Clobazam is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970 and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.
Medical uses
Clobazam is used for epilepsy. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. As of 2005, clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for treatment of anxiety. In India, clobazam is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam is approved for short-term relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the US until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age or older. It is also approved for adjunctive therapy for epilepsy in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is also approved as a short-term adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation. Clobazam is also available as an oral suspension in the UK, under the trade name of Tapclob. Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to tolerance which may render long-term therapy less effective. Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.
Contraindications
Clobazam should be used with great care in patients with the following disorders:
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbidpsychiatric disorders.
Side effects
Common
Common side effects include fever, lethargy, sleepiness, drooling, and constipation.
Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
Classic benzodiazepines in animal studies have been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.
Dependence and withdrawal
In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or overrapid withdrawal. Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.
Pharmacology
Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels. Like other 1,5-benzodiazepines, the active metaboliteN-desmethyl-clobazam has less affinity for the α1subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity. In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam. The α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam. In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam, work by enhancing GABA-activated chloride currents at GABAA-receptor-coupled Cl− channels. It was also reported that these effects were inhibited by the GABA antagonistflumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.
Metabolism
Clobazam has two major metabolites: N-desmethyl-clobazam and 4-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.
Chemistry
Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions. It is not soluble in water and is available in oral form only.
History
Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of Sanofi.
