Introduction
Onfi (clobazam) is a benzodiazepine derivative medication approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older. Classified as a Schedule IV controlled substance, it offers a distinct pharmacological profile compared to other benzodiazepines due to its preferential affinity for benzodiazepine type 1 receptors.
Mechanism of Action
Clobazam exerts its therapeutic effects through potentiation of gamma-aminobutyric acid (GABA)-ergic neurotransmission. It binds to the benzodiazepine site on GABA-A receptors, enhancing the inhibitory effects of GABA by increasing chloride ion channel opening frequency. This results in neuronal hyperpolarization and reduced neuronal excitability. Notably, clobazam demonstrates preferential binding to α2-containing GABA-A receptors over α1-containing receptors, which may contribute to its relatively favorable side effect profile compared to other benzodiazepines.
Indications
- Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older
- Off-label uses may include treatment of other refractory epilepsy syndromes, anxiety disorders, and acute seizure management (though not FDA-approved for these indications)
Dosage and Administration
Initial dosing:- Patients ≤30 kg: 5 mg daily
- Patients >30 kg: 10 mg daily
- May increase dosage every week based on tolerability and efficacy
- Maximum recommended dosage:
- Patients ≤30 kg: 20 mg daily - Patients >30 kg: 40 mg daily
Administration:- Administer once daily or divided twice daily
- Tablets may be swallowed whole or crushed and mixed with applesauce
- Oral suspension should be shaken well before use
- Dose reduction should be gradual when discontinuing (taper by 5-10 mg weekly)
- Geriatric: Use lower doses due to increased sensitivity
- Renal impairment: Caution advised in severe impairment
- Hepatic impairment: Reduce dose in moderate to severe impairment (Child-Pugh B or C)
Pharmacokinetics
Absorption: Well absorbed orally with bioavailability >90%. Tmax approximately 1-4 hours. Food does not significantly affect absorption. Distribution: Volume of distribution approximately 100 L. Protein binding 80-90%. Active metabolite N-desmethylclobazam has similar volume of distribution. Metabolism: Extensive hepatic metabolism primarily via CYP3A4 and to a lesser extent CYP2C19 and CYP2B6. N-demethylation to active metabolite N-desmethylclobazam (norclobazam), which is subsequently hydroxylated and conjugated. Elimination: Primarily renal excretion (82% in urine, 11% in feces). Terminal elimination half-life: clobazam 36-42 hours; N-desmethylclobazam 71-82 hours. CYP2C19 poor metabolizers have increased exposure to N-desmethylclobazam.Contraindications
- Hypersensitivity to clobazam or other benzodiazepines
- Acute narrow-angle glaucoma (can be used in open-angle glaucoma patients receiving appropriate therapy)
Warnings and Precautions
Boxed Warning:- Risks of concomitant use with opioids: Profound sedation, respiratory depression, coma, and death
- Sedation and fatigue: May impair mental and physical abilities
- Respiratory depression: Use with caution in patients with pulmonary disease
- Physical dependence and withdrawal: Abrupt discontinuation may cause withdrawal symptoms
- Suicidal behavior and ideation: Antiepileptic drugs may increase risk
- Depression and mood changes: Monitor for emergence or worsening
- Pregnancy: May cause fetal harm (Pregnancy Category C)
- Glaucoma: Use with caution in patients with glaucoma
Drug Interactions
Major interactions:- CNS depressants: Opioids, alcohol, other benzodiazepines, sedatives (additive CNS depression)
- CYP2C19 inhibitors: Strong inhibitors (e.g., fluconazole, fluvoxamine) may increase N-desmethylclobazam levels
- CYP3A4 inducers: Carbamazepine, phenytoin, rifampin may decrease clobazam levels
- Hormonal contraceptives: May reduce efficacy of oral contraceptives
- Valproic acid: May increase levels of N-desmethylclobazam
- CYP2C19 substrates: Clobazam may affect drugs metabolized by this pathway
Adverse Effects
Most common (>10%):- Somnolence
- Sedation
- Pyrexia
- Lethargy
- Drooling
- Aggression
- Insomnia
- Irritability
- Ataxia
- Fatigue
- Respiratory depression
- Suicidal ideation and behavior
- Severe dermatological reactions (including Stevens-Johnson syndrome)
- Physical dependence and withdrawal syndrome
- Paradoxical reactions (agitation, aggression)
- Hematological abnormalities
Monitoring Parameters
- Seizure frequency and characteristics
- Sedation and cognitive function
- Respiratory function, especially in patients with pulmonary compromise
- Mood changes, depression, and suicidal ideation
- Signs of physical dependence or withdrawal
- Complete blood count and liver function tests periodically
- Growth parameters in pediatric patients
- Therapeutic drug monitoring in special populations (consider target range 0.03-0.30 mg/L for clobazam + metabolite)
Patient Education
- Take medication exactly as prescribed; do not adjust dose without medical supervision
- Avoid alcohol and other CNS depressants
- Do not abruptly stop medication due to risk of withdrawal seizures
- May cause drowsiness; avoid driving or operating machinery until effects are known
- Use effective contraception during treatment
- Report any thoughts of self-harm or worsening mood
- Keep all appointments for monitoring
- Store securely away from children and others
- Inform all healthcare providers about Onfi use before procedures or new prescriptions
References
1. FDA Prescribing Information: Onfi (clobazam). 2021 2. Ng YT, Collins SD. Clobazam. Neurotherapeutics. 2007;4(1):138-144 3. Conry JA, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia. 2009;50(5):1158-1166 4. Gaston TE, Szaflarski JP. Clobazam: A newly approved but well-established anticonvulsant. Epilepsy Curr. 2012;12(3):105-107 5. Epilepsy Foundation. Lennox-Gastaut Syndrome Treatment Options. 2022 6. Micromedex Solutions. Clobazam Drug Monograph. 2023 7. Clinical Pharmacology [database online]. Clobazam. 2023