CLOBAZAM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CLOBAZAM (CLOBAZAM).
Clobazam is a benzodiazepine that enhances the effect of GABA at the GABA-A receptor, increasing chloride ion conductance and neuronal hyperpolarization. It has a high affinity for the α2 subunit, which may contribute to its anticonvulsant effects.
| Metabolism | Primarily via CYP3A4 and to a lesser extent CYP2C19 and CYP2B6. The active metabolite N-desmethylclobazam (norclobazam) is mainly metabolized by CYP2C19. |
| Excretion | Renal: ~82% as metabolites (mainly N-desmethylclobazam and hydroxylated metabolites), unchanged clobazam <1%; fecal: ~11%. |
| Half-life | Clobazam: 36–42 hours; N-desmethylclobazam: 71–82 hours. Steady state achieved in 5–10 days. |
| Protein binding | ~85% bound to serum proteins, primarily albumin. |
| Volume of Distribution | 0.9–1.8 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: ~87% (nearly complete). |
| Onset of Action | Oral: 30–60 minutes (peak effect at 1–4 hours). |
| Duration of Action | Anticonvulsant effect: 12–24 hours (due to active metabolite, longer with chronic dosing). |
10-60 mg orally once daily, divided into two doses. Typical starting dose: 10 mg twice daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended; however, monitor for prolonged sedation in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Mild to moderate impairment (Child-Pugh A or B): start at 5 mg once daily and titrate cautiously. Severe impairment (Child-Pugh C): not recommended. |
| Pediatric use | For seizures: 0.5-1 mg/kg/day orally divided into two doses, not to exceed 60 mg/day. For anxiety in adolescents: 5-10 mg once daily, titrate as needed. |
| Geriatric use | Initial dose: 5 mg once daily; may increase slowly to 10-20 mg daily. Reduce dose by half due to increased sensitivity and risk of falls. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CLOBAZAM (CLOBAZAM).
| Breastfeeding | Clobazam and its active metabolite N-desmethylclobazam are excreted in breast milk. Milk-to-plasma ratio (M/P) approximately 0.3. Monitor infant for sedation, poor feeding, and weight gain. Use caution, especially with prolonged exposure. |
| Teratogenic Risk | First trimester: Increased risk of oral clefts (odds ratio ~2.0). Second/third trimester: Risk of fetal benzodiazepine syndrome (hypotonia, respiratory depression, withdrawal) and neonatal sedation. Avoid unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate.
| Serious Effects |
Hypersensitivity to clobazam or any benzodiazepine; severe hepatic impairment; acute narrow-angle glaucoma; concurrent use with opioids (unless no alternatives); and myasthenia gravis.
| Precautions | Respiratory depression; sedation/somnolence (risk increases with dose); tolerance, physical dependence, and withdrawal reactions; risk of abuse and misuse; suicidal behavior and ideation; serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis); worsening of seizure control; use in renal/hepatic impairment; and interaction with CYP2C19 inhibitors (e.g., fluconazole, omeprazole). |
| Food/Dietary | No significant food interactions. Avoid grapefruit products as they may alter clobazam metabolism via CYP3A4 inhibition. Avoid alcohol. |
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| Maternal: Assess sedation, respiratory rate, liver function, CBC. Fetal/Neonatal: Ultrasound for structural anomalies if first-trimester exposure; monitor newborn for withdrawal (irritability, hypertonia, seizures) and respiratory depression. Consider therapeutic drug monitoring. |
| Fertility Effects | Limited data. No evidence of direct impairment of fertility. However, hormonal contraceptive efficacy may be reduced due to CYP3A4 induction; advise non-hormonal contraception. |
| Clinical Pearls | Clobazam is a 1,5-benzodiazepine with less sedation and tolerance than classic 1,4-benzodiazepines. It is FDA-approved for Lennox-Gastaut syndrome (≥2 years) and used off-label for anxiety, seizures, and catamenial epilepsy. Its active metabolite N-desmethylclobazam has a half-life of 36-46 hours, leading to accumulation. Monitor for CYP2C19 poor metabolizers, in whom metabolite levels are higher. Withdrawal should be gradual to avoid rebound seizures. Avoid abrupt discontinuation. |
| Patient Advice | Take clobazam exactly as prescribed; do not stop suddenly as this can cause withdrawal seizures. · Avoid alcohol and other CNS depressants due to additive sedation. · This drug may cause drowsiness, dizziness, or blurred vision; do not drive or operate heavy machinery until you know how it affects you. · Inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. · Report any new or worsening seizures, suicidal thoughts, or unusual mood changes immediately. · Store at room temperature away from moisture and heat. · Do not share this medication with others. |