ONFI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ONFI (ONFI).

How it works

GABA-A receptor positive allosteric modulator; increases the frequency of chloride channel opening in response to GABA.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ONFI (ONFI).

Breastfeeding	Clobazam is excreted into breast milk; M/P ratio approximately 0.5-0.6. Accumulation possible in neonates; monitor for sedation, poor feeding, apnea. Avoid if infant has impaired hepatic function or low birth weight. American Academy of Pediatrics recommends caution; use lowest effective maternal dose.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to clobazam or any component of formulation","Severe hepatic impairment"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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ONFI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ONFI (ONFI).

How it works

GABA-A receptor positive allosteric modulator; increases the frequency of chloride channel opening in response to GABA.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ONFI (ONFI).

Breastfeeding	Clobazam is excreted into breast milk; M/P ratio approximately 0.5-0.6. Accumulation possible in neonates; monitor for sedation, poor feeding, apnea. Avoid if infant has impaired hepatic function or low birth weight. American Academy of Pediatrics recommends caution; use lowest effective maternal dose.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to clobazam or any component of formulation","Severe hepatic impairment"]