Introduction
Clobazam is a benzodiazepine medication approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older. It is classified as a Schedule IV controlled substance due to its potential for abuse and dependence. Unlike traditional benzodiazepines that primarily act on α1-containing GABAA receptors, clobazam demonstrates preferential binding to α2-containing receptors, which may contribute to its distinct clinical profile with potentially less sedative effects at therapeutic doses.
Mechanism of Action
Clobazam exerts its anticonvulsant effects through positive allosteric modulation of the GABAA receptor complex. It enhances GABA-mediated inhibitory neurotransmission by increasing the frequency of chloride channel opening events, resulting in neuronal hyperpolarization and reduced neuronal excitability. Clobazam demonstrates preferential binding affinity for GABAA receptors containing α2 subunits over those containing α1 subunits, which may explain its relatively favorable side effect profile compared to other benzodiazepines.
Indications
- Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older
- Off-label uses may include treatment of anxiety disorders, acute agitation, and other refractory epilepsy syndromes (based on clinical judgment)
Dosage and Administration
Initial dosing:- Patients ≤30 kg: 5 mg daily
- Patients >30 kg: 10 mg daily
- Patients ≤30 kg: 20 mg
- Patients >30 kg: 40 mg
- Geriatric patients: Use lower initial doses and titrate slowly
- Hepatic impairment: Reduce dose by 50% in moderate to severe impairment
- Renal impairment: Use caution and consider dose reduction
- CYP2C19 poor metabolizers: Reduce starting dose by 50%
Pharmacokinetics
Absorption: Well absorbed orally with bioavailability >90%. Tmax approximately 1-4 hours. Distribution: Volume of distribution ~100 L. Protein binding ~80-90%. Metabolism: Extensive hepatic metabolism primarily via CYP3A4 and CYP2C19 to active metabolite N-desmethylclobazam (norclobazam). Norclobazam has approximately 1/5 the potency of parent drug but longer half-life. Elimination: Terminal half-life of clobazam ~36-42 hours; norclobazam ~71-82 hours. Excreted primarily in urine (82%) and feces (11%).Contraindications
- Hypersensitivity to clobazam or other benzodiazepines
- Acute narrow-angle glaucoma
- Significant respiratory depression
- Severe hepatic impairment
- Concurrent use with strong CYP2C19 inhibitors in patients known to be CYP2C19 poor metabolizers
Warnings and Precautions
Boxed Warning: Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients with inadequate treatment options and limit dosages and durations to minimum required. Additional warnings:- Abuse, misuse, and addiction potential
- Dependence and withdrawal symptoms upon discontinuation
- Somnolence and sedation (dose-related)
- Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
- Suicidal behavior and ideation
- Withdrawal seizures in patients with epilepsy
Drug Interactions
Major interactions:- Opioids: Increased CNS depression
- Alcohol: Additive CNS depression
- Strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine): Increased clobazam exposure
- Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin): Decreased clobazam exposure
- Other CNS depressants: Additive effects
- Hormonal contraceptives: Potential reduced efficacy
- Valproic acid: Possible increased norclobazam levels
Adverse Effects
Common (≥10%):- Somnolence (25-32%)
- Sedation (15-25%)
- Pyrexia (13-17%)
- Lethargy (10-15%)
- Drooling (9-14%)
- Aggression (7-12%)
- Insomnia (5-11%)
- Irritability (5-11%)
- Constipation (5-10%)
- Respiratory depression
- Suicidal ideation and behavior
- Severe dermatologic reactions
- Withdrawal symptoms
- Paradoxical reactions (agitation, aggression)
- Impairment in cognitive and motor performance
Monitoring Parameters
- Seizure frequency and characteristics
- Sedation and somnolence
- Respiratory function, especially with concomitant opioid use
- Signs of abuse, misuse, or addiction
- Mood changes and suicidal ideation
- Liver function tests (baseline and periodically)
- Complete blood count (periodically)
- Withdrawal symptoms during dose reduction or discontinuation
- Therapeutic drug monitoring (clobazam and norclobazam levels) in special populations
Patient Education
- Take medication exactly as prescribed; do not adjust dose without medical supervision
- Avoid alcohol and other CNS depressants
- Do not abruptly discontinue medication due to risk of withdrawal seizures
- May cause drowsiness or dizziness; avoid driving or operating machinery until effects are known
- Use effective contraception; discuss with provider if planning pregnancy
- Report any signs of skin rash, mood changes, or suicidal thoughts immediately
- Keep medication securely stored to prevent misuse by others
- Regular follow-up with healthcare provider is essential
References
1. FDA prescribing information: Onfi® (clobazam) tablets and oral suspension 2. Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77(15):1473-1481. 3. Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of refractory epilepsy: experience in 500 patients from a single center. Epilepsy Behav. 2009;15(2):207-211. 4. Gaston TE, Szaflarski JP. Clobazam for treatment of epilepsy. Expert Opin Pharmacother. 2018;19(16):1859-1867. 5. Epilepsy Foundation treatment guidelines for Lennox-Gastaut syndrome 6. American Epilepsy Society clinical practice guidelines 7. Micromedex® Drug Information 8. Lexicomp® Online Drug Information
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines.