1 INDICATIONS AND USAGE Morphine sulfate extended-release capsules are indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

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 ( 5.1 )] , reserve opioid analgesics, including morphine sulfate extended-release capsules 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 extended-release capsules are not indicated as an as-needed (prn) analgesic.

Morphine sulfate extended-release capsules are an opioid agonist indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

( 1 ) 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 extended-release capsules for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

( 1 , 5.1 ) Morphine sulfate extended-release capsules are not indicated as an as-needed (prn) analgesic.

( 1 )

6 ADVERSE REACTIONS 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 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.6 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (greater than or equal to 10%) are constipation, nausea, somnolence, vomiting and headache.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled and open-label clinical studies, 560 patients with chronic malignant or non-malignant pain were treated with morphine sulfate extended-release capsules.

The most common serious adverse events reported with administration of morphine sulfate extended-release capsules were vomiting, nausea, death, dehydration, dyspnea, and sepsis.

(Deaths occurred in patients treated for pain due to underlying malignancy.) Serious adverse events caused by morphine include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

The most common adverse events (seen in greater than 10%) reported by patients treated with morphine sulfate extended-release capsules during the clinical trials at least once during therapy were constipation, nausea, somnolence, vomiting, and headache.

Adverse events occurring in 5 to 10% of study patients were peripheral edema, diarrhea, abdominal pain, infection, urinary tract infection, accidental injury, flu syndrome, back pain, rash, sweating, fever, insomnia, depression, paresthesia, anorexia, dry mouth, asthenia and dyspnea.

Other less common side effects expected from opioid analgesics, including morphine, or seen in fewer than 5% of patients taking morphine sulfate extended-release capsules in the clinical trials were: 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.

Hemic and Lymphatic System: anemia, thrombocytopenia.

Metabolic and Nutritional Disorders: edema, weight loss.

Musculoskeletal: skeletal muscle rigidity.

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo.

Respiratory System: hiccup, hypoventilation, voice alteration.

Skin and Appendages: dry skin, urticaria.

Special Senses: amblyopia, eye pain, taste perversion.

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention.

Anaphylaxis has been reported with ingredients contained in morphine sulfate extended-release capsules.

Advise patients how to recognize such a reaction and when to seek medical attention.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of morphine.

Because these reactions are 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.

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 extended-release capsules.

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] .

Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.6 )] .

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).

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 ( 5.12 )] .

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 ( 9.2 )] , 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.