morphine sulfate

Morphine Sulfate Tablets are indicated for the management of:

• adult and pediatric patients weighing at least 50 kg and above 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. Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ], reserve opioid analgesics, including Morphine Sulfate Tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Morphine Sulfate Tablets are opioid agonists indicated for the management of:
• adults and pediatric patients weighing 50 kg and above 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. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Morphine Sulfate Tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• Morphine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
• 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 Tablets 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.
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
• 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.
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments.
• 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 Tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose.
• Initiate treatment with Morphine Sulfate Tablets in adults and pediatric patients 50 kg and above: 15 to 30 mg every 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Do not exceed 30 mg as an initial dose in pediatric patients. Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Tablets
• Periodically reassess patients receiving Morphine Sulfate Tablets 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.
• Do not rapidly reduce or abruptly discontinue Morphine Sulfate Tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. 2.1 Important Dosage and Administration Instructions Morphine Sulfate Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Tablets 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. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 ] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Morphine Sulfate Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ]. 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 ]. 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 ]. 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. 2.3 Initial Dosage Use of Morphine Sulfate Tablets as the First Opioid Analgesic (Opioid-naïve or Opioid-non-tolerant Patients) : Adults : The recommended dosage to initiate treatment in adults is 15 mg to 30 mg every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Tablets. Pediatric Patients Weighing at Least 50 kg : The recommended dosage to initiate treatment in pediatric patients weighing at least 50 kg and who are able to swallow oral tablets is 15 mg every 4 hours as needed for pain, and the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Morphine Sulfate Tablets. Do not exceed 30 mg as an initial dose. Morphine Sulfate Tablets are not recommended for use in pediatric patients who weigh less than 50 kg as the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg. Conversion from Parenteral Morphine to Morphine Sulfate Tablets For conversion from parenteral morphine to Morphine Sulfate Tablets, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine. Conversion from Other Opioids to Morphine Sulfate Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Morphine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Morphine Sulfate Tablets dosage than to overestimate the 24-hour Morphine Sulfate Tablets dosage and manage an adverse reaction due to overdose. Initiate dosing using Morphine Sulfate Tablets 15 mg to 30 mg every 4 hours. Conversion from Morphine Sulfate Tablets to Extended-Release Morphine For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Tablets, and extended-release morphine formulations. The extended duration of release of morphine sulfate from extended-release formulations results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from Morphine Sulfate Tablets to the same total daily dose of an extended-release formulation could lead to excessive sedation at peak serum levels. Therefore, conversion to extended-release morphine may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate Morphine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Morphine Sulfate Tablets Do not rapidly reduce or abruptly discontinue Morphine Sulfate Tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Morphine Sulfate Tablets, there are a variety of factors that should be considered, including the total daily dose of opioids (including Morphine Sulfate Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication-assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Morphine Sulfate Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions , Drug Abuse and Dependence ] .

12.1 Mechanism of Action Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

The 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 syndrome Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst Endocrine: hypogonadism Hemic and Lymphatic System: anemia, thrombocytopenia Metabolic and Nutritional Disorders: edema, weight loss Musculoskeletal: skeletal muscle rigidity, decreased bone mineral density Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, depression, dry mouth, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo, headache Respiratory System: hiccup, hypoventilation, voice alteration Skin and Appendages: dry skin, urticaria, pruritus Special Senses: amblyopia, eye pain, taste perversion Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention or hesitancy, anti-diuretic effect, amenorrhea Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. 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). Clinical Trial Experience in Pediatric Patients The safety of morphine sulfate was evaluated in 81 pediatric patients with acute pain [see Use in Specific Populations ] . Morphine Tablets are not recommended for use in pediatric patients weighing less than 50 kg. The adverse reaction profile in pediatric patients is similar to adults. The most common adverse reactions reported on initiation of therapy in at least 5% of patients were: nausea (17%), vomiting (10%), constipation (6%), decreased oxygen saturation (5%), and flatulence (5%). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months:
• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. Most Common Adverse Reactions Seen on Initiation of Therapy are:
• Adults : constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, and sweating.
• Pediatrics (>5%) : nausea, vomiting, constipation, decreased oxygen saturation, and flatulence. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch

Table 1 includes clinically significant drug interactions with Morphine Sulfate Tablets. Table 1: 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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration , Warnings and Precautions ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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 recommending or prescribing an opioid overdose reversal agent [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.

• Pregnanc y: 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 ]. There are no available data with Morphine Sulfate Tablets in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3 to 4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations: Fetal/Neonatal Adverse Reactions: Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ] . 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 Tablets are not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Tablets, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data: Human Data: The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Animal Data: Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35 to 322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100 to 500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10 to 50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater. Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

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 Morphine Sulfate Tablets and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Morphine Sulfate Tablets and any potential adverse effects on the breastfed infant from Morphine Sulfate Tablets or from the underlying maternal condition. Clinical Considerations: Monitor infants exposed to Morphine Sulfate Tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility: Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions and Clinical Pharmacology ] . In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology ]. 8.4 Pediatric Use The safety and effectiveness of Morphine Sulfate Tablets have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate. Use of Morphine Sulfate Tablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with post-operative acute pain. Patients were excluded if they had used opioids for more than 7 days within the previous 30 days prior to surgery or had received opioids in any form in the previous 7 days prior to surgery. Initial dosing was approximately 0.15 mg/kg to 0.3 mg/kg. Pharmacokinetic modeling and simulation indicate that an initial dose of 15 mg Morphine Sulfate Tablets to pediatric patients weighing at least 50 kg is expected to produce a maximum systemic exposure (C max ) similar to that achieved after single dose administration of 10 mg morphine sulfate oral solution to adults [see Clinical Pharmacology ] . Safety data were available in 81 patients who received single and multiple doses (63 patients aged 2 to 17 years received the oral solution; 18 patients aged 12 years to 17 years received the tablets). The median duration of treatment was 20 hours (range 4 hours to 36 hours). Opioid and non-opioid rescue analgesics were allowed. The safety profile in pediatric patients consisted primarily of opioid-related adverse reactions and is similar to that observed in adults [see Adverse Reactions ]. The safety and effectiveness of Morphine Sulfate Tablets have not been established for the management of pediatric patients weighing less than 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg [see Dosage and Administration ] . The safety and effectiveness of Morphine Sulfate Tablets have not been established for the management of pediatric patients with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphine Sulfate Tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ] . Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ]. 8.7 Renal Impairment Morphine sulfate pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphine Sulfate Tablets and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ].