SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Morphine Sulfate Injection BP Minijet™

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Morphine Sulfate 1mg/ml For excipients, see 6.1.

3    PHARMACEUTICAL FORM

Sterile aqueous solution for intravenous, intramuscular or subcutaneous injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2    Posology and method of administration

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 - 20mg 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 - 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 (e.g. 1 - 3mg every 5 minutes) reaching a maximum cumulative dose of 2 - 3mg/kg. (This is the preferred regimen for patients with myocardial infarction.)

Chronic pain:

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.

4.3 Contraindications

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, 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 sulfate, 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

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 sedative effects of morphine may be potentiated and prolonged by central nervous system depressants such as alcohol, anaesthetics, analgesics, antihistamines, barbiturates, narcotics, phenothiazines, sedatives, anxiolytics, 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 Sulfate 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.

4.6 Fertility, pregnancy and lactation

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.

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 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.

4.7 Effects on ability to drive and use machines

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

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if: o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 - 2.0mg intravenously. This dose should be repeated at 2 - 3 minute intervals if improvement is not achieved, up to a total of 10mg. Fluid and electrolyte levels should be maintained.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

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.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Disodium edetate

Sulphuric acid (1M; pH adjustment)

Water for Injection

6.2    Incompatibilities

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

6.3    Shelf life

24 months

6.4    Special precautions for storage

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

Nature and contents of container

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 Sulfate Injection 1mg/ml: 2ml (Minijet™)

10ml (Minijet™)

6.6    Special precautions for disposal

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

The 50ml container is designed for use with a syringe driver.

7    MARKETING AUTHORISATION HOLDER

International Medication Systems (UK) Ltd

21 St Thomas Street

Bristol

United Kingdom BS1 6JS

8    MARKETING AUTHORISATION NUMBER(S)

PL 03265/0037

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/1978

10 DATE OF REVISION OF THE TEXT

20/09/2016