Clorazepate Handout Clorazepate is a benzodiazepine derivative, similar to diazepam (Valium). In fact, one of the principal metabolites of valium is nordiazepam, the active ingredient of clorazepate. In the acidic environment of the stomach, clorazepate is metabolized to nordiazepam, the form of the drug that is absorbed. Nordiazepam is the metabolite that is measured by therapeutic drug monitoring. It has about 30% of the anticonvulsant efficacy of diazepam. Although less effective, dogs do not seem to develop the tolerance to nordiazepam that they can with diazepam. This may be particularly true if used in combination with phenobarbital. The therapeutic range of clorazepate in dogs has not been well established, and is based on extrapolations from humans. The recommended range of 600 to 1500 ng/ml is for patients not receiving phenobarbital concurrently. Drug levels in our patients, who were receiving phenobarbital as well, ranged from 100 to 400 ng/ml. The mechanism of action of all benzodiazepines is thought to be potentiation of gabaminergic receptors (note that gamma amino butyric acid is one of the most important inhibitory neurotransmitters in the central nervous system). The benzodiazepines are eliminated by hepatic metabolism. Their elimination is relatively rapid, thus drug half-lives tend to be no more than several hours. Therefore, unlike phenobarbital and potassium bromide, it is important that a pet not miss a dose. If a dose is missed, it should be administered as close to the recommended dosing interval as possible. Note that doubling the dose (after missing a dose) may result in more grogginess than usual. Also note, that if a patient is seizuring, or appears to be seizuring, a single dose of clorazepate may help offset the seizures. This is not true for phenobarbital unless several (4 to 5 or more) doses are administered. Clorazepate appears to be safe. Adverse effects are "non-lethal" but undesirable. The most notable is sedation or grogginess and a change in appetite (remember, valium is a potent stimulant of the appetite in anorexic cats). These behaviors tend to resolve with time, but may not. In some animals, they have become so severe that the drug must be discontinued. Because of its short half-life, you can expect that close to 100% of the drug will be eliminated within 24 hours of administration. Although no drug interactions between phenobarbital and clorazepate have been reported, we have noticed that phenobarbital concentrations dramatically increase (sometimes double) to potentially toxic concentrations one to two months into therapy. This increase is most often noted symptomatically as severe grogginess. Animals on the study for 6 months or longer should be beyond that stage. However, because of this potential interaction, patients should be monitored a minimum of monthly (both peak and trough levels) for 3 months for the first year and every 6 months thereafter when on clorazepate. Because of the short half-life of clorazepate, both peak and trough samples are recommended: peak at 5 hours and trough at 12 hours. Again, because of the short half-life, monitoring for clorazepate can begin two days after administration. We suggest waiting about a week, however, just to make sure that concentrations have reached their maximum. We also recommend collecting samples for both phenobarbital and clorazepate monthly for the first 3 months, until we feel more comfortable about the drug interactions between phenobarbital and clorazepate. Also note that if grogginess persists, but seizures are likely to occur if the dose is decreased in an attempt to alleviate grogginess, an 8 hour rather than 12 hour dosing interval may help (same total daily dose, but divided and given tid rather than bid). If an exact 8 hour interval can not be maintained, an interval as close to that as possible should be attempted. Tranxene is the current human clorazepate preparation sold by Abbott. However, it is more expensive than the generic preparation. The bioavailability of the generic preparations is the same as the trade product, hence we recommend one of these cheaper sources. However, note that the largest tablet size that we could find was 15 mg, which is inconveniently small if you are administering the drug to large dogs. The current dose we used for our study was 2 mg/kg; however, we now decrease phenobarbital by 25% and/or start patients at 1 mg/kg because of the likelihood that phenobarbital concentrations will increase as clorazepate is added. Note that the dose of clorazepate may need to be increased with time because its elimination appears to increase with time and concentrations may become non-therapeutic. Monitoring of both clorazepate and phenobarbital is indicated when using clorazepate in conjunction with phenobarbital for control of seizures. Clients whose pets are receiving this drug for the first time should be warned that their pet is apt to become groggy and its appetite will increase. We encourage them to be patient; most of these signs hopefully will resolve. Some recommended sources for clorazepate: Goldline Labs PO Box 96884 Chicago, IL 60693 Phone 800-452-2378 Henry Schein, Inc 5 Harbor Park Dr. Post Washington, NY 11050 Phone 800-872-4346 [back to top]