Morphine Sulfate

1 INDICATIONS AND USAGE Morphine Sulfate Injection is indicated in adult and pediatric patients 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 in adult and pediatric patients 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 ) 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.

2 DOSAGE AND 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 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 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 )‎ • Do not inject directly. Morphine Sulfate Injection is intended for continuous intravenous infusion only, after dilution in large volume parenteral solutions. ( 2.1 , 2.5 ) • Initial and maintenance dosage in adults : See full prescribing information for recommended dosages in adult patients. ( 2.2 , 2.3 ) • Initial and maintenance dosage in pediatric patients : See full prescribing information for recommended dosage in pediatric patients. ( 2.2 , 2.3 ) • 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 ) • See full prescribing information for preparation and storage instructions. ( 2.5 ) 2.1 Important Dosage and Administration Instructions • Morphine Sulfate Injection is for intravenous use only. It is not for intrathecal or epidural use. • Do not inject directly. Morphine Sulfate Injection is intended for continuous intravenous infusion only, after dilution in large volume parenteral solutions [see Dosage and Administration (2.5) ] . • 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 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 variability in the opioid analgesic dose and duration needed to ‎adequately manage…

5 WARNINGS AND PRECAUTIONS • Cardiovascular Instability : High doses are excitatory. Have naloxone injection and resuscitative equipment immediately available. ( 5.5 ) • Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced ‎Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically ‎causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider ‎appropriately decreasing the dose of the current opioid analgesic or ‎opioid rotation. ‎‎( 5.6 )‎ • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.7 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) • Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Injection in patients with circulatory shock. ( 5.10 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of Morphine Sulfate Injection in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Morphine Sulfate Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6) ] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Injection, and monitor all patients receiving morphine sulfate for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Morphine Sulfate Injection but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Injection along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Consider these risks when prescribing or dispensing Morphine Sulfate Injection. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene) , depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal res…

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 (5.7) ] • 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 )

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with Morphine Sulfate Injection. Table 2: 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. 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, 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 risk of urin…

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 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 overdose reversal agent, such as naloxone or nalmefene, 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 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…

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 Studie…