Morphine Sulfate

1 INDICATIONS AND USAGE Preservative-free morphine sulfate injection is indicated for: • the management of pain severe enough to require use of an opioid analgesic by intravenous administration, and for which alternative treatments are not expected to be adequate. • the epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. Preservative-free morphine sulfate injection is an opioid agonist, indicated for: 1. the management of pain severe enough to require use of an opioid analgesic by intravenous administration and for which alternative treatments are not expected to be adequate. 2. the epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. ( 1 ) Limitations of Use Preservative-free morphine sulfate injection is not for use in Continuous Microinfusion Devices. 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 preservative-free 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 , 5.2 ) Limitations of Use Preservative-free morphine sulfate injection is not for use in Continuous Microinfusion Devices. 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 (5.2) ] , reserve opioid analgesics, including preservative-free 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 • Preservative-free 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 ) • Should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration. ( 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 preservative-free 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. ( 2.2 , 5 ) • 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 , 5.2 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with preservative-free morphine sulfate injection. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2 , 5.3 ) • Dosage for Intravenous Administration : 2 mg to 10 mg/70 kg of body weight. ( 2.3 ) • Dosage for Epidural Administration : Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours. If adequate pain relief is not achieved within one hour, carefully administer incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness. Administer no more than 10 mg/24 hr. ( 2.4 ) • Dosage for Intrathecal Administration : A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. Repeated intrathecal injections of preservative-free morphine sulfate injection are not recommended. ( 2.5 ) • Periodically reassess patients receiving preservative-free morphine sulfate injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and the development of addiction, abuse or misuse. ( 2.6 ) • Do not rapidly reduce or abruptly discontinue preservative-free morphine sulfate injection abruptly in a physically-dependent patient. ( 2.6 , 5.16 ) 2.1 Important Dosage and Administration Instructions Do Not Use Preservative-free morphine sulfate injection in Continuous Microinfusion Devices. Preservative-free morphine sulfate injection should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration and the labeling, and should take place only in settings where adequate patient monitoring is possible. • Preservative-free 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. • Because of the risk of delayed respiratory depression, patients should be observed in a fully equipped and staffed environment for at least 24 hours. Respiratory depression (both early and late onset) has occurred more frequently following intrathecal administration than epidural administration. • Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible. • For safety reasons, it is recommended that administration of preservative-free morphine sulfate injection by the epidural or intrathecal routes be limited to the lumbar area. • Have resuscitative equipment and an opioid overdose reversal agent (e.g., naloxone, nalmefene) immediately available for the management of respiratory depression as well as complications which might result from inadvertent int…

5 WARNINGS AND PRECAUTIONS • Risk of Tolerance and Myoclonic Activity : Monitor patients for unusual acceleration of neuraxial morphine, which may cause myoclonic-like spasm of lower extremities. Detoxification may be required. ( 5.6 ) • Chest Wall Rigidity : Rapid intravenous administration may result in chest wall rigidity. ( 5.7 ) • 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 a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety). ( 5.8 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.9 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) • Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of preservative-free morphine sulfate injection in patients with circulatory shock. ( 5.12 ) • 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 preservative-free morphine sulfate injection in patients with impaired consciousness or coma. ( 5.13 ) 5.1 Risks with Neuraxial Administration Control of pain by neuraxial opioid delivery is always accompanied by considerable risk to the patient and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care. In the case of epidural or intrathecal administration, preservative-free morphine sulfate injection should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential. Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible. For safety reasons, it is recommended that administration of preservative-free morphine sulfate injection by the epidural or intrathecal routes be limited to the lumbar area. Thoracic epidural administration has been shown to dramatically increase the incidence of early and late respiratory depression even with doses of 1 to 2 mg. Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose. The facility must be equipped to resuscitate patients with severe opiate overdosage, and the personnel must be familiar with the use and limitations of specific opioid overdose reversal agents (naloxone, naltrexone) in such cases. Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage. 5.2 Addiction, Abuse, and Misuse Preservative-free morphine sulfate injection contains morphine, a Schedule II controlled substance. As an opioid, preservative-free 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 preservative-free mo…

4 CONTRAINDICATIONS Preservative-free morphine sulfate injection is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3) ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9) ] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10) , Drug Interactions (7) ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14) ] • Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6) ] Neuraxial administration of preservative-free morphine sulfate injection is contraindicated in patients with: • Infection at the injection microinfusion site [see Warnings and Precautions (5.1) ] • Concomitant anticoagulant therapy [see Warnings and Precautions (5.1) ] • Uncontrolled bleeding diathesis [see Warnings and Precautions (5.1) ] • The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. Preservative-free morphine sulfate injection is contraindicated in patients with: • Significant respiratory depression ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting 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 or intolerance to morphine ( 4 ) Neuraxial administration of preservative-free morphine sulfate injection is contraindicated in patients with: • Infection at the injection microinfusion site ( 4 ) • Concomitant anticoagulant therapy ( 4 ) • Uncontrolled bleeding diathesis ( 4 ) • The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous. ( 4 )

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with preservative-free morphine sulfate injection. Table 1 Clinically Significant Drug Interactions with Preservative-Free 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. The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression [see Warnings and Precautions (5.4) ] . 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 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, psychotropic drugs, antihistamines, neuroleptics, 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 preservative-free 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase 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 (5.10) ]. Intervention: Do not use preservative-free 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, hydromorphone, 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 preservative-free 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 preservative-free morphine sulfate injection and/or the muscle relaxant as necessary. Examples: Cyclobenzaprine, metaxalone. 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 o…

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5) ] . Available data with preservative-free morphine sulfate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. 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 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 (5.5) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic 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. Preservative-free 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 preservative-free 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 ti…

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 (5.2) ] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3) ] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4) ] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5) ] • Myoclonic Activity [see Warnings and Precautions (5.6) ] • Opioid Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8) ] • Adrenal Insufficiency [see Warnings and Precautions (5.11) ] • Severe Hypotension [see Warnings and Precautions (5.12) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14) ] • Seizures [see Warnings and Precautions (5.15) ] • Withdrawal [see Warnings and Precautions (5.16) ] • Urinary Retention [see Warnings and Precautions (5.17) ] • Orthostatic Hypotension [see Warnings and Precautions (5.18) ] 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. The most serious adverse reactions encountered during administration of preservative-free morphine sulfate injection were respiratory depression and/or respiratory arrest. Cardiovascular System : While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Central Nervous System : Myoclonus, seizures, dysphoric reactions, toxic psychosis, dizziness, euphoria, anxiety, confusion, headache. Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation and generally responds to bed rest and/or other conventional therapy. Gastrointestinal System : Nausea, vomiting, constipation. Skin : Generalized pruritus, urticaria, wheals, and/or local tissue irritation. Single-dose epidural or intrathecal administration is accompanied by a high incidence of dose-related generalized pruritus. Urinary System : Urinary retention, oliguria. Peripheral edema : There are several reports of peripheral edema. Other : Other adverse reactions reported following morphine therapy include depression of cough reflex, interference with thermal regulation, peripheral edema. 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 preservative-free 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 (5.8) ]. 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 (5.14) ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating …