Morphine Sulfate

• Morphine Sulfate Extended-Release Capsules expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and regularly evaluate for these behaviors and conditions. (

  5.1 Addiction, Abuse, and Misuse

  Morphine Sulfate Extended-Release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-Release Capsules expose users to the risks of addiction, abuse, and misuse.

  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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see

  Postmarketing Experience (6.2)

  ].

  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 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 re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (2.2)

  and

  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 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 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 may occur. Regularly evaluate closely, especially upon initiation or following a dose increase. Instruct patients to swallow Morphine Sulfate Extended-Release Capsules whole to avoid exposure to a potentially fatal dose of morphine. (

  5.2 Life-Threatening Respiratory Depression

  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 is essential

  [see Dosage and Administration (2)]

  . Overestimating the Morphine Sulfate Extended-Release Capsules dosage 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)

  and

  Overdosage (10)]

  .

  )
• Accidental ingestion of Morphine Sulfate Extended-Release Capsules, especially by children, can result in fatal overdose of morphine. (

  5.2 Life-Threatening Respiratory Depression

  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 is essential

  [see Dosage and Administration (2)]

  . Overestimating the Morphine Sulfate Extended-Release Capsules dosage 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)

  and

  Overdosage (10)]

  .

  )
• Instruct patients not to consume alcohol or any products containing alcohol while taking Morphine Sulfate Extended-Release Capsules because co-ingestion can result in fatal plasma morphine levels. (

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  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, gabapentinoids and 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 an opioid overdose reversal agent

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)

  and

  Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Extended-Release Capsules 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)]

  .

  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.

  )
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  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, gabapentinoids and 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 an opioid overdose reversal agent

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)

  and

  Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Extended-Release Capsules 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)]

  .

  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.

  ,

  7 DRUG INTERACTIONS

  Table 1 includes clinically significant drug interactions with Morphine Sulfate Extended-Release Capsules.

  Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release Capsules

  Alcohol
  Clinical Impact:	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.
  Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on Morphine Sulfate Extended-Release Capsules therapy [see Warnings and Precautions (5.3)] .
  Benzodiazepines and Other Central Nervous System (CNS) Depressants
  Clinical Impact:	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.
  Intervention:	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 an opioid overdose reversal agent [see Dosage and Administration (2.1, 2.2) and Warnings and Precautions (5.1, 5.2, 5.3)].
  Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, other opioids, alcohol.
  Serotonergic Drugs
  Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
  Intervention:	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.
  Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3receptor 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).
  Monoamine Oxidase Inhibitors (MAOIs)
  Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.8)].
  Intervention:	Do not use Morphine Sulfate Extended-Release Capsules in patients taking MAOIs or within 14 days of stopping such treatment.
  Examples:	phenelzine, tranylcypromine, linezolid
  Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
  Clinical Impact:	May reduce the analgesic effect of Morphine Sulfate Extended-Release Capsules and/or precipitate withdrawal symptoms.
  Intervention:	Avoid concomitant use.
  Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
  Muscle Relaxants
  Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
  Intervention:	Monitor 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 muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) and Warnings and Precautions (5.2, 5.3)]
  Examples:	cyclobenzaprine, metaxalone
  Cimetidine
  Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
  Intervention:	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.
  Diuretics
  Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
  Intervention:	Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
  Anticholinergic Drugs
  Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
  Intervention:	Evaluate patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Extended-Release Capsules are used concomitantly with anticholinergic drugs.
  P-Glycoprotein (PGP-Inhibitors)
  Clinical Impact:	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.
  Intervention:	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.

  • Serotonergic Drugs
    : Concomitant use may result in serotonin syndrome. Discontinue Morphine Sulfate Extended-Release Capsules if serotonin syndrome is suspected.
  • Monoamine Oxidase Inhibitors (MAOIs)
    : Can potentiate effects of morphine. Avoid concomitant use in patients taking MAOIs or within 14 days of stopping treatment with an MAOI.
  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
    : Avoid use with Morphine Sulfate Extended-Release Capsules because they may reduce analgesic effect of Morphine Sulfate Extended-Release Capsules or precipitate withdrawal symptoms. ( 5.13, 7
    )

  )
• Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of Morphine Sulfate Extended-Release Capsules 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)

  and

  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. (

  5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

  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:

  • Complete a
    REMS-compliant education program
    offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
  • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The
    Patient
    Counseling Guide (PCG)
    can be obtained at this link:
    www.fda.gov/OpioidAnalgesicREMSPCG.
  • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
  • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

  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.

  )

• Periodically reassess patients receiving Morphine Sulfate Extended-Release Capsules to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (
  2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program)

  [see Warnings and Precautions (5.2)]

  .

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.
  )
• Do not rapidly reduce or abruptly discontinue Morphine Sulfate Extended-Release Capsules in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.3 Initial Dosage

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

  The starting dose for patients who are not opioid tolerant is Morphine Sulfate Extended-Release Capsules 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 one-half of the patient's total daily oral morphine dose as Morphine Sulfate Extended-Release Capsules twice daily or by administering the total daily oral morphine dose as Morphine Sulfate Extended-Release Capsules once daily. There are no data to support the efficacy or safety of prescribing Morphine Sulfate Extended-Release Capsules more frequently than every 12 hours.

  Morphine Sulfate Extended-Release Capsules are not bioequivalent to other Extended-Release morphine preparations. Conversion from the same total daily dose of another extended-release morphine product to Morphine Sulfate Extended-Release Capsules may lead to either excessive sedation at peak or inadequate analgesia at trough. Therefore, monitor patients closely when initiating Morphine Sulfate Extended-Release Capsules therapy and adjust the dosage of Morphine Sulfate Extended-Release Capsules as needed.

  Conversion from Parenteral Morphine, or Other Opioids 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 mg and 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of oral morphine that is three times the daily parenteral morphine requirement is sufficient.

  Other Oral or Parenteral Opioids to Oral Morphine Ratios

  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.
  ,
  5.14 Withdrawal

  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 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 analgesics (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 agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms

  [see Drug Interactions (7)]

  .
  )
• 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. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  )
• Morphine Sulfate Extended-Release Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  )
• Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg of oral oxycodone per day, 8 mg of oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  )
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  ,
  5 WARNINGS AND PRECAUTIONS

  • Opioid-Induced Hyperalgesia and Allodynia
    : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes and increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
    : Regularly evaluate patients, particularly during initiation and titration.
  • Adrenal Insufficiency
    : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.9
    )
  • Severe Hypotension
    : Regularly evaluate patients during dosage initiation and titration Avoid use of Morphine Sulfate Extended-Release Capsules in patients with circulatory shock. ( 5.10
    )
  • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
    : Monitor patients for sedation and respiratory depression. Avoid use of Morphine Sulfate Extended-Release Capsules in patients with impaired consciousness or coma. ( 5.11
    )

  5.1 Addiction, Abuse, and Misuse

  Morphine Sulfate Extended-Release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-Release Capsules expose users to the risks of addiction, abuse, and misuse.

  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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see

  Postmarketing Experience (6.2)

  ].

  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 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 re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (2.2)

  and

  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 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 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.

  5.2 Life-Threatening Respiratory Depression

  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 is essential

  [see Dosage and Administration (2)]

  . Overestimating the Morphine Sulfate Extended-Release Capsules dosage 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)

  and

  Overdosage (10)]

  .

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  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, gabapentinoids and 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 an opioid overdose reversal agent

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)

  and

  Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Extended-Release Capsules 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)]

  .

  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.

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of Morphine Sulfate Extended-Release Capsules 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)

  and

  Patient Counseling Information (17)]

  .

  5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

  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:

  • Complete a
    REMS-compliant education program
    offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management or Support of Patients with Pain.
  • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The
    Patient
    Counseling Guide (PCG)
    can be obtained at this link:
    www.fda.gov/OpioidAnalgesicREMSPCG.
  • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
  • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

  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.

  5.6 Opioid-Induced Hyperalgesia and Allodynia

  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)]

  .

  5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

  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)

  and

  Drug Interactions (7)]

  . Alternatively, consider the use of non-opioid analgesics in these patients.

  5.8 Interaction with Monoamine Oxidase Inhibitors

  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.

  5.9 Adrenal Insufficiency

  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.

  5.10 Severe Hypotension

  Morphine Sulfate Extended-Release Capsules 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 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.

  5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

  In patients who may be susceptible to the intracranial effects of CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Morphine Sulfate Extended-Release Capsules may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Regularly evaluate 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.

  5.12 Risk of Gastrointestinal Complications

  Morphine Sulfate Extended-Release Capsules is 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.

  Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate.

  5.13 Increased Risk of Seizures in Patients with Seizure Disorders

  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.

  5.14 Withdrawal

  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 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 analgesics (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 agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms

  [see Drug Interactions (7)]

  .

  5.15 Risks of Driving and Operating Machinery

  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)]

  .
  )
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (
  5.1 Addiction, Abuse, and Misuse

  Morphine Sulfate Extended-Release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-Release Capsules expose users to the risks of addiction, abuse, and misuse.

  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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see

  Postmarketing Experience (6.2)

  ].

  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 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 re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (2.2)

  and

  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 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 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.
  )
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  ,
  5.2 Life-Threatening Respiratory Depression

  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 is essential

  [see Dosage and Administration (2)]

  . Overestimating the Morphine Sulfate Extended-Release Capsules dosage 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)

  and

  Overdosage (10)]

  .
  )
• Instruct patients to swallow Morphine Sulfate Extended-Release Capsules intact, or to sprinkle the capsule contents on applesauce and immediately swallow without chewing. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  ,
  2.6 Administration of Morphine Sulfate Extended-Release Capsules

  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:

  • Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
  • Rinse the mouth to ensure all pellets have been swallowed.
  • Discard any unused portion of the Morphine Sulfate Extended-Release Capsules after the contents have been sprinkled on applesauce.

  The contents of the Morphine Sulfate Extended-Release Capsules (pellets) may be administered through a French gastrostomy tube.

  • Flush the gastrostomy tube with water to ensure that it is wet.
  • Sprinkle the Morphine Sulfate Extended-Release Capsules (pellets) into 10 mL of water.
  • Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
  • Rinse the beaker with a further 10 mL of water and pour this into the funnel.
  • Repeat rinsing until no pellets remain in the beaker.

  Do not administer Morphine Sulfate Extended-Release Capsules (pellets) through a nasogastric tube.
  )
• Instruct patients not to cut, break, chew, crush, or dissolve the pellets in Morphine Sulfate Extended-Release Capsules to avoid the risk of release and absorption of potentially fatal dose of morphine. (
  2.1 Important Dosage and Administration Instructions

  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 Capsules 100 mg and 200 mg capsules, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, 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 daily, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

  [see Warnings and Precautions (5)]

  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Extended-Release Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

  Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

  [see Warnings and Precautions (5.1)].

  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Extended-Release Capsules. Consider this risk when selecting an initial dose and when making dose adjustments

  [see Warnings and Precautions (5.2)]

  .

  Instruct patients to swallow Morphine Sulfate Extended-Release capsules whole

  [see Patient Counseling Information (17)].

  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)]

  .

  Instruct patients who are unable to swallow Morphine Sulfate Extended-Release Capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing

  [see Dosage and Administration (2.6)]

  .

  Morphine Sulfate Extended-Release Capsules are administered orally at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
  ,
  2.6 Administration of Morphine Sulfate Extended-Release Capsules

  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:

  • Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing.
  • Rinse the mouth to ensure all pellets have been swallowed.
  • Discard any unused portion of the Morphine Sulfate Extended-Release Capsules after the contents have been sprinkled on applesauce.

  The contents of the Morphine Sulfate Extended-Release Capsules (pellets) may be administered through a French gastrostomy tube.

  • Flush the gastrostomy tube with water to ensure that it is wet.
  • Sprinkle the Morphine Sulfate Extended-Release Capsules (pellets) into 10 mL of water.
  • Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel.
  • Rinse the beaker with a further 10 mL of water and pour this into the funnel.
  • Repeat rinsing until no pellets remain in the beaker.

  Do not administer Morphine Sulfate Extended-Release Capsules (pellets) through a nasogastric tube.
  ,
  5.1 Addiction, Abuse, and Misuse

  Morphine Sulfate Extended-Release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-Release Capsules expose users to the risks of addiction, abuse, and misuse.

  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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see

  Postmarketing Experience (6.2)

  ].

  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 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 re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (2.2)

  and

  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 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 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.
  )
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Morphine Sulfate Extended-Release Capsules, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (
  2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program)

  [see Warnings and Precautions (5.2)]

  .

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.
  ,
  5.1 Addiction, Abuse, and Misuse

  Morphine Sulfate Extended-Release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-Release Capsules expose users to the risks of addiction, abuse, and misuse.

  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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see

  Postmarketing Experience (6.2)

  ].

  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 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 re-evaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration (2.2)

  and

  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 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 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.
  ,
  5.2 Life-Threatening Respiratory Depression

  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 is essential

  [see Dosage and Administration (2)]

  . Overestimating the Morphine Sulfate Extended-Release Capsules dosage 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 an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions (5.1, 5.2, 5.3)]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.2)

  and

  Overdosage (10)]

  .
  ,
  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  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, gabapentinoids and 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 an opioid overdose reversal agent

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)

  and

  Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Extended-Release Capsules 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)]

  .

  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.
  )
• For opioid-naïve patients, initiate treatment using an immediate-release morphine formulation and then convert patients to Morphine Sulfate Extended-Release Capsules. For opioid non-tolerant patients, initiate with a 30 mg capsule orally every 24 hours. Dosage adjustments may be made every one to two days. (
  2.3 Initial Dosage

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

  The starting dose for patients who are not opioid tolerant is Morphine Sulfate Extended-Release Capsules 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 one-half of the patient's total daily oral morphine dose as Morphine Sulfate Extended-Release Capsules twice daily or by administering the total daily oral morphine dose as Morphine Sulfate Extended-Release Capsules once daily. There are no data to support the efficacy or safety of prescribing Morphine Sulfate Extended-Release Capsules more frequently than every 12 hours.

  Morphine Sulfate Extended-Release Capsules are not bioequivalent to other Extended-Release morphine preparations. Conversion from the same total daily dose of another extended-release morphine product to Morphine Sulfate Extended-Release Capsules may lead to either excessive sedation at peak or inadequate analgesia at trough. Therefore, monitor patients closely when initiating Morphine Sulfate Extended-Release Capsules therapy and adjust the dosage of Morphine Sulfate Extended-Release Capsules as needed.

  Conversion from Parenteral Morphine, or Other Opioids 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 mg and 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of oral morphine that is three times the daily parenteral morphine requirement is sufficient.

  Other Oral or Parenteral Opioids to Oral Morphine Ratios

  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.
  .
  2.4 Titration and Maintenance of Therapy

  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 the use of opioid analgesics.

  Patients who experience breakthrough pain may require a dosage adjustment 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. In patients experiencing inadequate analgesia with once daily dosing of Morphine Sulfate Extended-Release Capsules, consider a twice daily regimen. Because steady-state plasma concentrations are approximated within 24 to 36 hours, Morphine Sulfate Extended-Release Capsules dosage adjustments may be done every 1 to 2 days.

  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.
  )

Morphine Sulfate Extended-Release Capsules: 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg. Morphine Sulfate Extended-Release Capsules contain white to off-white or tan colored polymer coated extended-release pellets of morphine sulfate and are available in six dose strengths:

20 mg size 4 capsule, light yellow opaque cap and body with radial printing "N" on the cap and "20" on the body of the capsule.

30 mg size 4 capsule, lavender opaque cap and body with radial printing "N" on the cap and "30" on the body of the capsule.

50 mg size 2 capsule, blue opaque cap and body with radial printing "N" on the cap and "50" on the body of the capsule.

60 mg size 1 capsule, pink opaque cap and body with radial printing "N" on the cap and "60" on the body of the capsule.

80 mg size 0 capsule, yellow opaque cap and body with radial printing "N" on the cap and "80" on the body of the capsule.

100 mg size 0 capsule, green opaque cap and body with radial printing "N" on the cap and "100" on the body of the capsule.

• Pregnancy
  : May cause fetal harm. (
  8.1 Pregnancy

  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 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 3-4 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 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 overdose reversal agent, such as naloxone or nalmefene, 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 (35-322 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 pregestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).
  )
• Lactation
  : Not recommended. (
  8.2 Lactation

  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 Sulfate Extended-Release Capsules 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.
  )