Ismelin®ampoules l0mg/ml

Guanethidine monosulphate Ph.Eur. 10mg/ml

A colourless solution in a clear glass l ml ampoule, for intramuscular administration.

Control of hypertensive crises, and to obtain more rapid blood pressure control.

Adults:

Ismelin should be given by intramuscular injection. One injection of 10 to 20mg will generally cause a fall in blood pressure within 30 minutes which reaches a maximum in one to two hours and is maintained for four to six hours. If a further dose of 10 to 20mg is deemed necessary, then three hours should be allowed to elapse between doses.

In hypertensive patients with moderate renal insufficiency, the intervals between dosing should be extended or the dosage reduced to avoid accumulation as the drug is renally excreted. (For patients with renal failure, see Section 4.3, "Contraindications").

Children: not recommended.

Elderly: Clinical evidence would indicate that no special dosage regime is necessary, but concurrent coronary or cerebral insufficiency should be taken into account.

Cases of phaeochromocytoma and patients previously treated with monoamine oxidase inhibitors (see Section 4.5, "Interactions with other medicaments and other forms of interaction"); in such cases, Ismelin may lead to the release of large quantities of catecholamines, which may cause a hypertensive crisis.

Patients with known hypersensitivity to guanethidine and related derivatives. Heart failure due to causes other than hypertension. Renal failure (creatinine clearance 10 to 40ml/min).

Heat and physical exertion may increase the antihypertensive effect of Ismelin.

Ismelin should be used with caution in patients with moderate renal insufficiency (creatinine clearance 41 to 65ml/min), or with coronary and/or cerebral arteriosclerosis; abrupt lowering of blood pressure should be avoided. Caution should be exercised in asthmatic patients or in patients with a history of gastrointestinal ulceration.

The concurrent administration of guanethidine and βblockers may provoke severe bradycardia.

When patients have to undergo surgery, it is recommended that treatment with Ismelin be withdrawn a few days before the operation. To avoid excessive bradycardia during anaesthesia, it is advisable to premedicate with larger than usual doses of atropine.

After prolonged treatment with Ismelin, latent heart failure may develop. This is due to salt and water retention, and mild negative inotropic and chronotropic effects. Concomitant administration of diuretics can readily correct this condition.

If patients develop fever, the dose of Ismelin should be lowered.

Monoamine oxidase inhibitors should be withdrawn at least fourteen days before starting treatment with Ismelin (See Section 4.3, "Contraindications").

Concurrent administration of Ismelin with antiarrhythmic agents and digitalis may lead to sinus bradycardia.

The anti-hypertensive action of Ismelin may be enhanced by other anti-hypertensive agents such as reserpine, methyldopa, vasodilators (especially minoxidil), calcium antagonists, βblockers, ACE inhibitors and alcohol.

The anti-hypertensive action of Ismelin may be reduced by chlorpromazine, phenothiazine derivatives, tricyclic antidepressants and related anti-psychotic drugs, and oral contraceptives. Consequently if larger doses of Ismelin are prescribed, care must be taken upon the withdrawal of any of the drugs listed, as severe hypotension may ensue if the dose of Ismelin is not adjusted in advance.

After prolonged treatment with Ismelin, it may be necessary to adjust the dosage of insulin or oral antidiabetic drugs.

Patients on Ismelin may become hypersensitive to adrenaline, amphetamines or other sympathomimetic agents. Therefore caution should be exercised when taking or using preparations containing these drugs.

No foetal toxicity or fertility studies have been carried out in animals. Therefore the drug should only be used if there is no safer alternative. However, in particular, it should not be used during the first trimester of pregnancy nor within at least two weeks prior to the birth or during labour since it may induce paralytic ileus in the newborn infant.

In mothers receiving Ismelin in therapeutic doses, the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness, blurred vision or drowsiness.

Side effects are often an indication of excessive dosage. The following effects may occur:

Central nervous system: Particularly at the start of treatment: dizziness, tiredness, lethargy, paraesthesia and headache. Occasional: blurred vision and depression. Rare: myalgia and muscular tremor.

Cardiovascular system: Postural hypotension (which may be associated with cerebral or myocardial ischaemia in severe cases) especially when getting up in the morning or after physical exertion, sicksinus syndrome, oedema, exacerbation of intermittent claudication and bradycardia. Occasional: heart failure. Rare: angina pectoris.

Gastrointestinal tract: Diarrhoea and gaseous distension. Occasional: vomiting, nausea and dry mouth. Rare: swelling of parotid glands.

Respiratory tract: Nasal congestion. Rare: asthma.

Urogenital system: Raised BUN levels or uraemia in patients with latent or manifest renal failure, and ejaculation disturbances.

Skin and hair: Occasional: dermatitis. Rare: hair loss.

Blood: Isolated reports of anaemia, leucopenia, and/or thrombocytopenia.

Symptoms: may include postural hypotension which may cause syncope, sinus bradycardia (although tachycardia has been observed), tiredness, dizziness, blurring of vision, muscular weakness, nausea, vomiting, severe diarrhoea and oliguria.

Treatment: Postural hypotension may be overcome by keeping the patient recumbent, or by instituting fluid and electrolyte replacement, and if necessary, by cautious administration of pressor agents (see Section 4.5, "Interactions with other medicaments and other forms of interaction"). Sinus bradycardia can be treated with atropine, and diarrhoea with an anticholinergic agent.

Ismelin is a peripheral sympathetic blocking drug which lowers blood pressure by depleting and inhibiting reformation of noradrenaline in postganglionic nerve endings. Guanethidine, being highly polar, does not cross the bloodbrain barrier and is unlikely therefore to exert any effect on the central nervous system. In addition, guanethidine has no effect on the parasympathetic nervous system.

Guanethidine may be excreted more slowly in those patients with moderate to severely compromised renal function, therefore the potential for accumulation of the drug will be higher.

There are no preclinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.

Sodium chloride, sulphuric acid and water for injections.

None known.

5 years.

None.

Clear glass type I, l ml ampoules containing l0mg/ml: Boxes of 5.

None

Amdipharm Plc

Regency House

Miles Gray Road

Basildon

Essex SS14 3AF

United Kingdom

PL 20072/0027

18^th April 2005

POM