MORPHINE SULFATE

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) or 4 mg (equivalent to 3.50 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. morph-struc-01.jpg

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, which can occur at any dosage or duration ( 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 Morphine Sulfate Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Morphine Sulfate Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [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 Morphine Sulfate Injection should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

• Morphine Sulfate Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Morphine Sulfate Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating the following dosage increases with Morphine Sulfate Injection. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) • 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 abruptly discontinue Morphine Sulfate Injection 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 two 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. • 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. • Morphine Sulfate Injection should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Morphine Sulfate Injection for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. • There is a variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . • Respiratory depression can occur at any time during opioid therapy, especially when initiating the following dosage increases with Morphine Sulfate Injection. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . • Inspect Morphine Sulfate Injection for particulate matter and discoloration prior to administration. 2.2 Initial Dosage Direct Intravenous Injection Initiate treatment with Morphine Sulfate Injection in adults at a dosing range of 0.1 mg to 0.2 mg per kg every 4 hours as needed to manage pain, and at the lowest dose necessary to achieve adequate analgesia. Administer the injection slowly. Intramuscular Injection The initial IM dose is 10 mg every 4 hours (based on a 70 kg adult) as needed to manage pain, and at the lowest dose necessary to achieve adequate analgesia. 2.3 Titration and Maintenance of Therapy Titrate the dose based upon individual patient’s response to their initial dose of Morphine Sulfate Injection. 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, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.14 )] . If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Morphine Sulfate Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Safe Reduction or 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 regularly evaluating 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 ( 5.14 ), Drug Abuse and Dependence ( 9.3 )] .

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 ( 5.7 )] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.8 )]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] • 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 )

The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] • Cardiovascular Instability [see Warnings and Precautions ( 5.5 )] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.6 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] • Severe Hypotension [see Warnings and Precautions ( 5.10 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] • Seizures [see Warnings and Precautions ( 5.13 )] • Withdrawal [see Warnings and Precautions ( 5.14 )] 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. Morphine may alter temperature regulation in susceptible individuals and will depress the cough reflex. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.6 )] 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. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). 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.

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 [see Warnings and Precautions ( 5.3 )] . 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. Monitor patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.3 )] . 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 ( 5.8 )]. 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, oxymorphone, hydrocodone, 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 co-administration 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 )