Morphine Sulfate

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 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.3 )] Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Cardiovascular Instability [see Warnings and Precautions ( 5.5 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.8 )] Severe Hypotension [see Warnings and Precautions ( 5.9 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.11 )] Seizures [see Warnings and Precautions ( 5.12 )] Withdrawal [see Warnings and Precautions ( 5.13 )] 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. Other possible adverse reactions include: Central Nervous System – Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations and disorientation. Gastrointestinal – Constipation, biliary tract spasm. Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope and orthostatic hypotension. Genitourinary – Oliguria and urinary retention; an antidiuretic effect has been reported. Allergic – Pruritus, urticaria and skin rashes. Anaphylactoid reactions have been reported following intravenous administration. 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. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] . Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Injection. 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. The most serious adverse reactions encountered are respiratory depression, apnea, circulatory depression, respiratory arrest, shock and cardiac arrest. Other common frequently observed adverse reactions include: sedation, lightheadedness, dizziness, nausea, vomiting, constipation and diaphoresis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

4 CONTRAINDICATIONS Morphine Sulfate Injection is 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 ( 5.6 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.7 )]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.11 )] 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 ) Hypersensitivity to morphine. ( 4 )

11 DESCRIPTION Morphine sulfate is an opioid agonist. Morphine Sulfate Injection, USP is available as a sterile, nonpyrogenic solution of morphine sulfate, free of antioxidants and preservatives in single-dose prefilled syringes for intravenous and intramuscular administration. The chemical name for Morphine Sulfate is 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6 α-diol sulfate (2: 1) (salt), pentahydrate. The molecular weight is 758.83. Its molecular formula is (C 17 H 19 NO 3 ) 2 • H 2 SO 4 • 5H 2 O and it has the following chemical structure. Morphine sulfate is a fine white powder. When exposed to air it gradually loses water of hydration, and darkens on prolonged exposure to light. It is soluble in water and ethanol at room temperature. Each 1 mL single-dose pre-filled syringe contains 2 mg (equivalent to 1.75 mg Morphine), 4 mg (equivalent to 3.50 mg Morphine), 5 mg (equivalent to 4.37 mg) Morphine), 8 mg (equivalent to 6.99 mg Morphine) or 10 mg (equivalent to 8.73 mg Morphine) of Morphine Sulfate USP in 1 mL total volume of water for injection solution with inactive ingredients. The inactive ingredients in Morphine Sulfate Injection, USP include: For the 2 mg/mL and 4 mg/mL products: 8.4 mg sodium chloride, 2.3 mg of sodium citrate, 0.74 mg of citric acid, 0.111 mg of edetate disodium, 0.053 mg of calcium chloride and water for injection. For the 5 mg/mL, 8 mg/mL and 10 mg/mL products: 7.5 mg sodium chloride, 3.45 mg of sodium citrate, 1.11 mg of citric acid, 0.111 mg of edetate disodium, 0.053 mg of calcium chloride and water for injection. Chemical Structure

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) Direct Intravenous Injection : Initiate treatment with 0.1 mg to 0.2 mg per kg every 4 hours as needed to manage pain. ( 2.2 ) Intramuscular Injection : Initiate treatment with 10 mg, every 4 hours as needed to manage pain (based on a 70 kg adult). ( 2.2 ) Do not stop Morphine Sulfate Injection abruptly in a physically dependent patient. ( 2.4 ) 2.1 Important Dosage and Administration Instructions Morphine Sulfate Injection is intended for intravenous and intramuscular administration. Morphine Sulfate Injection is available in five concentrations for direct injection. Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine injections of different concentrations when prescribing, dispensing, and administering Morphine Sulfate Injection. Ensure that the dose is communicated and dispensed accurately. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5.1 )]. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Morphine Sulfate Injection and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )]. Administration of Morphine Sulfate Injection should be limited to use by those familiar with the management of respiratory depression. Morphine must be injected slowly; rapid intravenous administration may result in chest wall rigidity. Inspect Morphine Sulfate Injection for particulate matter and discoloration prior to administration. 2.2 Initial Dosage Direct Intravenous Injection The usual starting dose in adults is 0.1 mg to 0.2 mg per kg every 4 hours as needed to manage pain. Administer the injection slowly. Intramuscular Injection The initial IM dose is 10 mg every 4 hours as needed to manage pain (based on a 70 kg adult). 2.3 Titration and Maintenance of Therapy Individually titrate Morphine Sulfate Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphine Sulfate Injection to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 )] . If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Discontinuation of Morphine Sulfate Injection When a patient who has been taking Morphine Sulfate Injection regularly and may be physically dependent or no longer requires therapy with Morphine Sulfate Injection, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Morphine Sulfate Injection in a physically dependent patient [see Warnings and Precautions ( 5.13 ), Drug Abuse and Dependence ( 9.3 )] .

1 INDICATIONS AND USAGE Morphine Sulfate Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Morphine Sulfate Injection is an opioid agonist indicated for the management of 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 Injection, 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 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 Injection 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

9.2 Abuse Morphine Sulfate Injection contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine Sulfate Injection can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 )]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Morphine Sulfate Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.1 Controlled Substance Morphine Sulfate Injection contains morphine, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Morphine Sulfate Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration ( 2.4 )]. If Morphine Sulfate Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. 9.2 Abuse Morphine Sulfate Injection contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphine Sulfate Injection can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1 )]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Morphine Sulfate Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Morphine Sulfate Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration ( 2.4 )]. If Morphine Sulfate Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )] .

10 OVERDOSAGE Clinical Presentation Acute overdose with Morphine Sulfate Injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose [see Clinical Pharmacology ( 12.2 )] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Morphine Sulfate Injection. Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection 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 [see Warnings and Precautions ( 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 Injection 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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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 ( 5.7 )]. Intervention: Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Injection 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 Injection and/or the muscle relaxant as necessary. Cimetidine Clinical Impact: The concomitant administration of morphine sulfate and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report. Intervention: Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs. Oral P2Y 12 Inhibitors Clinical Impact: The co-administration of oral P2Y 12 inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y 12 inhibitors and delay the onset of antiplatelet effect. Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring coadministration of intravenous morphine sulfate. Examples: clopidogrel, prasugrel, ticagrelor Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Morphine Sulfate Injection because they may reduce analgesic effect of Morphine Sulfate Injection or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on the Central Nervous System Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Morphine may also cause spasm of the sphincter of the urinary bladder. Effects on the Cardiovascular System In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Morphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. [see Adverse Reactions ( 6 )]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon . Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance. [see Dosage and Administration ( 2.1 , 2.3 )] Onset of analgesia occurs with 5-20 minutes following intramuscular administration of morphine, rising to peak analgesia sixty minutes after a single intramuscular injection. The duration of analgesia after a single injection is usually three to four hours. Concentration–Adverse Reaction Relationships There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 )] . 12.3 Pharmacokinetics Absorption: Average peak morphine plasma levels of 67.4 ± 22.5 ng/mL were noted around 5 to 30 minutes following intramuscular injection of 10 mg morphine sulfate from a prefilled syringe. Distribution: Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage . Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g., intravenously ), plasma concentrations of morphine remain higher than the corresponding CSF morphine sulfate levels. Elimination : Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours. Metabolism The major pathway of clearance is hepatic glucuronidation to morphine -3-glucuronide, which is pharmacologically inactive. Excretion The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Specific Populations Sex While evidence of greater post-operative Morphine Sulfate Injection consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of Morphine Sulfate Injection USP, including respiratory depression, in women compared to men. Hepatic Impairment Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine sulfate AUC ratio is also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted. Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

12.1 Mechanism of Action Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics Effects on the Central Nervous System Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Morphine may also cause spasm of the sphincter of the urinary bladder. Effects on the Cardiovascular System In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Morphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. [see Adverse Reactions ( 6 )]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon . Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance. [see Dosage and Administration ( 2.1 , 2.3 )] Onset of analgesia occurs with 5-20 minutes following intramuscular administration of morphine, rising to peak analgesia sixty minutes after a single intramuscular injection. The duration of analgesia after a single injection is usually three to four hours. Concentration–Adverse Reaction Relationships There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 )] .

12.3 Pharmacokinetics Absorption: Average peak morphine plasma levels of 67.4 ± 22.5 ng/mL were noted around 5 to 30 minutes following intramuscular injection of 10 mg morphine sulfate from a prefilled syringe. Distribution: Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage . Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g., intravenously ), plasma concentrations of morphine remain higher than the corresponding CSF morphine sulfate levels. Elimination : Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours. Metabolism The major pathway of clearance is hepatic glucuronidation to morphine -3-glucuronide, which is pharmacologically inactive. Excretion The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Specific Populations Sex While evidence of greater post-operative Morphine Sulfate Injection consumption in men compared to women is present in the literature, clinically significant differences in analgesic outcomes and pharmacokinetic parameters have not been consistently demonstrated. Some studies have shown an increased sensitivity to the adverse effects of Morphine Sulfate Injection USP, including respiratory depression, in women compared to men. Hepatic Impairment Morphine pharmacokinetics are altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine sulfate AUC ratio is also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted. Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

20210203

5

3 DOSAGE FORMS AND STRENGTHS Morphine Sulfate Injection, USP is available in the following strengths for intravenous (IV) and intramuscular (IM) administration. 2 mg/mL in 1 mL single‐dose prefilled syringe for IV or IM use. 4 mg/mL in 1 mL single‐dose prefilled syringe for IV or IM use. 5 mg/mL in 1 mL single‐dose prefilled syringe for IV or IM use. 8 mg/mL in 1 mL single‐dose prefilled syringe for IV or IM use. 10 mg/mL in 1 mL single‐dose prefilled syringe for IV or IM use. Injection, 2 mg/mL, 4 mg/mL, 5 mg/mL, 8 mg/mL, and 10 mg/mL in a single-dose prefilled syringe for intravenous or intramuscular use. ( 3 )

Morphine Sulfate Morphine Sulfate Morphine Sulfate Morphine Sodium chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Edetate Disodium Calcium Chloride Water Morphine Sulfate Morphine Sulfate Morphine Sulfate Morphine Sodium chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Edetate Disodium Calcium Chloride Water Morphine Sulfate Morphine Sulfate Morphine Sulfate Morphine Sodium chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Edetate Disodium Calcium Chloride Water Morphine Sulfate Morphine Sulfate Morphine Sulfate Morphine Sodium chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Edetate Disodium Calcium Chloride Water Morphine Sulfate Morphine Sulfate Morphine Sulfate Morphine Sodium chloride Trisodium Citrate Dihydrate Citric Acid Monohydrate Edetate Disodium Calcium Chloride Water

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been conducted. Mutagenesis No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was also reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in these species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila. Impairment of Fertility No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported. Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD). Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD). Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of morphine have not been conducted. Mutagenesis No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was also reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in these species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila. Impairment of Fertility No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported. Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD). Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD). Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).

NDA204223

Morphine Sulfate

Morphine Sulfate

76045-005

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,INTRAVENOUS

PACKAGE LABEL - PRINCIPAL DISPLAY – Morphine 1 mL Carton Panel Rx only NDC 76045-004-11 Morphine Sulfate Injection, USP CII 2 mg/mL For Intramuscular or Intravenous use. Do NOT dilute for IV push. Do NOT place syringe on a Sterile Field. 10 x 1 mL single-dose prefilled syringes Discard unused portion. PACKAGE LABEL - PRINCIPAL DISPLAY – Morphine 1 mL Carton Panel

Warnings and Precautions 10/2019

17 PATIENT COUNSELING INFORMATION Serotonin Syndrome Opioids can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [ see Drug Interactions ( 7 ) ] . Constipation Advise patients of the potential for severe constipation [see Clinical Pharmacology ( 12.2 )] .

INSTRUCTIONS FOR USE Figure 1: Outer Packaging (MicroVault) and Prefilled Syringe NOTES: - Do not introduce any other fluid into the syringe at any time. - Do not dilute for IV push. - Do not re-sterilize the syringe. - Do not use this product on a sterile field. - This product is for single dose only. Once removed from the bundle, inspect the outer packaging by verifying: - Integrity of the tube and the cap. - Tamper evident seal is intact (outer shrink wrap is not broken). Do not use if the outer packaging has been damaged. Hold the outer packaging with both hands. To break the tamper evident seal, hold the tube and the cap close to the seal, and twist until broken. (See Figure 2 ) Figure 2 Remove the cap of the outer packaging by pulling it straight away from the tube to avoid dislodging the plunger rod of the syringe. (See Figure 3 ) Figure 3 Remove the syringe from the tube. Visually inspect the syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Twist off the syringe tip cap. Do not remove the plastic wrap label around the luer lock collar. (See Figure 4 ) Figure 4 Expel air bubble(s). Adjust the dose (if applicable). Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. Discard the used syringe into an appropriate receptacle. For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The brand names mentioned in this document are the trademarks of their respective owners. U.S. Patents 9,072,781; 9,192,608; 9,731,082; and 10,064,998 Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451652 Issued: 11/2019 Figure 1 Figure 2 Figure 3 Figure 4 Fresenius Kabi Logo

8.5 Geriatric Use The pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphine Sulfate Injection slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.6 )] . Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.4 Pediatric Use The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established.

8.1 Pregnancy 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 Injection 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 3-4 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. 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 2-4% and 15-20%, 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. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphine Sulfate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Animal Data Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater. Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) 8.1 Pregnancy 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 Injection 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 3-4 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. 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 2-4% and 15-20%, 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. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphine Sulfate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Animal Data Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater. Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD). 8.2 Lactation Risk Summary Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with Morphine Sulfate Injection and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Morphine Sulfate Injection and any potential adverse effects on the breastfed infant from Morphine Sulfate Injection or from the underlying maternal condition. Clinical Considerations Infants exposed to Morphine Sulfate Injection through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 )]. In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology ( 13 )] . 8.4 Pediatric Use The safety and effectiveness of Morphine Sulfate Injection in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use The pharmacodynamic effects of morphine in the elderly are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphine Sulfate Injection slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.6 )] . Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Hepatic Impairment Morphine sulfate pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )]. 8.7 Renal Impairment Morphine sulfate pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than normal dosage of Morphine Sulfate Injection and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Morphine Sulfate Injection, USP is available for intravenous (IV) or intramuscular (IM) use as: Product Code Unit of Sale Strength Each 764411 NDC 76045-004-11 Unit of 10 2 mg/mL NDC 76045-004-01 1 mL single‐dose prefilled syringe 764511 NDC 76045-005-11 Unit of 10 4 mg/mL NDC 76045-005-01 1 mL single‐dose prefilled syringe 764611 NDC 76045-006-11 Unit of 10 5 mg/mL NDC 76045-006-01 1 mL single‐dose prefilled syringe 764711 NDC 76045-007-11 Unit of 10 8 mg/mL NDC 76045-007-01 1 mL single‐dose prefilled syringe 764811 NDC 76045-008-11 Unit of 10 10 mg/mL NDC 76045-008-01 1 mL single‐dose prefilled syringe Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. DO NOT FREEZE .

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning . Morphine Sulfate Injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.2 ) 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. If prolonged opioid use is required 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 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.4 , 7 ) 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 and Precautions ( 5.1 )]. 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 CNS effect with intravenously administered morphine (30 min), rapid IV administration may result in overdosing [see Warnings and Precautions ( 5.2 )]. 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 and Precautions ( 5.3 )]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [ see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. 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.