1. Name Of The Medicinal Product
Diamorphine Hydrochloride BP 100 mg Lyophilisate for Solution for Injection.
2. Qualitative And Quantitative Composition
Each ampoule contains 100 mg of Diamorphine Hydrochloride BP.
3. Pharmaceutical Form
Lyophilisate for solution for injection.
A white to off-white, sterile, freeze dried powder of Diamorphine Hydrochloride BP for reconstitution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Diamorphine may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema.
4.2 Posology And Method Of Administration
Diamorphine may be given by the intramuscular, intravenous or subcutaneous routes. Glucose intravenous infusion is the preferred diluent, particularly when the drug is administered by a continuous infusion pump over 24 to 48 hours, although it is also compatible with sodium chloride intravenous infusion.
The dose should be suited to the individual patient.
Adults:
Acute pain, 5 mg repeated every four hours if necessary (up to 10 mg for heavier, well muscled patients) by subcutaneous or intramuscular injection. By slow intravenous injection, one quarter to one half the corresponding intramuscular dose.
Chronic pain, 5-10 mg regularly every four hours by subcutaneous or intramuscular injection. The dose may be increased according to individual needs.
Myocardial infarction, 5 mg by slow intravenous injection (1 mg/minute) followed by a further 2.5 mg to 5 mg if necessary.
Acute pulmonary oedema, 2.5 mg to 5 mg by slow intravenous injection (1mg/minute).
If breakthrough pain occurs give a subcutaneous (preferable) or intramuscular injection of diamorphine equivalent to one-sixth of the total 24-hour subcutaneous infusion dose. It is kinder to give an intermittent bolus injection subcutaneously—absorption is smoother so that the risk of adverse effects at peak absorption is avoided (an even better method is to use a subcutaneous butterfly needle).
To minimise the risk of infection no individual subcutaneous infusion solution should be used for longer than 24 hours.
If treatment continues for more than 24 hours it may be appropriate to use a syringe driver (Burne R, Hunt A, Palliative Medicine 1987, 1, 27-30)
Children and Elderly:
Diamorphine has been used in the treatment of terminally ill children. Diamorphine has been administered in reduced doses to children with neoplastic disease when it becomes difficult to give treatment orally. The starting dose should be selected according to age, size, symptoms and previous analgesic requirements and administered 4 hourly; the dose being titrated according to the degree of pain.
As diamorphine has a respiratory depressant effect, care should be taken when giving the drug to the very young and the elderly and a lower starting dose than normal is recommended.
Patients with hepatic or renal dysfunction:
Diamorphine undergoes biotransformation to an active metabolite, morphine-6-glucuronide (M6G). This metabolite can accumulate and result in greater pharmacological effect, because it is more active than morphine. Less diamorphine will therefore be needed. Care needs to be taken with unconscious intensive care patients on fixed dose schedules where their renal function is impaired.
A wide range of doses of diamorphine can be given intravenously or subcutaneously starting with the “standard” 5-10mg regularly every four hours recommended in the SmPC. Lower starting doses are recommended for patients with hepatic or renal impairment. Ultimately, the dose given to the individual is arrived at by “titrating to therapeutic effect”.
Instructions for use and handling
Instructions for preparation: see Section 6.6.
Further advice on use and handling can be found in the current British National Formulary (BNF/BNFC) (Prescribing in Palliative Care and Syringe Drivers).
4.3 Contraindications
Respiratory depression and obstructive airways disease.
Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).
Raised intracranial pressure.
Concurrent use of monoamine oxidase inhibitors or within two weeks of their discontinuation.
4.4 Special Warnings And Precautions For Use
Diamorphine should be administered with care to patients with head injuries as there is an increased risk of respiratory depression which may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.
Repeated administration of diamorphine may lead to dependence and tolerance developing. Abrupt withdrawal in patients who have developed dependence may precipitate a withdrawal syndrome. Great caution should be exercised in patients with a known tendency or history of drug abuse.
Use with caution in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, kyphoscoliosis, acute alcoholism, delirium tremens, severe inflammatory or obstructive bowel disorders, adrenal insufficiency or severe diarrhoea. Care should be exercised in treating the elderly or debilitated patients and those with hepatic or renal impairment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The depressant effects of diamorphine may be exaggerated and prolonged by phenothiazines, monoamine oxidase inhibitors, tricyclic antidepressants, anxiolytics and hypnotics. There may be antagonism of the gastrointestinal effects of cisapride, domperidone and metoclopramide. The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine). There may be increased risk of toxicity with 4-quinolone antibacterials.
Alcohol may enhance the sedative and hypotensive effects of diamorphine.
Cimetidine inhibits metabolism of opioid analgesics.
Hyperpyrexia and CNS toxicity have been reported when opioid analgesics are used with selegiline.
4.6 Pregnancy And Lactation
Safety has not been established in pregnancy.
Administration during labour may cause respiratory depression in the neonate and gastric stasis during labour, increasing the risk of inhalation pneumonia.
Diamorphine should not be given to women who are breast-feeding as there is limited information available on diamorphine in breast milk.
4.7 Effects On Ability To Drive And Use Machines
Diamorphine causes drowsiness and mental clouding. If affected patients should not drive or use machines.
4.8 Undesirable Effects
The most serious hazard of therapy is respiratory depression although circulatory depression is also possible. The most common side effects are sedation, nausea and vomiting, constipation and sweating. Other side effects include dizziness, miosis, confusion, urinary retention, biliary spasm, orthostatic hypotension, facial flushing, vertigo, palpitations, mood changes, dry mouth, dependence, urticaria, pruritus and raised intracranial pressure.
4.9 Overdose
a) Symptoms
Respiratory depression, pulmonary oedema, muscle flaccidity, coma or stupor, constricted pupils, cold, clammy skin and occasionally bradycardia and hypotension.
b) Treatment
Respiration and circulation should be maintained and naloxone is indicated if coma or bradypnoea are present. A dose of 0.4 to 2 mg repeated at intervals of two to three minutes (up to 10 mg) may be given by subcutaneous, intramuscular or intravenous injection. The usual initial dosage for children is 10 micrograms per kg body weight. Naloxone may also be given by continuous intravenous infusion, 2 mg diluted in 500 ml, at a rate adjusted to the patient's response. Oxygen and assisted ventilation should be administered if necessary.
5. Pharmacological Properties
ATC code: NO2AA09
5.1 Pharmacodynamic Properties
Diamorphine is a narcotic analgesic which acts primarily on the central nervous system and smooth muscle. It is predominantly a central nervous system depressant but it has stimulant actions resulting in nausea, vomiting and miosis.
5.2 Pharmacokinetic Properties
Diamorphine is a potent opiate analgesic which has a more rapid onset of activity than morphine as the first metabolite, monoacetylmorphine, more readily crosses the blood brain barrier. In man, diamorphine has a half life of two to three minutes. Its first metabolite, monoacetylmorphine, is more slowly hydrolysed in the blood to be concentrated mainly in skeletal muscle, kidney, lung, liver and spleen. Monoacetylmorphine is metabolised to morphine. Morphine forms conjugates with glucuronic acid. The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine. About 7-10 % is eliminated via the biliary system into the faeces.
Diamorphine does not bind to protein. However, morphine is about 35 % bound to human plasma proteins, mainly to albumin. The analgesic effect lasts approximately three to four hours.
5.3 Preclinical Safety Data
There are no additional pre-clinical data of relevance to the prescriber.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
3 years.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8 °C, unless reconstitution/dilution (etc.) has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Store below 25ºC. Protect from light.
Keep container in the outer carton.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
5 ml clear Ph. Eur. Class 1 glass ampoules containing 100 mg Diamorphine Hydrochloride BP lyophilisate each.
The ampoules are packed into a carton of 5.
6.6 Special Precautions For Disposal And Other Handling
The product is prepared by dissolving Diamorphine Hydrochloride Lyophilisate for Solution for Injection in the requisite amount of water for injection immediately before use.
The reconstituted lyophilisate is a clear solution.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Continuous subcutaneous infusion should be monitored regularly both to check for precipitation (and discoloration) and to ensure that the infusion is running at the correct rate.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Auralis
Daresbury Innovation Centre,
Keckwick Lane, Daresbury, Halton WA4 4FS
United Kingdom
8. Marketing Authorisation Number(S)
PL 30956/0001
9. Date Of First Authorisation/Renewal Of The Authorisation
12/02/2008
10. Date Of Revision Of The Text
03/09/2008
11 DOSIMETRY (IF APPLICABLE)
Not applicable.
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
Not applicable.
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