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Clomethiazole

Drug Approvals

(British Approved Name, rINN)

Synonyms: Chlormethiazole; Clomethiazolum; Clometiazol; Klometiatsoli; Klometiazol
BAN: Clomethiazole
INN: Clomethiazole [rINN (en)]
INN: Clometiazol [rINN (es)]
INN: Clométhiazole [rINN (fr)]
INN: Clomethiazolum [rINN (la)]
INN: Клометиазол [rINN (ru)]
Chemical name: 5-(2-Chloroethyl)-4-methyl-1,3-thiazole
Molecular formula: C6H8ClNS =161.7
CAS: 533-45-9
ATC code: N05CM02
Read code: y01wt; y07dP

Pharmacopoeias. In British.

British Pharmacopoeia 2008 (Clomethiazole). A colourless to slightly yellowish-brown liquid with a characteristic odour. Slightly soluble in water miscible with alcohol, with chloroform, and with ether. A 0.5% solution in water has a pH of 5.5 to 7.0. Store at a temperature of 2° to 8°.

Drug Approvals

(British Approved Name Modified, rINNM)

Synonyms: Chlormethiazole Edisylate; Chlormethiazole Ethanedisulphonate; Clometiazol, edisilato de; NEX-002
BAN: Clomethiazole Edisilate [BANM]
USAN: Clomethiazole Edisylate
INN: Clomethiazole Edisilate [rINNM (en)]
INN: Edisilato de clometiazol [rINNM (es)]
INN: Clométhiazole, Edisilate de [rINNM (fr)]
INN: Clomethiazoli Edisilas [rINNM (la)]
INN: Клометиазола Едизилат [rINNM (ru)]
Chemical name: 5-(2-Chloroethyl)-4-methylthiazole ethane-1,2-disulphonate
Molecular formula: (C6H8ClNS)2,C2H6O6S2 =513.5
CAS: 1867-58-9
ATC code: N05CM02
Read code: y00Jz [CNS Use]; y08Cn [Hypnotic]; y0195 [Anaesthesia]

Pharmacopoeias. In British and Poland.

British Pharmacopoeia 2008 (Clomethiazole Edisilate). A white crystalline powder with a characteristic odour. Freely soluble in water soluble in alcohol practically insoluble in ether.

Incompatibility. Several studies have shown that clomethiazole edisilate may permeate through or be sorbed onto plastics used in intravenous infusion bags or giving sets. The drug may also react with and soften the plastic. The manufacturers of clomethiazole edisilate have suggested that thrombophlebitis, fever, and headache reported in young children during prolonged infusions may have been due to reaction with plastic giving sets and silastic cannulae. Recommendations for intravenous use have therefore included the use of a motor-driven glass syringe in preference to a plastic drip set in small children, changing plastic drip sets at least every 24 hours when used in older patients, and use of teflon intravenous cannulas.

Clomethiazole

Dependence and Withdrawal

Dependence may develop, particularly with prolonged use of higher than recommended doses of clomethiazole. Features of dependence and withdrawal are similar to those of barbiturates (see Amobarbital).

Adverse Effects, Treatment, and Precautions

Clomethiazole may produce nasal congestion and irritation, sneezing, and conjunctival irritation sometimes associated with a headache. Nasopharyngeal or bronchial secretions may be increased. Skin rashes and urticaria have also occurred and in rare cases bullous eruptions have been reported. Gastrointestinal disturbances including nausea and vomiting, have been reported after oral doses. Reversible increases in liver enzyme values and blood-bilirubin concentrations have also been noted. Clomethiazole can cause excessive drowsiness, particularly in high doses drowsiness may persist the next day, and patients affected should not drive or operate machinery. Paradoxical excitation or confusion may occur rarely. Anaphylaxis has also been reported rarely.

Excessive doses may produce coma, respiratory depression, hypotension, and hypothermia pneumonia may follow increased respiratory secretion. Treatment is as for barbiturate overdose (see Amobarbital). Clomethiazole is contra-indicated in patients with acute pulmonary insufficiency, and should be given with care to patients with sleep apnoea syndrome, chronic pulmonary insufficiency, or renal, liver, cerebral, or cardiac disease. Clomethiazole should be given with caution to elderly patients as there may be increased bioavailability and delayed elimination. Paradoxical worsening of epilepsy may occur in the Lennox Gastaut syndrome.

Administration by intravenous infusion. Severe adverse effects have followed the intravenous use of clomethiazole, and intravenous preparations are no longer generally available. Facilities for intubation and resuscitation were required when clomethiazole was given intravenously, with care taken to ensure that the patient’s airway was maintained since there is a risk of mechanical obstruction during deep sedation. At too high a rate of infusion, sleep induced with clomethiazole could lapse into deep unconsciousness and patients required close and constant observation. Rapid infusion has also caused transient apnoea and hypotension, and special care was needed in patients susceptible to cerebral or cardiac complications, including the elderly. With prolonged infusion there was also a risk of electrolyte imbalance due to the water load involved with the glucose vehicle. Recovery has been considerably delayed after prolonged infusion.

Effects on the heart. Cardiac arrest in 2 chronic alcoholics might have been associated with clomethiazole infusion.

Overdosage. A report of clomethiazole poisoning on 16 occasions in 13 patients, some of whom had also taken other drugs and alcohol. There was increased salivation on 7 occasions otherwise the clinical features were those of barbiturate poisoning (see Adverse Effects of Amobarbital). The highest plasma-clomethiazole concentration was 36 micrograms/mL, with the highest value in a conscious patient 11.5 micrograms/mL. All the patients survived following intensive supportive treatment as for barbiturate poisoning.

Parotitis. Acute bilateral parotitis has been reported in a patient given clomethiazole. The swelling disappeared after withdrawal of clomethiazole and recurred on rechallenge.

Pregnancy. There have been reports of neonates being adversely affected by clomethiazole given to their mothers for toxaemia of pregnancy.lt Effects included sedation, hypotonia, and apnoea. In a report it was suggested that the effects might have been due to a synergistic interaction between clomethiazole and diazoxide as these drugs were given to most of the mothers with affected infants.

Interactions

The sedative effects of clomethiazole are enhanced by CNS depressants such as alcohol, barbiturates, other hypnotics and sedatives, and antipsychotics.

Alcohol. Although clomethiazole has been a popular choice for the treatment of alcohol withdrawal symptoms, if it is given long-term, patients readily transfer dependency to it if they also continue to abuse alcohol this may lead to severe self-poisoning with deep coma and potentially fatal respiratory depression.

Beta blockers. Sinus bradycardia developed in an 84-year-old woman taking propranolol for hypertension 3 hours after she took a second dose of clomethiazole 192 mg. Her pulse rate increased on stopping propranolol and clomethiazole and later stabilised when she took propranolol with haloperidol.

Diazoxide. For a report of adverse reactions in neonates born to mothers given clomethiazole and diazoxide, see Pregnancy under Adverse Effects, Treatment, and Precautions, above.

Histamine H2-antagonists. A study of the pharmacokinetics of clomethiazole edisilate 1 g orally in 8 healthy subjects, before and after doses of cimetidine 1 g daily for 1 week, showed that mean clearance of clomethiazole was reduced by 31% by cimetidine. This was associated with an increase in the mean peak plasma concentration of the hypnotic from 2.664 to 4.507 micrograms/mL and an increase in the mean elimination half-life from 2.33 to 3.63 hours. After the original dose of clomethiazole subjects slept for 30 to 60 minutes, whereas after cimetidine, most slept for at least 2 hours. Ranitidine did not significantly affect the pharmacokinetics of clomethiazole in a study in 7 healthy subjects.

Pharmacokinetics

Clomethiazole is rapidly absorbed from the gastrointestinal tract, peak plasma concentrations occurring about 15 to 90 minutes after oral doses depending on the formulation used. It is widely distributed in the body and is reported to be 65% bound to plasma proteins. Clomethiazole is extensively metabolised, probably by first-pass metabolism in the liver with only small amounts appearing unchanged in the urine. The elimination half-life has been reported to be about 4 hours but this may be increased to 8 hours or longer in the elderly or in patients with hepatic impairment. Clomethiazole crosses the placenta and is distributed into breast milk.

Hepatic impairment. Studies in 8 patients with advanced cirrhosis of the liver and in 6 healthy men showed that the amount of unmetabolised clomethiazole reaching the circulation after an oral dose was about 10 times higher in the patients than in the controls. Low concentrations in the controls were related to extensive first-pass metabolism in the liver.

Uses and Administration

Clomethiazole is a hypnotic and sedative with anticonvulsant effects. It is used orally in the treatment of agitation and restlessness (see Disturbed Behaviour) in elderly patients, in the short-term management of severe insomnia in the elderly, and in the treatment of acute alcohol withdrawal symptoms. It was also given as an intravenous infusion in the management of status epilepticus and impending or actual eclampsia however, a parenteral formulation of clomethiazole no longer appears to be available.

In the UK, clomethiazole (as Heminevrin AstraZeneca) is available as capsules containing 192 mg of clomethiazole base and as syrup containing 250 mg of the edisilate in 5 mL. As a result of differences in the bioavailability of these preparations, 192 mg of the base in the capsules is considered therapeutically equivalent to 250 mg (5 mL) of the edisilate in the syrup, i.e. one capsule or 5 mL of syrup are equivalent in their effects. The usual hypnotic dose of clomethiazole for insomnia is 1 or 2 capsules (192 or 384 mg of the base) or the equivalent. For restlessness and agitation in the elderly 1 capsule (192 mg of the base), or the equivalent dose as one of the other dosage forms, may be given 3 times daily.

Various clomethiazole regimens have been suggested for the treatment of alcohol withdrawal, usually starting with 9 to 12 capsules, or the equivalent, divided into 3 or 4 doses, on the first day, and gradually reducing the dosage over the next 5 days. Treatment should be carried out in hospital or in specialist centres, and use for longer than 9 days is not recommended because of the risk of dependence (see above).

Porphyria. Clomethiazole is one of the drugs that has been used for seizure prophylaxis in patients with porphyria who continue to experience convulsions while in remission.

Stroke. Clomethiazole has been studied’ as a neuroprotective drug in the acute management of patients with stroke, but no beneficial effect on long-term outcome was found.

Substance dependence. For a discussion of the management of opioid withdrawal symptoms, including mention of the use of clomethiazole.

Preparations

British Pharmacopoeia 2008: Clomethiazole Capsules Clomethiazole Intravenous Infusion Clomethiazole Oral Solution.

Proprietary Preparations

 

Australia: Hemineurin

Belgium: Distraneurine

Czech Republic: Heminevrin

Denmark: Heminevrin

Finland: Heminevrin

Germany: Distraneurin

Greece: Distraneurine Heminevrin

Hong Kong: Heminevrin

Hungary: Heminevrin

Ireland: Heminevrin

Norway: Heminevrin

Poland: Heminevrin

Spain: Distraneurine

Sweden: Heminevrin

Switzerland: Distraneurin

UK: Heminevrin

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