DIAMORPHINE HYDROCHLORIDE BP 10 MG LYOPHILISATE FOR SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Diamorphine Hydrochloride BP 10 mg Lyophilisate for Solution for Injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule contains 10 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

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

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

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 online, 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.

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.

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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of diamorphine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe diamorphine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Sedative medicines such as benzodiazepines or related drugs

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

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 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:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely.

4.8 Undesirable effects

The most serious hazard of therapy is respiratory depression although circulatory depression is also possible.

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.

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

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

5.1 Pharmacodynamic properties

ATC code: NO2AA09

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

Do not store above 25°C. 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

2 ml clear Ph. Eur. Class 1 ampoules containing 10 mg Diamorphine Hydrochloride BP lyophilisate each.

The ampoules are packed into a carton of 5.

6.6 Special precautions for disposal

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.

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0676