Morphine Sulfate

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. (1) Limitations of Use (1) 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

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)
• Known hypersensitivity to morphine. (4)

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. (5.5)
• Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.7)
• Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of morphine sulfate suppositories in patients with circulatory shock. (5.8)
• 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 suppositories in patients with impaired consciousness or coma. (5.9)

5.1Addiction, Abuse, and Misuse

Morphine sulfate suppositories contain morphine, a Schedule II controlled substance. As an opioid, morphine sulfate suppositories 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.

Asses each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate suppositories, and monitor all patients receiving morphine sulfate suppositories for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as morphine sulfate suppositories, but use in such patients necessitates intensive counseling about the risks and proper use of morphine sulfate suppositories along with the intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)] .

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing morphine sulfate suppositories. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)] . 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.

Table 1 includes clinically significant drug interactions with morphine sulfate suppositories. Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Suppositories Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 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 (5.4)] 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.

8.1Pregnancy Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)] . There are no available data with morphine sulfate suppositories 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

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 Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.