Morphine Sulfate Prescribing Information
Morphine sulfate tablets contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate tablets expose users to the risks of addiction, abuse, and misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate tablets, and reassess all patients receiving morphine sulfate tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate tablets, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate tablets, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential
Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
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
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate tablets, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential
Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.
Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
Table 1 includes clinically significant drug interactions with morphine sulfate tablets.
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 [see Warnings and Precautions ] . |
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration , Warnings and Precautions ] . |
Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 tablets if serotonin syndrome is suspected. |
Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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 ] . |
Intervention: | Do not use morphine sulfate tablets 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 tablets 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: | Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration , Warnings and Precautions ] . |
Examples: | Cyclobenzaprine, metaxalone |
Cimetidine | |
Clinical Impact: | The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. |
Intervention: | Evaluate patients for increased respiratory and CNS depression when morphine sulfate tablets are used concomitantly with cimetidine. |
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 tablets are used concomitantly with anticholinergic drugs. |
P-Glycoprotein (P-gp) Inhibitors | |
Clinical Impact: | The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
Intervention: | Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate tablets and/or the P-gp inhibitor as necessary. |
Examples: | Quinidine, verapamil. |
- Serotonergic Drugs:Concomitant use may result in serotonin syndrome. Discontinue morphine sulfate tablets if serotonin syndrome is suspected.
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:Avoid use with morphine sulfate tablets because they may reduce analgesic effect of morphine sulfate tablets or precipitate withdrawal symptoms.
Use of morphine sulfate tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
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 Health Care 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: https://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.
| Boxed Warning | 12/2023 |
| Dosage and Administration | 12/2023 |
| Warnings and Precautions | 12/2023 |
Morphine Sulfate Tablets are indicated for the management of:
- adults with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
- adults with chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Morphine sulfate tablets contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate tablets expose users to the risks of addiction, abuse, and misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate tablets, and reassess all patients receiving morphine sulfate tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate tablets, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
- Have not been tolerated or are not expected to be tolerated,
- Have not provided adequate analgesia or are not expected to provide adequate analgesia.
- Each 15 mg tablet for oral administration contains: 15 mg morphine sulfate USP (equivalent to 11.25 mg morphine) and is a white, biconvex tablet, debossed “M” on one side, and “15” with a score on the other side.
- Each 30 mg tablet for oral administration contains: 30 mg morphine sulfate USP (equivalent to 22.5 mg morphine) and is a white, biconvex tablet, debossed “M” on one side, and “30” with a score on the other side.
Morphine sulfate tablets are contraindicated in patients with:
- Significant respiratory depression [see Warnings and Precautions (.)]
5.2 Life-Threatening Respiratory DepressionSerious, 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 ]. 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 tablets, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential
[see Dosage and Administration (2.3,2.4)]. Overestimating the morphine sulfate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
[see Patient Counseling Information ].Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[seeDosage and Administration , Warnings and Precautions ]. - Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (
5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated PatientsThe use of morphine sulfate tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary DiseaseMorphine sulfate tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of morphine sulfate tablets
[see Warnings and Precautions ].Elderly, Cachectic, or Debilitated PatientsLife-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
[see Warnings and Precautions ].Regularly evaluate patients, particularly when initiating and titrating morphine sulfate tablets and when morphine sulfate tablets are given concomitantly with other drugs that depress respiration
[see Warnings and PrecautionsAlternatively, consider the use of non-opioid analgesics in these patients., Drug Interactions ].)]. - Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (
5.8 Interaction with Monoamine Oxidase InhibitorsMonoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine sulfate tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
) and Drug Interactions (.)]7 DRUG INTERACTIONSTable 1 includes clinically significant drug interactions with morphine sulfate tablets.
Table 1: Clinically Significant Drug Interactions with Morphine Sulfate TabletsBenzodiazepines and Other Central Nervous System (CNS) DepressantsClinical 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
[see Warnings and Precautions ].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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration , Warnings and Precautions ].Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic DrugsClinical 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 tablets if serotonin syndrome is suspected.
Examples:Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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 ].Intervention:Do not use morphine sulfate tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:Phenelzine, tranylcypromine, linezolid.
Mixed Agonist/Antagonist and Partial Agonist Opioid AnalgesicsClinical Impact:May reduce the analgesic effect of morphine sulfate tablets and/or precipitate withdrawal symptoms.
Intervention:Avoid concomitant use.
Examples:Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle RelaxantsClinical Impact:Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine sulfate tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration , Warnings and Precautions ].Examples:Cyclobenzaprine, metaxalone
CimetidineClinical Impact:The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.
Intervention:Evaluate patients for increased respiratory and CNS depression when morphine sulfate tablets are used concomitantly with cimetidine.
DiureticsClinical 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 DrugsClinical 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 tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) InhibitorsClinical Impact:The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate tablets and/or the P-gp inhibitor as necessary.
Examples:Quinidine, verapamil.
- Serotonergic Drugs:Concomitant use may result in serotonin syndrome. Discontinue morphine sulfate tablets if serotonin syndrome is suspected.
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:Avoid use with morphine sulfate tablets because they may reduce analgesic effect of morphine sulfate tablets or precipitate withdrawal symptoms.
- Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (
5.12 Risks of Use in Patients with Gastrointestinal ConditionsMorphine sulfate tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
The morphine in morphine sulfate tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
)]. - Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (.)]
6 ADVERSE REACTIONSThe following serious adverse reactions are described, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse[see Warnings and Precautions ]
- Life-Threatening Respiratory Depression[see Warnings and Precautions ]
- Interactions with Benzodiazepine or Other CNS Depressants[see Warnings and Precautions ]
- Neonatal Opioid Withdrawal Syndrome[see Warnings and Precautions ]
- Opioid-Induced Hyperalgesia and Allodynia[see Warnings and Precautions ]
- Adrenal Insufficiency[see Warnings and Precautions ]
- Severe Hypotension[see Warnings and Precautions ]
- Gastrointestinal Adverse Reactions[see Warnings and Precautions ]
- Seizures[see Warnings and Precautions ]
- Withdrawal[see Warnings and Precautions ]
The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included: constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.
Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:
Body as a Whole:malaise, withdrawal syndromeCardiovascular System:bradycardia, hypertension, hypotension, palpitations, syncope, tachycardiaDigestive System:biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirstEndocrine:hypogonadismHemic and Lymphatic System:anemia, thrombocytopeniaMetabolic and Nutritional Disorders:edema, weight lossMusculoskeletal:skeletal muscle rigidity, decreased bone mineral densityNervous System:abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headacheRespiratory System:hiccup, hypoventilation, voice alterationSkin and Appendages:dry skin, urticaria, pruritusSpecial Senses:amblyopia, eye pain, taste perversionUrogenital System:abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrheaSerotonin Syndrome:Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.Adrenal Insufficiency:Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.Anaphylaxis:Anaphylaxis has been reported with ingredients contained in morphine sulfate tablets.Androgen Deficiency:Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time[see Clinical Pharmacology ].Hyperalgesia and Allodynia:Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration[see Warnings and Precautions ]Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids.Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).Pediatric use information is approved for Hikma Pharmaceuticals USA Inc.’s Morphine Sulfate Tablets. However, due to Hikma Pharmaceuticals USA Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.Most Common Adverse Reactions Seen on Initiation of Therapy are:
- Adults: constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.
To report SUSPECTED ADVERSE REACTIONS, contactMallinckrodt at 1-800-778-7898or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. - Addiction, Abuse, and Misuse
The following serious adverse reactions are described, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse [see Warnings and Precautions ()]
5.1 Addiction, Abuse, and MisuseMorphine sulfate tablets contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate tablets expose users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence ].Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate tablets, and reassess all patients receiving morphine sulfate tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate tablets, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration and Warnings and Precautions ].Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
- Life-Threatening Respiratory Depression [see Warnings and Precautions ()]
5.2 Life-Threatening Respiratory DepressionSerious, 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 ]. 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 tablets, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential
[see Dosage and Administration (2.3,2.4)]. Overestimating the morphine sulfate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered
[see Patient Counseling Information ].Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[seeDosage and Administration , Warnings and Precautions ]. - Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ()]
5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS DepressantsProfound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
[see Drug Interactions ].If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.
Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration , Warnings and Precautions , Overdosage ].Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine sulfate tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
[see Drug Interactions ]. - Neonatal Opioid Withdrawal Syndrome[see Warnings and Precautions ()]
5.4 Neonatal Opioid Withdrawal SyndromeUse of morphine sulfate tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations ]. - Opioid-Induced Hyperalgesia and Allodynia[see Warnings and Precautions ()]
5.6 Opioid-Induced Hyperalgesia and AllodyniaOpioid-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 ].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 , Warnings and Precautions ]. - Adrenal Insufficiency [see Warnings and Precautions ()]
5.9 Adrenal InsufficiencyCases 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.
- Severe Hypotension [see Warnings and Precautions ()]
5.10 Severe HypotensionMorphine sulfate tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)
[see Drug Interactions ]. Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of morphine sulfate tablets. In patients with circulatory shock, morphine sulfate tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate tablets in patients with circulatory shock. - Gastrointestinal Adverse Reactions [see Warnings and Precautions ()]
5.12 Risks of Use in Patients with Gastrointestinal ConditionsMorphine sulfate tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
The morphine in morphine sulfate tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
- Seizures [see Warnings and Precautions ()]
5.13 Increased Risk of Seizures in Patients with Seizure DisordersThe morphine in morphine sulfate tablets may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during morphine sulfate tablets therapy.
- Withdrawal [see Warnings and Precautions ()]
5.14 WithdrawalDo not abruptly discontinue morphine sulfate tablets in a patient physically dependent on opioids. When discontinuing morphine sulfate tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
[see Dosage and Administration (2.5) and Drug Abuse and Dependence ].Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including morphine sulfate tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms
[see Drug Interactions ].
The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serious adverse reactions associated with morphine use included: respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.
The common adverse reactions seen on initiation of therapy with morphine in adults were dose-dependent and were typical opioid-related adverse reactions. The most frequent of these included: constipation, nausea, and somnolence. Other commonly observed adverse reactions included: lightheadedness, dizziness, sedation, vomiting, and sweating. The frequency of these events depended upon several factors including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual.
Other less frequently observed adverse reactions from opioid analgesics, including morphine sulfate included:
Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date
Opioids have been shown to have a variety of effects on components of the immune system in
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance
There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions