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MORPHINE SULFATE INJECTION BP (1 mg/mL and 2 mg/mL)
Faulding
Opioid Analgesic
 
Action And Clinical Pharmacology: Morphine exerts its main actions by acting as an agonist at specific receptor sites in the CNS.

Morphine produces many effects including analgesia, decreased gastrointestinal motility, respiratory depression, nausea, vomiting, drowsiness, changes in mood and alterations of the endocrine and autonomic nervous systems.

Maximum analgesia occurs within 50 to 90 minutes after s.c. administration, and 20 minutes after i.v. administration. Analgesia persists for 2.5 to 7 hours.

Morphine is rapidly metabolized by the liver and excreted in the urine primarily as the active metabolite, morphine-6-glucuronide. The half-life of morphine in young adults is about 2 hours; the half-life of morphine-6-glucuronide is somewhat longer. In older patients, the volume of distribution is considerably smaller and initial concentrations of morphine are correspondingly higher.

Indications And Clinical Uses: For the symptomatic relief of severe pain of various categories.

Contra-Indications: Hypersensitivity to any of the components of the drug product. The Rapiject syringe formulation contains sodium metabisulfite which may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in non-asthmatic individuals.

Respiratory insufficiency or depression; severe CNS depression, attack of bronchial asthma; heart failure secondary to chronic lung disease; cardiac arrhythmias; increased intracranial or cerebrospinal pressure; head injuries, brain tumor; acute alcoholism; delirium tremens; convulsive disorders; after biliary tract surgery; suspected surgical abdomen; surgical anastomosis; concomitantly with MAO inhibitors or within 14 days of such treatment.

Manufacturers' Warnings In Clinical States: Morphine can produce dependence and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of morphine.

Morphine should be used with caution and in reduced dosage in patients who are concurrently receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants (including alcohol). Respiratory depression, hypotension and profound sedation or coma may result.

The respiratory depressant effects of morphine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, morphine must be used with extreme caution and only if its use is deemed essential.

Morphine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with pre-existing respiratory depression, hypoxia or hypercapnia. In such patients, even usual therapeutic doses of opioids may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Precautions: Acute Abdominal Condition: The administration of morphine or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Hypotensive Effect: The administration of morphine may result in severe hypotension in the postoperative patient or any individual whose ability to maintain blood pressure has been compromised by a depleted blood volume or the administration of such drugs as the phenothiazines or certain anesthetics.

Supraventricular Tachycardias: Because of possible vagolytic action that may produce a significant increase in the ventricular response rate, morphine should be used with caution in patients with atrial flutter and other supraventricular tachycardias.

Convulsions: Morphine may aggravate pre-existing convulsions in patients with convulsive disorders. If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders.

Other Special Risk Patients: Morphine should be given with caution to certain patients, such as the elderly or debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture.

Morphine should be used with extreme caution in patients with disorders characterized by hypoxia, since even usual therapeutic doses of opioids may decrease respiratory drive to the point of apnea while simultaneously increasing airway resistance.

Morphine may have a prolonged duration and cumulative effect in patients with kidney or liver dysfunction. In these patients, analgesia may last for 6, 8 or even up to 24 hours following a standard dose. Continuous infusions should be avoided.

In patients with shock, impaired perfusion may prevent complete absorption following s.c. or i.m. injection of morphine. Repeated administration may result in overdosage due to an excessive amount of morphine suddenly being absorbed when circulation is restored.

Information for the Patient: Occupational Hazards: Morphine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. Morphine in combination with other opioid analgesics, phenothiazines, sedative-hypnotics or alcohol has additive depressant effects. The patient should be cautioned accordingly.

Drug Interactions: Morphine in combination with other opioid analgesics, general anesthetics, phenothiazines, tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) has additive depressant effects. Dosage reduction of one or both agents is required.

Pregnancy: Animal reproduction studies have not been conducted with morphine. It is not known whether it can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. On the basis of the historical use of morphine during all stages of pregnancy, there is no known risk of fetal abnormality. Morphine should be given to a pregnant woman only if clearly needed.

Labor and Delivery: The use of morphine in obstetrics may prolong labor. It passes the placental barrier and may produce respiratory depression in the newborn. In resuscitation and severe depression, the administration of an opioid antagonist such as naloxone or nalorphine may be required.

Lactation: Morphine appears in the milk of nursing mothers. Breast-feeding should be discontinued if morphine is required.

Children: Safety and efficacy of morphine in neonates and children have not been established.

Adverse Reactions: The major hazards of morphine, as with other opioid analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock and cardiac arrest have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.

Rapid i.v. injection of the drug may result in an increased frequency of opiate-induced adverse effects; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, chest wall rigidity, cardiac arrest and possible anaphylactoid reactions.

Other adverse reactions include: CNS: euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, transient hallucinations and disorientation, visual disturbances.

Gastrointestinal: dry mouth, constipation, biliary tract spasm.

Cardiovascular: flushing of the face, tachycardia, bradycardia, palpitation, faintness, syncope.

Genitourinary: urinary retention.

Allergic: pruritus, urticaria, other skin rashes, wheal and flare over the vein with i.v. injection.

Other: pain at injection site; local tissue irritation and induration following s.c. injection, particularly when repeated; antidiuretic effect.

Symptoms And Treatment Of Overdose: Symptoms: Overdosage with morphine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. tag_Treatment

Treatment: Immediate attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.

Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated.

The opioid antagonist naloxone is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to opioids. The recommended adult dose of naloxone is 0.4 to 2 mg i.v. every 2 to 3 minutes as necessary, simultaneously with assisted respiration.

An antagonist should only be administered in cases of clinically significant respiratory or cardiovascular depression.

In an individual physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care at about 10 to 20% the usual initial dose administered.

Dosage And Administration: Morphine sulfate should be given in the smallest effective dose and as infrequently as possible in order to minimize the development of tolerance and physical dependence. Following successful relief of severe pain, periodic attempts to reduce the opioid dose should be made. Lower doses or complete discontinuation of the opioid analgesic may become feasible due to physiological change or improved mental state of the patient.

Reduced dosage is indicated in patients with renal dysfunction or with respiratory problems, in very young or elderly patients, and in patients receiving CNS depressants. Wide patient variability exists. Titrate dosage individually. In patients with severe chronic pain, adjust dosage according to the severity of the pain and the response and tolerance of the patient. In patients with exceptionally severe chronic pain and/or in those who have become tolerant to the analgesic effect of opiate agonists, it may be necessary to exceed the usual dosage.

In cases of chronic pain of malignant disease, it is important that the analgesic be given regularly around the clock, day and night, and not on a when needed basis.

Morphine sulfate injection B.P. 1 or 2 mg/mL may be administered by s.c. or slow i.v. injection or by i.v. infusion. Alternatively s.c. infusion using a portable pump is suggested.

S.C. or Slow I.V. Injection: For i.v. administration, 2.5 to 15 mg of morphine may be diluted in 4 to 5 mL of sterile water for injection and injected i.v. slowly over 4 to 5 minutes in adults; it is preferable for the patient to be in the recumbent position.

Children may receive a s.c. morphine dose of 0.1 to 0.2 mg/kg every 4 hours as necessary; a single pediatric dose should not exceed 15 mg.

To relieve pain of myocardial infarction in adults, 8 to 15 mg of morphine may be administered parenterally. For very severe pain, additional smaller doses may be given every 3 to 4 hours.

Continuous I.V. or S.C. Infusion: Useful in patients who are not able to tolerate oral or rectal routes and require frequent s.c., i.m. or i.v. injections; have poor pain control with intermittent injections; require high doses of intermittent injections; and in cachectic or thrombocytopenic patients and those with coagulation disorders.

If a patient is presently in pain and was previously poorly controlled on analgesics, start loading dose of 1 to 2 mg/min until pain is relieved. Administer loading dose in 4 to 5 mL of i.v. fluid slowly over 1 minute. Check vital signs. If diastolic blood pressure decreases more than 10% or if respiration rate is less than 10/min, postpone further dosing until vital signs are acceptable.

If the patient's pain is presently controlled, calculate previous day's 24-hour opioid requirement (keeping route and analgesic equivalents in mind) and calculate hourly dose.

When morphine is administered by continuous i.v. or s.c. infusion for relief of severe chronic pain associated with cancer, the dosage of the drug must be individualized according to the response and tolerance of the patient. Continuous i.v. infusions of the drug have been initiated at 0.8 to 10 mg/hour in adults and then increased to an effective dosage as necessary; an i.v. loading dose of 15 mg or more can be administered for initial relief of pain prior to initiating continuous i.v. infusion of the drug. In adults with severe chronic pain, maintenance dosages usually have ranged from 0.8 to 80 mg/hour infused i.v., although higher (e.g., 150 mg/hour) maintenance dosages occasionally have been required. In addition, relatively high dosages (e.g., 275 to 440 mg/hour) occasionally have been infused i.v. for several hours or days to provide relief of exacerbations of chronic pain in adults previously stabilized on lower dosages or whose dosage had been gradually titrated to relatively high levels; subsequent dosage reductions according to patient response generally were possible.

When morphine is administered by multiple, slow i.v. injections for patient-controlled analgesia (PCA), dosage is adjusted according to the severity of the pain and response of the patient; the operator's manual for the patient-controlled infusion device should be consulted for directions on administering the drug at the desired rate of infusion. Care must be exercised to avoid overdosage, which could result in respiratory depression, or abrupt cessation of therapy with the drug, which could precipitate opiate withdrawal.

If a patient has low muscle mass or is cachectic or has no accessible peripheral veins, s.c. infusion using a portable pump may be indicated. When switching from i.v. to s.c. infusion, use the same dose and monitor the same parameters. The maximum dose that can be safely given has not been defined but doses as high as 480 mg/24 hours have been given. Erythema around the injection site may occur. Change needle site periodically (every 7 to 10 days although some clinicians prefer every 48 hours).

Stability and Storage: Store at room temperature below 25C. Protect from light. Do not autoclave.

Morphine sulfate injection 1 mg/mL and 2 mg/mL and dilutions of morphine sulfate injection in dextrose 5% injection or sodium chloride 0.9% injection may be stored in portable infusion pump cassettes, syringes and PVC infusion bags. Protected from light, they will stay stable for 24 hours at room temperature or for 72 hours if kept refrigerated. Proper aseptic technique must be used in order to minimize contamination of the solution.

Warning: As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate or leakage should not be used. Development of a yellow color in morphine solutions does not indicate toxicity nor loss of potency or efficacy.

Availability And Storage: Each mL of clear, colorless or pale yellow, sterile solution contains: morphine sulfate BP 1 mg or 2 mg, with 0.9 mg sodium metabisulfite, sodium chloride 7.6 mg, citric acid 0.4 mg, sodium citrate 0.2 mg, in sterile water for injection. Sodium hydroxide or citric acid may be added for pH adjustment. Rapiject prefilled, single dose syringes of 50 mL.

Medication, needle and fluid pathway are sterile in the unopened, intact Rapiject system with caps in place.

These products contain no bacteriostat or antimicrobial agents and are intended as single dose units. When the dosing requirement is completed, the unused portion should be discarded in an appropriate manner.

Directions for Use of Rapiject Prefilled Syringe: 1. Remove protective caps from vial and injector. 2. Insert vial into injector. 3. Rotate vial 3 turns in a clockwise direction until some resistance occurs. Then rotate vial another turn or two. The needle will then be in contact with the morphine solution. 4. Remove the needle cap and expel air. 5. The Rapiject is now ready for use.