FDA label 939f020c-e4d6-4aef-aa63-f4792d690a63

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL . See full prescribing information for complete boxed warning Morphine Sulfate Extended-release Capsules exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and monitor regularly for development of these behaviors or conditions. ( ) 5.1 Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Morphine Sulfate Extended-release Capsules whole to avoid exposure to a potentially fatal dose of morphine. ( ) 5.2 Accidental ingestion of Morphine Sulfate Extended-release Capsules, especially in children, can result in fatal overdose of morphine. ( ) 5.3 Prolonged use of Morphine Sulfate Extended-release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available ( ). 5.3 Instruct patients not to consume alcohol or any products containing alcohol while taking Morphine Sulfate Extended-release Capsules because co-ingestion can result in fatal plasma morphine levels. ( ) 5.4 Addiction, Abuse, and Misuse Morphine Sulfate Extended-release Capsules expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing Morphine Sulfate Extended-release Capsules, and monitor all patients regularly for the development of these behaviors or conditions . [see ] Warnings and Precautions (5.1) Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Morphine Sulfate Extended-release Capsules. Monitor for respiratory depression, especially during initiation of Morphine Sulfate Extended-release Capsules or following a dose increase. Instruct patients to swallow Morphine Sulfate Extended-release Capsules whole; crushing, chewing, or dissolving Morphine Sulfate Extended-release Capsules can cause rapid release and absorption of a potentially fatal dose of morphine . [see ] Warnings and Precautions (5.2) Accidental Ingestion Accidental ingestion of even one dose of Morphine Sulfate Extended-release Capsules, especially by children, can result in a fatal overdose of morphine . [see ] Warnings and Precautions (5.2) Neonatal Opioid Withdrawal Syndrome Prolonged use of Morphine Sulfate Extended-release Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available . [see ] Warnings and Precautions (5.3) Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking Morphine Sulfate Extended-release Capsules. The co-ingestion of alcohol with Morphine Sulfate Extended-release Capsules may result in increased plasma levels and a potentially fatal overdose of morphine . [see ] Warnings and Precautions (5.4)

5 WARNINGS AND PRECAUTIONS Interaction with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. ( ) 5.4 Elderly, cachectic, debilitated patients and those with chronic pulmonary disease: Monitor closely because of increased risk for life threatening respiratory depression. ( , ) 5.5 5.6 Hypotensive effect: Monitor during dose initiation and titration ( ) 5.7 Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression and avoid use of Morphine Sulfate Extended-release Capsules in patients with impaired consciousness or coma susceptible to intracranial effects of CO retention. ( ) 2 5.8 5.1 Addiction, Abuse, and Misuse Morphine Sulfate Extended-release Capsules contain morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Extended-release Capsules expose users to the risks of addiction, abuse, and misuse . As modified-release products such as Morphine Sulfate Extended-release Capsules deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present. [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 Extended-release Capsules and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Extended-release Capsules, and monitor all patients receiving Morphine Sulfate Extended-release Capsules 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Morphine Sulfate Extended-release Capsules for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Morphine Sulfate Extended-release Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Extended-release Capsules along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of Morphine Sulfate Extended-release Capsules by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death . [see ] Overdosage (10) Opioid agonists such as Morphine Sulfate Extended-release Capsules 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 Extended-release Capsules. 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 . 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. [see ] Patient Counseling Information (17) 5.2 Life Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, 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 . Carbon dioxide (CO ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. [see ] Overdosage (10) 2 While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Morphine Sulfate Extended-release Capsules, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with Morphine Sulfate Extended-release Capsules and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Extended-release Capsules are essential . Overestimating the Morphine Sulfate Extended-release Capsules dose when converting patients from another opioid product can result in fatal overdose with the first dose. [see ] Dosage and Administration (2) Accidental ingestion of even one dose of Morphine Sulfate Extended-release Capsules, especially by children, can result in respiratory depression and death due to an overdose of morphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of Morphine Sulfate Extended-release Capsules during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. 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. 5.4 Interactions with Central Nervous System Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Morphine Sulfate Extended-release Capsules therapy. The co-ingestion of alcohol with Morphine Sulfate Extended-release Capsules may result in increased plasma levels and a potentially fatal overdose of morphine Hypotension, profound sedation, coma, respiratory depression, and death may result if Morphine Sulfate Extended-release Capsules are used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). [see ]. Clinical Pharmacology (12.3) When considering the use of Morphine Sulfate Extended-release Capsules in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Morphine Sulfate Extended-release Capsules are made, start with a low dose of Morphine Sulfate Extended-release Capsules (30 mg or lower) every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant . [see ] Drug Interactions (7) 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating Morphine Sulfate Extended-release Capsules and when Morphine Sulfate Extended-release Capsules are given concomitantly with other drugs that depress respiration . [see ] Warnings and Precautions (5.2) 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with Morphine Sulfate Extended-release Capsules, as in these patients, even usual therapeutic doses of Morphine Sulfate Extended-release Capsules may decrease respiratory drive to the point of apnea . Consider the use of alternative non-opioid analgesics in these patients if possible. [see ] Warnings and Precautions (5.2) 5.7 Hypotensive Effect Morphine Sulfate Extended-release Capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) . Monitor these patients for signs of hypotension after initiating or titrating the dose of Morphine Sulfate Extended-release Capsules. In patients with circulatory shock, Morphine Sulfate Extended-release Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphine Sulfate Extended-release Capsules in patients with circulatory shock. [see ] Drug Interactions (7.2) 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking Morphine Sulfate Extended-release Capsules who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with Morphine Sulfate Extended-release Capsules. Morphine Sulfate Extended-release Capsules may reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure Opioids may also obscure the clinical course in a patient with a head injury. 2 2 . Avoid the use of Morphine Sulfate Extended-release Capsules in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions Morphine Sulfate Extended-release Capsules are contraindicated in patients with paralytic ileus. Avoid the use of Morphine Sulfate Extended-release Capsules in patients with other GI obstruction. The morphine in Morphine Sulfate Extended-release Capsules may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.10 Use in Patients with Convulsive or Seizure Disorders The morphine in Morphine Sulfate Extended-release Capsules may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during Morphine Sulfate Extended-release Capsules therapy. 5.11 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including Morphine Sulfate Extended-release Capsules. In these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing Morphine Sulfate Extended-release Capsules, gradually taper the dose . Do not abruptly discontinue Morphine Sulfate Extended-release Capsules. [see ] Dosage and Administration (2.3) 5.12 Driving and Operating Machinery Morphine Sulfate Extended-release Capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Morphine Sulfate Extended-release Capsules and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: 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 Other CNS Depressants [see ] Warnings and Precautions (5.4) Hypotensive Effect [see ] Warnings and Precautions (5.7) Gastrointestinal Effects [see ] Warnings and Precautions (5.9) Seizures [see ] Warnings and Precautions (5.10) In the randomized study, the most common adverse reactions with Morphine Sulfate Extended-release Capsules therapy were drowsiness, constipation, nausea, dizziness, and anxiety. The most common adverse reactions leading to study discontinuation were nausea, constipation (may be severe), vomiting, fatigue, dizziness, pruritus, and somnolence. Most common adverse reactions (>10%): constipation, nausea, and somnolence. ( ) 6.1 To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories at 1-855-899-9180 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. Clinical trial patients with chronic cancer pain (n=227) (AE by Body System as seen in 2% or more of patients) Percentage % CENTRAL NERVOUS SYSTEM 28 Drowsiness 9 Dizziness 6 Anxiety 5 Confusion 4 Dry Mouth 3 Tremor 2 GASTROINTESTINAL 26 Constipation 9 Nausea 7 Diarrhea 3 Anorexia 3 Abdominal pain 3 Vomiting 2 BODY AS A WHOLE 16 Pain 3 Disease progression 3 Chest pain 2 Diaphoresis 2 Fever 2 Asthenia 2 Accidental Injury 2 RESPIRATORY 3 Dyspnea 3 SKIN & APPENDAGES 3 Rash 3 METABOLIC & NUTRITIONAL 3 Peripheral edema 3 HEMIC & LYMPHATIC 4 Anemia 2 Leukopenia 2 In clinical trials in patients with chronic cancer pain, the most common adverse events reported by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%), dizziness (6%), and anxiety (6%). Other less common side effects expected from Morphine Sulfate Extended-release Capsules or seen in less than 2% of patients in the clinical trials were: Body as a Whole: Headache, chills, flu syndrome, back pain, malaise, withdrawal syndrome Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pallor, facial flushing, palpitations, bradycardia, syncope Central Nervous System: Confusion, anxiety, abnormal thinking, abnormal dreams, lethargy, depression, loss of concentration, insomnia, amnesia, paresthesia, agitation, vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation, euphoria, apathy, seizures, myoclonus Endocrine: Hyponatremia due to inappropriate ADH secretion, gynecomastia Gastrointestinal: Dysphagia, dyspepsia, stomach atony disorder, gastro-esophageal reflux, delayed gastric emptying, biliary colic Hemic and Lymphatic: Thrombocytopenia Metabolic and Nutritional: Hyponatremia, edema Musculoskeletal: Back pain, bone pain, arthralgia Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, respiratory insufficiency, voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema Skin and Appendages: Decubitus ulcer, pruritus, skin flush Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced libido, reduced potency, prolonged labor Four-Week Open-Label Safety Study In the open-label, 4-week safety study, 1418 patients ages 18 to 85 with chronic, non-malignant pain (e.g., back pain, osteoarthritis, neuropathic pain) were enrolled. The most common adverse events reported at least once during therapy were constipation (12%), nausea (9%), and somnolence (3%). Other less common side effects occurring in less than 3% of patients were vomiting, pruritus, dizziness, sedation, dry mouth, headache, fatigue, and rash. 6.2 Post-Marketing Experience 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.

<table width="75%"><col width="75%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Clinical trial patients with chronic cancer pain (n=227) (AE by Body System as seen in 2% or more of patients)</th><th styleCode="Rrule" valign="bottom">Percentage %</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">CENTRAL NERVOUS SYSTEM</content></td><td styleCode="Rrule"><content styleCode="bold">28</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Drowsiness</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Confusion</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry Mouth</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tremor</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">GASTROINTESTINAL</content></td><td styleCode="Rrule"><content styleCode="bold">26</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anorexia</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">BODY AS A WHOLE</content></td><td styleCode="Rrule"><content styleCode="bold">16</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pain</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Disease progression</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Chest pain</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diaphoresis</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fever</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Accidental Injury</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">RESPIRATORY</content></td><td styleCode="Rrule"><content styleCode="bold">3</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">SKIN &amp; APPENDAGES</content></td><td styleCode="Rrule"><content styleCode="bold">3</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">METABOLIC &amp; NUTRITIONAL</content></td><td styleCode="Rrule"><content styleCode="bold">3</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral edema</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">HEMIC &amp; LYMPHATIC</content></td><td styleCode="Rrule"><content styleCode="bold">4</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"> Leukopenia</td><td styleCode="Rrule">2</td></tr></tbody></table>