Morphine Sulphate Injection BP Minijet^TM

Morphine Sulphate 1 mg/ml

For excipients, see 6.1.

Sterile aqueous solution for intravenous, intramuscular or subcutaneous injection.

For intravenous, intramuscular or subcutaneous injection.

For the relief of moderate to severe pain such as in myocardial infarction, severe injuries, neoplastic disease, surgery, renal colic, terminal disease and other conditions where non-narcotic analgesia has failed.

Morphine is effective in the control of post-operative pain and anxiety.

Morphine may be used for its sedative effect in the management of the severe dyspnoea in terminal lung cancer or other terminal respiratory disease.

Morphine should be used as a sedative or hypnotic generally only when pain relief and sedation are required. It is used in pre-anaesthetic medication for surgery, where it reduces anxiety and also the amount of anaesthetic required.

For open-heart surgery, especially in high risk patients with cardiac disease, morphine may be used to produce anaesthesia.

The dose and dosing regimen should be tailored to the individual patient's needs.

Adults and children over 12 years:

Intramuscular or subcutaneous administration

5-20 mg every 4 hours as necessary, dependent upon the patient's response and cause of pain.

For the relief of pain and as pre-anaesthetic, the usual dose is 10mg every 4 hours depending on the severity of the condition and the patient's response. The usual individual dose range is 5-15mg. The usual daily dose range is 12-120mg.

Intravenous administration

Acute pain:

2 to 15mg by slow intravenous injection.

or

Loading dose as above, followed by 2.5 - 5mg every hour by infusion. If using Patient Controlled Analgesia (PCA), bolus doses of 1 - 2mg may be given with a lock out of 5 - 20 minutes. A commonly applied dose limit used in PCA is 30mg in 4 hours, although some patients may require higher doses.

or

Frequent small doses ( eg 1 -3 mg every 5 minutes) reaching a maximum cumulative dose of 2 - 3mg/kg. (This is the preferred regimen for patients with myocardial infarction.)

Chronicpain:

Loading doses of 15mg or more. Maintenance doses for infusion are in the range 0.8 - 80mg/hour, although higher maintenance doses of 150-200mg/hour may be required.

Similar doses have been given by subcutaneous infusion.

Open heart surgery

Large doses (0.5 - 3mg/kg) may be administered intravenously by slow continuous infusion as the sole anaesthetic agent.

Elderly:

Morphine should be administered with caution in the elderly and a reduced starting dose titrated to provide optimal pain relief.

Children under 12 years:

Intramuscular or subcutaneous administration:

Up to 1 month : 150mcg/kg every 4 hours

1-12 months : 200mcg/kg every 4 hours

1-5 years : 2.5-5mg every 4 hours

6-12 years : 5-10mg every 4 hours

Slow intravenous infusion:

Up to 6 months : up to 10mcg/kg/hour with respiratory support. Bolus injection to be avoided.

6 months - 12 years : 10-30mcg/kg/hour. A loading dose of 100-200mcg/kg may be given initially with bolus top-up doses of 50-100mcg/kg every 4 hours.

Subcutaneous infusion:

6 months - 12 years : 30-60mcg/kg/hour. For the relief of pain in terminal disease.

Morphine is contraindicated in patients with obstructive airways disease; respiratory depression; known morphine sensitivity; sensitivity to any of the other ingredients; head injuries; coma; convulsive disorders and raised intracranial pressure; biliary colic; acute alcoholism; cerebral oedema; concurrent treatment with monoamine oxidase inhibitors or within two weeks of their discontinuation of treatment with them; phaeochromocytoma and those at risk of paralytic ileus.

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. Dependence may occur after 1-2 weeks of treatment.

Morphine should be given with caution where there is a reduced respiratory reserve as in emphysema, chronic cor pulmonale, kyphoscoliosis and excessive obesity. 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 hypothyroidism, adrenocortical insufficiency, impaired kidney or liver function, prostatic hypertrophy or shock.

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

Monoamine oxidase inhibitors markedly potentiate the action of morphine; morphine should not be administered to patients receiving monoamine oxidase inhibitors (see section 4.3).

The depressant effects of morphine may be potentiated and prolonged by central nervous system depressants such as alcohol, anaesthetics, analgesics, antihistamines, barbiturates, narcotics, phenothiazines, sedatives, hypnotics and tricyclic antidepressants.

Chlorpromazine and some other phenothiazines appear to enhance the sedative action but diminish the analgesic effect of morphine. The use of tricyclic antidepressants, aspirin and other NSAIDs may increase the extent of pain relief of morphine. They also increase the risks of adverse effects.

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 pre-medication when ciprofloxacin is given for surgical prophylaxis as serum levels of ciprofloxacin are reduced and adequate cover may not be obtained during surgery.

There is inadequate evidence of safety in human pregnancy. Morphine is known to cross the placenta and it may cause respiratory depression by this route. It is not advised to administer morphine during pregnancy or during labour. It may reduce uterine contractions, cause respiratory depression in the foetus and neonate, and may have significant effects on the foetal heart rate.

Only small amounts of morphine are secreted in breast milk and the quantity that may reach the neonate via breast milk is probably insufficient to cause major problems of dependence or adverse effects. However, caution is advised on the use of morphine in breast-feeding 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.

Morphine may cause drowsiness. Patients receiving morphine should not drive or operate machinery.

The commonest side effects are nausea, vomiting, constipation, drowsiness and confusion. Psychological and physical dependence may occur. Other side effects include bronchospasm, angioedema, urinary retention, ureteric or biliary spasm, dry mouth, sweating, rash, facial flushing, vertigo, tachycardia, bradycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, mood change, hallucinations, seizures (adults and children) and miosis, headache and allergic reactions (including anaphylaxis) and decreased libido or potency. Raised intracranial pressure occurs in some patients. Muscle rigidity may occur with high doses.

Morphine has been reported to increase liver enzymes as a result of spasm of the sphincter of Oddi.

Large doses can produce respiratory depression, hypotension with circulatory failure and coma. Convulsions may occur in children and infants. Rhabdomyolysis may progress to renal failure. Death may occur from respiratory depression or from pulmonary oedema after overdose.

Urticaria, pruritus, hypotension and flushing may be caused by a morphine dose-related histamine release. Contact dermatitis may occur. Pain at the site of the injection has been reported.

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 acute poisoning, 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.

ATC Code: N02A A01

Morphine is the principle alkaloid of opium and is a potent analgesic. It exerts its primary effects on the central nervous system and smooth muscle. Pharmacological effects include analgesia, drowsiness, alteration in mood, reduction in body temperature, dose-related respiratory depression, interference with adrenocortical response to stress (at high doses) and a reduction in peripheral resistance with little or no effect on cardiac index and miosis. Morphine, as other opioids, acts as an agonist interacting with stereospecific and saturable binding sites/receptors in the brain, spinal cord and other tissues.

Morphine acts on the cough centre to suppress coughing and also directly stimulates the chemoreceptor trigger zone in the medulla to produce nausea and vomiting. Morphine provokes the release of histamine.

After subcutaneous or intramuscular injection, morphine is readily absorbed into the blood. Peak analgesia occurs 50-90 minutes after SC injection, 30-60 minutes after IM and 20 minutes after IV infusion. The effect persists for up to 4-5 hours.

Most of the morphine dose is conjugated with glucoronide in the liver (first pass effect), resulting in morphine-3-glucoronide (inactive) and morphine-6-glucuronide (active). Other active metabolites are formed in small amounts.

About 35% of the dose is protein bound. Morphine can cross the placenta and blood-brain barrier and its metabolites have been detected in the cerebrospinal fluid. Morphine is distributed throughout the body, mainly into skeletal muscle, kidneys, liver, intestinal tract, lungs and spleen.

The mean plasma elimination half life for morphine is 1.5-2.0 hours and for the 3-glucuronide ranges from 2.5-7.0 hours.

Approximately 90% of a parenteral dose of morphine appears in the urine within 24 hours, primarily as the product of glucuronide conjugation with only a small amount as the unchanged drug. 7-10% is excreted in the bile and eliminated in the faeces.

Not applicable, since morphine sulphate has been used in clinical practice for many years and its effects on man are well known.

Disodium edetate

Sodium metabisulphite

Water for Injection

Morphine salts may be precipitated in alkaline solution. Compatibility should be checked before admixture with other drugs.

24 months.

Do not store above 25°C. Protect from light.

The solution is contained in a Type I USP glass vial with a rubber closure which meets all the relevant USP specifications for elastomeric closures.

The following volumes are available:

Morphine Sulphate Injection 1mg/ml : 2ml (Minijet^TM)

10ml (Minijet^TM)

The 2ml and 10ml containers are designed for use with the IMS Minijet^TM injector.

International Medication Systems (UK) Ltd

208 Bath Road

Slough

Berkshire

SL1 3WE

UK

PL 03265/0037

Date first granted: 14 March 1978

Date renewed: 12 October 2002

February 2005

POM