These Highlights Do Not Include All The Information Needed To Use Preservative-free Morphine Sulfate Injection, Usp Safely And Effectively. See Full Prescribing Information For Preservative-free Morphine Sulfate Injection.

Limitations of Use

Preservative-free morphine sulfate injection is not for use in Continuous Microinfusion Devices.

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2)], reserve preservative-free 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.

Preservative-free 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.

PROTECT FROM LIGHT. Keep stored in carton until time of use. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. DO NOT FREEZE. Preservative-free morphine sulfate injection contains no preservative or antioxidant. Each 10 mL vial of preservative-free morphine sulfate injection is intended for SINGLE-DOSE ONLY. Discard any unused portion. Do not heat-sterilize.

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-800-441-4100.

Preservative-free morphine sulfate injection contains morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, nontherapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of preservative-free morphine sulfate injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of preservative-free morphine sulfate injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of preservative-free morphine sulfate injection abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use preservative-free morphine sulfate injection in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Preservative-free morphine sulfate injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Preservative-free morphine sulfate injection

Abuse of preservative-free morphine sulfate injection poses a risk of overdose and death. The risk is increased with concurrent use of preservative-free morphine sulfate injection with alcohol and/or other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Preservative-free morphine sulfate injection (morphine sulfate injection) is an opioid agonist, available as a sterile, nonpyrogenic isobaric solution of morphine sulfate in strengths of 0.5 mg or 1 mg morphine sulfate per mL, free of antioxidants, preservatives or other potentially neurotoxic additives, and is intended for intravenous, epidural, or intrathecal administration. Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, chemically identified as 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula:

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).

Each mL of preservative-free morphine sulfate injection contains morphine sulfate, USP 0.5 mg (5 mg/10 mL) or 1 mg (10 mg/10 mL) and sodium chloride 9 mg in Water for Injection. The pH range is 2.5 – 6.5. Contains no preservative. Each 10 mL vial of preservative-free morphine sulfate injection is intended for SINGLE DOSE ONLY.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Preservative-free morphine sulfate injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6)]. If preservative-free morphine sulfate injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically-dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including preservative-free morphine sulfate injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing preservative-free morphine sulfate injection, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue preservative-free morphine sulfate injection [see Drug Abuse and Dependence (9.3)].

Adequate studies to establish the safety and effectiveness of spinal morphine in pediatric patients have not been performed, and usage in this population is not recommended.

Elderly patients (aged 65 years or older) may have increased sensitivity to preservative-free morphine sulfate injection. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of preservative-free morphine sulfate injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ].

The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. Patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial doses should be based on careful clinical observation following “test doses”, after making due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine.

Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

The starting dose of preservative-free morphine sulfate injection must be individualized.

• •
  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 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.
• •
  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 (5.2)].
• •
  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 [see Warnings and Precautions (5)].

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.

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).

Table 1 includes clinically significant drug interactions with preservative-free morphine sulfate injection.

The morphine in preservative-free morphine sulfate injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during preservative-free morphine sulfate injection therapy.

Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously.

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 may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of preservative-free morphine sulfate injection. In patients with circulatory shock, preservative-free morphine sulfate injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of preservative-free morphine sulfate injection in patients with circulatory shock.

Rapid intravenous administration may result in chest wall rigidity.

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.

Preservative-free morphine sulfate injection contains morphine, a Schedule II controlled drug substance.

• •
  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)

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

• •
  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)
• •
  Do not abruptly discontinue preservative-free morphine sulfate injection abruptly in a physically-dependent patient. (2.6, 5.16)

Injection: 5 mg/10 mL (0.5 mg/mL) Preservative-free fliptop vials

Injection: 10 mg/10 mL (1 mg/mL) Preservative-free fliptop vials

• •
  Pregnancy: May cause fetal harm. (8.1)

The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering preservative-free morphine sulfate injection epidurally to patients with these conditions. High blood morphine levels, due to reduced clearance, may take several days to develop.

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 morphine sulfate injection. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing preservative-free morphine sulfate injection, and monitor all patients receiving preservative-free morphine sulfate injection 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 preservative-free morphine sulfate injection, but use in such patients necessitates intensive counseling about the risks and proper use of preservative-free 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 preservative-free 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.

Addiction, Abuse, and Misuse

Inform patients that the use of preservative-free morphine sulfate injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting preservative-free morphine sulfate injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)].

Hyperalgesia and Allodynia

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8), Adverse Reactions (6)].

Preservative-free morphine sulfate injection (morphine sulfate injection, USP) is a preservative-free solution, available as 5 mg/10 mL (0.5 mg/mL) and 10 mg/10 mL (1 mg/mL), in vials, for single dose administration.

Preservative-free morphine sulfate injection is supplied in sealed vials. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water.

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 narcotic antagonists (naloxone, naltrexone) in such cases.

Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

Prolonged use of preservative-free morphine sulfate injection during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.

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 antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO₂) retention from opioid induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of preservative-free morphine sulfate injection, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention.

• •
  Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing.
• •
  Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.
• •
  Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
• •
  Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
• •
  Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at 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 narcotic antagonists (naloxone, naltrexone) in such cases.

To reduce the risk of respiratory depression, proper dosing and titration of preservative-free morphine sulfate injection are essential [see Dosage and Administration (2)]. Overestimating the preservative-free morphine sulfate injection dosage can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized.

Opioid Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. 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) [see Dosage and Administration (2.6), Warnings and Precautions (5.16)].

10 mL Single-dose

Preservative-Free

CII

MORPHINE

Sulfate Inj., USP

5 mg/10 mL (0.5 mg/mL)

For I.V., Epidural or Intrathecal Use.

Dist. by Hospira, Inc.,

Lake Forest, IL 60045 USA

Hospira

10 mL Single-dose

Preservative-Free

CII

MORPHINE

Sulfate Inj., USP

10 mg/10 mL (1 mg/mL)

For I.V., Epidural or Intrathecal Use.

Dist. by Hospira, Inc.,

Lake Forest, IL 60045 USA

Hospira

10 mL

Single-dose

5 Fliptop Vials

Preservative-Free

NDC 0409-3814-12

Contains 5 of NDC 0409-3814-11

MORPHINE Sulfate

Injection, USP

CII

5 mg/10 mL (0.5 mg/mL)

Rx only

For Intravenous, Epidural or Intrathecal use.

Protect from light. Store in carton until time of use.

Hospira

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

10 mL

Single-dose

5 Fliptop Vials

Preservative-Free

NDC 0409-3815-12

Contains 5 of NDC 0409-3815-11

MORPHINE Sulfate

Injection, USP

CII

10 mg/10 mL (1 mg/mL)

Rx only

For Intravenous, Epidural or Intrathecal use. Protect from light. Store in carton until time of use.

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Preservative-free morphine sulfate injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions (7)].

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 a specific antagonist (naloxone injection) immediately available for the management of respiratory depression as well as complications which might result from inadvertent intrathecal or intravascular injection (note: intrathecal dosage is usually 1/10 that of epidural dosage).

Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

Preservative-free morphine sulfate injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in preservative-free morphine sulfate injection may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

When a patient who has been treated with a regimen of opioid analgesics including preservative-free morphine sulfate injection regularly and may be physically-dependent or no longer requires therapy with preservative-free morphine sulfate injection, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue preservative-free morphine sulfate injection in a physically-dependent patient [see Warnings and Precautions (5.16) , Drug Abuse and Dependence (9.3)].

Profound sedation, respiratory depression, coma, and death may result from concomitant use of preservative-free morphine sulfate injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

Risks with Neuraxial Administration

Single-dose neuraxial administration may result in acute or delayed respiratory depression up to 24 hours. Because of the risk of severe adverse reactions when preservative-free morphine sulfate injection is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose [see Warnings and Precautions (5.1)].

Addiction, Abuse, and Misuse

Because the use of preservative-free morphine sulfate injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of preservative-free morphine sulfate injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of preservative-free morphine sulfate injection are essential [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of preservative-free morphine sulfate injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5)].

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), preservative-free morphine sulfate injection may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with preservative-free morphine sulfate injection. Preservative-free morphine sulfate injection should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.6)]. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of preservative-free morphine sulfate injection in patients with impaired consciousness or coma.

The use of preservative-free morphine sulfate injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Limitations of Use

Preservative-free morphine sulfate injection is not for use in Continuous Microinfusion Devices.

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions (5.2)], reserve preservative-free 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.

Preservative-free 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.

PROTECT FROM LIGHT. Keep stored in carton until time of use. Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. DO NOT FREEZE. Preservative-free morphine sulfate injection contains no preservative or antioxidant. Each 10 mL vial of preservative-free morphine sulfate injection is intended for SINGLE-DOSE ONLY. Discard any unused portion. Do not heat-sterilize.

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-800-441-4100.

Preservative-free morphine sulfate injection contains morphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, nontherapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of preservative-free morphine sulfate injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of preservative-free morphine sulfate injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of preservative-free morphine sulfate injection abuse include those with a history of prolonged use of any opioid, including products containing morphine, those with a history of drug or alcohol abuse, or those who use preservative-free morphine sulfate injection in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Preservative-free morphine sulfate injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Preservative-free morphine sulfate injection

Abuse of preservative-free morphine sulfate injection poses a risk of overdose and death. The risk is increased with concurrent use of preservative-free morphine sulfate injection with alcohol and/or other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Preservative-free morphine sulfate injection (morphine sulfate injection) is an opioid agonist, available as a sterile, nonpyrogenic isobaric solution of morphine sulfate in strengths of 0.5 mg or 1 mg morphine sulfate per mL, free of antioxidants, preservatives or other potentially neurotoxic additives, and is intended for intravenous, epidural, or intrathecal administration. Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, chemically identified as 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula:

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).

Each mL of preservative-free morphine sulfate injection contains morphine sulfate, USP 0.5 mg (5 mg/10 mL) or 1 mg (10 mg/10 mL) and sodium chloride 9 mg in Water for Injection. The pH range is 2.5 – 6.5. Contains no preservative. Each 10 mL vial of preservative-free morphine sulfate injection is intended for SINGLE DOSE ONLY.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Preservative-free morphine sulfate injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6)]. If preservative-free morphine sulfate injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically-dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including preservative-free morphine sulfate injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing preservative-free morphine sulfate injection, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue preservative-free morphine sulfate injection [see Drug Abuse and Dependence (9.3)].

Adequate studies to establish the safety and effectiveness of spinal morphine in pediatric patients have not been performed, and usage in this population is not recommended.

Elderly patients (aged 65 years or older) may have increased sensitivity to preservative-free morphine sulfate injection. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of preservative-free morphine sulfate injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ].

The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. Patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial doses should be based on careful clinical observation following “test doses”, after making due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine.

Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

The starting dose of preservative-free morphine sulfate injection must be individualized.

• •
  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 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.
• •
  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 (5.2)].
• •
  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 [see Warnings and Precautions (5)].

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.

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).

Table 1 includes clinically significant drug interactions with preservative-free morphine sulfate injection.

The morphine in preservative-free morphine sulfate injection may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during preservative-free morphine sulfate injection therapy.

Excitation of the central nervous system, resulting in convulsions, may accompany high doses of morphine given intravenously.

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 may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of preservative-free morphine sulfate injection. In patients with circulatory shock, preservative-free morphine sulfate injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of preservative-free morphine sulfate injection in patients with circulatory shock.

Rapid intravenous administration may result in chest wall rigidity.

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.

Preservative-free morphine sulfate injection contains morphine, a Schedule II controlled drug substance.

• •
  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)

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

• •
  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)
• •
  Do not abruptly discontinue preservative-free morphine sulfate injection abruptly in a physically-dependent patient. (2.6, 5.16)

Injection: 5 mg/10 mL (0.5 mg/mL) Preservative-free fliptop vials

Injection: 10 mg/10 mL (1 mg/mL) Preservative-free fliptop vials

• •
  Pregnancy: May cause fetal harm. (8.1)

The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering preservative-free morphine sulfate injection epidurally to patients with these conditions. High blood morphine levels, due to reduced clearance, may take several days to develop.

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 morphine sulfate injection. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing preservative-free morphine sulfate injection, and monitor all patients receiving preservative-free morphine sulfate injection 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 preservative-free morphine sulfate injection, but use in such patients necessitates intensive counseling about the risks and proper use of preservative-free 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 preservative-free 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.

Addiction, Abuse, and Misuse

Inform patients that the use of preservative-free morphine sulfate injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2)].

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting preservative-free morphine sulfate injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)].

Hyperalgesia and Allodynia

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8), Adverse Reactions (6)].

Preservative-free morphine sulfate injection (morphine sulfate injection, USP) is a preservative-free solution, available as 5 mg/10 mL (0.5 mg/mL) and 10 mg/10 mL (1 mg/mL), in vials, for single dose administration.

Preservative-free morphine sulfate injection is supplied in sealed vials. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water.

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 narcotic antagonists (naloxone, naltrexone) in such cases.

Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

Prolonged use of preservative-free morphine sulfate injection during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.

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 antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO₂) retention from opioid induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of preservative-free morphine sulfate injection, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention.

• •
  Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing.
• •
  Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.
• •
  Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
• •
  Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
• •
  Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at 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 narcotic antagonists (naloxone, naltrexone) in such cases.

To reduce the risk of respiratory depression, proper dosing and titration of preservative-free morphine sulfate injection are essential [see Dosage and Administration (2)]. Overestimating the preservative-free morphine sulfate injection dosage can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine. After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine. Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized.

Opioid Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. 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) [see Dosage and Administration (2.6), Warnings and Precautions (5.16)].

10 mL Single-dose

Preservative-Free

CII

MORPHINE

Sulfate Inj., USP

5 mg/10 mL (0.5 mg/mL)

For I.V., Epidural or Intrathecal Use.

Dist. by Hospira, Inc.,

Lake Forest, IL 60045 USA

Hospira

10 mL Single-dose

Preservative-Free

CII

MORPHINE

Sulfate Inj., USP

10 mg/10 mL (1 mg/mL)

For I.V., Epidural or Intrathecal Use.

Dist. by Hospira, Inc.,

Lake Forest, IL 60045 USA

Hospira

10 mL

Single-dose

5 Fliptop Vials

Preservative-Free

NDC 0409-3814-12

Contains 5 of NDC 0409-3814-11

MORPHINE Sulfate

Injection, USP

CII

5 mg/10 mL (0.5 mg/mL)

Rx only

For Intravenous, Epidural or Intrathecal use.

Protect from light. Store in carton until time of use.

Hospira

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

10 mL

Single-dose

5 Fliptop Vials

Preservative-Free

NDC 0409-3815-12

Contains 5 of NDC 0409-3815-11

MORPHINE Sulfate

Injection, USP

CII

10 mg/10 mL (1 mg/mL)

Rx only

For Intravenous, Epidural or Intrathecal use. Protect from light. Store in carton until time of use.

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Preservative-free morphine sulfate injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions (7)].

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 a specific antagonist (naloxone injection) immediately available for the management of respiratory depression as well as complications which might result from inadvertent intrathecal or intravascular injection (note: intrathecal dosage is usually 1/10 that of epidural dosage).

Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

Preservative-free morphine sulfate injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in preservative-free morphine sulfate injection may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

When a patient who has been treated with a regimen of opioid analgesics including preservative-free morphine sulfate injection regularly and may be physically-dependent or no longer requires therapy with preservative-free morphine sulfate injection, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue preservative-free morphine sulfate injection in a physically-dependent patient [see Warnings and Precautions (5.16) , Drug Abuse and Dependence (9.3)].

Profound sedation, respiratory depression, coma, and death may result from concomitant use of preservative-free morphine sulfate injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

Risks with Neuraxial Administration

Single-dose neuraxial administration may result in acute or delayed respiratory depression up to 24 hours. Because of the risk of severe adverse reactions when preservative-free morphine sulfate injection is administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose [see Warnings and Precautions (5.1)].

Addiction, Abuse, and Misuse

Because the use of preservative-free morphine sulfate injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of preservative-free morphine sulfate injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of preservative-free morphine sulfate injection are essential [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of preservative-free morphine sulfate injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5)].

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), preservative-free morphine sulfate injection may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with preservative-free morphine sulfate injection. Preservative-free morphine sulfate injection should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.6)]. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of preservative-free morphine sulfate injection in patients with impaired consciousness or coma.

The use of preservative-free morphine sulfate injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.