Clobazam

MECHANISM OF ACTION

Clobazam works by enhancing the activity of the inhibitory neurotransmitter GABA in the brain. It binds to GABA(A) receptors as a positive allosteric modulator, increasing chloride ion influx into neurons. This leads to neuronal hyperpolarization, decreased excitability, and ultimately anticonvulsant and anxiolytic effects. As a 1,5-benzodiazepine, clobazam has a distinct chemical structure that allows it to act as a partial agonist and preferentially influence certain GABA(A) receptor subunits, such as α2. This selective action is thought to provide therapeutic benefits with a lower likelihood of sedation compared with typical benzodiazepines. Both clobazam and its active metabolite, N-desmethylclobazam (norclobazam), contribute to its clinical effects.

PHARMACOKINETICS

Absorption

Clobazam is quickly and efficiently absorbed after oral administration, achieving peak plasma concentrations within about 0.5 to 4 hours (Tmax) and demonstrating high oral bioavailability of approximately 87%.

Distribution

Clobazam exhibits a large volume of distribution, generally reported to be about 99–120 liters, or approximately 0.87–1.83 L/kg, indicating extensive distribution into body tissues.

Metabolism

Clobazam is primarily metabolized in the liver through the action of cytochrome P450 enzymes. It is converted to its active metabolite, N-desmethylclobazam (norclobazam), primarily through N-demethylation mediated by CYP3A4 and hydroxylation involving CYP2C19 and CYP2C18. Norclobazam plays a major role in the drug’s antiseizure activity and, during long-term treatment, reaches much higher plasma concentrations than the parent compound. This metabolic process is affected by genetic differences in CYP2C19 individuals who are poor metabolizers tend to have elevated norclobazam levels as well as by drug-drug interactions, making careful dose adjustment important.

Excretion

Clobazam is eliminated mainly through the urine and, to a lesser extent, the feces following extensive hepatic metabolism, predominantly to its active metabolite norclobazam (N-CLB). About 82% of clobazam is excreted in the urine and roughly 11% in the feces, with only around 3% of the original drug eliminated unchanged.

PHARMACODYNAMICS

Clobazam is a 1,5-benzodiazepine that functions as a positive allosteric modulator of the GABA{A}receptor. Its pharmacodynamic profile is characterized by high anticonvulsant and anxiolytic efficacy with a reduced sedative profile compared to traditional 1,4-benzodiazepines like diazepam. 

DOSAGE AND ADMINISTRATION

• Administered orally (tablet, suspension, oral film)

• Can be taken with or without food

Starting dose:

• ≥30 kg: 10 mg/day.

• <30 kg: 5 mg/day.

Maximum dose:

• ≥30 kg: 40 mg/day

• <30 kg: 20 mg/day

• Dose should be divided twice daily

DRUG INTERACTIONS

Clobazam is associated with important drug interactions that can markedly increase the risk of serious adverse effects, including extreme sedation, respiratory depression, coma, and death, especially when combined with opioids, alcohol, sedative-hypnotics, anti-anxiety medications, and certain antidepressants. Such combinations should be avoided whenever possible or used only under careful medical supervision. It also interacts with some antifungal agents, select antibiotics, and other antiepileptic drugs-for example, valproate may increase clobazam or norclobazam concentrations. Additionally, clobazam can reduce the effectiveness of hormonal contraceptives, and its levels may be increased or decreased by CYP3A4 inhibitors or inducers. Patients should always inform their healthcare provider about all medications, supplements, and alcohol use, as dose adjustments and close monitoring are often necessary.

FOOD INTERACTIONS

Clobazam has minimal specific food restrictions, but certain considerations are important: avoid alcohol, as it can increase drowsiness and dizziness; limit grapefruit, which may elevate drug levels; and note that high-fat meals can slow absorption. A notable interaction occurs with the ketogenic diet, which can significantly reduce clobazam levels and may require dose adjustments. In general, most foods do not affect absorption, but patients should consult their doctor before making any dietary changes or adding supplements.

CONTRAINDICATIONS

Clobazam is contraindicated in individuals with hypersensitivity to benzodiazepines, a history of drug or alcohol dependence, severe respiratory conditions such as sleep apnea or respiratory insufficiency, severe liver disease, and during the first trimester of pregnancy due to the risk of fetal harm. It can also exacerbate muscle weakness in conditions like myasthenia gravis. Combining clobazam with opioids, alcohol, or other central nervous system depressants should be strictly avoided, as this can lead to profound sedation and dangerous respiratory depression.

SIDE EFFECTS

• Drowsiness, sleepiness, tiredness.

• Dizziness, poor coordination, unsteady walk.

• Irritability, aggression, restlessness.

• Fatigue.

• Headache.

• Nausea, constipation, dry mouth, decreased appetite.

• Difficulty concentrating, memory problems.

• Speech problems.

OVERDOSE

• Extreme drowsiness, weakness, lethargy, dullness.

• Confusion, impaired mental function, disorientation, memory problems.

• Slurred speech, trouble speaking, difficulty forming words.

• Unsteadiness, poor muscle control, or difficulty walking.

• Slow or shallow breathing.

• Dizziness, lightheadedness, fainting.

• Bluish tint to lips or nails (cyanosis).

• Coma or loss of consciousness. 

TOXICITY

Clobazam toxicity primarily causes central nervous system depression, with overdose symptoms including marked drowsiness, confusion, impaired coordination, slow or shallow breathing, and loss of consciousness, which can progress to respiratory failure. It may also rarely trigger severe skin reactions, such as DRESS syndrome, and poses potential developmental risks during pregnancy. Any signs of overdose or hypersensitivity require immediate medical attention.