morphine sulfate 30 MG Oral Capsule

INDICATIONS AND USAGE Morphine Sulfate Oral Solution 2 mg/mL and 4 mg/mL is indicated for the management of: adults with acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. pediatric patients 2 years of age and older with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Morphine Sulfate Oral Solution 20 mg/mL is indicated for the relief of acute and chronic pain in opioid-tolerant adult patients. Morphine Sulfate Oral Solution is an opioid agonist. Morphine Sulfate 2 mg/mL and 4 mg/mL is indicated for the management of: adults with acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) pediatric patients 2 years of age and older with acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Morphine Sulfate Oral Solution 20 mg/mL is indicated for: the relief of acute and chronic pain in opioid-tolerant adult patients. ( 1 ) Limitations of Use ( 1 ): Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration ( 5.2 ), reserve Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated Have not provided adequate analgesia or are not expected to provide adequate analgesia Morphine Sulfate Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2) ] , reserve Morphine Sulfate Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated or are not expected to be tolerated, Have not provided adequate analgesia or are not expected to provide adequate analgesia. Morphine Sulfate Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

DOSAGE AND ADMINISTRATION 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. ( 2.1 ) 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. ( 2.1 , 5 ) 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. ( 2.1 ) 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. ( 2.1 , 5.1 ) 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. ( 2.1 , 5.2 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) 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 ( 2.3 , 2.4 ) Do not abruptly discontinue morphine sulfate tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.14 ) 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 ( 5 )]. 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 ( 5.1 )]. 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 ( 5 )] . 2.2 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 [see Warnings and Precautions ( 5.2 )]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 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 an

WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.6 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. ( 5.7 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of morphine sulfate tablets in patients with circulatory shock. ( 5.10 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of morphine sulfate tablets in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Morphine sulfate tablets contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate tablets expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate tablets, and reassess all patients receiving morphine sulfate tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as morphine sulfate tablets but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.2 )]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing morphine sulfate tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )]. Carbon dioxide (CO 2 ) retention from opioid- induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate tablets are essential [see Dosage and Administration ( 2.3 , 2.4 )]. Overestimating the morphine sulfate tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of morphine sulfate tablets, especially by children, can result in respiratory depression and death due to an overdose of morphine. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17 )]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 )]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of morphine sulfate tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential

CONTRAINDICATIONS Preservative-free morphine sulfate injection is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3) ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9) ] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10) , Drug Interactions (7) ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14) ] • Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6) ] Neuraxial administration of preservative-free morphine sulfate injection is contraindicated in patients with: • Infection at the injection microinfusion site [see Warnings and Precautions (5.1) ] • Concomitant anticoagulant therapy [see Warnings and Precautions (5.1) ] • Uncontrolled bleeding diathesis [see Warnings and Precautions (5.1) ] • The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. Preservative-free morphine sulfate injection is contraindicated in patients with: • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting in absence of resuscitative equipment ( 4 ) • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) • Hypersensitivity or intolerance to morphine ( 4 ) Neuraxial administration of preservative-free morphine sulfate injection is contraindicated in patients with: • Infection at the injection microinfusion site ( 4 ) • Concomitant anticoagulant therapy ( 4 ) • Uncontrolled bleeding diathesis ( 4 ) • The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. ( 4 )

CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics CNS Depressant/Alcohol Interaction Additive pharmacodynamic effects may be expected when morphine sulfate extended-release is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Effects on the Central Nervous System Morphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the 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 reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reaction (6.2) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3 )] Concentration–Adverse Reaction Relationships There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.3 , 2.4 )] . 12.3 Pharmacokinetics Absorption Morphine sulfate extended-release is an extended-release tablet containing morphine sulfate. Morphine is released from morphine sulfate extended-release somewhat more slowly than from immediate-release oral preparations. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is morphine sulfate extended-release or an immediate-release formulation. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment. The oral bioavailability of morphine is approximately 20 to 40%. When morphine sulfate extended-release is given on a fixed dosing regimen, steady-state is achieved in about a day. Food Effect The effect of food upon the systemic bioavailability of morphine sulfate extended-release has not been systematically evaluated for all strengths. One study, conducted with the 30 mg morphine sulfate extended-release tablets, showed no significant differences in C max and AUC (0-24h) values, whether the tablet was taken while fasting or with a high-fat breakfast. Distribution Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses placental membranes and has been found in breast milk. The volume of distribution (Vd) for morphine is approximately 3 to 4 liters per kilogram and morphine is 30 to 35% reversibly bound to plasma proteins. Elimination Metabolism The major pathways of morphine metabolism include glucuronidation to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity. Excretion The elimination of morphine occurs primarily as renal excretion of M3G and its effective half-life after intravenous administration is normally 2 to 4 hours. Approximately 10% of the dose is excreted unchanged in urine. In some studies involving longer periods of plasma sampling, a longer terminal half-life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling. Specific Populations Sex A sex analysis of pharmacokinetic data from healthy subjects taking morphine sulfate extended-release indicated that morphine concentrations were similar in males and females. Race/Ethnicity Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 ml/min compared to 1495 +/- 80 ml/min). Hepatic Impairment Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these patients, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted. Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased, and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with rena