Clorazepate

Clorazepate (marketed under the brand names Tranxene and Novo-Clopate), also known as clorazepate dipotassium, is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate was discontinued in February 2006 in the United Kingdom. Clorazepate is a prodrug for desmethyldiazepam which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

Indications
Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant. it is also used as a premedication.

Clorazepate is principally prescribed in the treatment of alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life. The normal starting dosage range of Clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, Clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg. Clorazepate SD (controlled release) is available in 11.25 and 22.5 mg tablets. Clorazepate SD is only prescribed when the patient has become adjusted to a certain dosage, and is taken once a day. Clorazepate is available in generic form. Clorazepate begins to act on the central nervous system within one or two hours, and its effects may be felt for an entire day or longer in some individuals. It is contraindicated for those with impaired renal or hepatic function.

Pharmacology
Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include alprazolam, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam. Clorazepate is a long acting benzodiazepine drug. Clorazepate produces the metabolite desmethyl-diazepam which has a half life of 36 – 200 hours.

Interactions
All sedatives or hypnotics eg other benzodiazepines, alcohol, antihistamines, opiates, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs which may interact with clorazepate include, digoxin, disulfiram, fluoxetine, isoniazid, ketoconazole, levodopa, metoprolol, hormonal contraceptives, probenecid, rifampin, theophylline, valproic acid.

Cimetidine, trade name Tagamet, inhibits breakdown of Clorazepate, and leads to increased levels of the drug in the system.

Tolerance, dependence and withdrawal
In humans tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use. However, tolerance to the active metabolite of clorazepate may occur more slowly than with other benzodiazepines. Regular use of benzodiazepines causes the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.

Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Chlorazepate if used late in pregnancy, the third trimester, causes a definite risk a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the new born may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Legal status
Clorazepate is listed under Schedule IV of the Controlled Substances Act.