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  • Morphine
    / Rafa


    Active Ingredient
    Morphine Sulphate 1 mg/ml, 20 mg/ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Ampoule

    5 x 5 mg/5 ml

    not in the basket chart 10066 13354

    Ampoule

    5 X 100 mg/5 ml

    full basket chart 35315 13137

    Related information


    Dosage

    Subcutaneous or Intramuscular Injection
    Adults: The usual dose by subcutaneous or intramuscular injection is 5-20 mg, every 4 hours.
    Children: Up to 1 month of age: 150 mcg/kg body weight. 1-12 months of age: 200 mcg/kg body weight. 1-5 years of age: 2.5-5 mg. 6-12 years of age: 5-10 mg. Intravenous Injection: Doses of up to 15 mg have been given by slow intravenous injection, sometimes as a loading dose for continuous or patient-controlled infusion.
    Highly Concentrated Ampules: 20 mg/ml: 5 x 5 ml (100 mg).
    S.C. or I.M. injection:
    Adults: The usual dose by subcutaneous or intramuscular injection is 5-20 mg, every 4 hours.
    Children: Up to 1 month of age: 150 mcg/kg body weight. 1-12 months of age: 200 mcg/kg body weight. 1-5 years of age: 2.5-5 mg. 6-12 years of age: 5-10 mg. I.V. injection: Doses of up to 15 mg have been given by slow I.V. injection, sometimes as a loading dose for continuous or patient-controlled infusion.


    Indications

    HIGHLY CONCENTRATED AMPOULES: For I.V., epidural and intrathecal infusion in intractible chronic pain. Continuous microinfusion devices may require dilution.
    AMPOULES: For I.V., epidural and intrathecal routes in treatment of pain that does not respond to non-opioid analgesics.


    Contra-Indications

    Known hypersensitivity to any ingredient of the preparation, or to other opiates. Morphine should not be administered to patients with respiratory depression or obstructive airways disease, especially in the presence of cyanosis and excessive bronchial secretion, or other conditions where respiratory reserve is depleted, such as severe emphysema, chronic bronchitis or kyphoscoliosis. Morphine is contraindicated in the following conditions: cor pulmonale, severe CNS depression, diabetic acidosis where there is a danger of coma, severe liver disease or incipient hepatic hepatic encephalopathy and following surgery of the biliary tract or surgical anastomosis, biliary colic; gastrointestinal obstruction; suspected surgical abdomen, cardiac arrhythmias; heart failure secondary to pulmonary disease. Morphine is contraindicated in patients who are receiving monoamine oxidase inhibitors or those who have recently received such agents. Therapeutic doses of morphine have occasionally precipitated unpredictable, severe, and sometimes fatal reactions in patients who have received monoamine oxidize inhibitors within the last 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. In other reactions, the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia and hypertension. Morphine is contraindicated in acute alcoholism, head injuries, conditions in which intracranial or cerebrospinal pressure is raised, brain tumors, delirium tremens, convulsive disorders such as status epilepticus, tetanus or strychnine poisoning, acute bronchial asthma and heart failure secondary to chronic lung disease. Morphine is contraindicated in any patient who has or is suspected of having a paralytic ileus. Morphine is usually not recommended for use in infants under 1 year of age. Morphine is contraindicated in premature infants or during labor for delivery of a premature infant. Morphine is contraindicated in case of diarrhea caused by poisoning, until the toxic material has been eliminated from the gastrointestinal tract, or diarrhea associated with Pseudomembranous colitis caused by antibiotics. The continuous intravenous infusion of morphine in patients with hepatic or renal disease is contraindicated.
    NOTE: This preparation contains a preservative. Therefore, it should not be used for intrathecal or epidural injection. Morphine Injection contains sodium metabisulfite as a preservative. As with othersulfites, sodium metabisulfite may cause allergic-type reactions in certain susceptiblepatients, including anaphylactic symptoms and life-threatening, or less severe,asthmatic episodes. The overall prevalence of sulfite sensitivity in the generalpopulation is unknown, and probably low. Sulfite sensitivity is seen more frequently inasthmatic rather than in nonasthmatic patients. Morphine administration should be limited to use by those familiar with the management of respiratory depression. Facilities where morphine is administered must be equipped with resuscitativeequipment, oxygen, naloxone injection, and other resuscitative drugs. Morphine delays gastric emptying, which may be expected to increase the risks ofaspiration, either associated with morphine induced CNS depression or coma, orduring or after general anaesthesia.
    Intravenous Use:  Morphine may be administered intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Administration should only be performed when a narcotic antagonist and facilities for assisted or controlled respiration are immediately available. When morphine is administered parenterally, especially intravenously, the patient should be lying down. Rapid I.V. injection of narcotic analgesics, including morphine, increases the incidence of adverse reactions such as severe respiratory depression, apnea, hypotension, peripheral circulatory collapse and cardiac arrest.
    Head Injury and Increased Intracranial Pressure:  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 preexisting increase in intracranial pressure. Furthermore, narcotics 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 when deemed essential.
    Impaired Respiration:  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, including confusion, miosis andvomiting, which may obscure the clinical course of patients with head injuries. Morphine should only be used in such patients with extreme caution, and only if it is judged to be essential.
    Shock Patients: In patients with shock, impaired perfusion may prevent complete absorption following subcutaneous or intramuscular injection of morphine. Repeated administration may result in overdose due to an excessive amount of morphine suddenly being absorbed when circulation is restored.
    Asthma and Other Respiratory Conditions: Morphine should be used with extreme caution in patients undergoing an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, and patients with a substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even unusual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.


    Special Precautions

    Morphine should always be administered with caution, and in reduced dosage, to elderly and debilitated patients, and patients with head injuries, severe hepatic or renal impairment, biliary tract disorders, cardiovascular disease, delirium, tremens, cerebral arteriosclerosis, fever, toxic psychosis, severe CNS depression, coma, hypothyroidism, adrenocortical insufficiency, shock, prostatic hypertrophy, urethral stricture or Addison’s disease, or a history of drug abuse. Caution is also required in patients exhibiting acute alcoholism, raised intracranial pressure, obstructive bowel disorders, myasthenia gravis or convulsive disorders. Morphine, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Morphine should be used with extreme caution in patients with disorders characterized by hypoxia, since even usual therapeutic doses of narcotics may decrease respiratory drive to the point of apnea, while simultaneously increasing airway resistance. Care is also urged in patients who have a decreased respiratory reserve (e.g., emphysema, severe obesity, kyphoscoliosis).
    Supraventricular Tachycardia: Morphine should be used with caution in patients with atrial flutter and other supraventricular tachycardias, because of a possible vagolytic action which may produce a significant increase in the ventricular response rate.
    Acute Abdominal Conditions: As with other narcotics, morphine may obscure the diagnosis or clinical course in patients with acute abdominal conditions. . Morphine should be used with caution in patients with inflammatory or obstructive bowel disorders, or with ulcerative colitis, and should only be used when necessary in patients with acute pancreatitis.
    Cardiovascular: Patients with reduced circulating blood volume, impaired myocardial function or on
    sympatholytic drugs should be observed carefully for orthostatic hypotension, particularly in ambulatory patients.
    Asthma and Other Respiratory Conditions: Patients with chronic obstructive pulmonary disease and asthmatic attack may develop acute respiratory failure with administration of morphine. Use in these patients should be reserved for those whose conditions require endotracheal intubation and respiratory support or control of ventilation.
    Convulsions: Morphine may aggravate preexisting convulsions in patients with convulsive disorders. Convulsions may occur in individuals without a history of convulsive disorders, following use of a higher than recommended dosage.
    Kidney or Liver Dysfunction: Morphine may have a prolonged duration and cumulative effect in patients with reduced metabolic rates and hepatic or renal dysfunction. analgesia may last for 6, 8 or even up to 24 hours following a standard dose. Continuous infusions are contraindicated in these patients (see Contraindications). Therefore, care should be exercised in administering morphine in these conditions, particularly with repeated dosing. Patients may experience drowsiness while receiving morphine, and should therefore be cautioned against engaging in potentially hazardous activities requiring mental alertness, such as driving a car or operating machinery. The same precaution applies to childhood activities such as bicycle riding or playing near traffic.
    Use With Other CNS Depressants: Morphine should be used with caution and in reduced dosage in patients who are concurrently receiving other opioid analgesics, general anaesthetics, phenothiazines, other tranquillisers, sedative hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension and profound sedation or coma may result.
    Other Special Risk Patients: Morphine should be given with caution, and in reduced dosages, to certain patients, such as the elderly or debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, myxoedema, and prostatic hypertrophy or urethral stricture. Caution should also be observed if morphine is administered to patients with toxic psychosis or myasthenia gravis. Morphine should be used with extreme caution in patients with disorders characterised by hypoxia, since even usual therapeutic doses of opioids may decrease respiratory drive to the point of apnoea while simultaneously increasing airway resistance.
    Effects on Ability to Drive and Use Machines: 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 and alcohol have additive depressant effects. Patients should becautioned accordingly.


    Side Effects

    As with other narcotic analgesics, the major hazards of morphine are respiratory depression, apnea and, to a lesser degree, circulatory depression. Respiratory arrest, shock and cardiac arrest have occurred. Naloxone injection and resuscitative equipment should be immediately available for administration in case of life-threatening or intolerable side effects. Because of a delay in maximum CNS effects with intravenously administered drug (30 minutes), rapid administration may result in overdosing. The most frequently observed adverse reactions include constipation, lightheadedness (especially in ambulatory patients), dizziness and sedation, nausea, vomiting, dysphoria, euphoria and sweating. Some adverse reactions in ambulatory patients may be alleviated by lying down.
    Other adverse reactions are listed below:
    Central Nervous System: Euphoria, dysphoria, delirium, insomnia, agitation, anxiety, fear, hallucinations, disorientation, confusion, lethargy, impairment of mental and physical performance, coma, mood changes, weakness, restlessness, anxiety, agitation, uncoordinated muscle movements, insomnia, dizziness, vertigo, delirium, confusional symptoms and occasionally hallucinations, headache, visual disturbances (blurred vision, nystagmus, diplopia and miosis), tremor, psychic dependence and miosis. Convulsions or myoclonus may rarely occur when high doses of morphine are given I.V. or intraspinally.
    Sedation: Most patients receiving morphine will experience initial drowsiness. This usually disappears in three to five days and is not a cause for concern unless it is excessive, or accompanied with unsteadiness or confusion. Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal insufficiency, exacerbated respiratory failure, tolerance to the dose used, especially in older patients, disease severity and the patient’s general condition. If the dose of morphine has been reduced and pain is not adequately controlled, the dose may be carefully increased again after a few days. Dizziness and unsteadiness may be associated with morphine-induced postural hypotension particularly in elderly or debilitated patients. The dosage should be adjusted according to individual needs but, because of reduced clearance, dosage may be lower in patients over 50 years of age.
    Gastrointestinal : Dry mouth, anorexia, constipation, constipation, cramps, laryngospasm, colic, taste
    alterations and biliary tract cramps and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility. Toxic dilatation has been reported in patients with acute ulcerative colitis.
    Nausea and vomiting are common after single doses of morphine or as an early undesirable effect of regular opioid therapy. The prescription of a suitable antiemetic should be considered. The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in such patients.
    Virtually all patients suffer from constipation while taking opioids on a chronic basis. Some patients, particularly elderly, debilitated or bedridden patients, may become impacted. Patients must be cautioned accordingly and laxatives, softeners and other appropriate treatments should be initiated at the beginning of opioid therapy.
    Cardiovascular: Facial flushing, chills, hypotension (more frequent), hypertension, peripheral circulatory collapse, tachycardia, bradycardia, arrhythmia, palpitations, faintness, chest wall rigidity and syncope. 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.
    Allergic: Urticaria, pruritus, other skin rashes, diaphoresis, laryngospasm, edema, and rarely hemorrhagic urticaria. Allergic reactions may be due to histamine release, and may be more frequent in asthmatic patients. Anaphylactic reactions following intravenous injection have been reported rarely. A case of thrombocytopenia induced by morphine has been reported. Wheals, phlebitis and pain may occur at the site of I.V. injection. Effects induced by histamine release e.g., decreased blood pressure, fast heartbeat, increased sweating, redness or flushing of the face, wheezing or troubled breathing.
    Genitourinary: Urinary retention or hesitance, anti-diuretic effect, and reduced libido and/or potency.
    Endocrine: A syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free-water excretion may occur (monitoring of electrolytes may be necessary). Morphine stimulates prolactin release, and may also cause hyperglycaemia.
    Withdrawal (Abstinence) Syndrome: Chronic use of opioid analgesics may be associated with the development of physical dependence, with or without psychological dependence. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered. Withdrawal symptoms that may be observed after discontinuation of opioid use include; body aches, diarrhea, piloerection, anorexia, nervousness or restlessness, rhinorrhoea, sneezing, tremors or shivering, abdominal colic, nausea, sleep disturbance, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. With appropriate dose adjustments and gradual withdrawal these symptoms are usually mild.
    Other: Pain at the injection site. In general, side effects are amenable to reversal by narcotic antagonists. Patients experiencing these adverse reactions should receive lower doses of the drug and/or symptomatic treatment of the side effect (e.g. laxatives for constipation). During chronic opioid use, tolerance develops to many of the side effects, which gradually subside. In general, side effects of morphine are amenable to reversal by narcotic antagonists, but should be used only after careful consideration of the risks.


    Drug interactions

    Acidifying agents generally increase the clearance of morphine, thus antagonising its effects, while alkalising agents decrease clearance and so potentiate the effects of morphine
    Morphine/ Other CNS Depressants (including Alcohol)/ Anesthetics/Phenothiazines/Anticholinergics/Neuromuscular Blocking Agents: The effect of morphine may be potentiated by concurrent administration with other central nervous system depressants such as sedatives, antihistaminics, alcohol, anticholinergics, neuromuscular blocking agents or psychotropic drugs (e.g. phenothiazines, butyrophenones and tricyclic antidepressants). Significant impairment of motor function has also been noted following concomitant morphine administration and alcohol ingestion. Concurrent administration with tricyclic antidepressants or beta-blockers may enhance the CNS depressant effects of morphine. Diazepam, when used following high doses of morphine, exacerbates the hypotensive effects produced by morphine, and is associated with reduced plasma catecholamine levels. Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Premedication or intra-anesthetic use of neuroleptics with morphine may increase the risk of respiratory depression. Concomitant administration of morphine with phenothiazines may induce severe hypotension. Patients should be instructed to avoid alcohol while under treatment, since the individual response cannot be foreseen.
    Morphine/Zidovudine: Because morphine may decrease the clearance of zidovudine, concurrent use should be avoided because the toxicity of either or both of these medications may be potentiated.
    Morphine/Diuretics: Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.
    Morphine/Amphetamines: Dexamphetamine and other amphetamines may enhance the analgesic effects, and decrease the sedation and lack of alertness caused by morphine.
    Morphine/Anticoagulants: Morphine may potentiate the anticoagulant activity of coumarin anticoagulant agents.
    Morphine/Metoclopramide: Morphine may antagonise the effects of metoclopramide on gastrointestinal motility. Intravenous metoclopramide antagonises the effects of morphine on gastric emptying.
    Opioid Analgesics/Opioid Antagonist/Mixed Agonist-Antagonist Opioid Analgesics: Administration of an opioid antagonist such as naloxone or naltrexone will block the therapeutic effect of morphine, and will precipitate withdrawal symptoms in patients physically dependent on opioids; such symptoms may persist for up to 48 hours and be difficult to reverse. Similarly, administration of a mixed agonist/antagonist opioid analgesic (e.g., pentazocine, buprenorphine) to a patient receiving therapy with a pure agonist opioid such as morphine may reduce the analgesic effect, or precipitate withdrawal.
    Opioid Analgesics/Antidiarrheals: Concurrent use of opioid analgesics with antidiarrheals may increase the risk of severe constipation, as well as CNS depression.
    Opioid Analgesics/Antihypertensives: Patients receiving concurrent antihypertensive medication and opioid analgesics, including morphine, should be monitored closely, due to the increased risk of orthostatic hypotension.
    Opioid Analgesics/Cimetidine: Case reports have described CNS toxicity (confusion, disorientation, respiratory depression, apnea, seizures) following concurrent administration of cimetidine and opioid analgesics, though no clear-cut cause and effect relationship has been established. A potentially lethal interaction between cimetidine and morphine, in which the patient exhibited apnoea, a significantly reduced respiratory rate and suffered a grand mal seizure, has been reported. Administration of naloxone increased the respiratory rate; however, confusion, disorientation, generalised twitching and periods of apnoea persisted for 80 hours. Confusion has also been associated with concomitant use of ranitidine and morphine.
    Morphine/ Monoamine Oxidase Inhibitors: for full details see prescribing information.


    Pregnancy and Lactation

    Pregnancy: Safety of use in pregnancy has not been established. The placental transfer of opioids is rapid and can produce respiratory depression in the neonate if it is administered during labour. Infants born to mothers receiving opioid analgesics during labour should be observed closely for signs of respiratory depression. In such infants, a specific opioid antagonist, naloxone hydrochloride, should be available for reversal of opioid-induced respiratory depression. Maternal addiction following illicit use, resulting in withdrawal symptoms in the
    neonate, is well documented. Withdrawal symptoms include irritability, excessive crying, yawning, sneezing, increased respiratory rate, tremors, hyperreflexia, fever, vomiting, increased stools and diarrhea. These symptoms usually appear during the first days of life. Morphine should therefore be given to pregnant women only if clearly needed. Morphine should not be used in pregnant women prior to the labor period unless the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development.
    Labor and Delivery: The use of morphine in obstetrics may reduce the strength, duration and frequency of uterine contractions resulting in prolonged labor. It passes the placental barrier and may produce depression of respiration in the newborn. In resuscitation and severe depression, the administration of a narcotic antagonist such as naloxone or nalorphine may be required. Naloxone and resuscitative equipment should be available for reversal of narcotic-induced respiratory depression in the neonate. Morphine is contraindicated during labor for delivery of a premature infant.
    Lactation: Morphine is secreted in breast milk. Therefore, mothers receiving this medication should not nurse. Withdrawal symptoms have been observed in breast-fed infants when maternal administration of morphine is stopped.


    Overdose

    Manifestations: Signs of overdose include pin-point pupils, depressed respiration (a decrease in respiratory rate and /or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor and coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe poisoning there may be dilation of the pupils, shock, severe respiratory depression and pulmonary edema, circulatory collapse and cardiac arrest and death.
    Treatment: Immediate attention should be given to the re-establishment of adequate respiratory exchange through provision of a patient airway and institution of assisted or controlled ventilation. Intensive supportive therapy should be carried out. Naloxone is a recommended antidote, 400 mcg of naloxone hydrochloride should be administered S.C., I.M. or I.V., and repeated at intervals of 2-3 minutes if necessary. In children a dose of 5-10 mcg/kg body weight may be administered. In neonates a dose of 10 mcg/kg body weight may be administered. If naloxone is not available, nalorphine hydrobromide may be administered I.V. in doses of 5-10 mg, and if necessary, repeated every 15 minutes, up to a total of 40 mg. In severe poisoning, a single dose of 40 mg may be administered. Alternatively, 1 mg of levallorphan tartrate may be administered I.V, followed if necessary by 1 or 2 doses each of 500 mcg. In individuals who are physically dependent upon morphine, the administration of the usual dose of naloxone will precipitate an acute withdrawal syndrome. The severity of the syndrome is dependent upon the degree of physical dependence and the dose of naloxone given. If at all possible, the use of an antagonist should be avoided in such individuals. However, if absolutely necessary, the naloxone should be administered with extreme caution, using only 10-20% of the usual initial dose given. When naloxone is used to reverse postoperative opioid depression, particular caution should be exercised in cardiac patients. Supportive measures should be employed. The patient should be observed for a rise in temperature or pulmonary complications that may require antibiotic therapy. Morphine toxicity may be a result of overdose but because of the large interindividual variation in sensitivity to opioids, it is difficult to assess the exact dose of any opioid that is toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain or tolerance. Patients having chronic morphine therapy have been known to take in excess of 3,000 mg/day with no apparent toxic effects being present.
    For full details see prescribing information.


    Manufacturer
    Rafa Laboratories Ltd.
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