FDA label 54815a22-91e2-4902-b361-719a878ed69a

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Morphine Sulfate Injection exposes 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 Injection, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS ) . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Morphine Sulfate Injection. Monitor for respiratory depression, especially during initiation of Morphine Sulfate Injection or following a dose increase. Because of delay in maximum central nervous system (CNS) effect with intravenously administered morphine (30 min), rapid intravenous administration may result in overdosing (see WARNINGS ). Neonatal Opioid Withdrawal Syndrome Prolonged use of Morphine Sulfate Injection 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 ) . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS , Drug Interactions ) . • Reserve concomitant prescribing of Morphine Sulfate Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation.

WARNINGS Contains Sulfites The product which contains antioxidant (25 mg/mL and 50 mg/mL concentrations – see DESCRIPTION and HOW SUPPLIED ), contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Addiction, Abuse, and Misuse Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Injection exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE ). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Morphine Sulfate Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Injection, and monitor all patients receiving morphine sulfate 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 Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Injection along with intensive monitoring for signs of addiction, abuse, and misuse. 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 Injection. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. 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. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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 (see OVERDOSAGE ) . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Morphine Sulfate Injection, the risk is greatest during the initiation of therapy or following a dosage increase. Because of a delay in the maximum CNS effect with intravenously administered Morphine Sulfate Injection (30 min), rapid administration may result in overdosing. The respiratory depression may be severe and could require intervention (see OVERDOSAGE ) . Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of Morphine Sulfate Injection. To reduce the risk of respiratory depression, proper dosing and titration of Morphine Sulfate Injection are essential (see DOSAGE AND ADMINISTRATION ) . Overestimating the Morphine Sulfate Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (see DOSAGE AND ADMINISTRATION ) . Neonatal Opioid Withdrawal Syndrome Prolonged use of Morphine Sulfate Injection during pregnancy can result in withdrawal 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Pregnancy ) . Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphine Sulfate Injection with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions ) . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Morphine Sulfate Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions ) . Cardiovascular Instability While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines. Have naloxone injection and resuscitative equipment immediately available for use in case of life-threatening or intolerable side effects and whenever morphine therapy is being initiated. Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphine Sulfate Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. When discontinuing Morphine Sulfate Injection in a physically-dependent patient, gradually taper the dosage . Do not abruptly discontinue Morphine Sulfate Injection in these patients (see DRUG ABUSE AND DEPENDENCE ). Risks of Driving and Operating Machinery Morphine Sulfate Injection 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 Injection and know how they will react to the medication.

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see WARNINGS ) • Life-Threatening Respiratory Depression (see WARNINGS ) • Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) • Interactions with Benzodiazepines or Other CNS Depressants (see WARNINGS ) • Cardiovascular Instability (see WARNINGS ) • Adrenal Insufficiency (see WARNINGS ) • Severe Hypotension (see PRECAUTIONS ) • Gastrointestinal Adverse Reactions (see PRECAUTIONS ) • Seizures (see PRECAUTIONS ) • Withdrawal (see WARNINGS ) 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 Sulfate Injection included respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously. The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, constipation, and diaphoresis. Lightheadedness, dizziness, sedation, nausea, vomiting and sweating seem to be more prominent in ambulatory patients and in those who are not suffering from severe pain. In such individuals, lower doses are advisable. Other possible adverse reactions included: CNS – Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations, disorientation, delirium, somnolence, drowsiness, miosis, pinpoint pupils, coma, insomnia, impairment of mental and physical performance, mental clouding, lethargy, anxiety, fear, psychic dependence, mood changes, confusion. Gastrointestinal – Constipation, biliary tract spasm, dry mouth, anorexia. Patients with chronic ulcerative colitis may experience increased colonic motility; toxic dilatation has been reported in patients with acute ulcerative colitis. Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension, peripheral circulatory collapse, hypotension, phlebitis following intravenous injection. Genitourinary – Oliguria and urinary retention or hesitancy; an antidiuretic effect has been reported; ureteral spasm and spasm of vesical sphincters, reduced libido and/or potency. Allergic – Pruritus, urticaria, skin rashes, edema, and (rarely) hemorrhagic urticaria. Flare over the vein with intravenous injection may occur. Anaphylactoid reactions have been reported following intravenous administration. An isolated case of thrombocytopenia has been reported to be induced by morphine. Other – Opioid-induced histamine release may be responsible for the flushing of the face, diaphoresis, and pruritus often seen with these drugs. Wheals and urticaria at the site of injection are probably related to histamine release. Local tissue irritation, pain, and induration have been reported following repeated subcutaneous injection. Morphine may alter temperature regulation in susceptible individuals and will depress the cough reflex. 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 Injection. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids ( see CLINICAL PHARMACOLOGY ) .