Clobazam

Clobazam is a benzodiazepine anticonvulsant medication marketed under the brand names Onfi and Frisium. It is approved by the U.S. Food and Drug Administration for adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome.

The drug is also used off-label for anxiety disorders in some regions. Clobazam works by binding to GABA_A receptors in the brain, enhancing the inhibitory effect of the neurotransmitter GABA and reducing neuronal excitability.

After absorption, clobazam is metabolized in the liver—primarily by the CYP2C19 enzyme—into an active metabolite (N-desmethylclobazam) that contributes to its anticonvulsant effects, before being eliminated by the kidneys.

The primary gene influencing clobazam response is CYP2C19, which encodes a liver enzyme responsible for converting clobazam into its active metabolite, N-desmethylclobazam. Drug metabolism refers to the chemical modifications a medication undergoes in the body, usually to facilitate its elimination.

Genetic variations in CYP2C19 can lead to different metabolizer phenotypes—such as poor or ultra-rapid metabolizers—which directly affect how quickly clobazam is processed and cleared. These differences can impact drug exposure, efficacy, and the risk of adverse effects.

Variations in the CYP2C19 gene classify patients into metabolizer groups that alter clobazam and metabolite exposure. Ultra-rapid and rapid metabolizers may clear the drug too quickly—potentially reducing efficacy—whereas intermediate and poor metabolizers experience slower clearance, increasing the risk of sedation and other adverse effects.

Ultrarapid/Rapid Metabolizer

• Effect: Faster clearance leading to lower drug and active metabolite levels
• Clinical consequence: Potential reduced seizure control due to subtherapeutic exposure
• Side effects: Generally fewer sedation-related effects; mild and infrequent

Normal Metabolizer

• Effect: Expected drug and metabolite levels within the therapeutic range
• Clinical consequence: Typical efficacy and tolerability
• Side effects: Mild sedation or dizziness; occurs occasionally

Intermediate Metabolizer

• Effect: Slower clearance leading to moderately elevated drug and metabolite levels
• Clinical consequence: Increased risk of sedation and adverse reactions
• Side effects: Moderate sedation and dizziness; more frequent than in normal metabolizers

Poor Metabolizer

• Effect: Significantly reduced clearance, resulting in high drug and metabolite accumulation
• Clinical consequence: Elevated risk of severe sedation, respiratory depression, and toxicity
• Side effects: Severe sedation and central nervous system depression; frequent

Indeterminate/Not Available

• Effect: Unknown impact on metabolism and drug levels
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
• Side effects: Unknown; monitor for standard benzodiazepine-related adverse events

CYP2C19 Dosing Guideline

The FDA pharmacogenetic guideline does not specify alternative treatments based on CYP2C19 genotype. Clinicians may consider other anticonvulsants with different metabolic pathways—such as valproate or levetiracetam—when dose adjustment of clobazam is not appropriate. These are examples only and not medical advice.

• FDA – Table of Pharmacogenetic Associations