ONFI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ONFI (ONFI).
GABA-A receptor positive allosteric modulator; increases the frequency of chloride channel opening in response to GABA.
| Metabolism | Hepatic via CYP3A4 and CYP2C19; primary metabolite N-desmethylclobazam is active. |
| Excretion | Clobazam (ONFI) undergoes extensive hepatic metabolism. Approximately 82% of the dose is eliminated in urine (as unchanged drug and metabolites) and about 11% in feces. Unchanged clobazam accounts for <1% of urinary excretion. The major metabolite, N-desmethylclobazam, is excreted primarily renally. |
| Half-life | The terminal elimination half-life of clobazam is 36–42 hours. The active metabolite N-desmethylclobazam has a half-life of 71–82 hours. The long half-life permits once-daily dosing but also leads to slow accumulation; steady-state is achieved after 2–3 weeks. |
| Protein binding | Clobazam is approximately 80–90% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The apparent volume of distribution is approximately 100 L (range 77–120 L), or roughly 1.4 L/kg. This large Vd indicates extensive tissue distribution and accumulation in fatty tissues. |
| Bioavailability | Oral bioavailability is nearly complete (>90%). Clobazam is well absorbed after oral administration with only minor first-pass metabolism. |
| Onset of Action | Oral: Time to peak plasma concentration is 0.5–4 hours. Clinical effects (anxiolytic, anticonvulsant) may be noted within 30–60 minutes, but maximal effect for seizure control may take several days to weeks due to accumulation. |
| Duration of Action | The duration of anticonvulsant effect is prolonged due to the long half-life and active metabolite. Once-daily dosing provides sustained effect over 24 hours. Some patients experience residual sedation lasting up to 12–24 hours, especially early in therapy. |
| Molecular Weight | 300.74 |
Initial: 10 mg orally twice daily; may increase by 10 mg/day after 1 week to maintenance of 20–40 mg/day in two divided doses. Maximum: 60 mg/day.
| Dosage form | TABLET |
| Renal impairment | No specific GFR-based dose adjustments; use with caution in severe impairment (CrCl < 30 mL/min) due to potential for increased sedation. |
| Liver impairment | Mild to moderate (Child-Pugh A/B): Initial 5 mg orally twice daily; may increase by 5 mg/day after 1 week to maximum 20 mg/day. Severe (Child-Pugh C): Not recommended. |
| Pediatric use | Clobazam (ONFI) for seizures: Age 2 to <6 years, body weight ≥12.5 kg: Initial 5 mg orally once daily; titrate to maintenance 5 mg twice daily. Age ≥6 years: Weight ≤30 kg: Initial 5 mg once daily; titrate to 5 mg twice daily (max 20 mg/day). Weight >30 kg: same as adult dosing. Administer with food. |
| Geriatric use | Elderly (≥65 years): Initial 5 mg orally twice daily; increase slowly to lowest effective maintenance due to increased sensitivity and risk of falls. Avoid doses above 20 mg/day unless clearly necessary. |
| 1st trimester | Associated with increased risk of congenital malformations, particularly cleft lip/palate (odds ratio ~2.0) with exposure in first trimester. Use only if clearly needed. |
| 2nd trimester | Continued risk of teratogenicity; consider alternative therapies. Risk of neural tube defects and cardiac anomalies remains. |
| 3rd trimester | Use near term can cause neonatal withdrawal syndrome (irritability, hypertonia, feeding difficulties) and floppy infant syndrome (hypotonia, respiratory depression). Avoid in late pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for ONFI (ONFI).
| Placental transfer | Clobazam and n-desmethylclobazam cross the placenta; fetal plasma concentrations are similar to maternal concentrations. Protein binding ~85% in maternal plasma. |
| Breastfeeding | Clobazam and its active metabolite n-desmethylclobazam are excreted into breast milk in low concentrations. Estimated infant dose is 0.5-1.2% of maternal weight-adjusted dose. Monitor infant for sedation, poor feeding, and weight gain. Use with caution, especially with prolonged exposure. |
■ FDA Black Box Warning
Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant use for patients for whom alternative treatment options are inadequate.
| Serious Effects |
Hypersensitivity to clobazam or any componentSevere hepatic impairment (Child-Pugh C)Acute narrow-angle glaucomaMyasthenia gravisSevere respiratory insufficiencyHistory of substance abuse (relative)
| Precautions | Risk of respiratory depression, especially with opioids, Sedation and somnolence, Risk of abuse and dependence, Withdrawal seizures on abrupt discontinuation, Increased risk of suicidal thoughts or behavior |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase clobazam levels. No other significant food interactions are known. CNS depressant effects may be potentiated by alcohol. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category C. First trimester: increased risk of major malformations including cleft lip/palate (OR 2.0-3.0); second/third trimester: risk of neonatal withdrawal, hypotonia, poor feeding, respiratory depression, and hypothermia; consistent exposure may cause floppy infant syndrome. Late pregnancy exposure linked to neonatal benzodiazepine withdrawal syndrome. |
| Fetal Monitoring | Monitor for maternal oversedation, dizziness, ataxia; weekly LFTs for hepatic toxicity; fetal ultrasound for cleft palate risk; nonstress test (NST) and biophysical profile (BPP) in third trimester; neonatal monitoring for withdrawal signs (respiratory rate, muscle tone, feeding status) for 48-72 hours post-delivery. |
| Fertility Effects | In animal studies, decreased fertility indices (reduced conception rates, increased preimplantation loss) at human therapeutic doses. Human data limited; potential for menstrual irregularities due to CNS depression; no definitive evidence of permanent infertility. |
| Clinical Pearls | ONFI (clobazam) is a benzodiazepine indicated for seizures associated with Lennox-Gastaut syndrome. Titrate slowly to minimize sedation. Monitor for withdrawal symptoms upon discontinuation; taper over several weeks. Not recommended for use in patients with severe hepatic impairment (Child-Pugh C). For patients on other CNS depressants, consider dose reduction. Clobazam's active metabolite, N-desmethylclobazam, has a long half-life (36-46 hours) and can accumulate, especially in poor CYP2C19 metabolizers. In such patients, consider lower doses and monitor for excessive sedation. |
| Patient Advice | Take ONFI exactly as prescribed; do not stop suddenly as withdrawal seizures may occur. · Avoid alcohol and other sedatives while taking this medication due to increased risk of drowsiness and respiratory depression. · Report any unusual mood changes, depression, or suicidal thoughts to your healthcare provider. · Do not drive or operate heavy machinery until you know how ONFI affects you, as it can cause dizziness and drowsiness. · If you are pregnant, planning to become pregnant, or breastfeeding, discuss with your doctor before using ONFI. · Store at room temperature, away from moisture and heat. |