Heminevrin 192 mg Capsules.

Clomethiazole 192 mg Capsules.

Clomethiazole 192 mg (base) per capsule.

10 mg Sorbitol (E420) per capsule.

For a full list of excipients, see 6.1.

Soft Capsules.

Greyish-brown, soft gelatin capsules.

Clomethiazole is a short acting hypnotic and sedative with anticonvulsant effect. It is used for the: management of restlessness and agitation in the elderly, short term treatment of severe insomnia in the elderly and treatment of alcohol withdrawal symptoms where close hospital supervision is also provided.

For oral use.

The capsules should be swallowed whole.

Management of restlessness and agitation in the elderly: one capsule three times daily.

Severe insomnia in the elderly: 1 - 2 capsules before going to bed. The lower dose should be tried first. As with all psychotropic drugs, treatment should be kept to a minimum, reviewed regularly and discontinued as soon as possible.

Alcohol withdrawal states: Clomethiazole is not a specific 'cure' for alcoholism. Alcohol withdrawal should be treated in hospital or, in exceptional circumstances, on an outpatient basis by specialist units when the daily dosage of clomethiazole must be monitored closely by community health staff. The dosage should be adjusted to patient response. The patient should be sedated but rousable. A suggested regimen is:

Administration for more than nine (9) days is not recommended.

Known sensitivity to clomethiazole. Acute pulmonary insufficiency.

Clomethiazole should be used cautiously in patients with sleep apnoea syndrome and chronic pulmonary insufficiency. Clomethiazole may potentiate or be potentiated by centrally acting depressant drugs including alcohol and benzodiazepines. Fatal cardiorespiratory collapse has been reported when clomethiazole was combined with other CNS depressant drugs. When used concomitantly dosage should be appropriately reduced.

Hypoxia, resulting from, for example, cardiac and/or respiratory insufficiency, can manifest itself as an acute confusional state. Recognition and specific treatment of the cause is essential in such patients and in such cases sedatives/hypnotics should be avoided.

Moderate liver disorders associated with alcoholism do not preclude the use of clomethiazole, though an associated increase in systemic availability of oral doses and delayed elimination of the drug may require reduced dosage. Great caution should be observed in patients with gross liver damage and decreased liver function, particularly as sedation can mask the onset of liver coma.

Caution should be observed in patients with chronic renal disease.

Caution must be exercised in prescribing for individuals known to be addiction prone or for those whose histories suggest they may increase the dose on their own initiative since clomethiazole is not free from the risk of producing psychological and/or physical dependence. After prolonged administration of high doses, physical dependence has been reported with withdrawal symptoms such as convulsions, tremors, and organic psychosis. These reports have mainly been associated with indiscriminate prescribing to outpatient alcoholics and clomethiazole should not be prescribed to patients who continue to drink or abuse alcohol.

Alcoholism: Alcohol combined with clomethiazole particularly in alcoholics with cirrhosis can lead to fatal respiratory depression even with short term use. It should not therefore be prescribed for alcoholics who continue to drink alcoholic beverages.

Elderly: Caution is advised as there may be increased bioavailability and delayed elimination of clomethiazole.

Children: Oral clomethiazole is not recommended for use in children.

One capsule contains 10 mg of sorbitol. When taken according to the dosage recommendations each dose supplies up to 40 mg of sorbitol. Unsuitable in hereditary fructose intolerance.

A combination of clomethiazole and diazoxide should be avoided as an adverse neonatal reaction suspected to be due to the maternal administration of this combination has been reported.

The combination of propranolol and clomethiazole has produced profound bradycardia in one patient possibly due to increased bioavailability of propranolol.

There is evidence to indicate that the metabolism of clomethiazole is inhibited by cimetidine, thus the co-administration of these drugs may lead to increased blood/plasma levels of clomethiazole.

When clomethiazole was administered by intravenous infusion in combination with carbamazepine, the clearance of clomethiazole increased by 30%, resulting in decreased plasma concentrations to the same extent. This interaction has not been studied after oral administration of clomethiazole. However, co-administration of carbamazepine and oral clomethiazole could result in both decreased bioavailability and increased clearance. Higher doses of clomethiazole could therefore be needed to obtain an effect when co-administered with carbamazepine or another potent inducer of the CYP3A4 enzyme.

Do not use in pregnancy especially during the first and last trimesters, unless there are compelling reasons. There is no evidence of safety in human pregnancy, nor is there evidence from animal studies that it is entirely free from hazard.

Clomethiazole is excreted into the breast milk. The effect of even small quantities of sedative/hypnotic and anticonvulsant drugs on the infant brain is not established.

Clomethiazole should only be used in nursing mothers where the physician considers that the benefit outweighs the possible hazard to the infant.

As with all centrally acting depressant drugs, the driving of vehicles and the operating of machinery are to be avoided when under treatment.

The most common side-effect is nasal congestion and irritation, which may occur 15 to 20 minutes after drug ingestion. Conjunctival irritation has also been noted in some cases. Occasionally, these symptoms may be severe and may be associated with severe headache. This is commonest with the initial dose following which it decreases in severity with subsequent doses. Increased nasopharyngeal/bronchial secretions can occur.

Rash and urticaria have been reported. In rare cases, bullous skin eruptions have been reported.

Gastrointestinal disturbances have been reported.

Reversible increases of transaminases or bilirubin have been reported.

In rare cases anaphylactic reactions have occurred.

When clomethiazole has been given at higher than recommended doses for other than recommended indications over prolonged periods of time, physical dependence, tolerance and withdrawal reactions have been reported.

Great caution is required in prescribing clomethiazole for patients with a history of chronic alcoholism, drug abuse or marked personality disorder.

When used as a night-time hypnotic, hangover effects in the elderly may occur but are uncommon due to the short half-life.

Excessive sedation may occur, especially with higher doses or when given to the elderly for daytime sedation. Paradoxical excitement or confusion may occur rarely.

The main effects to be expected with overdose of clomethiazole are: coma, respiratory depression, hypotension and hypothermia.

Hypothermia is thought to be due to a direct central effect as well as a result of lying unconscious for several hours. In addition, patients have increased secretion in the upper airways, which in one series was associated with a high incidence of pneumonia. The effects of overdosage are not usually severe in patients with no evidence of alcoholic liver disease, but they may be exacerbated when clomethiazole is taken in combination with alcohol and/or CNS depressant drugs, particularly those that are metabolised by the liver. There is no specific antidote to clomethiazole. Treatment of overdosage should therefore be carried out on a symptomatic basis, applying similar principles to those used in the treatment of barbiturate overdosage.

Charcoal column haemoperfusion is not and cannot be expected to be effective in treating clomethiazole poisoning.

Clomethiazole is pharmacologically distinct from both the benzodiazepines and the barbiturates.

Clomethiazole has sedative, muscle relaxant and anticonvulsant properties. It is used for hypnosis in elderly and institutionalised patients, for preanaesthetic sedation and especially in the management of withdrawal from ethanol. Given alone its effects on respiration are slight and the therapeutic index high.

Clomethiazole has a short half-life, low oral bioavailability, high plasma clearance and shows no evidence of accumulation or altered pharmacokinetics after repeated dosage. It is excreted in urine after extensive metabolism in the liver. The rate of elimination is decreased by about 30% in liver cirrhosis.

Extensive clinical use and experience with clomethiazole has provided a well established safety profile for this drug.

Medium-chain triglycerides, Gelatin, Glycerol (85%), Sorbitol (E420), Mannitol, Oligosaccharides, Titanium Dioxide (E171), Brown Iron Oxide (E172).

Not applicable.

Amber glass bottles: 24 months.

Aluminium foil blister packs: 24 months.

Do not store above 25°C.

Store in the original container.

Amber glass bottle with either a screw cap or clic-loc cap containing 60 or 100 capsules.

Transparent plastic bag in a cardboard outer for bulk packaging of 20,000 capsules.

Aluminium foil blister packs each containing 10 capsules.

Not all pack sizes may be marketed.

The capsules should remain in the container in which they are supplied.

The capsules should be swallowed whole.

CHEPLAPHARM Arzneimettel GmbH

Bahnhofstrasse 1A

D-17498 Mesekenhagen

Germany

PL 27041/0001

18^th March 2002 / 7^th March 2003

28 March 2011

(IF APPLICABLE)

(IF APPLICABLE)