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1. Morphine Sulphate Injection Bp 30mg/Ml
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Document: spc-doc_PL 35104-0014 change

• spc-doc_PL 17907-0599
• spc-doc_PL 35104-0014

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Morphine Sulphate Injection BP 30mg in 1ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Morphine Sulphate Injection BP 30mg in 1ml.

3 PHARMACEUTICAL FORM

Sterile aqueous solution for parenteral administration to human beings.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Morphine is used for the symptomatic relief of severe pain; relief of dyspnoea of left ventricular failure and pulmonary oedema; pre-operative use.

4.2 Posology and method of administration

The injection may be given by the intravenous, intramuscular or subcutaneous route.

Adults: The dosage should be based on the severity of the pain and the response and tolerance of the patient. The usual adult subcutaneous or intramuscular dose is 10mg every 4 hours if necessary, but may range from 5mg to 20mg.

The usual adult intravenous dose is 2.5mg to 15mg not more than 4 hourly, where necessary, but dosage and dosing interval must be titrated against the patient’s response and adjustments made until analgesia is achieved.

Elderly: Because of the depressant effect on respiration, caution is necessary when giving morphine to the elderly and reduced doses may be required.

Children: Use in children is not recommended.

4.3 Contraindications

Respiratory depression, obstructive airways disease, concurrent treatment with monoamine oxidase inhibitors or within two weeks of their discontinuation of treatment with them.

Known morphine sensitivity, or sensitivity to any of the ingredients. Cerebral oedema, head injuries, coma, convulsive disorders and raised intracranial pressure, biliary colic and acute alcoholism.

Administration of morphine is contra-indicated in patients with phaeochromocytoma those at risk of paralytic ileus and in patients with acute diarrhoea caused by poisoning or invasive pathogens

4.4 Special warnings and precautions for use

Morphine is a potent medicine but with considerable potential for harmful effect, including addiction. It should be used only if other drugs with fewer hazards are inadequate, and with the recognition that it may possibly mask significant manifestations of disease which should be identified for proper diagnosis and treatment. It should be used with special caution in patients with a history of drug abuse. Dependence may occur after 1-2 weeks of treatment.

Morphine should be given with caution where there is a reduced respiratory reserve e.g. in conditions including but not restricted to the following: emphysema, asthma, chronic cor pulmonale, kyphoscoliosis, excessive obesity and sleep apnoea. Opiates should also be used cautiously in patients with cardiac arrhythmias, myasthenia gravis or inflammatory or obstructive bowel disorders.

Morphine should be administered with caution or in reduced doses to patients with hypotension, hypothyroidism, adrenocortical insufficiency, impaired kidney or liver function, prostatic hypertrophy, urethral stricture or shock.

Morphine should be given with great care to infants, especially neonates. Dosage should be reduced in elderly and debilitated patients.

Disappearance of opioid analgesic effects, particularly when associated with an unexplained increase in pain, may indicate the development of tolerance or opioid-induced hyperalgesia. An unexplained increase in abdominal pain associated with disturbed intestinal motility, symptoms of constipation, bloating, abdominal distension and increased gastroesophageal reflux during treatment with morphine sulphate, may indicate the development of opioid-induced bowel dysfunction or narcotic bowel syndrome. In such situations consider the use of alternative analgesics and a morphine detoxification.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of other CNS depressants, including hypnotics and anxiolytics, may potentiate the sedative effects.

Morphine should not be administered to patients receiving monoamine oxidase inhibitors (see section 4.3).

Anticholinergic agents such as atropine antagonise morphine-induced respiratory depression and can partially reverse biliary spasm but are additive to the gastro-intestinal and urinary tract effects. Consequently, severe constipation and urinary retention may occur during intensive anticholinergic-analgesic therapy.

Morphine sulphate should not be used for premedication when ciprofloxacin is given for surgical prophylaxis as serum levels of ciprofloxacin are reduced and adequate cover may not be obtained during surgery.

4.6 Fertility, pregnancy and lactation

Pregnancy:    Since morphine rapidly crosses the placental barrier, it is not

advised to administer morphine during pregnancy and labour. It may reduce uterine contractions, cause respiratory depression in the foetus and new born infant, and may have significant effects on foetal heart rate.

As with all drugs it is not advisable to administer morphine during pregnancy.

Lactation:    The amount of morphine secreted in breast milk after a single

dose administration seems to be compatible with breast feeding and insufficient to cause major problems or dependence. However long-term treatment with morphine in high doses may cause significant plasma concentration. That is why caution is advised on the use of morphine in breastfeeding patient and the benefit must outweigh the risk to the infant. If breast feeding is continued, the infant should be observed for possible adverse effects.

4.7 Effects on ability to drive and use machines

Morphine may cause drowsiness. If this occurs the patient should not be allowed to drive or operate machinery.

4.8 Undesirable effects

Morphine may cause the following adverse events:

Nervous system disorders:

allodynia, coma, convulsion, drowsiness, headache, increased intracranial pressure, myoclonus, opioid-induced hyperalgesia (or hyperaesthesia), vertigo

Psychiatric disorders:

confusional state, decreased libido, hallucinations, mood swings, physical and psychological dependence, restlessness

Eye disorders:

blurred vision, miosis, nystagmus Respiratory, thoracic and mediastinal disorders:

bronchospasm, pulmonary oedema, which can lead to death, respiratory depression, respiratory failure, which also can lead to death

Cardiac disorders:

bradycardia, circulatory failure, palpitations, tachycardia

Vascular disorders: hypotension, orthostatic hypotension

Gastrointestinal disorders:

dry mouth, constipation, intestinal functional disorder, paralytic ileus, narcotic bowel syndrome, nausea, vomiting

Hepatobiliary disorders:

biliary spasm, hepatic enzyme increase, spasm of the sphincter of Oddi,

Reproductive system and breast disorders: erectile dysfunction

Renal and urinary disorders:

renal failure, urethral spasm, urinary retention

Immune system disorders: anaphylactic reaction, hypersensitivity

Musculoskeletal and connective tissue disorders: muscle rigidity, rhabdomyolysis

Skin and subcutaneous tissue disorders: angioedema, contact dermatitis, pruritus, rash, urticaria

General disorders and administration site conditions:

drug tolerance, fatigue, facial flushing, hyperhidrosis, hypothermia, injection site pain, injection site irritation, withdrawal syndrome

Babies born to opioid-dependent mothers also risk to present withdrawal syndrome.

4.9 Overdose

Symptoms: respiratory depression, pin-point pupils and coma. In addition, shock, reduced body temperature and hypotension may occur. In mild overdose, symptoms include nausea and vomiting, tremor, miosis, dysphoria, hypothermia, hypotension, confusion and sedation. In cases of severe poisoning, hypotension with circulatory failure, rhabdomyolosis progressing to renal failure, respiratory collapse and death may occur.

Treatment: the patient must be given respiratory support and the specific antagonist, naloxone, should be administered at a dose of 0.4-2.0 mg intravenously. This dose should be repeated at 2-3 minute intervals if improvement is not achieved, up to a total of 10 mg. Fluid and electrolyte levels should be maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Morphine is a narcotic analgesic obtained from opium, which acts mainly on the central nervous system and smooth muscle.

5.2 Pharmacokinetic properties

Absorption:    Variably absorbed after oral administration; rapidly

absorbed after subcutaneous or intramuscular administration.

Blood concentration: After an oral dose of 10mg as the sulphate, peak serum concentrations of free morphine of about 10ng/ml are attained in 15 to 60 minutes; after an intramuscular does of 10mg, peak serum concentrations of 70 to 80ng/ml are attained in 10 to 20 minutes; after an intravenous does of 10mg, serum concentrations of about 60ng/ml are obtained in 15 minutes falling to 30ng/ml after 30 minutes and to 10ng/ml after 3 hours; subcutaneous doses give similar concentrations to intramuscular doses at 15 minutes but remain slightly higher during the following 3 hours; serum concentrations measured soon after administration correlate closely with the ages of the subjects studied and are increased in the aged.

Half life:    Serum half life in the period 10 minutes to 6 hours

following intravenous administration, 2 to 3 hours; serum half life in the period 6 hours onwards, 10 to 44 hours.

Distribution:    Widely distributed throughout the body, mainly in the

kidneys, liver, lungs and spleen; lower concentrations appear in the brain and muscles; morphine crosses the placenta and traces are secreted in sweat and milk; protein binding, about 35% bound to albumin and to immunoglobulins at concentrations within the therapeutic range.

Metabolic reactions: Mainly glucuronic acid conjugation to form morphine-3 and 6-glucuronides, with sulphate conjugation. N-demethylation, 0-methylation and N-oxide glucuronide formation occurs in the intestinal mucosa and liver; N-demethylation occurs to a greater extent after oral than parenteral administration; the 0-methylation pathway to form codeine has been challenged and codeine and norcodeine metabolites in urine may be formed from codeine impurities in the morphine sample studied.

Excretion:    After an oral dose, about 60% is excreted in the urine in

24 hours, with about 3% excreted as free morphine in 48 hours; after parenteral dose, about 90% is excreted in 24 hours, with about 10% as free morphine, 65 to 70% as conjugated morphine, 1% as normorphine and 3% as normorphine glucuronide; after administration of large doses to addicts about 0.1% of a dose is excreted as norcodeine; urinary excretion of morphine appears to be pH dependent to some extent: as the urine becomes more acid more free morphine is excreted and as the urine becomes more alkaline more of the glucuronide conjugate is excreted; up to 10% of a dose may be excreted in the bile.

5.3 Preclinical safety data

None available

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium metabisulphite Sodium hydroxide (as in solution) Sulphuric acid (as in solution) Water for injection

6.2 Incompatibilities

Morphine salts may be precipitated in alkaline solution.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25°C and protect from light.

6.5 Nature and contents of container

Ceramically printed, ring snap ampoule manufactured from white neutral glass type 1, conforming to European Pharmacopoeia test for hydrolytic resistance containing morphine sulphate injection 30mg in 1ml, packed in cartons of 5 or 10 ampoules and 60mg in 2ml, packed in cartons of 5 ampoules.

Ring snap ampoule manufactured from white neutral glass type 1 conforming to European Pharmacopoeia test for hydrolytic resistance to which will be attached an adhesive vinyl label after filling containing morphine sulphate injection 300mg in 10ml, packed in cartons of 1 ampoule.

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