What is clobazam?

Clobazam: A 1,5-Benzodiazepine Anticonvulsant Medication

Clobazam is a 1,5-benzodiazepine primarily FDA-approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older, though it is used worldwide for various types of epilepsy and sometimes for anxiety disorders. 1

Pharmacology and Mechanism of Action

Clobazam differs structurally from classic 1,4-benzodiazepines (like diazepam, lorazepam, and clonazepam) as it is a 1,5-benzodiazepine. This structural difference contributes to its unique properties:

• Works by allosterically activating GABA-A receptors, enhancing inhibitory neurotransmission in the CNS 2
• Binds less to GABA-A receptor subunits that mediate sedative effects compared to other benzodiazepines 2
• Has a half-life of approximately 37.5 hours 2
• Metabolized in the liver via cytochrome P450 pathway to its active metabolite, N-desmethylclobazam 2
• The active metabolite has a longer half-life (67.5 hours) and reaches concentrations approximately 8 times higher than the parent drug 3

Clinical Uses

Clobazam is primarily used for:

1. FDA-approved indication: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years or older 1

2. Off-label uses:

   • Treatment of various refractory epilepsies 4
   • Anxiety disorders (in some countries) 5

Dosage and Administration

• Initial dosing typically starts at 5-10 mg daily, with gradual titration based on response and tolerability 4
• For insomnia, when used off-label, the recommended initial dose is 0.25 mg before bedtime, with effective usual doses ranging from 0.25-1.0 mg per night 6
• Maximum doses generally range up to 40 mg daily, depending on patient weight, efficacy, and tolerability 4
• Can be taken with or without food 1

Safety Profile and Side Effects

Common side effects include:

• Drowsiness/sedation (though reportedly less than with 1,4-benzodiazepines) 2
• Dizziness 2
• Ataxia 2

Serious risks include:

• Physical dependence and withdrawal symptoms if stopped abruptly 1
• Respiratory depression, especially when combined with other CNS depressants 1
• Potential for abuse (Schedule IV controlled substance) 1
• Serious skin reactions (rare but can occur, especially within first 8 weeks) 1
• Risk of suicidal thoughts or actions (as with other antiepileptic medications) 1

Important Warnings and Precautions

• Never stop clobazam suddenly as this can cause serious withdrawal symptoms including seizures, mental changes, depression, hallucinations, and suicidal thoughts 1
• Avoid alcohol and other CNS depressants while taking clobazam 1
• Use caution when driving or operating machinery due to potential sedative effects 1
• Monitor for signs of skin reactions, especially during the first 8 weeks of treatment 1
• Use with caution in patients with liver or kidney problems, respiratory disease, or history of depression 1
• May reduce the effectiveness of hormonal contraceptives 1

Unique Properties Compared to Other Benzodiazepines

• Less sedative effects than classic 1,4-benzodiazepines 2
• May have less impact on cognitive function 2
• Longer duration of action due to its active metabolite 3
• Approximately 20 times more potent than diazepam on a milligram-per-milligram basis 6

Clobazam represents an important therapeutic option for patients with epilepsy, particularly those with Lennox-Gastaut syndrome, offering efficacy with potentially fewer sedative effects than other benzodiazepines.