Clobazam

Authorised indications

UK-SmPC: adjunctive therapy in epilepsy

FDA-PI: not licensed.

Clinical applications

Clobazam is a very useful AED, both as polytherapy and monotherapy(1-9). It is neglected in current clinical practice, mainly because it is erroneously considered to (1) induce high dependence/tolerance and (2) be of similar effectiveness regarding seizure type to clonazepam.

The main clinical applications of clobazam are:

• Adjunctive medication in all forms of drug-resistant epilepsy in adults and children. It is particularly effective in focal rather than generalised seizures. Clobazam was found to have equivalent efficacy to carbamazepine and phenytoin monotherapy in childhood epilepsies(1,10)
  
• Intermittent administration 5 days prior and during the menses in catamenial epilepsy (11) is the most popular textbook recommendation.

The CYP2C19 genotype had an impact on the metabolism, efficacy and ADRs of clobazam (11,12)

Dosage and titration

Adults and children over 12 years: start treatment with 5–10 mg/day at night and increase at weekly intervals in increments of 5 mg/day up to a total of 40 mg/day. In my experience 10 mg taken before sleep is often therapeutic in focal seizures. I do not use a dose of more than 20 mg in children.

Children under 12 years: start with 0.1–0.2 mg/kg/day and slowly increase at weekly intervals in increments of 0.1 mg/kg/day up to a total of 0.8 mg/kg/day.

Dosing: once or twice daily; a smaller dose in the day time and a larger dose prior to sleep.

TDM: not useful except when unusual ADRs appear (12)

Reference range: norclobazam (active metabolite) 60–200 μg/l (200–670 nmol/l).

Main ADRs

As for all benzodiazepines but much milder than with most. Somnolence may be partly prevented by administering the drug in small doses 1 hour prior to going to sleep. The cognitive and behavioural effects of clobazam appear to be similar to those of standard monotherapy with carbamazepine or phenytoin (1)

Severe aggressive outbursts, hyperactivity, insomnia and depression with suicidal ideation may occur, particularly in children.

Tolerance may develop, but this aspect has been largely overemphasised, as documented in many studies (13,14,15). More than a third of patients do not develop tolerance. When clobazam is effective, most patients continue to benefit for years without drug dependence or unwanted ADRs.

Main mechanism of action

GABA_A-receptor agonist

Pharmacokinetics

Oral bioavailability: 90%. Protein binding: 85%. Metabolism: hepatic oxidation and then conjugation. N-desmethyl clobazam (norclobazam) is its principal and active metabolite. Elimination half-life: 20 hours, but this is about 50 hours of its principal metabolite, norclobazam.

Drug interactions

Minor and not clinically significant. Potentiates the effect of CNS depressants such as alcohol, barbiturates and neuroleptics.

Main disadvantages

Sedation and development of tolerance (though the latter may have been exaggerated).

Useful clinical notes

Clobazam should be tried as adjunctive medication in all drug-resistant epilepsies at a dose of 10–30 mg nocte (half this dose in children >5 years old). It is more effective in focal than generalised epilepsies and can also be used as monotherapy. Probably only one out of ten patients will have a clinically significant improvement, but this may be very dramatic and render the patient seizure-free.

Unlike clonazepam, clobazam is much less effective in myoclonic jerks and absences.

Avoid overmedication. Small doses 10–20 mg given 1 hour prior to going to sleep may be therapeutic and well tolerated.

Withdrawal should be very slow, occurring over months. Rapid discontinuation may lead to withdrawal symptoms, siezures and status epilepticus.

References

1. Bawden HN, Camfield CS, Camfield PR, Cunningham C, Darwish H,Dooley JM, et al. The cognitive and behavioural effects of clobazamand standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy. Epilepsy Res 1999;33:133–43.
2. Mehndiratta MM, Krishnamurthy M, Rajesh KN, Singh G. Clobazam monotherapy in drug naive adult patients with epilepsy. Seizure 2003;12:226–8.
3. Montenegro MA, Ferreira CM, Cendes F, Li LM, Guerreiro CA. Clobazam as add-on therapy for temporal lobe epilepsy and hippocampal sclerosis. Can J Neurol Sci 2005;32:93–6.
4. Ng YT, Collins SD. Clobazam. Neurother 2007;4:138–44.
5. Silva RC, Montenegro MA, Guerreiro CA, Guerreiro MM. Clobazam as add-on therapy in children with epileptic encephalopathy. Can J Neurol Sci 2006;33:209–13.
6. Sugai K. Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan. Epilepsia 2004;45 Suppl 8:20–5.
7. Conry JA, Ng YT, Paolicchi JM et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009;50:1158-66.
8. Montenegro MA, Arif H, Nahm EA, Resor SR, Jr., Hirsch LJ. Efficacy of clobazam as add-on therapy for refractory epilepsy: experience at a US epilepsy center. Clin Neuropharmacol 2008;31:333-8.
9. Seo T, Nagata R, Ishitsu T et al. Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy. Pharmacogenomics 2008;9:527-37.
10. Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Canadian Study Group for Childhood Epilepsy. Epilepsia 1998;39:952–9.
11. Feely M, Gibson J. Intermittent clobazam for catamenial epilepsy: tolerance avoided. J Neurol Neurosurg Psychiatry 1984;47:1279–82.
12. Parmeggiani A, Posar A, Sangiorgi S, Giovanardi-Rossi P. Unusual side effects due to clobazam: a case report with genetic study of CYP2C19. Brain Dev 2004;26:63–6.
13. Barcs G, Halasz P. Effectiveness and tolerance of clobazam in temporal lobe epilepsy. Acta Neurol Scand 1996;93:88–93.
14. Uhlmann C, Froscher W. Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study. CNS Neurosci Ther 2009;15:24-31.
15. Remy C. Clobazam in the treatment of epilepsy: a review of the literature. Epilepsia 1994;35 Suppl 5:S88–91.