DIAMORPHINE HYDROCLORIDE 10 MG FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Diamorphine Hydrochloride 10mg For Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Diamorphine Hydrochloride 10mg.

3 PHARMACEUTICAL FORM

A freeze dried powder, which when in aqueous solution is suitable for parenteral administration.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the relief of severe pain such as that associated with cancer, acute myocardial infarction and in the treatment of acute pulmonary oedema.

4.2 Posology and method of administration

Method of administration

By intramuscular, subcutaneous or intravenous injection, the latter 2 routes using either bolus injection or infusion.

Posology

It is important that dosage be suited to the individual patient, taking into account the properties of the drug, the nature of the pain, the total condition of the patient and previous or concurrent medication.

Adults:     Cancer: Use of diamorphine or other narcotic analgesics although

very important, should be only one part of the comprehensive

approach to total pain control, which ideally should include nondrug measures and psycho-social support. Diamorphine may be used parenterally when oral administration of narcotic analgesics is no longer possible because of the dosage required, impaired absorption, intestinal disorders, nausea and vomiting or difficulty in swallowing.

An initial dosage of 5 to 10mg every 4 hours may be suitable, but higher doses are reported in the literature (Dover SB, BMJ 1987, 294, 553–555). The initial dosage will usually depend on the doses and drugs given previously.

Persistent pain is controlled by titrating the dose against the degree of pain, until the smallest dose required to remove the pain is reached. This dose is maintained and the patient’s condition continually re-assessed, the dose being increased or decreased as necessary. The therapeutic objective must be to control the pain by regular administration of the correct dose when this is determined, and continuous infusion may be preferred to intermittent therapy.

Acute myocardial infarction: A dose of 5mg may be given by slow intravenous injection (1mg per minute), followed by 2.5 to 5mg if necessary.

Acute pulmonary oedema: A dose of 2.5 to 5mg may be given by slow intravenous injection (1mg per minute).

Equivalent Doses of Morphine Sulphate by mouth (as oral solution or standard tablets or as modified-release tablets) or of Diamorphine Hydrochloride by Intramuscular Injection or by Subcutaneous Infusion:

These equivalences are approximate only and may need to be adjusted according to response:

Children: 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. 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)

Elderly:     Mainly because of its respiratory depressant effect caution should

be exercised when giving the drug to the elderly and a reduced dose should be used.

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore the dose should be gradually reduced prior to discontinuation.

4.3 Contraindications

Respiratory depression, obstructive airways disease. Concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of treatment with them. Biliary Colic. Phaeochromocytoma.

4.4 Special warnings and precautions for use

Tolerance and physical dependence on the drug is likely to develop in most patients after a few weeks of treatment, but this does not prevent reduction of dosage or discontinuation when considered necessary, and drug abuse is not normally a problem in patients with severe pain. Caution should be exercised, however, in using the drug in patients with a known tendency to, or history of, drug abuse. Care should be exercised in treating the elderly, debilitated patients, and those with hepatic or renal impairment. It is recommended that a lower than normal initial dose is given to these patients. Administration to patients with head injuries or raised intracranial pressure increases the risk of respiratory depression and further elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient. The drug can cause hypotension in patients who already have conditions or drug therapy that interfere with the ability to maintain normal blood pressure. Careful consideration should be given before treating patients with myxoedema or hypothyroidism, adrenocortical insufficiency, toxic psychoses, CNS depression, prostatic hypertrophy or urethral stricture, kyphoscoliosis, acute alcoholism and delirium tremens, severe inflammatory bowel disease and severe diarrhoea.

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

Due to a possible association between ACS_and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Decreased Sex Hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required

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).

Morphine has an abuse potential similar to other strong agonist opioids, and should be used with particular caution in patients with a history of alcohol or drug abuse.

Dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. The risk increases with the time the drug is used, and with higher doses. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

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).

Concurrent administration of other CNS sedative/hypnotic drugs may have an addictive effect necessitating their dosage reduction. Administration of drugs having anti-muscarinic activity (atrophine and synthetic anti-cholinergics) may increase the risk of severe constipation and/or urinary retention.

4.6 Fertility, Pregnancy and lactation

Fertility

Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).

Pregnancy

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome.

Treatment may include an opioid and supportive care.

Use during labour is not advisable due to the risk of respiratory depression in the new-born.

There is limited information on diamorphine levels in breast milk and it is, therefore, not advisable for patients on high doses of diamorphine to breastfeed.

4.7 Effects on ability to drive and use machines

May impair ability to drive and use 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

The most serious hazards of therapy are respiratory depression and arrest, although circulatory depression, shock and cardiac arrest can occur.

The most common side-effects are: sedation, nausea and vomiting, constipation and sweating.

Other side-effects include:

Nervous system disorders:

frequency unknown: allodynia, hyperalgesia (see section 4.4), hyperhidrosis, faintness and syncope, euphoria, dysphoria, weakness, insomnia, dizziness, confusional

symptoms and occasionally hallucinations

Immune system disorders:

frequency unknown: anaphylactoid reactions

Gastrointestinal disorders:

frequency unknown: dry mouth, anorexia, cramps, taste alterations

Psychiatric disorders:

frequency unknown: dependence

General disorders and administration site:

frequency unknown: drug withdrawal (abstinence) syndrome

Cardiac disorders:

frequency unknown: tachycardia, postural hypotension, palpitations,;,;

Vascular disorders:

frequency unknown: postural hypotension

Renal and urinary disorders:

frequency unknown: urinary retention

Reproductive system and breast disorders: frequency unknown: reduced libido or potency

Skin and subcutaneous tissue disorders:

frequency unknown: pruritus, urticaria and other skin rashes

Drug withdrawal symptoms:

Dysphoric mood, anxiety have also been reported.

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. For management, see 4.4.

Physiological withdrawal symptoms include: Body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis. Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved.

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:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.

4.9 Overdose

Symptoms

The symptoms of serious overdosage are respiratory depression, pneumonia aspiration, stupor or coma, muscle flaccidity, cold clammy skin, constricted pupils and occasionally bradycardia and hypotension. Death may occur from respiratory failure.

Management

The specific antidote naloxone is indicated if coma or bradypnoea are present. A dose of 0.4 to 2mg may be given by s.c., i.m. or i.v. injection repeated at intervals of 2–3 minutes up to a maximum of 10mg if respiratory function does not improve. The dosage for children is 10 micrograms per kilogram body weight. Alternatively, naloxone may be given by continuous i.v. infusion; 2mg diluted in 500ml intravenous solution, at a rate adjusted to the patient’s response.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other Nervous System Drugs, Drugs used in opioid dependence, ATC code: N07BC06

Diamorphine is a narcotic analgesic obtained from opium which acts mainly on the central nervous system and smooth muscle. It can provoke the release of endogenous histamine and thereby induce catecholamine release.

5.2 Pharmacokinetic properties

Excretion:    Up to 80% of a dose is recovered in the urine in 24 hours, after

oral or parenteral administration, most of the dose is recovered as morphine-3-glucuronide with about 5 to 7% as free morphine, 1% as 6-monoacetylmorphine, 0.1% as unchanged drug and trace amounts of the other metabolites.

5.3 Preclinical safety data

In male rats, reduced fertility and chromosomal damage in gametes have been reported.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None detectable

6.2 Incompatibilities

Diamorphine is incompatible with mineral acids and alkalis.

Physicochemical incompatibility (formation of precipitates) has been demonstrated between solutions of morphine sulphate and 5– fluorouracil.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C. Protect from light.

6.5 Nature and contents of container

Five 2ml type 1 neutral glass ampoules contained in a printed tamper evident cardboard carton.

6.6 Special precautions for disposal

Reconstitute in 1ml of water for injections. 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 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

7 MARKETING AUTHORISATION HOLDER

Ennogen Healthcare Limited

Unit G2-G4, Riverside Industrial Estate,

Riverside Way,

Dartford,

DA1 5BS

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 40739/0242

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/02/2001