Morphine Sulfate

Boxed Warning 12/2023 Indications and Usage (1) 12/2023 Dosage and Administration (2.1, 2.2, 2.3) 12/2023 Warnings and Precautions (5.6) 12/2023 Boxed Warning 12/2025 Indications and Usage ( 1 ) 12/2025 Dosage and Administration ( 2.4 ) 12/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.12 , 5.14 ) 12/2025

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. Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including Morphine Sulfate Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. 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 Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Morphine Sulfate Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1, 5.1 ) 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 out weigh 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, prioranalgesictreatmentandresponse,andriskfactorsforaddiction,abuse,and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and 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 : The usual starting dose in adults is 0.1 mg to 0.2 mg per kg every 4 hours as needed for pain management. ( 2.2 ) Periodically reassess patients receiving Morphine Sulfate Injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.3) Do not rapidly reduce or abruptly discontinue Morphine Sulfate Injection in a physically - dependent patient. ( 2. 4, 5.14 )

2 DOSAGE AND ADMINISTRATION Morphine sulfate injection is intended for intravenous administration. 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 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 and 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 : The usual starting dose in adults is 0.1 mg to 0.2 mg per kg every 4 hours as needed for pain management. ( 2.2 ) Periodically reassess patients receiving Morphine Sulfate Injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.3 ) Do not rapidly reduce or abruptly discontinue Morphine Sulfate Injection in a physically - dependent patient. ( 2.4 , 5.14 ) 2.1 Important Dosage and Administration Instructions Morphine Sulfate Injection is for intravenous administration. Morphine Sulfate Injection is available in three concentrations for intravenous administration. 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. 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 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 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 and following dosage increases with Morphine Sulfate Injection. Consider this risk when selecting an initial dose and when m …

3 DOSAGE FORMS AND STRENGTHS Single Dose 1 mL Syringes: Morphine Sulfate Injection is available as 2 mg/mL, 4 mg/mL, sterile solution in single dose prefilled syringes for intravenous (IV) administration. Morphine Sulfate Injection USP, 2 mg/mL and 4 mg/mL, are available in 1 mL single dose prefilled syringes for intravenous administration. ( 3 )

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 )

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 )] 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 included: 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. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Injection. Androgen deficiency : Cases of androgen deficiency have occurred with 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 )]. 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). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.12)]. Adverse Reactions from Observational Studies A prospective, observa …

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 [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. Follow patients closely for signs of respiratory depression and sedation Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin),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 (5.2 , 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, hydrocodone, 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. Examples: Cyclobenzaprine, metaxalone Cimetidine Clinical Impact: Concomitant administration of Morphine Sulfate Injection 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 ris …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm ( 8.1 ) Geriatric Patients: Use caution during dose selection, starting at the low end of the dosing range while carefully monitoring for side effects. ( 8.5 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. There are no available data with Morphine Sulfate Injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations ). 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] . 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 women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphine Sulfate Injection, can prolong labor through actions that 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 dilatation, 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 f …

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.

11 DESCRIPTION Morphine Sulfate Injection is an opioid agonist, available as 1 mg/mL (in a 30 mL vial) for use with a compatible Alaris® infusion device. The chemical name is 7, 8-didehydro-4, 5α-epoxy-17-methylmorphinan-3, 6α-diol sulfate (2:1) (salt), pentahydrate. 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 USP is an odorless, white crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4). Preservative-free Morphine Sulfate Injection, is a sterile, nonpyrogenic solution of morphine sulfate in water for injection, to be administered by the intravenous route with a compatible Alaris ® infusion device. Preservative-free Morphine Sulfate Injection contains morphine sulfate, (pentahydrate) 1 mg and sodium chloride, USP, 9 mg in water for injection, USP. May contain sodium hydroxide and/or hydrochloric acid for pH adjustments. The pH range for preservative-free Morphine Sulfate Injection is 2.5 to 6.5. Morphine Sulfate Injection, contains no antioxidant, bacteriostatic or antimicrobial agent, and is intended only as a single-dose unit, to provide analgesia via the intravenous route, using a compatible Alaris ® infusion device. structure

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, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [ 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Preservative-free Morphine Sulfate Injection, USP, a clear, colorless to pale yellow solution, is supplied as 10 individual cartons shrink wrapped as a group of 10 cartons containing single-dose 30 mL PCA vials and injectors in each carton as follows: NDC Number Stock No. System Concentration (mg/mL) Total Morphine (mg/30 mL) 76329-1912-1 1912 Pump-Jet ® 1 30 This vial is only for use with Alaris ® PCA Module, Model 8120 NOTE: PCA set is sold separately. CONTAINS NO PRESERVATIVES. DISCARD UNUSED PORTION. DO NOT HEAT-STERILIZE. Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Protect from light. Store in carton until time of use. Syringe Assembly Directions: USE ASEPTIC TECHNIQUE Do not assemble until ready to use. Refer to Alaris ® PCA Module, Model 8120 Directions for Use for administration set compatibility and syringe installation instructions. *CAUTION: IMPROPER ENGAGING OR PUMP INSTALLATION MAY CAUSE GLASS BREAKAGE AND SUBSEQUENT INJURY. Preservative-free Morphine Sulfate Injection is supplied in sealed PCA vials. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. Each vial of Preservative-free Morphine Sulfate Injection contains a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures be taken to control this product within the hospital or clinic. Preservative-free Morphine Sulfate Injection should be subject to rigid accounting, rigorous control of wastage and restricted access. assembly