Clorazepate

Clorazepate (marketed under the brand names Tranxene and Tranxilium), is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

Clorazepate has been discontinued since February 2006 in the United Kingdom.

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Pharmacology

Clorazepate is a "classical" benzodiazepine, other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam.^[1] Clorazepate is a long acting benzodiazepine drug.^[2] The half life of Clorazepate is 36 - 200 hours.^[3]

Indications

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

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.^[4] 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. Clorazepate is listed under Schedule IV of the Controlled Substances Act. Clorazepate was approved for use in the United States by the Food and Drug Administration in 1972.

Tolerance and dependence

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused 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 symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more short acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. 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.^[5]

Pregnancy

Chlorazepate if taken in early pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations, however the data is inconclusive. 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.^[6]

Interactions

All sedatives are likely to magnify the effects of Clorazepate on the central nervous system. Cimetidine, trade name Tagamet, inhibits breakdown of Clorazepate, and leads to increased levels of the drug in the system.  

References

1. ^ Braestrup C; Squires RF. (Apr 1978). "Pharmacological characterization of benzodiazepine receptors in the brain.". Eur J Pharmacol 48 (3): 263-70. PMID 639854.
2. ^ The Committee on the Review of Medicines (CRM) (29). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines.". Br Med J. 280 (6218): 910-2. PMID 7388368.
3. ^ Professor heather Ashton (April 2007). BENZODIAZEPINE EQUIVALENCY TABLE. Retrieved on Sept 23, 2007.
4. ^ Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08
5. ^ Committee on the Review of Medicines (29). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines." (pdf). Br Med J. 280 (6218): 910-2. PMID 7388368.
6. ^ McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation.". Reprod Toxicol. 8 (6): 461-75. PMID 7881198.