MORPHINE SULFATE

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

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.

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

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.

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 ) .

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, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary. Cimetidine Clinical Impact: Concomitant administration of Morphine Sulfate Injection and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. Intervention: Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs. Oral P2Y 12 Inhibitors Clinical Impact: The co-administration of oral P2Y 12 inhibitors and intravenous morphine sulfate can decrease the absorption and peak concentration of oral P2Y 12 inhibitors and delay the onset of the antiplatelet effect. Intervention: Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome requiring co-administration of intravenous morphine sulfate. Examples: clopidogrel, prasugrel, ticagrelor

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