Morphine Sulfate

FDA Drug Information • Also known as: Duramorph, Infumorph 200, Infumorph 500, Mitigo, Morphine Sulfate, Morphine Sulfate Er, Morphine...

Brand Names: Duramorph, Infumorph 200, Infumorph 500, Mitigo, Morphine Sulfate, Morphine Sulfate Er, Morphine Sulfate Extended Release, Ms Contin
Route: INTRAMUSCULAR, INTRAVENOUS
Dosage Form: INJECTION, SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse 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 Morphine Sulfate Injection, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS ) . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Morphine Sulfate Injection. Monitor for respiratory depression, especially during initiation of Morphine Sulfate Injection or following a dose increase. Because of delay in maximum central nervous system (CNS) effect with intravenously administered morphine (30 min), rapid intravenous administration may result in overdosing (see WARNINGS ). Neonatal Opioid Withdrawal Syndrome Prolonged use of Morphine Sulfate Injection during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS ) . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS , Drug Interactions ) . Reserve concomitant prescribing of Morphine Sulfate Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Description

DESCRIPTION Morphine is a tertiary nitrogen base containing a phenanthrene nucleus; it has two hydroxyl groups, one phenolic and the other alcoholic (secondary). The sulfate salt occurs as white, feathery, silky crystals, cubical masses of crystals, or white, crystalline powder. The chemical name of morphine sulfate is 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol sulfate (2:1) (salt), pentahydrate. It has the following chemical structure: (C 17 H 19 NO 3 ) 2 ∙ H 2 SO 4 ∙ 5H 2 O M.W. 758.83 Morphine Sulfate Injection, USP is a sterile solution of morphine sulfate pentahydrate in Water for Injection, USP. Morphine Sulfate Injection, USP is available in the following concentrations: Each mL of Morphine Sulfate Injection, USP, Preservative Free (no bacteriostat or antioxidant added) contains 25 mg Morphine Sulfate in Water for Injection. Sulfuric acid added for adjustment of pH to 3.5 (2.5 to 6.5). Each mL of Morphine Sulfate Injection, USP, (no bacteriostat added), contains 25 mg or 50 mg Morphine Sulfate, 0.75 mg Edetate Disodium, 1 mg Sodium Metabisulfite (added during manufacture) as an antioxidant, in Water for Injection. Sulfuric acid added for adjustment of pH to 3.5 (2.5 to 6.5). NOTE: These products are intended for intravenous use only. They are not intended for intrathecal or epidural use. They are for use after dilution, not for direct infusion, and is intended as a single-dose unit. It contains no antimicrobial preservatives. When the dosing requirement is completed, the unused portion should be discarded in an appropriate manner. Chemical Structure

What Is Morphine Sulfate Used For?

INDICATIONS AND USAGE Morphine sulfate is indicated for the relief of severe pain. It is used preoperatively to sedate the patient and allay apprehension, facilitate anesthesia induction and reduce anesthetic dosage. It is likewise effective in the control of post-operative pain. The use of morphine for the relief of pain should be reserved for the more severe manifestations of pain, as in myocardial infarction, severe injuries, or in severe chronic pain associated with terminal cancer after all non-narcotic analgesics have failed. Effective analgesic therapy of severe chronic pain associated with terminal cancer continues to be a difficult problem. Intermittent administration of intramuscular morphine may be effective; however, the mode of therapy has significant limitations. Morphine has a short plasma half-life of 2.5 to 3.0 hours; therefore, frequent administration (every 1 to 2 hours) often becomes necessary to control severe pain associated with cancer. Tolerance develops to the analgesic effects and increasingly higher doses of morphine are required to produce analgesia. The higher morphine doses produce significant and often life-threatening side effects (see ADVERSE REACTIONS ) . The peak and trough effects produced by intermittent administration cause fluctuations in pain control. Repeated intramuscular injections are frequently unacceptable due to the lack of muscle mass in the debilitated patient, the tendency for bruising and bleeding at the injection site, and the anxiety and pain associated with the injection. Continuous intravenous infusion of morphine (see DOSAGE AND ADMINISTRATION ) has been employed as an alternative to traditional modes of administration. Lower doses of morphine produce uniform pain control because a steady morphine concentration is maintained. Titration of the dosage to the patient's needs is easily achieved by adjusting the infusion rate. The lag time between the patient's request for pain medication and administration of the dose and the amount of nursing time necessary for preparation and administration of frequent doses are reduced. The degree of respiratory depression and sedation may be decreased, and the anxiety experienced by the patient in anticipation of intramuscular administration is avoided. Some Investigators feel that tolerance to the analgesic effects may develop more slowly with continuous intravenous infusion. In addition to analgesia, the drug may relieve anxiety and reduce left ventricular work by reducing preload pressure. Morphine is also used in the therapy of dyspnea associated with acute left ventricular and pulmonary edema. Care must be taken to avoid inducing respiratory depression in such patients. For open-heart surgery, especially in high risk patients with cardiac disease, some anesthesiologists use morphine to produce anesthesia.

Dosage and Administration

DOSAGE AND ADMINISTRATION THESE PRODUCTS ARE INTENDED FOR SLOW INTRAVENOUS USE ONLY. RAPID INTRAVENOUS ADMINISTRATION MAY RESULT IN CHEST WALL RIGIDITY. NOT FOR INTRATHECAL OR EPIDURAL USE. For Relief of Pain and as Pre-anesthetic The usual adult dose of 10 mg every 4 hours, depending on the severity of the condition and the patient's response. The usual individual dose range is 5 to 15 mg. The usual daily dose range is 12 to 120 mg. Usual Pediatric Dose Analgesic - Intravenous, 50 to 100 µg (0.05 to 0.1 mg) per kg of body weight, administered very slowly. Not to exceed 10 mg per dose. For Open-Heart Surgery Large doses (0.5 to 3 mg/kg) of morphine are administered intravenously as the sole anesthetic or with a suitable anesthetic agent. The patients are given oxygen and cardiovascular function is not depressed by morphine, as long as adequate ventilation is maintained. For Severe Chronic Pain Associated with Terminal Cancer Continuous Intravenous infusion Prior to the initiation of the morphine infusion (in concentrations between 0.2 to 1 mg/mL), a loading dose of 15 mg or higher of morphine sulfate may be administered by intravenous push to alleviate pain. The infusion dosage range is 0.8 mg/hr to 80 mg/hr, though doses of up to 144 mg/hr have been used. Thus, for the 1 mg/mL solution, the infusion may be run from 0.8 mL /hr to 80 mL /hr, and for the 0.5 mg/mL solution, the infusion may be run from 1.6 mL /hr to 160 mL /hr. A constant infusion rate must be maintained with an infusion pump in order to assure proper dosage control. Care must be taken to avoid overdosage (respiratory depression) or abrupt cessation of therapy, which may give rise to withdrawal symptoms. Administration of Morphine Sulfate Injection should be limited to use by those familiar with the management of respiratory depression. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. EXAMPLES OF INFUSION PREPARATION: Concentrate Diluent Final Concentration Morphine Sulfate Injection, USP Dextrose 5% in Water Morphine Sulfate 25 mg/mL 10 mL 490 mL 0.5 mg/mL 20 mL 480 mL 1.0 mg/mL 40 mL 960 mL 1.0 mg/mL Morphine Sulfate Injection, USP 50 mg/mL 10 mL 990 mL 0.5 mg/mL 20 mL 980 mL 1.0 mg/mL

Side Effects (Adverse Reactions)

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse (see WARNINGS ) Life-Threatening Respiratory Depression (see WARNINGS ) Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) Interactions with Benzodiazepines or Other CNS Depressants (see WARNINGS ) Cardiovascular Instability (see WARNINGS ) Adrenal Insufficiency (see WARNINGS ) Severe Hypotension (see PRECAUTIONS ) Gastrointestinal Adverse Reactions (see PRECAUTIONS ) Seizures (see PRECAUTIONS ) Withdrawal (see WARNINGS ) The following adverse reactions associated with the use of morphine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with Morphine Sulfate Injection included respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. Rarely, anaphylactoid reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously. The most frequently observed adverse reactions included sedation, lightheadedness, dizziness, nausea, vomiting, constipation, and diaphoresis. Lightheadedness, dizziness, sedation, nausea, vomiting and sweating seem to be more prominent in ambulatory patients and in those who are not suffering from severe pain. In such individuals, lower doses are advisable. Other possible adverse reactions included: CNS – Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, transient hallucinations, disorientation, delirium, somnolence, drowsiness, miosis, pinpoint pupils, coma, insomnia, impairment of mental and physical performance, mental clouding, lethargy, anxiety, fear, psychic dependence, mood changes, confusion. Gastrointestinal – Constipation, biliary tract spasm, dry mouth, anorexia. Patients with chronic ulcerative colitis may experience increased colonic motility; toxic dilatation has been reported in patients with acute ulcerative colitis. Cardiovascular – Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension, peripheral circulatory collapse, hypotension, phlebitis following intravenous injection. Genitourinary – Oliguria and urinary retention or hesitancy; an antidiuretic effect has been reported; ureteral spasm and spasm of vesical sphincters, reduced libido and/or potency. Allergic – Pruritus, urticaria, skin rashes, edema, and (rarely) hemorrhagic urticaria. Flare over the vein with intravenous injection may occur. Anaphylactoid reactions have been reported following intravenous administration. An isolated case of thrombocytopenia has been reported to be induced by morphine. Other – Opioid-induced histamine release may be responsible for the flushing of the face, diaphoresis, and pruritus often seen with these drugs. Wheals and urticaria at the site of injection are probably related to histamine release. Local tissue irritation, pain, and induration have been reported following repeated subcutaneous injection. Morphine may alter temperature regulation in susceptible individuals and will depress the cough reflex. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Morphine Sulfate Injection. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids ( see CLINICAL PHARMACOLOGY ) .

Warnings and Precautions

WARNINGS Contains Sulfites The product which contains antioxidant (25 mg/mL and 50 mg/mL concentrations – see DESCRIPTION and HOW SUPPLIED ), contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Addiction, Abuse, and Misuse Morphine Sulfate Injection contains morphine, a Schedule II controlled substance. As an opioid, Morphine Sulfate Injection exposes users to the risks of addiction, abuse, and misuse (see DRUG ABUSE AND DEPENDENCE ). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Morphine Sulfate Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Morphine Sulfate Injection, and monitor all patients receiving morphine sulfate for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Morphine Sulfate Injection, but use in such patients necessitates intensive counseling about the risks and proper use of Morphine Sulfate Injection along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphine Sulfate Injection. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (see OVERDOSAGE ) . Carbon dioxide (CO 2 ) 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 Morphine Sulfate Injection, the risk is greatest during...

Drug Interactions

Drug Interactions Morphine may increase the anticoagulant activity of coumarin and other anticoagulants. When morphine is to be administered to patients receiving propiomazine (Largon) , the dose of morphine should be reduced by one-quarter to one-half. Atropine antagonizes morphine respiratory depression. Levallorphan and nalorphine antagonize morphine actions, principally the respiratory depression. Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection Benzodiazepines and Other 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. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS ) . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) (see WARNINGS ). Intervention: Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol,...

Contraindications

CONTRAINDICATIONS Morphine Sulfate Injection is contraindicated in patients with: Significant respiratory depression (see WARNINGS ) Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see PRECAUTIONS ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see WARNINGS ) Known or suspected gastrointestinal obstruction, including paralytic ileus (see PRECAUTIONS ) Hypersensitivity to morphine (e.g., anaphylaxis) (see ADVERSE REACTIONS ) Because of its stimulating effect on the spinal cord, morphine should not be used in convulsive states, such as those occurring in status epilepticus, tetanus, and strychnine poisoning. Morphine is also contraindicated in the following conditions: heart failure secondary to chronic lung disease; cardiac arrhythmias; increased intracranial or cerebrospinal pressure; head injuries; brain tumor; acute alcoholism; and delirium tremens. The use of bisulfites is contraindicated in asthmatics. Bisulfites and morphine may potentiate each other, preventing use by causing severe adverse reactions. Use with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients with substantially decreased respiratory reserve, and patients with pre-existing respiratory depression, hypoxia or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Pregnancy and Breastfeeding

Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome (see WARNINGS ). There are no available data with Morphine Sulfate Injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. 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 HDD of 60 mg based on body surface area in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3–4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD (see Animal Data ) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or...

Overdosage

OVERDOSAGE Clinical Presentation Acute overdose with Morphine Sulfate Injection can be manifested by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations (see CLINICAL PHARMACOLOGY ). In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine sulfate overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine sulfate overdose. Because the duration of opioid reversal is expected to be less than the duration of action of morphine in Morphine Sulfate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature,...

How Supplied

HOW SUPPLIED Morphine Sulfate Injection, USP, is available in glass fliptop vials as follows: 25 mg/mL Morphine Sulfate Injection, USP, Preservative Free (no bacteriostat or antioxidant added). Single-dose vials. Contains no antimicrobial preservatives. Unit of Sale Concentration NDC 0409-1135-02 Carton of 1 Single-dose Fliptop Vial 250 mg/10 mL (25 mg/mL) 50 mg/mL Morphine Sulfate Injection, USP (no bacteriostat added). Single-dose vials. Unit of Sale Concentration NDC 0409-1134-03 Carton of 1 Single-dose Fliptop Vial 1,000 mg/20 mL (50 mg/mL) NDC 0409-1134-05 Carton of 1 Single-dose Fliptop Vial 2,500 mg/50 mL (50 mg/mL) FOR INTRAVENOUS USE ONLY AFTER DILUTION. NOT FOR DIRECT INJECTION. THESE PRODUCTS ARE INTENDED FOR INTRAVENOUS USE ONLY. NOT INTENDED FOR INTRATHECAL OR EPIDURAL USE. Storage Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Morphine sulfate solutions may darken with age. Do not use if injection is darker than pale yellow, discolored in any other way, or contains a precipitate. Do not heat-sterilize the Preservative Free (antioxidant free) formula. PROTECT FROM LIGHT

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.