This information is intended for use by health professionals

1. Name of the medicinal product

Diamorphine Hydrochloride 10mg for Injection

2. Qualitative and quantitative composition

Each ampoule contains 10mg of diamorphine hydrochloride

For full list of excipients, see section 6.1.

3. Pharmaceutical form

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

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.

Posology

The dose should be suited to the individual patient.

Adults:

Acute pain, 5mg repeated every four hours if necessary (up to 10mg 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, 5-10mg regularly every four hours by subcutaneous or intramuscular injection. The dose may be increased according to individual needs.

Myocardial infarction, 5mg by slow intravenous injection (1mg/minute) followed by a further 2.5mg to 5mg if necessary.

Acute pulmonary oedema, 2.5mg to 5mg by slow intravenous injection (1mg/minute).

Children and Elderly:

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.

Hepatic impairment:

A reduction in dosage should be considered in hepatic impairment.

Renal impairment:

The dosage should be reduced in moderate to severe renal impairment.

Debilitated patients:

A reduction in dosage should be considered in debilitated patients.

For concomitant illnesses/conditions where dose reduction may be appropriate see 4.4 Special Warnings and Precautions for Use.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with diamorphine hydrochloride in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

4.3 Contraindications

Acute respiratory depression.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).

Biliary colic (see also biliary tract disorders, 4.4 Special Warnings and Precautions).

Coma. Raised intracranial pressure. Head injuries, as there is an increased risk of respiratory depression that may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient

Acute alcoholism.

Diamorphine is also contra-indicated where there is a risk of paralytic ileus, or in acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated).

4.4 Special warnings and precautions for use

Morphine-like opioids should either be avoided in patients with biliary tract disorders or they should be given with an antispasmodic (use in biliary colic is a contraindication see 4.3 Contraindications).

Diamorphine should be given in reduced doses or with caution to patients with asthma or decreased respiratory reserve (including kyphoscoliosis, emphysema, severe obesity, cor pulmonale). Avoid use during an acute asthma attack (see 4.3 Contraindications).

Use with caution or in reduced doses in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, severe inflammatory or obstructive bowel disorders, hypotension, shock, convulsive disorders, adrenal insufficiency or debilitated patients.

Care should be exercised in treating the elderly, children or debilitated patients and those with hepatic or renal impairment (see 4.2 Posology for dosage recommendations).

Palliative care - in the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with diamorphine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Alcohol may enhance the sedative and hypotensive effects of diamorphine.

Anti-arrhythmics: Diamorphine may delay the absorption of mexiletine.

Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concomitant use of monoamine oxidase inhibitors (MAOIs) and pethidine. It is therefore possible that a similar interaction may occur with other opioid analgesics - avoid concomitant use and for two weeks after stopping MAOIs.

The depressant effects of diamorphine may be exaggerated and prolonged by tricyclic antidepressants, anxiolytics and hypnotics.

Antivirals: Plasma concentration of opioid analgesics (except methadone) is possibly increased by ritinovir.

Opioids potentiate the effects of CNS depressants including tricyclic antidepressants, anxiolytics and hypnotics.

Antipsychotics: enhanced sedative and hypotensive effect.

Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation.

Antimuscarinics: The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine).

Motility stimulants: There may be antagonism of the gastrointestinal effects of domperidone and metoclopramide.

Cimetidine inhibits metabolism of opioid analgesics.

4.6 Fertility, pregnancy and lactation

Pregnancy

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breast-feeding

Administration to nursing women is not recommended as diamorphine may be secreted in breast milk and may cause respiratory depression in the infant.

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.

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

The most serious hazard of therapy is respiratory (see also 4.9 Overdose).

The most common side effects are sedation, nausea and vomiting, constipation and sweating. Tolerance generally develops with long-term use, but not to constipation. Other side effects include the following:

Anaphylaxis: Anaphylactic reactions following intravenous injection have been reported rarely.

Cardiovascular: orthostatic hypotension, facial flushing, palpitations, tachycardia, bradycardia.

Central Nervous System: dizziness, vertigo, mental clouding, confusion (with large doses), hallucinations, headache, mood changes including dysphoria and euphoria.

Gastrointestinal: dry mouth, biliary spasm.

Disorders of the eye: blurred or double vision or other changes in vision, miosis.

Sexual dysfunction: long-term use may lead to a reversible decrease in libido or potency.

Skin: rash, pruritus, urticaria.

Urinary: urinary retention, difficulty with micturition, ureteric spasm, antidiuretic effect. Tolerance develops to the effects of opioids on the bladder.

Psychiatric disorders: drug dependence (see section 4.4).

General disorders and administration site conditions: drug 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 or search for MHRA Yellow Card in the Google Play or Apple App store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

a) Symptoms

The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops.

Pulmonary oedema after overdosage is a common cause of fatalities among diamorphine addicts.

Other opioid overdose symptoms include cold, clammy skin, hypotension, bradycardia, circulatory failure, muscle flaccidity, severe weakness, severe nervousness or restlessness, confusion, severe dizziness, severe drowsiness, hallucinations, convulsions (especially in infants and children), rhabdomyolysis progressing to renal failure.

b) Treatment

Respiration and circulation should be maintained and the specific opioid antagonist, naloxone is indicated if coma or bradypnoea are present, using one of the recommended dosage regimens. Oxygen and assisted ventilation should be administered if necessary.

5. Pharmacological properties
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

Water for Injections (Not detectable in the finished product).

6.2 Incompatibilities

Physical incompatibility has been reported with mineral acids and alkalis and with chlorocresol. Mixtures of diamorphine with cyclizine, haloperidol or dexamethasone may result in precipitation. Mixtures of diamorphine and metoclopramide may become discoloured and should be discarded. Specialised references should be consulted for specific compatibility information.

6.3 Shelf life

Three years from date of manufacture

6.4 Special precautions for storage

Do not store above 25°C.

Keep container in the outer carton

6.5 Nature and contents of container

2ml Neutral glass ampoules, PhEur. Type 1. Ampoules are packed into cartons of 5, 10 or 50.

6.6 Special precautions for disposal and other handling

The solution should be used immediately after preparation.

7. Marketing authorisation holder

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing authorisation number(s)

PL 29831/0063

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 22/03/1993

Date of latest renewal: 16/03/2007

10. Date of revision of the text

29/04/2020