FDA label 057c5ce2-4a59-48a8-91fa-afd10f61f5f0

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential Morphine sulfate extended-release tablets contain morphine; an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions ( 5.1 )] . Assess each patient’s risk for opioid abuse or addiction prior to prescribing morphine sulfate extended-release tablets. The risk for opioid abuse is 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 depressive disorder). Routinely monitor all patients receiving morphine sulfate extended-release tablets for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence ( 9 )]. Life-Threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of morphine sulfate extended-release tablets, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions ( 5.2 )] . Proper dosing and titration are essential and morphine sulfate extended-release tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of morphine sulfate extended-release tablets or following a dose increase . Instruct patients to swallow morphine sulfate extended-release tablets whole. Crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine. Accidental Exposure Accidental ingestion of morphine sulfate extended-release tablets, especially in children, can result in a fatal overdose of morphine [see Warnings and Precautions ( 5.3 )] . WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE See full prescribing information for complete boxed warning . Morphine sulfate extended-release tablets contain morphine sulfate, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during morphine sulfate extended-release tablet therapy ( 5.1 , 9 ). Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of morphine sulfate extended-release tablets to reduce the risk ( 5.2 ). Accidental ingestion of morphine sulfate extended-release tablets can result in fatal overdose of morphine, especially in children ( 5.3 ).

5 WARNINGS AND PRECAUTIONS Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.4 , 5.5 ) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.6 , 7.1 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of morphine sulfate extended-release tablets in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8 ) 5.1 Abuse Potential Morphine sulfate extended-release tablets contain morphine, an opioid agonist and a Schedule II controlled substance. Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists 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 tablets in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain. Assess each patient’s risk for opioid abuse or addiction prior to prescribing morphine sulfate extended-release tablets. The risk for opioid abuse is 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). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use. Misuse or abuse of morphine sulfate extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage ( 10 )] . 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 Respiratory depression is the chief hazard of opioid agonists, including morphine sulfate extended-release tablets. Respiratory depression if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. 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 )] . While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate extended-release tablets, 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 tablets and following dose increases. Instruct patients against use by individuals other than the patient for whom morphine sulfate extended-release tablets were prescribed and to keep morphine sulfate extended-release tablets out of the reach of children, as such inappropriate use may result in fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate extended-release tablets are essential [see Dosage and Administration ( 2 )] . Overestimating the morphine sulfate extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused. To further reduce the risk of respiratory depression, consider the following: • Proper dosing and titration are essential and morphine sulfate extended-release tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Morphine sulfate extended-release 100 mg and 200 mg tablets are for use in opioid-tolerant patients only. Ingestion of these strengths of morphine sulfate extended-release tablets may cause fatal respiratory depression when administered to patients not already tolerant to high doses of opioids. • Instruct patients to swallow morphine sulfate extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed. The resulting morphine dose may be fatal, particularly in opioid-naïve individuals. • Morphine sulfate extended-release tablets are contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications ( 4 )] . 5.3 Accidental Exposure Accidental consumption of morphine sulfate extended-release tablets, especially in children, can result in a fatal overdose of morphine. 5.4 Elderly, Cachectic, and Debilitated Patients 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. Therefore, monitor such patients closely, particularly when initiating and titrating morphine sulfate extended-release tablets and when morphine sulfate extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 )] . 5.5 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 tablets, as in these patients, even usual therapeutic doses of morphine sulfate extended-release tablets may decrease respiratory drive to the point of apnea [see Warnings and Precautions ( 5.2 )] . Consider the use of alternative non-opioid analgesics in these patients if possible. 5.6 Interactions with Alcohol, CNS Depressants, and Illicit Drugs Hypotension, and profound sedation, coma or respiratory depression may result if morphine sulfate extended-release tablets are used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids). When considering the use of morphine sulfate extended-release tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If morphine sulfate extended-release tablet therapy is to be initiated in a patient taking a CNS depressant, start with a lower morphine sulfate extended-release tablet dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions ( 7.1 )]. 5.7 Hypotensive Effects Morphine sulfate extended-release tablets 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) [see Drug Interactions ( 7.1 )] . Monitor these patients for signs of hypotension after initiating or titrating the dose of morphine sulfate extended-release tablets. In patients with circulatory shock, morphine sulfate extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of morphine sulfate extended-release tablets in patients with circulatory shock. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking morphine sulfate extended-release tablets that may be susceptible to the intracranial effects of CO 2 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 tablets. Morphine sulfate extended-release tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of morphine sulfate extended-release tablets in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions Morphine sulfate extended-release tablets are contraindicated in patients with paralytic ileus. Avoid the use of morphine sulfate extended-release tablets in patients with other GI obstruction. The morphine in morphine sulfate extended-release tablets 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 tablets 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 tablet therapy. 5.11 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including morphine sulfate extended-release tablets. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing morphine sulfate extended-release tablets, gradually taper the dose [see Dosage and Administration ( 2.3 )] . Do not abruptly discontinue morphine sulfate extended-release tablets. 5.12 Driving and Operating Machinery Morphine sulfate extended-release tablets 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 tablets and know how they will react to the medication.

6 ADVERSE REACTIONS The following adverse reactions described elsewhere in the labeling include: Respiratory Depression [see Warnings and Precautions ( 5.2 )] Chronic Pulmonary Disease [see Warnings and Precautions ( 5.5 )] Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions ( 5.8 )] Interactions with Other CNS Depressants [see Warnings and Precautions ( 5.6 )] Hypotensive Effect [see Warnings and Precautions ( 5.7 )] Gastrointestinal Effects [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Most common adverse reactions: constipation, nausea, and sedation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals L.P. at 1-888-827-0616 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Morphine sulfate extended-release tablets may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage ( 10 )] . Most Frequently Observed Reactions In clinical trials, the most common adverse reactions with morphine sulfate extended-release tablets were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood. Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Reactions Cardiovascular disorders: tachycardia, bradycardia, palpitations Eye disorders: visual impairment, vision blurred, diplopia, miosis Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: reduced libido and/or potency Respiratory, thoracic and mediastinal disorders: laryngospasm Skin and subcutaneous tissue disorders: pruritus, urticaria, rash Vascular disorders: flushing, hypotension, hypertension 6.2 Post-Marketing Experience The following adverse reactions have been identified during postapproval use of morphine sulfate extended-release tablets: amenorrhea, asthenia, bronchospasm, confusional state , drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo . Anaphylaxis has been reported with ingredients contained in morphine sulfate extended-release tablets. Advise patients how to recognize such a reaction and when to seek medical attention.