MORPHINE SULFATE

Morphine sulfate suppositories are an opioid agonist, available in 5 mg, 10 mg, 20 mg, and 30 mg strengths for rectal administration. The chemical name is morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-, (5a,6a)-, sulfate (2:1) (salt), pentahydrate. The molecular weight is 758. Its molecular formula is (C 17 H 19 NO 3 ) 2 · H 2 SO 4 · 5H 2 O, and it has the following chemical structure: Morphine sulfate USP is a white to off-white crystalline powder or a fine white to light yellow powder. It is soluble in water and slightly soluble in alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). The inactive ingredients in morphine sulfate suppositories include: butylated hydroxyanisole, butylated hydroxytoluene, colloidal silicon dioxide, glyceryl monostearate, hydrogenated vegetable oil, polysorbate 80.

Morphine sulfate suppositories are indicated for the management of acute and chronic pain severe enough to require and opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)] , reserve morphine sulfate suppositories for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: • 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 suppositories is an opioid agonist indicated for the management of acute and 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, and misuse with opioids, even at recommended doses, reserve morphine sulfate suppositories 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

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1) • Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) • Usual adult dosage of morphine sulfate suppositories is 10 to 20 mg every 4 hours as needed. (2.2) • Do not stop morphine sulfate suppositories abruptly in a physically-depended patient. (2.4) 2.1 Important Dosage and Administration Instructions Morphine sulfate suppositories are available in four strengths: 5 mg per suppository, 10 mg per suppository, 20 mg per suppository, and 30 mg per suppository. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)] . Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with morphine sulfate suppositories and adjust the dosage accordingly [see Warnings and Precautions (5.2) ]. 2.2 Initial Dosage Initiating Treatment with Morphine Sulfate Suppositories Initiate treatment with morphine sulfate suppositories in a dosing range of 10 – 20 mg, rectally, every 4 hours. Conversion from Other Opioids to Morphine Sulfate Suppositories There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised with determining the total daily dosage of morphine sulfate suppositories. It is safer to underestimate a patient’s 24-hour morphine sulfate dosage than to overestimate the 24-hour dosage and manage and adverse reaction due to overdose. Conversion from Morphine Sulfate Suppositories to Extended-Release Morphine The relative bioavailability of morphine sulfate suppositories compared to extended-release morphine is unknown, so conversion to extended-release drug product must be accompanied by close observation for signs of excessive sedation and respiratory depression. 2.3 Titration and Maintenance of Therapy Individually titrate morphine sulfate suppositories to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving morphine sulfate suppositories to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the morphine sulfate suppositories dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Discontinuation of Morphine Sulfate Suppositories When a patient who has been taking morphine sulfate suppositories regularly and may be physically dependent no longer requires therapy with morphine sulfate suppositories, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue morphine sulfate suppositories in a physically-dependent patient [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)] .

Morphine sulfate suppositories are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6), Drug Interactions (7)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)] • Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6)] • Significant respiratory depression. (4) • Acute or severe bronchial asthma in an unmonitored setting or 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 to morphine. (4)

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)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)] • Adrenal Insufficiency [see Warnings and Precautions (5.7)] • Severe Hypotension [see Warnings and Precautions (5.8)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Withdrawal [see Warnings and Precautions (5.12)] 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 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 : anorexia, 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 suppositories. Androgen Deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)] . Most common adverse reactions are constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, sweating. (6) To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 1 includes clinically significant drug interactions with morphine sulfate suppositories. Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Suppositories Alcohol, Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)] . 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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate suppositories 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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2, 5.6)] Intervention: Do not use morphine sulfate suppositories 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 suppositories and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate suppositories and/or the muscle relaxant as necessary. 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: Monitor patients for increased respiratory and CNS depression when morphine sulfate suppositories are used concomitantly with cimetidine. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor 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: Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate suppositories 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 twofold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate suppositories and/or the P-gp inhibitor as necessary. Examples: quinidine, verapamil • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue morphine sulfate suppositories if serotonin syndrome is suspected. (7) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with morphine sulfate suppositories because they may reduce analgesic effect of morphine sulfate suppositories or precipitate withdrawal symptoms. (7)