Clobazam

Clobazam is a 1,5-benzodiazepine used as adjunct therapy for refractory epilepsy, particularly Lennox-Gastaut syndrome, and for intermittent use in seizure clusters. Tolerance develops over weeks to months, and it carries dependence, withdrawal and opioid co-prescribing risks.

Mechanism. Positive allosteric modulator of GABA-A receptors, with relative selectivity for the alpha-2 subunit.

Pharmacokinetics. Bioavailability near 100%. Half-life is 36 to 42 hours. The active metabolite N-desmethylclobazam has a half-life of 71 to 82 hours and accumulates. Cytochrome P450 3A4 and 2C19 are involved, and poor 2C19 metabolisers have much higher metabolite exposure.

Alternative and specialist use. Adjunct for Lennox-Gastaut syndrome, and for refractory focal and generalised seizures.

• Adults, oral clobazam: start 10 mg at night, increase by 5 to 10 mg each week to a usual 20 to 30 mg daily. Usual maximum 60 mg daily. Give doses over 10 mg in two divided doses.

• Children 2 years and over with Lennox-Gastaut: under 30 kg, 5 mg daily, increased to 10 mg then 20 mg daily; over 30 kg, 10 mg daily, increased to 20 mg then 40 mg daily, at weekly steps.

• Short-term anxiety (where licensed): 20 to 30 mg daily for up to 4 weeks, maximum 60 mg daily in severe cases.

• Intermittent use for seizure clusters is specialist-directed.

Emergency use. Clobazam is not used for status epilepticus.

Kidney, liver, weight and age.

• Kidney: no adjustment in mild to moderate impairment; severe impairment not studied.

• Liver: in mild to moderate impairment, start 5 mg daily and titrate to half the usual maximum. Avoid in severe impairment.

• CYP2C19 poor metabolisers: start 5 mg daily and titrate more slowly.

• Older adults: start 5 mg daily.

Contraindications. Myasthenia gravis, severe respiratory insufficiency, sleep apnoea, severe hepatic impairment and hypersensitivity. Avoid in people with current substance dependence.

Serious adverse effects. Respiratory depression and death with opioids (boxed-warning-level risk), tolerance, dependence, withdrawal seizures, abuse and misuse, Stevens-Johnson syndrome and toxic epidermal necrolysis (rare), suicidal ideation, and paradoxical aggression.

Common adverse effects. Drowsiness, hypersalivation, ataxia, irritability, aggression, fever, cough and constipation. Falls are frequent in older adults.

Interactions.

• Opioids, alcohol and other sedatives add respiratory depression.

• Cytochrome P450 2C19 inhibitors (omeprazole, fluconazole, fluvoxamine) raise N-desmethylclobazam. Enzyme inducers lower clobazam.

• It may lower hormonal contraceptive efficacy and raise levels of drugs cleared by cytochrome P450 2D6.

Common prescribing errors. Prescribing with opioids without warning. Abrupt withdrawal. Failing to anticipate tolerance.

Special groups.

• Pregnancy: neonatal sedation, hypotonia and withdrawal near term; use the lowest effective dose and inform neonatal staff.

• Breastfeeding: infant sedation; avoid regular use, or monitor closely.

• Children: hypersalivation and behavioural change are frequent.

Formulations. Tablets 10 mg (and 5 or 20 mg in some markets). Oral suspension in some markets. Take with or without food.

Monitoring. Sedation, respiratory status, mood and behaviour, falls and signs of misuse at each review. Reassess benefit if seizure control fades. Levels are not routine.

Stopping. Taper gradually, reducing by 5 to 10 mg each week. Abrupt withdrawal can precipitate status epilepticus.

Referral and escalation. Refer for tolerance, uncontrolled seizures, planned pregnancy or suspected dependence. Respiratory depression needs airway support and reversal of any opioid.