doses." }

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

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

Accidental Ingestion

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

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. " }

Interactions with Benzodiazepines and Other CNS Depressants

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

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with morphine sulfate extended-release capsules. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine.

{ "type": "p", "children": [], "text": "Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with morphine sulfate extended-release capsules. The co-ingestion of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine." }

Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate extended-release capsules are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.3), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate extended-release capsules are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.3), Drug Interactions (7)]." }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

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

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

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

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

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

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

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

If naloxone is prescribed, also advise patients and caregivers:

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

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

Hyperalgesia and Allodynia

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

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7); Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7); Adverse Reactions (6.2)]." }

Serotonin Syndrome

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

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

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

MAOI Interaction

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

Inform patients not to take morphine sulfate extended-release capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate extended-release capsules [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Inform patients not to take morphine sulfate extended-release capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate extended-release capsules [see Warnings and Precautions (5.8)]." }

Important Administration Instructions

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

Instruct patients how to properly take morphine sulfate extended-release capsules, including the following:

{ "type": "p", "children": [], "text": "Instruct patients how to properly take morphine sulfate extended-release capsules, including the following:" }

{ "type": "ul", "children": [ "Swallowing morphine sulfate extended-release capsules whole or sprinkling the capsule contents on applesauce and then swallowing immediately without chewing [see Dosage and Administration (2.1, 2.5)]\n", "Not crushing, chewing, or dissolving the pellets in the capsules [see Dosage and Administration (2.1)]\n", "Using morphine sulfate extended-release capsules exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.2)]\n", "Not discontinuing morphine sulfate extended-release capsules without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.4)]\n" ], "text": "" }

Important Discontinuation Instructions

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

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate extended-release capsules without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4)]

{ "type": "p", "children": [], "text": "In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate extended-release capsules without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4)]\n" }

Driving or Operating Heavy Machinery

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

Inform patients that morphine sulfate extended-release capsules may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.15)].

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate extended-release capsules may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.15)]." }

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)].

{ "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)]." }

Adrenal Insufficiency

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

Inform patients that morphine sulfate extended-release capsules 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 (5.9)].

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate extended-release capsules 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 (5.9)]." }

Hypotension

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

Inform patients that morphine sulfate extended-release capsules may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate extended-release capsules may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.10)]." }

Anaphylaxis

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

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

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

Pregnancy

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

Neonatal Opioid Withdrawal Syndrome

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

Inform female patients of reproductive potential that use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential that use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]." }

Embryo-Fetal Toxicity

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

Inform female patients of reproductive potential that morphine sulfate extended-release capsules can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

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

Lactation

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

Advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules [see Use in Specific Populations (8.2)]

{ "type": "p", "children": [], "text": "Advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules [see Use in Specific Populations (8.2)]\n" }

Infertility

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

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].\n" }

DEA Order Form Required.

{ "type": "p", "children": [], "text": "\nDEA Order Form Required.\n" }

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

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

Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Manufactured For:\nTeva Pharmaceuticals\nParsippany, NJ 07054" }

Rev. A 9/2024 

{ "type": "p", "children": [], "text": "Rev. A 9/2024 " }

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

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

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="7.65in"/> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> </p> <p> <span class="Bold">Morphine Sulfate (mor' feen sul' fate) Extended-Release Capsules, USP (Once Daily), CII</span> </p> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Morphine sulfate extended-release capsules are:</span> </p> <ul class="Disk"> <li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine when other pain medicines do not treat your pain well enough or you cannot tolerate them.</li> <li>A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li> <li>Not to be taken on an “as needed” basis.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Important information about morphine sulfate extended-release capsules:</span> </p> <ul class="Disc"> <li> <span class="Bold">Get emergency help or call 911 right away if you take too many morphine sulfate extended-release capsules (overdose). </span>When you first start taking morphine sulfate extended-release capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li> <li>Taking morphine sulfate extended-release capsules with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li> <li>Never give anyone else your morphine sulfate extended-release capsules. They could die from taking it. Selling or giving away morphine sulfate extended-release capsules is against the law.</li> <li>Store morphine sulfate extended-release capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Do not take morphine sulfate extended-release capsules if you have:</span> </p> <ul class="Disc"> <li>severe asthma, trouble breathing, or other lung problems.</li> <li>a bowel blockage or have narrowing of the stomach or intestines.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Before taking morphine sulfate extended-release capsules, tell your healthcare provider if you have a history of:</span> </p> <ul class="Disc"> <li>head injury, seizures      ● liver, kidney, thyroid problems</li> <li>problems urinating         ● pancreas or gallbladder problems</li> <li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">Tell your healthcare provider if you are:</span> </p> <ul class="Disk"> <li>noticing your pain getting worse. If your pain gets worse after you take morphine sulfate extended-release capsules, do not take more of morphine sulfate extended-release capsules without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking morphine sulfate extended-release capsules.</li> <li> <span class="Bold">Are pregnant or planning to become pregnant.</span> Use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</li> <li> <span class="Bold">breastfeeding.</span> Not recommended during treatment with morphine sulfate extended-release capsules. It may harm your baby.</li> <li>living in a household where there are small children or someone who has abused street or prescription drugs.</li> <li>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking morphine sulfate extended-release capsules with certain other medicines can cause serious side effects.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">When taking morphine sulfate extended-release capsules:</span> </p> <ul class="Disc"> <li>Do not change your dose. Take morphine sulfate extended-release capsules exactly as prescribed by your healthcare provider. Use the lowest does possible for the shortest time needed.</li> <li>Take your prescribed dose every 24 hours, at the same time every day. Do not take more than your prescribed dose in 24 hours. If you miss a dose, take your next dose at your usual time the next day.</li> <li>Swallow morphine sulfate extended-release capsules whole. Do not cut, break, chew, crush, dissolve, snort, or inject morphine sulfate extended-release capsules because this may cause you to overdose and die.</li> <li>If you cannot swallow morphine sulfate extended-release capsules, see the detailed Instructions for Use.</li> <li> <span class="Bold">Call your healthcare provider if the dose you are taking does not control your pain.</span> </li> <li> <span class="Bold">Do not stop taking morphine sulfate extended-release capsules without talking to your healthcare provider.</span> </li> <li>Dispose of expired, unwanted, or unused morphine sulfate extended-release capsules by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit <a href="http://www.fda.gov/drugdisposal">www.fda.gov/drugdisposal</a> for additional information on disposal of unused medicines.</li> </ul> </td> </tr> <tr> <td class="Toprule"> <p class="First"> <span class="Bold">While taking morphine sulfate extended-release capsules DO NOT:</span> </p> <ul class="Disc"> <li>Drive or operate heavy machinery, until you know how morphine sulfate extended-release capsules affect you. Morphine sulfate extended-release capsules can make you sleepy, dizzy, or lightheaded.</li> <li>Drink alcohol, or use prescription or over-the-counter medicines containing alcohol. Using products containing alcohol during treatment with morphine sulfate extended-release capsules may cause you to overdose and die.</li> </ul> </td> </tr> <tr class="Last"> <td class="Toprule"> <span class="Bold">The possible side effects of morphine sulfate extended-release capsules are:</span> <ul class="Disc"> <li>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. <p class="First"> <span class="Bold">Get emergency medical help or call 911 right away if you have:</span> </p> </li> <li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li> </ul> <p class="First">These are not all the possible side effects of morphine sulfate extended-release capsules. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class="Bold">For more information go to dailymed.nlm.nih.gov.</span> </p> <p>Manufactured For: <span class="Bold">Teva Pharmaceuticals, </span>Parsippany, NJ 07054</p> <p>For additional product information about morphine sulfate extended-release capsules, contact Teva at 1-888-838-2872.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\">\n<col width=\"7.65in\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE</span>\n</p>\n<p>\n<span class=\"Bold\">Morphine Sulfate (mor' feen sul' fate) Extended-Release Capsules, USP (Once Daily), CII</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Morphine sulfate extended-release capsules are:</span>\n</p>\n<ul class=\"Disk\">\n<li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine when other pain medicines do not treat your pain well enough or you cannot tolerate them.</li>\n<li>A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li>\n<li>Not to be taken on an “as needed” basis.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Important information about morphine sulfate extended-release capsules:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Get emergency help or call 911 right away if you take too many morphine sulfate extended-release capsules (overdose). </span>When you first start taking morphine sulfate extended-release capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li>\n<li>Taking morphine sulfate extended-release capsules with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li>\n<li>Never give anyone else your morphine sulfate extended-release capsules. They could die from taking it. Selling or giving away morphine sulfate extended-release capsules is against the law.</li>\n<li>Store morphine sulfate extended-release capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take morphine sulfate extended-release capsules if you have:</span>\n</p>\n<ul class=\"Disc\">\n<li>severe asthma, trouble breathing, or other lung problems.</li>\n<li>a bowel blockage or have narrowing of the stomach or intestines.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking morphine sulfate extended-release capsules, tell your healthcare provider if you have a history of:</span>\n</p>\n<ul class=\"Disc\">\n<li>head injury, seizures      ● liver, kidney, thyroid problems</li>\n<li>problems urinating         ● pancreas or gallbladder problems</li>\n<li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n</p>\n<ul class=\"Disk\">\n<li>noticing your pain getting worse. If your pain gets worse after you take morphine sulfate extended-release capsules, do not take more of morphine sulfate extended-release capsules without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking morphine sulfate extended-release capsules.</li>\n<li>\n<span class=\"Bold\">Are pregnant or planning to become pregnant.</span> Use of morphine sulfate extended-release capsules for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</li>\n<li>\n<span class=\"Bold\">breastfeeding.</span> Not recommended during treatment with morphine sulfate extended-release capsules. It may harm your baby.</li>\n<li>living in a household where there are small children or someone who has abused street or prescription drugs.</li>\n<li>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking morphine sulfate extended-release capsules with certain other medicines can cause serious side effects.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">When taking morphine sulfate extended-release capsules:</span>\n</p>\n<ul class=\"Disc\">\n<li>Do not change your dose. Take morphine sulfate extended-release capsules exactly as prescribed by your healthcare provider. Use the lowest does possible for the shortest time needed.</li>\n<li>Take your prescribed dose every 24 hours, at the same time every day. Do not take more than your prescribed dose in 24 hours. If you miss a dose, take your next dose at your usual time the next day.</li>\n<li>Swallow morphine sulfate extended-release capsules whole. Do not cut, break, chew, crush, dissolve, snort, or inject morphine sulfate extended-release capsules because this may cause you to overdose and die.</li>\n<li>If you cannot swallow morphine sulfate extended-release capsules, see the detailed Instructions for Use.</li>\n<li>\n<span class=\"Bold\">Call your healthcare provider if the dose you are taking does not control your pain.</span>\n</li>\n<li>\n<span class=\"Bold\">Do not stop taking morphine sulfate extended-release capsules without talking to your healthcare provider.</span>\n</li>\n<li>Dispose of expired, unwanted, or unused morphine sulfate extended-release capsules by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit <a href=\"http://www.fda.gov/drugdisposal\">www.fda.gov/drugdisposal</a> for additional information on disposal of unused medicines.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">While taking morphine sulfate extended-release capsules DO NOT:</span>\n</p>\n<ul class=\"Disc\">\n<li>Drive or operate heavy machinery, until you know how morphine sulfate extended-release capsules affect you. Morphine sulfate extended-release capsules can make you sleepy, dizzy, or lightheaded.</li>\n<li>Drink alcohol, or use prescription or over-the-counter medicines containing alcohol. Using products containing alcohol during treatment with morphine sulfate extended-release capsules may cause you to overdose and die.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Toprule\"> <span class=\"Bold\">The possible side effects of morphine sulfate extended-release capsules are:</span>\n<ul class=\"Disc\">\n<li>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.\n <p class=\"First\">\n<span class=\"Bold\">Get emergency medical help or call 911 right away if you have:</span>\n</p>\n</li>\n<li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li>\n</ul>\n<p class=\"First\">These are not all the possible side effects of morphine sulfate extended-release capsules. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class=\"Bold\">For more information go to dailymed.nlm.nih.gov.</span>\n</p>\n<p>Manufactured For: <span class=\"Bold\">Teva Pharmaceuticals, </span>Parsippany, NJ 07054</p>\n<p>For additional product information about morphine sulfate extended-release capsules, contact Teva at 1-888-838-2872.</p> </td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                         Rev. A 9/2024

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration.                                                         Rev. A 9/2024" }

Morphine Sulfate (mor' feen sul' fate) Extended-Release Capsules, USP (Once Daily) CII

{ "type": "p", "children": [], "text": "\nMorphine Sulfate (mor' feen sul' fate) \nExtended-Release Capsules, USP (Once Daily) CII\n" }

{ "type": "ul", "children": [ "If you cannot swallow morphine sulfate extended-release capsules, tell your healthcare provider. There may be another way to take morphine sulfate extended-release capsules that may be right for you. If your healthcare provider tells you that you can take morphine sulfate extended-release capsules using this other way, follow these steps: " ], "text": "" }

Morphine sulfate extended-release capsules can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows:

{ "type": "p", "children": [], "text": "Morphine sulfate extended-release capsules can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows:" }

<div class="scrollingtable"><table> <col width="133px"/> <col width="234px"/> <col width="245px"/> <tbody class="Headless"> <tr class="First"> <td> <img alt="Open the morphine sulfate extended-release capsule and sprinkle the pellets over approximately one tablespoon of applesauce (Figure 1)." src="/dailymed/image.cfm?name=image-15.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680"/></td><td>        </td><td>Open the morphine sulfate extended-release capsule and sprinkle the pellets over approximately one tablespoon of applesauce <span class="Italics">(See Figure 1).</span></td> </tr> <tr> <td> <span class="Italics">Figure 1</span></td><td>  </td><td> </td> </tr> <tr> <td> <img alt="Swallow all of the applesauce and pellets right away. Do not save any of the applesauce and pellets for another dose (Figure 2)." src="/dailymed/image.cfm?name=image-16.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680"/></td><td>  </td><td>Swallow all of the applesauce and pellets right away. Do not save any of the applesauce and pellets for another dose<span class="Italics"> (See Figure 2).</span></td> </tr> <tr> <td> <span class="Italics">Figure 2</span></td><td>  </td><td> </td> </tr> <tr> <td> <img alt="Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets (Figure 3)." src="/dailymed/image.cfm?name=image-17.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680"/></td><td> </td><td>Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets <span class="Italics">(See Figure 3).</span></td> </tr> <tr> <td><span class="Italics"> Figure 3</span></td><td>  </td><td> </td> </tr> <tr> <td> <img alt="Flush the empty capsule down the toilet right away (Figure 4)." src="/dailymed/image.cfm?name=image-18.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680"/></td><td> </td><td>Flush the empty capsule down the toilet right away <span class="Italics">(See Figure 4).</span></td> </tr> <tr class="Last"> <td> <span class="Italics">Figure 4</span></td><td>  </td><td> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"133px\"/>\n<col width=\"234px\"/>\n<col width=\"245px\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td> <img alt=\"Open the morphine sulfate extended-release capsule and sprinkle the pellets over approximately one tablespoon of applesauce (Figure 1).\" src=\"/dailymed/image.cfm?name=image-15.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680\"/></td><td>        </td><td>Open the morphine sulfate extended-release capsule and sprinkle the pellets over approximately one tablespoon of applesauce <span class=\"Italics\">(See Figure 1).</span></td>\n</tr>\n<tr>\n<td> <span class=\"Italics\">Figure 1</span></td><td>  </td><td> </td>\n</tr>\n<tr>\n<td> <img alt=\"Swallow all of the applesauce and pellets right away. Do not save any of the applesauce and pellets for another dose (Figure 2).\" src=\"/dailymed/image.cfm?name=image-16.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680\"/></td><td>  </td><td>Swallow all of the applesauce and pellets right away. Do not save any of the applesauce and pellets for another dose<span class=\"Italics\"> (See Figure 2).</span></td>\n</tr>\n<tr>\n<td> <span class=\"Italics\">Figure 2</span></td><td>  </td><td> </td>\n</tr>\n<tr>\n<td> <img alt=\"Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets (Figure 3).\" src=\"/dailymed/image.cfm?name=image-17.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680\"/></td><td> </td><td>Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets <span class=\"Italics\">(See Figure 3).</span></td>\n</tr>\n<tr>\n<td><span class=\"Italics\"> Figure 3</span></td><td>  </td><td> </td>\n</tr>\n<tr>\n<td> <img alt=\"Flush the empty capsule down the toilet right away (Figure 4).\" src=\"/dailymed/image.cfm?name=image-18.jpg&amp;setid=2da87bfa-11fd-43e3-8fef-d16ebeb15680\"/></td><td> </td><td>Flush the empty capsule down the toilet right away <span class=\"Italics\">(See Figure 4).</span></td>\n</tr>\n<tr class=\"Last\">\n<td> <span class=\"Italics\">Figure 4</span></td><td>  </td><td> </td>\n</tr>\n</tbody>\n</table></div>" }

You should not receive morphine sulfate extended-release capsules through a nasogastric tube or gastric tube (stomach tube).

{ "type": "p", "children": [], "text": "You should not receive morphine sulfate extended-release capsules through a nasogastric tube or gastric tube (stomach tube)." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Manufactured For:\nTeva Pharmaceuticals\nParsippany, NJ 07054" }

Rev. A 9/2024

{ "type": "p", "children": [], "text": "Rev. A 9/2024" }

NDC 0228-3090-11

{ "type": "p", "children": [], "text": "NDC 0228-3090-11" }

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 30 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 30 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

Rx only

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

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules\n\n" }

NDC 0228-3116-11

{ "type": "p", "children": [], "text": "NDC 0228-3116-11" }

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 45 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 45 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

Rx only

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

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules\n\n" }

NDC 0228-3091-11

{ "type": "p", "children": [], "text": "NDC 0228-3091-11" }

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 60 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 60 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

Rx only

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

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules\n\n" }

NDC 0228-3117-11

{ "type": "p", "children": [], "text": "NDC 0228-3117-11" }

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 75 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 75 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

Rx only

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

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules\n\n" }

NDC 0228-3092-11

{ "type": "p", "children": [], "text": "NDC 0228-3092-11" }

Rx only

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

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 90 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 90 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

{ "type": "p", "children": [], "text": "FOR USE IN OPIOID-TOLERANT PATIENTS ONLY" }

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules" }

NDC 0228-3093-11

{ "type": "p", "children": [], "text": "NDC 0228-3093-11" }

Rx only

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

CII (Once Daily) Morphine Sulfate Extended-Release Capsules, USP 120 mg

{ "type": "p", "children": [], "text": "CII\n\n(Once Daily)\nMorphine Sulfate Extended-Release Capsules, USP 120 mg" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the accompanying Medication Guide to each patient." }

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

{ "type": "p", "children": [], "text": "FOR USE IN OPIOID-TOLERANT PATIENTS ONLY" }

100 Capsules

{ "type": "p", "children": [], "text": "100 Capsules" }

Morphine Sulfate Tablets are indicated for the management of:

{ "type": "p", "children": [], "text": "Morphine Sulfate Tablets are indicated for the management of:" }

{ "type": "ul", "children": [ "adults with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.", "adults with chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate." ], "text": "" }

Limitations of Use

{ "type": "p", "children": [], "text": "Limitations of Use" }

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.1)] , reserve morphine sulfate tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

{ "type": "p", "children": [], "text": "\nBecause of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n , reserve morphine sulfate tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:\n\n \n" }

{ "type": "ul", "children": [ "Have not been tolerated or are not expected to be tolerated,", "Have not provided adequate analgesia or are not expected to provide adequate analgesia." ], "text": "" }

Morphine sulfate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

{ "type": "p", "children": [], "text": "\nMorphine sulfate tablets should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.\n" }

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

{ "type": "p", "children": [], "text": "\nPediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.\n" }

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

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

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1, 5.2, 5.3)].

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

Use of Morphine Sulfate Tablets as the First Opioid Analgesic (Opioid-Naïve or Opioid-Non-Tolerant Patients):

Adults:The recommended dosage to initiate treatment in adults is 15 mg to 30 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate tablets.  

Morphine sulfate tablets are not recommended for use in pediatric patients who weigh less than 50 kg as the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg.

Conversion from Parenteral Morphine to Morphine Sulfate Tablets

For conversion from parenteral morphine to morphine sulfate tablets, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion from Other Opioids to Morphine Sulfate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of morphine sulfate tablets. It is safer to underestimate a patient’s 24-hour morphine sulfate tablets dosage than to overestimate the 24-hour morphine sulfate tablets dosage and manage an adverse reaction due to overdose. Initiate dosing using morphine sulfate tablets 15 mg to 30 mg every 4 hours.

Conversion from Morphine Sulfate Tablets to Extended-Release Morphine

For a given dose, the same total amount of morphine sulfate is available from morphine sulfate tablets, and extended-release morphine formulations. The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from morphine sulfate tablets to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels. Therefore, conversion to extended-release morphine may lead to increased risk of excessive sedation and respiratory depression.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Individually titrate morphine sulfate tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1, 5.14)] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5)] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Do not abruptly discontinue morphine sulfate tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking morphine sulfate tablets, there are a variety of factors that should be considered, including the total daily dose of opioids (including morphine sulfate tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on morphine sulfate tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.14) and Drug Abuse and Dependence ( 9.3)] .

{ "type": "ul", "children": [ "Each 15 mg tablet for oral administration contains: 15 mg morphine sulfate USP (equivalent to 11.25 mg morphine) and is a white, biconvex tablet, debossed “M” on one side, and “15” with a score on the other side.", "Each 30 mg tablet for oral administration contains: 30 mg morphine sulfate USP (equivalent to 22.5 mg morphine) and is a white, biconvex tablet, debossed “M” on one side, and “30” with a score on the other side. \n \n" ], "text": "" }

Morphine sulfate tablets are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Morphine sulfate tablets are contraindicated in patients with:" }

{ "type": "ul", "children": [ "Significant respiratory depression\n \n [see Warnings and Precautions (\n \n 5.2)]\n \n .\n \n ", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment\n \n [see Warnings and Precautions (5.7)].\n \n ", "Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days\n \n [see Warnings and Precautions (5.8) and Drug Interactions (\n \n 7)]\n \n .\n \n ", "Known or suspected gastrointestinal obstruction, including paralytic ileus\n \n [see Warnings and Precautions (5.12)].\n \n ", "Hypersensitivity to morphine (e.g., anaphylaxis)\n \n [see Adverse Reactions (\n \n 6)]\n \n .\n \n " ], "text": "" }

Morphine sulfate tablets contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate tablets expose 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 morphine sulfate. 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 morphine sulfate tablets, and reassess all patients receiving morphine sulfate tablets 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 morphine sulfate tablets, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose  [see Dosage and Administration ( 2.2) and Warnings and Precautions ( 5.2)] .

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

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10)] . Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

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

To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential [see Dosage and Administration (2.3,2.4)]. Overestimating the morphine sulfate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.

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

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered  [see Patient Counseling Information ( 17)] .

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone  [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.1, 5.3)] .

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

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

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.2), Overdosage ( 10)] .

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

Use of morphine sulfate tablets 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)] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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 ( 2.5), Warnings and Precautions ( 5.14)] .

The use of morphine sulfate tablets 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

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

Elderly, Cachectic, or Debilitated Patients

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

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

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine sulfate tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

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

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

In patients who may be susceptible to the intracranial effects of CO 2retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine sulfate tablets may reduce respiratory drive, and the resultant CO 2retention can further increase intracranial pressure. Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy with morphine sulfate tablets.

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

Morphine sulfate tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

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

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

Do not abruptly discontinue morphine sulfate tablets in a patient physically dependent on opioids. When discontinuing morphine sulfate tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) and Drug Abuse and Dependence ( 9.3)] .

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including morphine sulfate tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions ( 7)] .

Morphine sulfate tablets 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 morphine sulfate tablets and know how they will react to the medication.

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

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

{ "type": "ul", "children": [ "Addiction, Abuse, and Misuse\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n \n", "Life-Threatening Respiratory Depression\n \n [see Warnings and Precautions (\n \n 5.2)]\n \n \n", "Interactions with Benzodiazepine or Other CNS Depressants\n \n [see Warnings and Precautions (\n \n 5.3)]\n \n \n", "\nNeonatal Opioid Withdrawal Syndrome\n \n [see Warnings and Precautions (\n \n 5.4)]\n \n \n", "\nOpioid-Induced Hyperalgesia and Allodynia\n \n [see Warnings and Precautions (\n \n 5.6)]\n \n  \n", "Adrenal Insufficiency\n \n [see Warnings and Precautions (\n \n 5.9)]\n \n \n", "Severe Hypotension\n \n [see Warnings and Precautions (\n \n 5.10)]\n \n \n", "Gastrointestinal Adverse Reactions\n \n [see Warnings and Precautions (\n \n 5.12)]\n \n \n", "Seizures\n \n [see Warnings and Precautions (\n \n 5.13)]\n \n \n", "Withdrawal\n \n [see Warnings and Precautions (\n \n 5.14)]\n \n \n" ], "text": "" }

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

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

Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

{ "type": "p", "children": [], "text": "Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest." }

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included: constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

{ "type": "p", "children": [], "text": "The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included: constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual." }

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

{ "type": "p", "children": [], "text": "Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:" }

Body as a Whole:malaise, withdrawal syndrome

{ "type": "p", "children": [], "text": "\nBody as a Whole:malaise, withdrawal syndrome\n\n " }

Cardiovascular System:bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

{ "type": "p", "children": [], "text": "\nCardiovascular System:bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia\n\n " }

Digestive System:biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

{ "type": "p", "children": [], "text": "\nDigestive System:biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst\n\n " }

Endocrine:hypogonadism

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

Hemic and Lymphatic System:anemia, thrombocytopenia

{ "type": "p", "children": [], "text": "\nHemic and Lymphatic System:anemia, thrombocytopenia\n\n " }

Metabolic and Nutritional Disorders:edema, weight loss

{ "type": "p", "children": [], "text": "\nMetabolic and Nutritional Disorders:edema, weight loss\n\n " }

Musculoskeletal:skeletal muscle rigidity, decreased bone mineral density

{ "type": "p", "children": [], "text": "\nMusculoskeletal:skeletal muscle rigidity, decreased bone mineral density\n\n " }

Nervous System:abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

{ "type": "p", "children": [], "text": "\nNervous System:abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache\n\n " }

Respiratory System:hiccup, hypoventilation, voice alteration

{ "type": "p", "children": [], "text": "\nRespiratory System:hiccup, hypoventilation, voice alteration\n\n " }

Skin and Appendages:dry skin, urticaria, pruritus

{ "type": "p", "children": [], "text": "\nSkin and Appendages:dry skin, urticaria, pruritus\n\n " }

Special Senses:amblyopia, eye pain, taste perversion

{ "type": "p", "children": [], "text": "\nSpecial Senses:amblyopia, eye pain, taste perversion\n\n " }

Urogenital System:abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea

{ "type": "p", "children": [], "text": "\nUrogenital System:abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea\n\n " }

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

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

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

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

Anaphylaxis:Anaphylaxis has been reported with ingredients contained in morphine sulfate tablets.

{ "type": "p", "children": [], "text": "\nAnaphylaxis:Anaphylaxis has been reported with ingredients contained in morphine sulfate tablets.\n\n " }

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

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

Hyperalgesia and Allodynia:Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.6)]

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia:Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration\n \n [see Warnings and Precautions (\n \n 5.6)]\n \n \n" }

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).

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

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

{ "type": "p", "children": [], "text": "\nPediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.\n" }

Table 1 includes clinically significant drug interactions with morphine sulfate tablets.

{ "type": "p", "children": [], "text": "Table 1 includes clinically significant drug interactions with morphine sulfate tablets." }

Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Tablets

{ "type": "p", "children": [], "text": "\nTable 1: Clinically Significant Drug Interactions with Morphine Sulfate Tablets\n" }

<div class="scrollingtable"><table> <col width="1px"/> <col width="71%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see Warnings and Precautions ( <a href="#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b">5.3</a>)] </span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#LINK_a316060c-90db-4527-b521-95515c681e74">2.2</a>), Warnings and Precautions ( <a href="#LINK_07c9c395-e15b-413c-acdd-6722d689cefc">5.1</a>, <a href="#LINK_d51f8096-50e6-4a6f-ac45-a35088f34b9a">5.2</a>, <a href="#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b">5.3</a>)] </span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate tablets if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">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_8727950f-3509-4b7d-bbfd-169749a3570b">5.8</a>)] </span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Do not use morphine sulfate tablets in patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Phenelzine, tranylcypromine, linezolid.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">May reduce the analgesic effect of morphine sulfate tablets and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Butorphanol, nalbuphine, pentazocine, buprenorphine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#LINK_a316060c-90db-4527-b521-95515c681e74">2.2</a>), Warnings and Precautions ( <a href="#LINK_d51f8096-50e6-4a6f-ac45-a35088f34b9a">5.2</a>, <a href="#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b">5.3</a>)] </span>. </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Cyclobenzaprine, metaxalone</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Cimetidine</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Evaluate patients for increased respiratory and CNS depression when morphine sulfate tablets are used concomitantly with cimetidine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Evaluate patients for signs of urinary retention or reduced gastric motility when morphine sulfate tablets are used concomitantly with anticholinergic drugs.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top">  <p class="First"> <span class="Bold">P-Glycoprotein (P-gp) Inhibitors</span> </p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top">  <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate tablets and/or the P-gp inhibitor as necessary.</p> </td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top">  <p class="First">Quinidine, verapamil.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"1px\"/>\n<col width=\"71%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b\">5.3</a>)]\n \n </span>.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#LINK_a316060c-90db-4527-b521-95515c681e74\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#LINK_07c9c395-e15b-413c-acdd-6722d689cefc\">5.1</a>,\n \n <a href=\"#LINK_d51f8096-50e6-4a6f-ac45-a35088f34b9a\">5.2</a>,\n \n <a href=\"#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b\">5.3</a>)]\n \n </span>.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \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 \n <p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate tablets if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#LINK_8727950f-3509-4b7d-bbfd-169749a3570b\">5.8</a>)]\n \n </span>.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Do not use morphine sulfate tablets in patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \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 \n <p class=\"First\">\n<span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">May reduce the analgesic effect of morphine sulfate tablets and/or precipitate withdrawal symptoms.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \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 \n <p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#LINK_a316060c-90db-4527-b521-95515c681e74\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#LINK_d51f8096-50e6-4a6f-ac45-a35088f34b9a\">5.2</a>,\n \n <a href=\"#LINK_71ff7e8c-f3e9-487b-98ec-33ea4f5cfa5b\">5.3</a>)]\n \n </span>.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Cyclobenzaprine, metaxalone</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Cimetidine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Evaluate patients for increased respiratory and CNS depression when morphine sulfate tablets are used concomitantly with cimetidine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Evaluate patients for signs of urinary retention or reduced gastric motility when morphine sulfate tablets are used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Bold\">P-Glycoprotein (P-gp) Inhibitors</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate tablets and/or the P-gp inhibitor as necessary.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n <p class=\"First\">Quinidine, verapamil.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4)] . There are no available data with morphine sulfate tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

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 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 signs 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. Morphine sulfate tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including morphine sulfate tablets, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data:The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data:Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with morphine sulfate tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

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

Clinical Considerations

Monitor infants exposed to morphine sulfate tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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) and Clinical Pharmacology ( 12.2)] .

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology ( 13)] .

The safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg [see Dosage and Administration ( 2.3)] .

The safety and effectiveness of morphine sulfate tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose 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 morphine sulfate tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.7)] .

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

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3)] .

Morphine sulfate pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of morphine sulfate tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3)] .

Morphine sulfate tablets contain morphine, a Schedule II controlled substance.

Morphine sulfate tablets contains morphine, 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 morphine sulfate tablets 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 morphine sulfate tablets with alcohol and 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 re-evaluation 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 morphine sulfate tablets abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use Morphine Sulfate Tablets 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.

Morphine sulfate tablets, 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 Morphine Sulfate Tablets

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

Morphine sulfate tablets are approved for oral use only.

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.

Do not abruptly discontinue morphine sulfate tablets in a patient physically dependent on opioids. Rapid tapering of morphine sulfate tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing morphine sulfate tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), and Warnings and Precautions ( 5.14)] .

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

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Acute overdose with morphine 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)] .

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Treatment of Overdose

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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.

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

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

Because the duration of opioid reversal is expected to be less than the duration of action of morphine in morphine sulfate tablets, 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.

{ "type": "p", "children": [], "text": "Because the duration of opioid reversal is expected to be less than the duration of action of morphine in morphine sulfate tablets, 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.

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

Morphine Sulfate Tablets are an opioid agonist, available for oral administration:

{ "type": "p", "children": [], "text": "Morphine Sulfate Tablets are an opioid agonist, available for oral administration:" }

{ "type": "ul", "children": [ "15 mg tablet: Each tablet contains 15 mg of morphine sulfate, USP (equivalent to 11.25 mg morphine).", "30 mg tablet: Each tablet contains 30 mg of morphine sulfate, USP (equivalent to 22.5 mg morphine)." ], "text": "" }

Chemically, morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol sulfate (2:1) (salt) pentahydrate. Morphine sulfate, USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pka is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Its molecular formula is (C 17H 19NO 3) 2• H 2SO 4• 5H 2O, and it has the following chemical structure:

{ "type": "p", "children": [], "text": "Chemically, morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol sulfate (2:1) (salt) pentahydrate. Morphine sulfate, USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pka is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Its molecular formula is (C\n \n 17H\n \n 19NO\n \n 3)\n \n 2• H\n \n 2SO\n \n 4• 5H\n \n 2O, and it has the following chemical structure:\n\n " }

Each tablet contains 15 or 30 mg of morphine sulfate, USP and the following inactive ingredients: Microcrystalline Cellulose (Avicel PH 102), Corn Starch, Pregelatinized Starch, Magnesium Stearate, Colloidal Silicon Dioxide, and Stearic Acid 50 Powder.

{ "type": "p", "children": [], "text": "Each tablet contains 15 or 30 mg of morphine sulfate, USP and the following inactive ingredients: Microcrystalline Cellulose (Avicel PH 102), Corn Starch, Pregelatinized Starch, Magnesium Stearate, Colloidal Silicon Dioxide, and Stearic Acid 50 Powder." }

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine 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

Morphine 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

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

Effects on the Endocrine System

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

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

Effects on the Immune System

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

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.4)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing morphine 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,  2.4)].

Absorption

Morphine, when administered as morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Administration of the 30 mg Morphine Sulfate Tablet and 30 mg of Morphine Sulfate Oral Solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC). The steady-state levels were achieved within 48 hours for both tablets and solution. The mean steady state C maxvalues were about 78 and 58 ng/mL for tablets and solution, respectively.

Food Effects:When morphine sulfate 30 mg tablet was administered 30 minutes after ingesting a high fat/high calorie meal, there was no change in the extent of absorption (AUC) of morphine sulfate. There was, however, an increase in the median T maxfrom 0.5 to 0.75 hours and an 11% decrease in C max. The tablet can be administered without regard to meals.

Distribution

Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20% to 35% reversibly bound to plasma proteins.

Elimination

Metabolism:The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion:Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Specific Populations

Race/Ethnicity:There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

Sex:While evidence of greater post-operative morphine sulfate consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of morphine sulfate, including respiratory depression, in women compared to men.

Hepatic Impairment:Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment:Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Carcinogenesis

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

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitroincreasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivomouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivoclastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitrostudies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.

Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e., testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

Morphine Sulfate Tablets are supplied as follows:

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Each 15 mg tablet for oral administration contains: 15 mg morphine sulfate USP and is a white, biconvex tablet, debossed “M” on one side, and “15” with a score on the other side. 

{ "type": "p", "children": [], "text": "Each 15 mg tablet for oral administration contains: 15 mg morphine sulfate USP and is a white, biconvex tablet, debossed “M” on one side, and “15” with a score on the other side. " }

15 mg bottles of 100: NDC 0406-5118-01 15 mg box of 100 unit dose: NDC 0406-5118-62

{ "type": "p", "children": [], "text": "15 mg bottles of 100: NDC 0406-5118-01 \n 15 mg box of 100 unit dose: NDC 0406-5118-62\n " }

Each 30 mg tablet for oral administration contains: 30 mg morphine sulfate USP and is a white, biconvex tablet, debossed “M” on one side, and “30” with a score on the other side. 

{ "type": "p", "children": [], "text": "Each 30 mg tablet for oral administration contains: 30 mg morphine sulfate USP and is a white, biconvex tablet, debossed “M” on one side, and “30” with a score on the other side. " }

30 mg bottles of 100: NDC 0406-5119-01 30 mg box of 100 unit dose: NDC 0406-5119-62

{ "type": "p", "children": [], "text": "30 mg bottles of 100: NDC 0406-5119-01 \n 30 mg box of 100 unit dose: NDC 0406-5119-62\n " }

Storage

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

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

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] \n \n" }

Protect from moisture.

{ "type": "p", "children": [], "text": "Protect from moisture." }

Store morphine sulfate tablets securely and dispose of properly [see Patient Counseling Information ( 17)] .

{ "type": "p", "children": [], "text": "Store morphine sulfate tablets securely and dispose of properly\n \n [see Patient Counseling Information (\n \n 17)]\n \n .\n\n " }

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

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

Storage and Disposal

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

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

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

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

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

Addiction, Abuse, and Misuse

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

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

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

Life-Threatening Respiratory Depression

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

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

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

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

Accidental Ingestion

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

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.2)] .

{ "type": "p", "children": [], "text": "Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death\n \n [see Warnings and Precautions (\n \n 5.2)]\n \n .\n\n " }

Interactions with Benzodiazepines and Other CNS Depressants

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

Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.3) and Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "Inform patients and caregivers that potentially fatal additive effects may occur if morphine sulfate tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider\n \n [see Warnings and Precautions (\n \n 5.3) and Drug Interactions (\n \n 7)]\n \n .\n\n " }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

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

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

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

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

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

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

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

If naloxone is prescribed, also advise patients and caregivers:

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

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

Hyperalgesia and Allodynia

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

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.6), Adverse Reactions ( 6)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain\n \n [see Warnings and Precautions (\n \n 5.6), Adverse Reactions (\n \n 6)].\n \n \n" }

Serotonin Syndrome

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

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

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

MAOI Interaction

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

Inform patients not to take morphine sulfate tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate tablets  [see Warnings and Precautions ( 5.8) and Drug Interactions ( 7)] .

{ "type": "p", "children": [], "text": "Inform patients not to take morphine sulfate tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate tablets \n \n [see Warnings and Precautions (\n \n 5.8) and Drug Interactions (\n \n 7)]\n \n .\n\n " }

Important Administration Instructions

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

Instruct patients how to properly take morphine sulfate tablets. Advise patients not to adjust the dose of morphine sulfate without consulting with a physician or other healthcare professional.

{ "type": "p", "children": [], "text": "Instruct patients how to properly take morphine sulfate tablets. Advise patients not to adjust the dose of morphine sulfate without consulting with a physician or other healthcare professional." }

Important Discontinuation Instructions

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

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].

{ "type": "p", "children": [], "text": "In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine sulfate tablets without first discussing a tapering plan with the prescriber\n \n [see Dosage and Administration (2.5)].\n\n " }

Driving or Operating Heavy Machinery

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

Inform patients that morphine sulfate tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.15)] .

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication\n \n [see Warnings and Precautions (\n \n 5.15)]\n \n .\n\n " }

Constipation

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

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

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

Adrenal Insufficiency

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

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.9)] .

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms\n \n [see Warnings and Precautions (\n \n 5.9)]\n \n .\n\n " }

Hypotension

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

Inform patients that morphine sulfate tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.10)] .

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position)\n \n [see Warnings and Precautions (\n \n 5.10)]\n \n .\n\n " }

Anaphylaxis

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

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

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

Pregnancy

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

Neonatal Opioid Withdrawal Syndrome:Inform patients of reproductive potential that use of morphine sulfate tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.4) and Use in Specific Populations ( 8.1)] .

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome:Inform patients of reproductive potential that use of morphine sulfate tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated\n \n [see Warnings and Precautions (\n \n 5.4) and Use in Specific Populations (\n \n 8.1)]\n \n .\n\n " }

Embryo-Fetal Toxicity:Inform female patients of reproductive potential that morphine sulfate tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1)] .

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity:Inform female patients of reproductive potential that morphine sulfate tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy\n \n [see Use in Specific Populations (\n \n 8.1)]\n \n .\n\n " }

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\n \n [see Use in Specific Populations (\n \n 8.2)]\n \n .\n\n " }

Infertility

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

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6); Use in Specific Populations ( 8.3)] .

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible\n \n [see\n \n Adverse Reactions (\n \n 6); Use in Specific Populations (\n \n 8.3)]\n \n .\n \n \n" }

Mallinckrodt, the “M” brand mark, and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.

{ "type": "p", "children": [], "text": "Mallinckrodt, the “M” brand mark, and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company." }

© 2023 Mallinckrodt.

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

SpecGx LLC Webster Groves, MO 63119 USA

{ "type": "p", "children": [], "text": "SpecGx LLC \n Webster Groves, MO 63119 USA\n " }

Mallinckrodt™ Pharmaceuticals

{ "type": "p", "children": [], "text": "\nMallinckrodt™ \n \nPharmaceuticals\n\n " }

Issued 12/2023

{ "type": "p", "children": [], "text": "Issued 12/2023" }

An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20M58.pdf or by calling 1-800-778-7898 for alternate delivery options.

{ "type": "p", "children": [], "text": "An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20M58.pdf or by calling 1-800-778-7898 for alternate delivery options." }

<div class="scrollingtable"><table> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Medication Guide</span> </p> <p> <span class="Bold">Morphine Sulfate (mor’ feen sul’ fate) Tablets CII</span> </p> <p> <span class="Bold">Rx only</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">Morphine sulfate tablets are:</span> </p> <ul> <li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short-term (acute) pain and long-term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</li> <li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">Important information about morphine sulfate tablets:</span> </p> <ul> <li> <span class="Bold">Get emergency help or call 911 right away if you take too many morphine sulfate tablets (overdose).</span> When you first start taking morphine sulfate tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. </li> <li>Taking morphine sulfate tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li> <li>Never give anyone else your morphine sulfate tablets. They could die from taking it. Selling or giving away morphine sulfate tablets is against the law.</li> <li>Store morphine sulfate tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">Do not take morphine sulfate tablets if you have:</span> </p> <ul> <li>Severe asthma, trouble breathing, or other lung problems.</li> <li>A bowel blockage or have narrowing of the stomach or intestines.</li> <li>An allergy to morphine.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">Before taking morphine sulfate tablets, tell your healthcare provider if you have a history of:</span> </p> </td> </tr> <tr> <td class="Lrule">  <ul> <li>Head injury, seizures.</li> </ul> </td><td class="Rrule">  <ul> <li>Liver, kidney, thyroid problems.</li> </ul> </td> </tr> <tr> <td class="Lrule">  <ul> <li>Problems urinating.</li> </ul> </td><td class="Rrule">  <ul> <li>Pancreas or gallbladder problems.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2">  <ul> <li>Abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2">  <p class="First"> <span class="Bold">Tell your healthcare provider if you are:</span> </p> <ul> <li> <span class="Bold">noticing your pain getting worse.</span>If your pain gets worse after you take morphine sulfate tablets, do not take more of morphine sulfate tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking morphine sulfate tablets. </li> <li> <span class="Bold">pregnant or planning to become pregnant.</span>Use of morphine sulfate for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. </li> <li> <span class="Bold">breastfeeding.</span>Morphine sulfate passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual) breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. </li> <li>Living in a household where there are small children or someone who has abused street or prescription drugs.</li> <li>Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking morphine sulfate tablets with certain other medicines can cause serious side effects that could lead to death.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">When taking morphine sulfate tablets:</span> </p> <ul> <li>Do not change your dose. Take morphine sulfate tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</li> <li>For acute (short-term) pain, you may only need to take morphine sulfate tablets for a few days. You may have some morphine sulfate tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused morphine sulfate tablets. </li> <li>Take your prescribed dose every 4 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</li> <li>Call your healthcare provider if the dose you are taking does not control your pain.</li> <li>If you have been taking morphine sulfate tablets regularly, do not stop taking morphine sulfate without talking to your healthcare provider.</li> <li>Dispose of expired, unwanted, or unused morphine sulfate tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">While taking morphine sulfate tablets DO NOT:</span> </p> <ul> <li>Drive or operate heavy machinery, until you know how morphine sulfate affects you. Morphine sulfate tablets can make you sleepy, dizzy, or lightheaded.</li> <li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with morphine sulfate tablets may cause you to overdose and die.</li> </ul> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2">  <p class="First"> <span class="Bold">The possible side effects of morphine sulfate tablets:</span> </p> <ul> <li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</li> </ul> <p> <span class="Bold">Get emergency medical help or call 911 right away if you have:</span> </p> <ul> <li>Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li> </ul> <p>These are not all the possible side effects of morphine sulfate tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class="Bold">For more information go to dailymed.nlm.nih.gov.</span> </p> <p>Manufactured by: SpecGx LLC, Webster Groves, MO 63119 USA, <br/> www.mallinckrodt.com or call 1-800-778-7898 <span class="Bold"> <br/> Mallinckrodt™ </span> </p> </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\">\n<p class=\"First\">\n<span class=\"Bold\">Medication Guide</span>\n</p>\n<p>\n<span class=\"Bold\">Morphine Sulfate (mor’ feen sul’ fate) Tablets CII</span>\n</p>\n<p>\n<span class=\"Bold\">Rx only</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Morphine sulfate tablets are:</span>\n</p>\n<ul>\n<li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short-term (acute) pain and long-term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</li>\n<li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Important information about morphine sulfate tablets:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Get emergency help or call 911 right away if you take too many morphine sulfate tablets (overdose).</span> When you first start taking morphine sulfate tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.\n \n </li>\n<li>Taking morphine sulfate tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li>\n<li>Never give anyone else your morphine sulfate tablets. They could die from taking it. Selling or giving away morphine sulfate tablets is against the law.</li>\n<li>Store morphine sulfate tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Do not take morphine sulfate tablets if you have:</span>\n</p>\n<ul>\n<li>Severe asthma, trouble breathing, or other lung problems.</li>\n<li>A bowel blockage or have narrowing of the stomach or intestines.</li>\n<li>An allergy to morphine.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Before taking morphine sulfate tablets, tell your healthcare provider if you have a history of:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\"> \n \n <ul>\n<li>Head injury, seizures.</li>\n</ul>\n</td><td class=\"Rrule\"> \n \n <ul>\n<li>Liver, kidney, thyroid problems.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\"> \n \n <ul>\n<li>Problems urinating.</li>\n</ul>\n</td><td class=\"Rrule\"> \n \n <ul>\n<li>Pancreas or gallbladder problems.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\"> \n \n <ul>\n<li>Abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">noticing your pain getting worse.</span>If your pain gets worse after you take morphine sulfate tablets, do not take more of morphine sulfate tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking morphine sulfate tablets.\n \n </li>\n<li>\n<span class=\"Bold\">pregnant or planning to become pregnant.</span>Use of morphine sulfate for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.\n \n </li>\n<li>\n<span class=\"Bold\">breastfeeding.</span>Morphine sulfate passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual) breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.\n \n </li>\n<li>Living in a household where there are small children or someone who has abused street or prescription drugs.</li>\n<li>Taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking morphine sulfate tablets with certain other medicines can cause serious side effects that could lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">When taking morphine sulfate tablets:</span>\n</p>\n<ul>\n<li>Do not change your dose. Take morphine sulfate tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</li>\n<li>For acute (short-term) pain, you may only need to take morphine sulfate tablets for a few days. You may have some morphine sulfate tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused morphine sulfate tablets. </li>\n<li>Take your prescribed dose every 4 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</li>\n<li>Call your healthcare provider if the dose you are taking does not control your pain.</li>\n<li>If you have been taking morphine sulfate tablets regularly, do not stop taking morphine sulfate without talking to your healthcare provider.</li>\n<li>Dispose of expired, unwanted, or unused morphine sulfate tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">While taking morphine sulfate tablets DO NOT:</span>\n</p>\n<ul>\n<li>Drive or operate heavy machinery, until you know how morphine sulfate affects you. Morphine sulfate tablets can make you sleepy, dizzy, or lightheaded.</li>\n<li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with morphine sulfate tablets may cause you to overdose and die.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"> \n \n <p class=\"First\">\n<span class=\"Bold\">The possible side effects of morphine sulfate tablets:</span>\n</p>\n<ul>\n<li>Constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</li>\n</ul>\n<p>\n<span class=\"Bold\">Get emergency medical help or call 911 right away if you have:</span>\n</p>\n<ul>\n<li>Trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li>\n</ul>\n<p>These are not all the possible side effects of morphine sulfate tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n \n <span class=\"Bold\">For more information go to dailymed.nlm.nih.gov.</span>\n</p>\n<p>Manufactured by: SpecGx LLC, Webster Groves, MO 63119 USA, \n <br/> www.mallinckrodt.com or call 1-800-778-7898\n \n <span class=\"Bold\">\n<br/> Mallinckrodt™\n </span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.      Revised: 12/2023 MG20M58

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Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

{ "type": "p", "children": [], "text": "\nPediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.\n" }

NDC 0406- 5118-01 100 TABLETS

{ "type": "p", "children": [], "text": "NDC 0406-\n \n 5118-01 \n 100 TABLETS\n\n " }

Morphine Sulfate Tablets

{ "type": "p", "children": [], "text": "\nMorphine Sulfate \n Tablets\n \n" }

CII

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

15 mg Rx only

{ "type": "p", "children": [], "text": "\n15 mg \n Rx only\n \n" }

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the Medication Guide provided separately to each patient." }

Mallinckrodt™

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

L0M143 Rev 09/2023

{ "type": "p", "children": [], "text": "L0M143 \n Rev 09/2023\n " }

NDC 0406- 5119-01 100 TABLETS

{ "type": "p", "children": [], "text": "NDC 0406-\n \n 5119-01 \n 100 TABLETS\n\n " }

Morphine Sulfate Tablets

{ "type": "p", "children": [], "text": "\nMorphine Sulfate \n Tablets\n \n" }

CII

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

30 mg Rx only

{ "type": "p", "children": [], "text": "\n30 mg \n Rx only\n \n" }

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

{ "type": "p", "children": [], "text": "PHARMACIST: Dispense the Medication Guide provided separately to each patient." }

Mallinckrodt™

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

L0M144 Rev 09/2023

{ "type": "p", "children": [], "text": "L0M144 \n Rev 09/2023\n " }

Morphine sulfate suppositories are indicated for the management of acute and chronic pain severe enough to require and opioid analgesic and for which alternative treatments are inadequate.

{ "type": "p", "children": [], "text": "Morphine sulfate suppositories are indicated for the management of acute and chronic pain severe enough to require and opioid analgesic and for which alternative treatments are inadequate." }

Limitations of Use

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Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)], reserve morphine sulfate suppositories for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

{ "type": "p", "children": [], "text": "Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)], reserve morphine sulfate suppositories for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:" }

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Morphine sulfate suppositories are available in four strengths: 5 mg per suppository, 10 mg per suppository, 20 mg per suppository, and 30 mg per suppository.

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

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

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with morphine sulfate suppositories and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate suppositories [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

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

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.2, 5.4, 5.6)].

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

Initiating Treatment with Morphine Sulfate Suppositories

Initiate treatment with morphine sulfate suppositories in a dosing range of 10 mg to 20 mg, rectally, every 4 hours.

Conversion from Other Opioids to Morphine Sulfate Suppositories

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised with determining the total daily dosage of morphine sulfate suppositories. It is safer to underestimate a patient’s 24-hour morphine sulfate dosage than to overestimate the 24-hour dosage and manage an adverse reaction due to overdose.

Conversion from Morphine Sulfate Suppositories to Extended-Release Morphine

The relative bioavailability of morphine sulfate suppositories compared to extended-release morphine is unknown, so conversion to extended-release drug product must be accompanied by close observation for signs of excessive sedation and respiratory depression.

Individually titrate morphine sulfate suppositories to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate suppositories to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate suppositories dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Do not abruptly discontinue morphine sulfate suppositories in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to

treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking morphine sulfate suppositories, there are a variety of factors that should be considered, including the dose of morphine sulfate suppositories the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an

appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on morphine sulfate suppositories who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Morphine Sulfate Suppositories are available in four strengths:

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories are available in four strengths:" }

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Morphine sulfate suppositories are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Morphine sulfate suppositories are contraindicated in patients with:" }

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Morphine sulfate suppositories contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate suppositories expose 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 morphine sulfate. Addiction can occur at recommended dosages and if the drug is misused or abused.

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

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing morphine sulfate suppositories. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

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 morphine sulfate suppositories, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of morphine sulfate suppositories.

To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate suppositories are essential [see Dosage and Administration (2)]. Overestimating the morphine sulfate suppositories dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental exposure of even one dose of morphine sulfate suppositories, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate suppositories. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing

requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is

prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.1, 5.4), Patient Counseling Information (17)].

Prolonged use of morphine sulfate suppositories during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

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

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

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

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

Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate suppositories are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

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

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

Monitor such patients closely, particularly when initiating and titrating morphine sulfate suppositories and when morphine sulfate suppositories are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine sulfate suppositories should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

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

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

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

Morphine sulfate suppositories is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The morphine in morphine sulfate suppositories 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 morphine in morphine sulfate suppositories 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 morphine sulfate suppositories therapy.

Do not abruptly discontinue morphine sulfate suppositories in a patient physically dependent on opioids. When discontinuing morphine sulfate suppositories in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including morphine sulfate suppositories. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

Morphine sulfate suppositories 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 morphine sulfate suppositories and know how they will react to the medication [see Patient Counseling Information (17)].

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

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

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Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

{ "type": "p", "children": [], "text": "Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest." }

The common adverse reactions seen on initiation of therapy with morphine were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.

{ "type": "p", "children": [], "text": "The common adverse reactions seen on initiation of therapy with morphine were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual." }

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

{ "type": "p", "children": [], "text": "Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:" }

Body as a Whole: malaise, withdrawal syndrome

{ "type": "p", "children": [], "text": "Body as a Whole: malaise, withdrawal syndrome" }

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

{ "type": "p", "children": [], "text": "\nCardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia" }

Digestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

{ "type": "p", "children": [], "text": "\nDigestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst" }

Endocrine: hypogonadism

{ "type": "p", "children": [], "text": "\nEndocrine: hypogonadism" }

Hemic and Lymphatic System: anemia, thrombocytopenia

{ "type": "p", "children": [], "text": "\nHemic and Lymphatic System: anemia, thrombocytopenia" }

Metabolic and Nutritional Disorders: edema, weight loss

{ "type": "p", "children": [], "text": "\nMetabolic and Nutritional Disorders: edema, weight loss" }

Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density

{ "type": "p", "children": [], "text": "\nMusculoskeletal: skeletal muscle rigidity, decreased bone mineral density" }

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

{ "type": "p", "children": [], "text": "\nNervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache" }

Respiratory System: hiccup, hypoventilation, voice alteration

{ "type": "p", "children": [], "text": "\nRespiratory System: hiccup, hypoventilation, voice alteration" }

Skin and Appendages: dry skin, urticaria, pruritus

{ "type": "p", "children": [], "text": "\nSkin and Appendages: dry skin, urticaria, pruritus" }

Special Senses: amblyopia, eye pain, taste perversion

{ "type": "p", "children": [], "text": "\nSpecial Senses: amblyopia, eye pain, taste perversion" }

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea

{ "type": "p", "children": [], "text": "\nUrogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea" }

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

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

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

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in morphine sulfate suppositories.

{ "type": "p", "children": [], "text": "\nAnaphylaxis: Anaphylaxis has been reported with ingredients contained in morphine sulfate suppositories." }

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

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

Table 1 includes clinically significant drug interactions with morphine sulfate suppositories.

{ "type": "p", "children": [], "text": "Table 1 includes clinically significant drug interactions with morphine sulfate suppositories." }

Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Suppositories

{ "type": "p", "children": [], "text": "\nTable 1: Clinically Significant Drug Interactions with Morphine Sulfate Suppositories\n" }

<div class="scrollingtable"><table width="100%"> <col width="21%"/> <col width="79%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" 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="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.4)]</span>.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate suppositories if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (5.4)]</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Do not use morphine sulfate suppositories in patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">phenelzine, tranylcypromine, linezolid</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">May reduce the analgesic effect of morphine sulfate suppositories and/or precipitate withdrawal symptoms.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Avoid concomitant use.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Morphine 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="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate suppositories and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.4)]</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cimetidine</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Monitor patients for increased respiratory and CNS depression when morphine sulfate suppositories are used concomitantly with cimetidine.</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="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate suppositories are used concomitantly with anticholinergic drugs.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">P-Glycoprotein (P-gp) Inhibitors</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The concomitant use of P-gp inhibitors can increase the exposure to morphine by twofold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate suppositories and/or the P-gp inhibitor as necessary.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">quinidine, verapamil</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"21%\"/>\n<col width=\"79%\"/>\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\">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=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.4)]</span>.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">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=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate suppositories 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=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that 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).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see Warnings and Precautions (5.4)]</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Do not use morphine sulfate suppositories in patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">phenelzine, tranylcypromine, linezolid</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">May reduce the analgesic effect of morphine sulfate suppositories 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=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Avoid concomitant use.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">butorphanol, nalbuphine, pentazocine, buprenorphine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Morphine 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=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" 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 morphine sulfate suppositories and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.4)]</span>\n</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\">Cimetidine</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Monitor patients for increased respiratory and CNS depression when morphine sulfate suppositories are used concomitantly with cimetidine.</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=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">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=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate suppositories are 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\">P-Glycoprotein (P-gp) Inhibitors</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The concomitant use of P-gp inhibitors can increase the exposure to morphine by twofold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate suppositories and/or the P-gp inhibitor as necessary.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">quinidine, verapamil</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with morphine sulfate suppositories in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

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. Morphine sulfate suppositories are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including morphine sulfate suppositories, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data: The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data: Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD).

Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary

Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with morphine sulfate suppositories and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

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

Clinical Considerations

Monitor infants exposed to morphine sulfate suppositories through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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), Clinical Pharmacology (12.2)]. In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13)].

The safety and effectiveness of morphine sulfate suppositories have not been established in pediatric patients.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose 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 morphine sulfate suppositories slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].

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

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of morphine sulfate suppositories and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of morphine sulfate suppositories and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine sulfate suppositories contains morphine, a Schedule II controlled substance.

Morphine sulfate suppositories contain morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine sulfate suppositories can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

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

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

Risks Specific to Abuse of Morphine Sulfate Suppositories

Morphine sulfate suppositories are for rectal use only. Abuse of morphine sulfate suppositories poses a risk of overdose and death. The risk is increased with concurrent abuse of morphine sulfate suppositories 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 is a physiological state in which the body adapts to the drug after a regular period of exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue morphine sulfate suppositories in a patient physically dependent on opioids. Rapid tapering of morphine sulfate suppositories in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing morphine sulfate suppositories, gradually taper the dosage using a patient-specific plan that considers the following: the dose of morphine sulfate suppositories the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking

opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.12)].

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

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Acute overdose with morphine sulfate suppositories 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)].

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Treatment of Overdose

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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.

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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 morphine overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.

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Because the duration of opioid reversal is expected to be less than the duration of action of morphine in morphine sulfate suppositories, 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.

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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.

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Morphine sulfate suppositories are an opioid agonist, available in 5 mg, 10 mg, 20 mg, and 30 mg strengths for rectal administration. The chemical name is morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-, (5a,6a)-, sulfate (2:1) (salt), pentahydrate. The molecular weight is 758. Its molecular formula is (C17H19NO3)2 · H2SO4 · 5H2O, and it has the following chemical structure:

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Morphine sulfate USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

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The inactive ingredients in morphine sulfate suppositories include: butylated hydroxyanisole, butylated hydroxytoluene, colloidal silicon dioxide, glyceryl monostearate, hydrogenated vegetable oil, polysorbate 80.

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Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine 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

Morphine 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

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

Effects on the Endocrine System

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

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)].

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. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.4)].

Concentration-Adverse Reaction Relationships

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

Absorption

Morphine, when administered as morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Distribution

Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20 to 35% reversibly bound to plasma proteins.

Elimination

Metabolism: The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion: Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Specific Populations

Race/Ethnicity: There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).

Sex: While evidence of greater post-operative morphine sulfate consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of morphine sulfate, including respiratory depression, in women compared to men.

Hepatic Impairment: Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment: Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Carcinogenesis

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

Mutagenesis

No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility

No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.

Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

Morphine Sulfate Suppositories are white to cream torpedo shaped suppositories

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories are white to cream torpedo shaped suppositories" }

<div class="scrollingtable"><table width="100%"> <col width="16%"/> <col width="21%"/> <col width="18%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Strength</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Carton Count</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC Number</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">5 mg</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 suppositories</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0574-7110-12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">10 mg</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 suppositories</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0574-7112-12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">20 mg</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 suppositories</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0574-7114-12</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30 mg</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 suppositories</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0574-7116-12</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"16%\"/>\n<col width=\"21%\"/>\n<col width=\"18%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Strength</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Carton Count</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC Number</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">5 mg</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 suppositories</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0574-7110-12</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">10 mg</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 suppositories</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0574-7112-12</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">20 mg</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 suppositories</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0574-7114-12</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">30 mg</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">12 suppositories</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0574-7116-12</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

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

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]." }

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

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

Storage and Disposal

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

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

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

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

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

of unused medicines.

{ "type": "p", "children": [], "text": "of unused medicines." }

Addiction, Abuse, and Misuse

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

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

{ "type": "p", "children": [], "text": "Inform patients that the use of morphine sulfate suppositories, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share morphine sulfate suppositories with others and to take steps to protect morphine sulfate suppositories 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 morphine sulfate suppositories or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting morphine sulfate suppositories or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop." }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

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

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

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

and Administration (2.2) and Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\nand Administration (2.2) and Warnings and Precautions (5.4)]." }

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

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

If naloxone is prescribed, also advise patients and caregivers:

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

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

Accidental Exposure

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

Inform patients that accidental exposure (including ingestion), especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients that accidental exposure (including ingestion), especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. " }

Interactions with Benzodiazepines and Other CNS Depressants

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

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

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

Serotonin Syndrome

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

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

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

MAOI Interaction

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

Inform patients not to take morphine sulfate suppositories while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate suppositories [see Warnings and Precautions (5.6), Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients not to take morphine sulfate suppositories while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking morphine sulfate suppositories [see Warnings and Precautions (5.6), Drug Interactions (7)]." }

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 (5.7)].

{ "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 (5.7)]." }

Important Discontinuation Instructions

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

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine

{ "type": "p", "children": [], "text": "In order to avoid developing withdrawal symptoms, instruct patients not to discontinue morphine" }

sulfate suppositories without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].

{ "type": "p", "children": [], "text": "sulfate suppositories without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)]." }

Hypotension

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

Inform patients that morphine sulfate suppositories may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate suppositories may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)]." }

Anaphylaxis

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

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

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

Pregnancy

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

Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of morphine sulfate suppositories during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of morphine sulfate suppositories during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]." }

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that morphine sulfate suppositories can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity: Inform female patients of reproductive potential that morphine sulfate suppositories can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

Lactation

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

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

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

Infertility

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

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

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

Driving or Operating Heavy Machinery

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

Inform patients that morphine sulfate suppositories may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Inform patients that morphine sulfate suppositories may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.13)]." }

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)].

{ "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)]." }

Dispense with Medication Guide available at: www.padagis.com/medguide/MRPHB.

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

Manufactured by Padagis®

{ "type": "p", "children": [], "text": "Manufactured by Padagis®\n" }

Minneapolis, MN 55427

{ "type": "p", "children": [], "text": "Minneapolis, MN 55427" }

www.padagis.com

{ "type": "p", "children": [], "text": "www.padagis.com" }

Rev 07-23

{ "type": "p", "children": [], "text": "Rev 07-23" }

2204532

{ "type": "p", "children": [], "text": "2204532" }

1R600 RC PH2

{ "type": "p", "children": [], "text": "1R600 RC PH2" }

Morphine Sulfate (mor’ feen sul’ fate) Suppositories, CII

{ "type": "p", "children": [], "text": "\nMorphine Sulfate (mor’ feen sul’ fate) Suppositories, CII\n" }

Morphine Sulfate Suppositories are:

{ "type": "p", "children": [], "text": "\nMorphine Sulfate Suppositories are:\n" }

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

Important information about morphine sulfate suppositories:

{ "type": "p", "children": [], "text": "\nImportant information about morphine sulfate suppositories:\n" }

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

Do not take morphine sulfate suppositories if you have:

{ "type": "p", "children": [], "text": "\nDo not take morphine sulfate suppositories if you have:\n" }

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

Before taking morphine sulfate suppositories, tell your healthcare provider if you have a history of:

{ "type": "p", "children": [], "text": "\nBefore taking morphine sulfate suppositories, tell your healthcare provider if you have a history of:\n" }

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

Tell your healthcare provider if you are:

{ "type": "p", "children": [], "text": "\nTell your healthcare provider if you are:\n" }

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

When taking morphine sulfate suppositories:

{ "type": "p", "children": [], "text": "\nWhen taking morphine sulfate suppositories:\n" }

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

While taking morphine sulfate suppositories DO NOT:

{ "type": "p", "children": [], "text": "\nWhile taking morphine sulfate suppositories DO NOT:\n" }

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

The possible side effects of morphine sulfate suppositories:

{ "type": "p", "children": [], "text": "\nThe possible side effects of morphine sulfate suppositories:\n" }

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

Get emergency medical help if you have:

{ "type": "p", "children": [], "text": "\nGet emergency medical help if you have:\n" }

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

These are not all the possible side effects of morphine sulfate suppositories. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of morphine sulfate suppositories. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.\n" }

Manufactured by Padagis®, Minneapolis, MN 55427

{ "type": "p", "children": [], "text": "Manufactured by Padagis®, Minneapolis, MN 55427" }

www.padagis.com or please call 1-866-634-9120

{ "type": "p", "children": [], "text": "www.padagis.com or please call 1-866-634-9120" }

1R600 RC MG1

{ "type": "p", "children": [], "text": "1R600 RC MG1" }

Issued: 7/2023

{ "type": "p", "children": [], "text": "Issued: 7/2023" }

NDC 0574-7110-12

{ "type": "p", "children": [], "text": "NDC 0574-7110-12" }

Rx Only

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

Morphine Sulfate Suppositories 5 mg

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories 5 mg" }

CII

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

FOR RECTAL USE ONLY

{ "type": "p", "children": [], "text": "FOR RECTAL USE ONLY" }

Warning: May be habit forming.

{ "type": "p", "children": [], "text": "Warning: May be habit forming." }

Print Medication Guides at:

{ "type": "p", "children": [], "text": "Print Medication Guides at: " }

www.padagis.com/medguide/MRPHB

{ "type": "p", "children": [], "text": "www.padagis.com/medguide/MRPHB" }

12 SUPPOSITORIES

{ "type": "p", "children": [], "text": "12 SUPPOSITORIES" }

UNIT DOSE

{ "type": "p", "children": [], "text": "UNIT DOSE" }

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

{ "type": "p", "children": [], "text": "The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation." }

NDC 0574-7112-12

{ "type": "p", "children": [], "text": "NDC 0574-7112-12" }

Rx Only

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

Morphine Sulfate Suppositories 10 mg

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories 10 mg" }

CII

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

FOR RECTAL USE ONLY

{ "type": "p", "children": [], "text": "FOR RECTAL USE ONLY" }

Warning: May be habit forming.

{ "type": "p", "children": [], "text": "Warning: May be habit forming." }

Print Medication Guides at:

{ "type": "p", "children": [], "text": "Print Medication Guides at: " }

www.padagis.com/medguide/MRPHB

{ "type": "p", "children": [], "text": "www.padagis.com/medguide/MRPHB" }

12 SUPPOSITORIES

{ "type": "p", "children": [], "text": "12 SUPPOSITORIES" }

UNIT DOSE

{ "type": "p", "children": [], "text": "UNIT DOSE" }

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

{ "type": "p", "children": [], "text": "The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation." }

NDC 0574-7114-12

{ "type": "p", "children": [], "text": "NDC 0574-7114-12" }

Rx Only

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

Morphine Sulfate Suppositories 20 mg

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories 20 mg" }

CII

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

FOR RECTAL USE ONLY

{ "type": "p", "children": [], "text": "FOR RECTAL USE ONLY" }

Warning: May be habit forming.

{ "type": "p", "children": [], "text": "Warning: May be habit forming." }

Print Medication Guides at:

{ "type": "p", "children": [], "text": "Print Medication Guides at: " }

www.padagis.com/medguide/MRPHB

{ "type": "p", "children": [], "text": "www.padagis.com/medguide/MRPHB" }

12 SUPPOSITORIES

{ "type": "p", "children": [], "text": "12 SUPPOSITORIES" }

UNIT DOSE

{ "type": "p", "children": [], "text": "UNIT DOSE" }

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

{ "type": "p", "children": [], "text": "The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation." }

NDC 0574-7116-12

{ "type": "p", "children": [], "text": "NDC 0574-7116-12" }

Rx Only

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

Morphine Sulfate Suppositories 30 mg

{ "type": "p", "children": [], "text": "Morphine Sulfate Suppositories 30 mg" }

CII

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

FOR RECTAL USE ONLY

{ "type": "p", "children": [], "text": "FOR RECTAL USE ONLY" }

Warning: May be habit forming.

{ "type": "p", "children": [], "text": "Warning: May be habit forming." }

Print Medication Guides at:

{ "type": "p", "children": [], "text": "Print Medication Guides at: " }

www.padagis.com/medguide/MRPHB

{ "type": "p", "children": [], "text": "www.padagis.com/medguide/MRPHB" }

12 SUPPOSITORIES

{ "type": "p", "children": [], "text": "12 SUPPOSITORIES" }

UNIT DOSE

{ "type": "p", "children": [], "text": "UNIT DOSE" }

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

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Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2)] , reserve Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):

Morphine Sulfate Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Morphine Sulfate Oral Solution is available in three concentrations: 2 mg/mL, 4 mg/mL, and 20 mg/mL [see Dosage Forms and Strengths (3)].

Ensure accuracy when prescribing, dispensing, and administering Morphine Sulfate Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other morphine sulfate oral solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Morphine Sulfate Oral Solution [see Warnings and Precautions (5.3)].

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

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.2, 5.3, 5.4)].

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

Initiating Treatment with Morphine Sulfate Oral Solution: Adults: Initiate treatment with Morphine Sulfate Oral Solution 2 mg/ mL and 4 mg/mL in adults in a dosing range of 10 mg to 20 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of Morphine Sulfate Oral Solution.

Do not initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL) in adult patients who are opioid naïve or in pediatric patients. The recommended dosage to initiate treatment with Morphine Sulfate Oral Solution 20 mg/mL in opioid tolerant adults is 10 mg to 20 mg every 4 hours as needed for pain.

Pediatric Patients 2 Years of Age and Older: Only use Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL in pediatric patients. Initiate treatment in pediatric patients with a dosing range of 0.15 mg/kg to 0.3 mg/kg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of Morphine Sulfate Oral Solution. Do not exceed 20 mg as an initial dose.

To ensure doses can be accurately measured, calculate the starting dose for pediatric patients by following the steps below:

For example: 0.855 mL rounds to 0.9 mL

Individually titrate Morphine Sulfate Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.2, 5.15)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Oral Solution dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Do not abruptly discontinue Morphine Sulfate Oral Solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Morphine Sulfate Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including Morphine Sulfate Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Morphine Sulfate Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.15), Drug Abuse and Dependence (9.3)].

Morphine Sulfate Oral Solution:

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Morphine Sulfate Oral Solution is contraindicated in patients with:

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Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine sulfate oral solutions of different concentrations, when prescribing, dispensing, and administering Morphine Sulfate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.

Morphine Sulfate Oral Solution contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Oral Solution 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 morphine sulfate. 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 Morphine Sulfate Oral Solution, and reassess all patients receiving Morphine Sulfate Oral Solution for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Morphine Sulfate Oral Solution but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

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

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

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

To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Oral Solution are essential [see Dosage and Administration (2)]. Overestimating the Morphine Sulfate Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Morphine Sulfate Oral Solution 20 mg/mL is for use only in opioid-tolerant adult patients. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids.

Accidental ingestion of even one dose of Morphine Sulfate Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of morphine.

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

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.

Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

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

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Dosage and Administration (2.3), Warnings and Precautions (5.2, 5.4), Overdosage (10)].

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

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

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.3), Overdosage (10)].

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

Use of Morphine Sulfate Oral Solution 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)]

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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 nonpainful 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 (2.6), Warnings and Precautions (5.15)].

The use of Morphine Sulfate Oral Solution 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: Morphine Sulfate Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Morphine Sulfate Oral Solution [see Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

Regularly evaluate patients, particularly when initiating and titrating Morphine Sulfate Oral Solution and when Morphine Sulfate Oral Solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.4), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Oral Solution should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

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

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

Morphine Sulfate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

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

The morphine in Morphine Sulfate Oral Solution may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Morphine Sulfate Oral Solution therapy.

Do not abruptly discontinue Morphine Sulfate Oral Solution in a patient physically dependent on opioids. When discontinuing Morphine Sulfate Oral Solution in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.6) and Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Sulfate Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

Morphine Sulfate Oral Solution 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 Morphine Sulfate Oral Solution and know how they will react to the medication.

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

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{ "type": "ul", "children": [ "Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2)]\n", "Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]\n", "Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)]\n", "Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]\n", "Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)]\n", "Adrenal Insufficiency [see Warnings and Precautions (5.10)]\n", "Severe Hypotension [see Warnings and Precautions (5.11)]\n", "Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]\n", "Seizures [see Warnings and Precautions (5.14)]\n", "Withdrawal [see Warnings and Precautions (5.15)]\n" ], "text": "" }

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

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

Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

{ "type": "p", "children": [], "text": "Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest." }

The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual.

{ "type": "p", "children": [], "text": "The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual." }

Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:

{ "type": "p", "children": [], "text": "Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:" }

Body as a Whole: malaise, withdrawal syndrome

{ "type": "p", "children": [], "text": "\nBody as a Whole: malaise, withdrawal syndrome" }

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia

{ "type": "p", "children": [], "text": "\nCardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia" }

Digestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst

{ "type": "p", "children": [], "text": "\nDigestive System: anorexia, biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst" }

Endocrine: hypogonadism

{ "type": "p", "children": [], "text": "\nEndocrine: hypogonadism" }

Hemic and Lymphatic System: anemia, thrombocytopenia

{ "type": "p", "children": [], "text": "\nHemic and Lymphatic System: anemia, thrombocytopenia" }

Metabolic and Nutritional Disorders: edema, weight loss

{ "type": "p", "children": [], "text": "\nMetabolic and Nutritional Disorders: edema, weight loss" }

Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density

{ "type": "p", "children": [], "text": "\nMusculoskeletal: skeletal muscle rigidity, decreased bone mineral density" }

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache

{ "type": "p", "children": [], "text": "\nNervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache" }

Skin and Appendages: dry skin, urticaria, pruritus

{ "type": "p", "children": [], "text": "\nSkin and Appendages: dry skin, urticaria, pruritus" }

Special Senses: amblyopia, eye pain, taste perversion

{ "type": "p", "children": [], "text": "\nSpecial Senses: amblyopia, eye pain, taste perversion" }

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, antidiuretic effect, amenorrhea

{ "type": "p", "children": [], "text": "\nUrogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, antidiuretic effect, amenorrhea" }

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

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

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

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Oral Solution.

{ "type": "p", "children": [], "text": "\nAnaphylaxis: Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Oral Solution." }

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

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

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

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

Hypoglycemia: 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).

{ "type": "p", "children": [], "text": "\nHypoglycemia: 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)." }

Clinical Trial Experience in Pediatric Patients 2 Years of Age and Older: The safety of morphine sulfate was evaluated in 81 pediatric patients 2 through 17 years of age with acute pain [see Use in Specific Populations (8.4)]. The safety profile in pediatric patients is similar to adults. The most common adverse reactions reported on initiation of therapy in at least 5% of patients across all age groups were: nausea (17%), vomiting (10%), constipation (6%), decreased oxygen saturation (5%), and flatulence (5%).

{ "type": "p", "children": [], "text": "\nClinical Trial Experience in Pediatric Patients 2 Years of Age and Older: The safety of morphine sulfate was evaluated in 81 pediatric patients 2 through 17 years of age with acute pain [see Use in Specific Populations (8.4)]. The safety profile in pediatric patients is similar to adults. The most common adverse reactions reported on initiation of therapy in at least 5% of patients across all age groups were: nausea (17%), vomiting (10%), constipation (6%), decreased oxygen saturation (5%), and flatulence (5%)." }

Table 1 includes clinically significant drug interactions with Morphine Sulfate Oral Solution.

{ "type": "p", "children": [], "text": "Table 1 includes clinically significant drug interactions with Morphine Sulfate Oral Solution." }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Oral Solution Benzodiazepines and Other Central</span> </caption> <col align="right" valign="middle" width="25%"/> <col align="left" valign="top" width="75%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see <a href="#S2.3">Dosage and Administration (2.3)</a> and <a href="#S5.2">Warnings and Precautions (5.2</a>, <a href="#S5.3">5.3</a>, <a href="#S5.4">5.4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see <a href="#S5.3">Warnings and Precautions (5.3</a>, <a href="#S5.9">5.9)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Phenelzine, tranylcypromine, linezolid.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Avoid concomitant use.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Butorphanol, nalbuphine, pentazocine, buprenorphine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Because respiratory depression may be greater than otherwise expected decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see <a href="#S2.3">Dosage and Administration (2.3)</a> and <a href="#S5.3">Warnings and Precautions (5.3</a>, <a href="#S5.4">5.4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Cyclobenzaprine, metaxalone.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Cimetidine</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Evaluate patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Diuretics</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Evaluate patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Oral Solution is used concomitantly with anticholinergic drugs.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">P-Glycoprotein (P-gp) Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">The concomitant use of P-gp inhibitors can increase the exposure to morphine by twofold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the P-gp inhibitor as necessary.</td> </tr> <tr class="Last"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Quinidine, verapamil</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Oral Solution Benzodiazepines and Other Central</span>\n</caption>\n<col align=\"right\" valign=\"middle\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"75%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class=\"Italics\">[see <a href=\"#S5.4\">Warnings and Precautions (5.4)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see <a href=\"#S2.3\">Dosage and Administration (2.3)</a> and <a href=\"#S5.2\">Warnings and Precautions (5.2</a>, <a href=\"#S5.3\">5.3</a>, <a href=\"#S5.4\">5.4)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class=\"Italics\">[see <a href=\"#S5.3\">Warnings and Precautions (5.3</a>, <a href=\"#S5.9\">5.9)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Phenelzine, tranylcypromine, linezolid.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Avoid concomitant use.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Butorphanol, nalbuphine, pentazocine, buprenorphine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Because respiratory depression may be greater than otherwise expected decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see <a href=\"#S2.3\">Dosage and Administration (2.3)</a> and <a href=\"#S5.3\">Warnings and Precautions (5.3</a>, <a href=\"#S5.4\">5.4)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Cyclobenzaprine, metaxalone.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Cimetidine</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Evaluate patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Evaluate patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Oral Solution is used concomitantly with anticholinergic drugs.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">P-Glycoprotein (P-gp) Inhibitors</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">The concomitant use of P-gp inhibitors can increase the exposure to morphine by twofold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the P-gp inhibitor as necessary.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Quinidine, verapamil</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary: Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. There are no available data with Morphine Sulfate Oral Solution in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects (see Human Data). In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD (see Animal Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

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 (5.5)].

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

Data: Human Data: The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.

Animal Data: Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/ kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.

Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.

An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.

In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.

Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).

Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first- and second-generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

Risk Summary: Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production.

Lactation studies have not been conducted with Morphine Sulfate Oral Solution and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

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

Clinical Considerations: Monitor infants exposed to Morphine Sulfate Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine 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) and Clinical Pharmacology (12.2)]. In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13)].

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4 mg/mL) have been established for the management of pediatric patients 2 to 17 years of age with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. Use of Morphine Sulfate Oral Solution in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain. Patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery. Initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg. Pharmacokinetic modeling and simulation indicate that an initial dose of 0.3 mg/kg in pediatric patients 2 years of age and older is expected to produce a maximum systemic exposure (Cmax) similar to that achieved after single dose administration of 10 mg Morphine Sulfate Oral Solution to adults [see Clinical Pharmacology (12.3)]. Safety data were available in 81 patients who received single and multiple doses (63 patients aged 2 to 17 years received Morphine Sulfate Oral Solution; 18 patients aged 12 to 17 years received Morphine Sulfate Tablets). The median duration of treatment was 20 hours (range 4 hours to 36 hours). Opioid and non-opioid rescue analgesics were allowed. The safety profile in pediatric patients consisted primarily of opioidrelated adverse reactions and is similar to that observed in adults [see Adverse Reactions (6)].

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4 mg/mL) have not been established for the management of pediatric patients 2 to 17 years of age with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.

The safety and effectiveness of Morphine Sulfate Oral Solution (2 mg/mL and 4 mg/mL) have not been established in pediatric patients less than 2 years of age. The safety and effectiveness of Morphine Sulfate Oral Solution 20 mg/mL have not been established in pediatric patients.

Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose 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 Morphine Sulfate Oral Solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8)].

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

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphine Sulfate Oral Solution and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Oral Solution and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Morphine Sulfate Oral Solution contains morphine, a Schedule II controlled substance.

Morphine Sulfate Oral Solution contains morphine, 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 (5.2)].

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 Morphine Sulfate Oral Solution 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 Morphine Sulfate Oral Solution 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 Morphine Sulfate Oral Solution abuse include those with a history of prolonged use of any opioids, including products containing morphine, those with a history of drug or alcohol abuse, or those who use Morphine Sulfate Oral Solution 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.

Morphine Sulfate Oral Solution, 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 Morphine Sulfate Oral Solution: Abuse of Morphine Sulfate Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Morphine Sulfate Oral Solution with alcohol and/or other CNS depressants.

Morphine Sulfate Oral Solution is approved for oral use only.

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

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

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

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

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

Do not abruptly discontinue Morphine Sulfate Oral Solution in a patient physically dependent on opioids. Rapid tapering of Morphine Sulfate Oral Solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing Morphine Sulfate Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Morphine Sulfate Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.6) and Warnings and Precautions (5.15)].

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 morphine 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 opioid overdose, administer an opioid antagonist.

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

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

Morphine Sulfate Oral Solution is an opioid agonist, available in the following concentrations for oral administration:

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The chemical name is 7,8-didehydro-4,5 alpha-epoxy-17 methyl-morphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate. The molecular weight is 758.83. Its molecular formula is (C17H21NO3)2∙H2SO4∙5H2O, and it has the following chemical structure.

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Morphine sulfate, USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

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For the 10 mg per 5 mL (2 mg/mL) concentration: Each 5 mL of oral solution contains 10 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3 (fast green), glycerin, sodium benzoate, sorbitol and purified water.

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For the 20 mg per 5 mL (4 mg/mL) concentration: Each 5 mL of oral solution contains 20 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3 (fast green), glycerin, methylparaben, propylparaben, sodium benzoate, sorbitol and purified water.

{ "type": "p", "children": [], "text": "For the 20 mg per 5 mL (4 mg/mL) concentration: Each 5 mL of oral solution contains 20 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, FD&C Green No. 3 (fast green), glycerin, methylparaben, propylparaben, sodium benzoate, sorbitol and purified water." }

For the 100 mg per 5 mL (20 mg/mL) concentration (only for opioid-tolerant adults): Each 5 mL of oral solution contains 100 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, glycerin, sodium benzoate, sorbitol and purified water. Additionally, the tinted solution contains D & C Red No. 33 and sucralose.

{ "type": "p", "children": [], "text": "For the 100 mg per 5 mL (20 mg/mL) concentration (only for opioid-tolerant adults): Each 5 mL of oral solution contains 100 mg of morphine sulfate, USP and the following inactive ingredients: citric acid anhydrous, disodium edetate, glycerin, sodium benzoate, sorbitol and purified water. Additionally, the tinted solution contains D & C Red No. 33 and sucralose." }

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Effects on the Central Nervous System: Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

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

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

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

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

Concentration–Efficacy Relationships: The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.2, 2.5)].

Concentration–Adverse Reaction Relationships: There is a relationship between increasing morphine 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 (2.2, 2.5)].

Absorption: Morphine, when administered as morphine sulfate is about two-thirds absorbed from the gastrointestinal tract with the maximum analgesic effect occurring 60 minutes post-administration. The oral bioavailability of morphine sulfate is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Administration of 30 mg of Morphine Sulfate Oral Solution every six hours for 5 days resulted in a comparable 24-hour exposure (AUC). The steady-state levels were achieved within 48 hours for both tablets and solution. The mean steady state Cmax values were about 78 and 58 ng/mL for tablet and solution, respectively.

Food Effects: Although the presence of a food effect was not assessed with Morphine Sulfate Oral Solution, significant food effect is not expected with a solution formulation.

Distribution: Once absorbed, morphine sulfate is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier.

Morphine sulfate also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine sulfate is approximately 1 to 6 L/kg, and morphine sulfate is 20% to 35% reversibly bound to plasma proteins.

Elimination: Metabolism: The major pathway of morphine sulfate detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine sulfate is demethylated, virtually all morphine sulfate is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion: Most of a dose of morphine sulfate is excreted in urine as M3G and M6G, with elimination of morphine sulfate occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulfate is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 mL/min/kg. The effective terminal half-life of morphine sulfate after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine sulfate of about 15 hours was reported.

Specific Populations: Pediatric Patients 2 Years of Age and Older: Morphine pharmacokinetics were analyzed in a population pharmacokinetic analysis of 66 pediatric patients aged 2 years to 17 years. Initially after dosing, the geometric mean plasma half-life of morphine was up to 1.8 hours. The geometric mean terminal elimination plasma half-life of morphine was 18.6 hours. For both the M3G metabolite and M6G metabolite, the single-dose geometric mean Cmax in pediatric patients was not greater than in adults.

Race/Ethnicity: There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine sulfate had a higher clearance when compared to Caucasian subjects (1,852 +/- 116 mL/min compared to 1,495 +/- 80 mL/min).

Sex: While evidence of greater post-operative morphine sulfate consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of morphine sulfate, including respiratory depression, in women compared to men.

Hepatic Impairment: Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment: Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

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

Mutagenesis: No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.

Impairment of Fertility: No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted.

Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/ kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported.

Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).

Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).

Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

Morphine Sulfate Oral Solution:

10 mg per 5 mL (2 mg/mL) Oral Solution is supplied as a clear, blue-green solution. Each 1 mL of clear, blue-green oral solution contains 2 mg of morphine sulfate, USP (equivalent to 1.5 mg morphine).

NDC 68094-001-62 5 mL per unit dose cup Thirty (30) cups per shipper

100 mg per 5 mL (20 mg/mL) Oral Solution (color added) (only for opioid-tolerant adults) is supplied as a clear, pink solution. Each 1 mL of clear, pink oral solution contains 20 mg of morphine sulfate, USP (equivalent to 15 mg morphine).

NDC 68094-045-580.5 mL per unit dose syringeFifty (50) syringes per shipper

NDC 68094-056-580.5 mL per unit dose ENFit syringeFifty (50) syringes per shipper

NDC 68094-156-581 mL per unit dose ENFit syringeFifty (50) syringes per shipper

NDC 68094-256-580.5 mL per unit dose syringeFifty (50) syringes per shipper

NDC 68094-356-581 mL per unit dose syringeFifty (50) syringes per shipper

NDC 68094-456-580.25 mL per unit dose syringeFifty (50) syringes per shipper

NDC 68094-556-580.25 mL per unit dose ENFit syringeFifty (50) syringes per shipper

Storage

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

Protect from moisture.

Store Morphine Sulfate Oral Solution securely and dispose of properly.

Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Morphine Sulfate Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Morphine Sulfate Oral Solution unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2, 5.3) and Drug Abuse and Dependence (9.2)].

Expired, unwanted, or unused Morphine Sulfate Oral Solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available.

Medication Errors: Morphine Sulfate Oral Solution is available in three concentrations: 2 mg/mL, 4 mg/mL, and 20 mg/mL. Inform patients and caregivers about which concentration they have been prescribed.

Addiction, Abuse, and Misuse: Inform patients that the use of Morphine Sulfate Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)]. Instruct patients not to share Morphine Sulfate Oral Solution with others and to take steps to protect Morphine Sulfate Oral Solution from theft or misuse.

Life-Threatening Respiratory Depression: Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Morphine Sulfate Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3)].

Accidental Ingestion: Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].

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

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Morphine Sulfate Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].

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

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

If naloxone is prescribed, also advise patients and caregivers:

Hyperalgesia and Allodynia: Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7), Adverse Reactions (6)].

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

MAOI Interaction: Inform patients not to take Morphine Sulfate Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Morphine Sulfate Oral Solution [see Warnings and Precautions (5.9) and Drug Interactions (7)].

Important Administration Instructions

Instruct patients how to properly take Morphine Sulfate Oral Solution [see Dosage and Administration (2), Warnings and Precautions (5.1)].

Morphine Sulfate Oral Solution 20 mg/mL

Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL

Important Discontinuation Instructions:

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Morphine Sulfate Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.6)].

Driving or Operating Heavy Machinery: Inform patients that Morphine Sulfate Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16)].

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

Adrenal Insufficiency: Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.10)].

Hypotension: Inform patients that Morphine Sulfate Oral Solution may cause orthostatic hypotension and syncope.

Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.11)].

Anaphylaxis Inform patients that anaphylaxis have been reported with ingredients contained in Morphine Sulfate Oral Solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) and Adverse Reactions (6)].

Pregnancy: Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that use of Morphine Sulfate Oral Solution for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that Morphine Sulfate Oral Solution can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

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

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

Packaged by: Precision Dose, Inc. South Beloit, IL 61080

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For inquiries call Precision Dose, Inc. at 1-800-397-9228 or email druginfo@precisiondose.com

{ "type": "p", "children": [], "text": "For inquiries call Precision Dose, Inc. at 1-800-397-9228 or email druginfo@precisiondose.com" }

LI1656 Rev. 04/24

{ "type": "p", "children": [], "text": "LI1656 Rev. 04/24" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="2">Medication Guide<br/>Morphine (mor-pheen) Sulfate<br/>Oral Solution, CII</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="2"><span class="Bold">This Medication Guide has been approved by the U.S. Food and Drug Administration</span></td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Morphine Sulfate Oral Solution is:</span> <ul> <li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) and long term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</li> <li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Important information about Morphine Sulfate Oral Solution:</span> <ul class="Disc"> <li> <span class="Bold">Get emergency help or call 911 right away if you take too much Morphine Sulfate Oral Solution (overdose).</span> When you first start taking Morphine Sulfate Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life- threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li> <li>Taking Morphine Sulfate Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li> <li>Never give anyone else your Morphine Sulfate Oral Solution. They could die from taking it. Selling or giving away Morphine Sulfate Oral Solution is against the law.</li> <li>Store Morphine Sulfate Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Do not take Morphine Sulfate Oral Solution if you have:</span> <ul> <li>severe asthma, trouble breathing, or other lung problems.</li> <li>a bowel blockage or have narrowing of the stomach or intestines.</li> <li>an allergy to morphine.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Before taking Morphine Sulfate Oral Solution, tell your healthcare provider if you have a history of:</span></td> </tr> <tr> <td align="left" class="Lrule"> <ul> <li>head injury, seizures</li> <li>problems urinating</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>liver, kidney, thyroid problems</li> <li>pancreas or gallbladder problems</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Tell your healthcare provider if you are:</span> <ul class="Disc"> <li> <span class="Bold">noticing your pain getting worse.</span> If your pain gets worse after you take Morphine Sulfate Oral Solution, do not take more of Morphine Sulfate Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Morphine Sulfate Oral Solution.</li> <li> <span class="Bold">pregnant or planning to become pregnant.</span> Use of Morphine Sulfate Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be lifethreatening if not recognized and treated.</li> <li> <span class="Bold">breastfeeding.</span> Morphine Sulfate Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</li> <li>living in a household where there are small children or someone who has abused street or prescription drugs.</li> <li>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Morphine Sulfate Oral Solution with certain other medicines can cause serious side effects that could lead to death</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">When taking Morphine Sulfate Oral Solution:</span> <ul class="Disc"> <li>Take Morphine Sulfate Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</li> <li>For acute (short-term) pain, you may only need to take Morphine Sulfate Oral Solution for a few days. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) unused Morphine Sulfate Oral Solution.</li> <li>Call your healthcare provider if the dose you are taking does not control your pain.</li> <li>If you have been taking Morphine Sulfate Oral Solution regularly, do not stop taking Morphine Sulfate Oral Solution without talking to your healthcare provider.</li> <li>Dispose of expired, unwanted, or unused Morphine Sulfate Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily</li> <li>available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">While taking Morphine Sulfate Oral Solution DO NOT:</span> <ul class="Disc"> <li>Drive or operate heavy machinery, until you know how Morphine Sulfate Oral Solution affects you. Morphine Sulfate Oral Solution can make you sleepy, dizzy, or lightheaded.</li> <li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Morphine Sulfate Oral Solution may cause you to overdose and die.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">The possible side effects of Morphine Sulfate Oral Solution:</span> <ul class="Disc"> <li>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Get emergency medical help or call 911 right away if you have:</span> <ul class="Disc"> <li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2">These are not all the possible side effects of Morphine Sulfate Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class="Bold">For more information go to dailymed.nlm.nih.gov.</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2">Packaged by:<br/> <span class="Bold">Precision Dose, Inc.</span> <br/>South Beloit, IL 61080</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="2">For inquiries call Precision Dose, Inc. at 1-800-397-9228 or email druginfo@precisiondose.com</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"70%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">Medication Guide<br/>Morphine (mor-pheen) Sulfate<br/>Oral Solution, CII</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"2\"><span class=\"Bold\">This Medication Guide has been approved by the U.S. Food and Drug Administration</span></td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Morphine Sulfate Oral Solution is:</span>\n<ul>\n<li>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) and long term (chronic) pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</li>\n<li>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Important information about Morphine Sulfate Oral Solution:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Get emergency help or call 911 right away if you take too much Morphine Sulfate Oral Solution (overdose).</span> When you first start taking Morphine Sulfate Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life- threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.</li>\n<li>Taking Morphine Sulfate Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</li>\n<li>Never give anyone else your Morphine Sulfate Oral Solution. They could die from taking it. Selling or giving away Morphine Sulfate Oral Solution is against the law.</li>\n<li>Store Morphine Sulfate Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Do not take Morphine Sulfate Oral Solution if you have:</span>\n<ul>\n<li>severe asthma, trouble breathing, or other lung problems.</li>\n<li>a bowel blockage or have narrowing of the stomach or intestines.</li>\n<li>an allergy to morphine.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Before taking Morphine Sulfate Oral Solution, tell your healthcare provider if you have a history of:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\">\n<ul>\n<li>head injury, seizures</li>\n<li>problems urinating</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>liver, kidney, thyroid problems</li>\n<li>pancreas or gallbladder problems</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Tell your healthcare provider if you are:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">noticing your pain getting worse.</span> If your pain gets worse after you take Morphine Sulfate Oral Solution, do not take more of Morphine Sulfate Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Morphine Sulfate Oral Solution.</li>\n<li>\n<span class=\"Bold\">pregnant or planning to become pregnant.</span> Use of Morphine Sulfate Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be lifethreatening if not recognized and treated.</li>\n<li>\n<span class=\"Bold\">breastfeeding.</span> Morphine Sulfate Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</li>\n<li>living in a household where there are small children or someone who has abused street or prescription drugs.</li>\n<li>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Morphine Sulfate Oral Solution with certain other medicines can cause serious side effects that could lead to death</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">When taking Morphine Sulfate Oral Solution:</span>\n<ul class=\"Disc\">\n<li>Take Morphine Sulfate Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</li>\n<li>For acute (short-term) pain, you may only need to take Morphine Sulfate Oral Solution for a few days. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) unused Morphine Sulfate Oral Solution.</li>\n<li>Call your healthcare provider if the dose you are taking does not control your pain.</li>\n<li>If you have been taking Morphine Sulfate Oral Solution regularly, do not stop taking Morphine Sulfate Oral Solution without talking to your healthcare provider.</li>\n<li>Dispose of expired, unwanted, or unused Morphine Sulfate Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily</li>\n<li>available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">While taking Morphine Sulfate Oral Solution DO NOT:</span>\n<ul class=\"Disc\">\n<li>Drive or operate heavy machinery, until you know how Morphine Sulfate Oral Solution affects you. Morphine Sulfate Oral Solution can make you sleepy, dizzy, or lightheaded.</li>\n<li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Morphine Sulfate Oral Solution may cause you to overdose and die.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">The possible side effects of Morphine Sulfate Oral Solution:</span>\n<ul class=\"Disc\">\n<li>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Get emergency medical help or call 911 right away if you have:</span>\n<ul class=\"Disc\">\n<li>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, lightheadedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">These are not all the possible side effects of Morphine Sulfate Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <span class=\"Bold\">For more information go to dailymed.nlm.nih.gov.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Packaged by:<br/>\n<span class=\"Bold\">Precision Dose, Inc.</span>\n<br/>South Beloit, IL 61080</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">For inquiries call Precision Dose, Inc. at 1-800-397-9228 or email druginfo@precisiondose.com</td>\n</tr>\n</tbody>\n</table></div>" }

LI1656 Rev. 04/24

{ "type": "p", "children": [], "text": "\nLI1656 Rev. 04/24\n" }

Morphine Sulfate Oral Solution* CII

{ "type": "p", "children": [], "text": "Morphine Sulfate Oral Solution* CII" }

*Color Added 20 mg† /1 mL • Delivers 1 mL

{ "type": "p", "children": [], "text": "*Color Added 20 mg† /1 mL • Delivers 1 mL" }

Store at 20 to 25°C (68 to 77°F)

{ "type": "p", "children": [], "text": "Store at 20 to 25°C (68 to 77°F)" }

ONLY FOR USE IN ADULTS WHO ARE OPIOID TOLERANT

{ "type": "p", "children": [], "text": "ONLY FOR USE IN ADULTS WHO ARE OPIOID TOLERANT" }

†Each 1 mL of oral solution contains 20 mg Morphine Sulfate, USP equivalent to 15 mg Morphine base.

{ "type": "p", "children": [], "text": "\n†Each 1 mL of oral solution contains 20 mg Morphine Sulfate, USP equivalent to 15 mg Morphine base." }

FOR ORAL USE ONLY

{ "type": "p", "children": [], "text": "FOR ORAL USE ONLY" }

Pkg: Precision Dose, Inc. S. Beloit, IL 61080

{ "type": "p", "children": [], "text": "Pkg: Precision Dose, Inc. S. Beloit, IL 61080" }