Dosing and uses of ONFI (clobazam)
Adult dosage forms and strengths
scored tablet: Schedule IV
- 10mg
- 20mg
oral suspension
- 2.5mg/mL
Seizures
Indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years or older
>30 kg: Initiate at 5 mg PO q12hr; may titrate as tolerated up to 40 mg/day divided q12hr
Dose escalation should not proceed more rapidly than once weekly
CYP2C19 poor metabolizers
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased
- Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose
- Additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21
Renal & Hepatic Impairment
Renal impairment
- Mild or moderate renal impairment: No dose adjustment required
- Severe renal impairment or ESRD: No experience
- Dialyzable: Unknown if clobazam or active metabolite is dialyzable
Hepatic impairment
- Limited data to characterize the effect of hepatic impairment on the pharmacokinetics; proceed with low and slow titration
- Mild-to-moderate (Child-Pugh 5-9): Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose; additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group may be started on day 21
- Severe hepatic impairment: Not recommended
Administration
Individualize weight-based dose according to clinical efficacy and tolerability
Doses above 5 mg/day should be administered in divided doses twice daily (5 mg dose can be administered as a single daily dose)
May be administered whole, or crushed and mixed in applesauce
May be taken without regard to food
When discontinuing, withdraw gradually; taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued
Pediatric dosage forms and strengths
scored tablet: Schedule IV
- 10mg
- 20mg
oral suspension
- 2.5mg/mL
Seizures
Indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years or older
≤30 kg
- Starting dose: 5 mg PO qDay; titrate as tolerated up to 20 mg PO daily
- After 7 days, may increase to 5 mg PO q12hr; if needed, may increase to 10 mg PO q12hr after an additional 7 days
>30 kg
- Starting dose: 5 mg PO q12hr; titrate as tolerated up to 40 mg PO daily
- After 7 days, may increase to 10 mg PO q12hr; if needed, may increase to 20 mg PO q12hr after an additional 7 days
CYP2C19 poor metabolizers
- In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam’s active metabolite, will be increased
- Starting dose should be 5 mg/day and titrated according to weight, but to half the typical dose
- Additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21
Renal & Hepatic Impairment
Renal impairment
- Mild or moderate renal impairment: No dose adjustment required
- Severe renal impairment or ESRD: No experience
- Dialyzable: Unknown if clobazam or active metabolite is dialyzable
Hepatic impairment
- Limited data to characterize the effect of hepatic impairment on the pharmacokinetics; proceed with low and slow titration
- Mild-to-moderate (Child-Pugh 5-9): Starting dose should be 5 mg/day and titrated according to weight, but to half the typical adult dose; additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21
- Severe hepatic impairment: Not recommended
Administration
Doses above 5 mg/day should be administered in divided doses twice daily (5 mg dose can be administered as a single daily dose)
May be administered whole, or crushed and mixed in applesauce
May be taken without regard to food
When discontinuing, withdraw gradually; taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued
Geriatric dosage forms and strengths
Plasma concentrations at any given dose are generally higher in the elderly; proceed slowly with dose escalation
Starting dose should be 5 mg/day for all elderly patients and titrated according to weight, but to half the typical adult dose
Additional titration to the maximum dose (20 mg/day or 40 mg/day), depending on the weight group) may be started on day 21
ONFI (clobazam) adverse (side) effects
>10%
Somnolence or sedation (26%)
Somnolence (22%)
Pyrexia (13%)
Upper respiratory tract infection (12%)
1-10%
Drooling (9%)
Aggression (8%)
Irritability (7%)
Vomiting (7%)
Insomnia (5%)
Ataxia (5%)
Sedation (5%)
Constipation (5%)
Fatigue (5%)
Cough (5%)
Psychomotor hyperactivity (4%)
Pneumonia (4%)
Urinary tract infection (4%)
Dysarthria (3%)
Decreased appetite (3%)
Increased appetite (3%)
Bronchitis (2%)
Dysphagia (2%)
Postmarketing Reports
Hypothermia
Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
Eye Disorders: Diplopia, vision blurred
Gastrointestinal Disorders: Abdominal distention
GU disorders: Urinary retention
Lab: Hepatic enzyme increased
Musculoskeletal: Muscle spasms
Respiratory Disorders: Aspiration, respiratory depression
Skin and Subcutaneous Tissue Disorders: Rash, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), urticaria
Warnings
Contraindications
History of hypersensitivity to drug or ingredients
Cautions
Somnolence or sedation; generally occurs within the first month of treatment and may diminish with continued treatment; caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy does not affect them adversely (eg, impair judgment, thinking or motor skills)
Serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported in both children and adults; monitor closely, especially during the first 8 weeks of treatment initiation or when reintroducing therapy; discontinue at the first sign of drug-related rash and do not resume
Consider history of substance abuse because of predisposition of such patients to physical and/or psychological dependence
Antiepileptic drugs increase the risk of suicidal thoughts or behavior
Avoid simultaneous use of other CNS depressants or alcohol; effects may be potentiated; alcohol increases clobazam blood levels by about 50%
CYP2C19 substrate; dose adjustment may be required when coadministered with strong or moderate CYP2C19 inhibitors (may result in increased systemic exposure to active metabolite, N-desmethlclobazam)
CYP2D6 inhibitor; lower doses of major CYP2D6 substrates may be required
Weak CYP3A4 inducer; may diminish effectiveness of combination oral contraceptives
WithdrawaL
- As with all antiepileptic drugs, withdraw gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus
- Avoid abrupt discontinuation; taper by decreasing dose each week by 5-10 mg/day until discontinued
- Withdrawal symptoms (eg, convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) occur following abrupt discontinuation, risk is greater with higher doses
Pregnancy and lactation
Pregnancy category: C
Encourage pregnant patients (or their caregivers) to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; toll free number 1-888-233-2334; https://www.aedpregnancyregistry.org
Available animal data suggest developmental toxicity, including increased incidence of fetal abnormalities at doses similar to those used clinically in humans; data for other benzodiazepines suggest the possibility of adverse effects in animals and humans
Long-term effects on neurobehavioral and immunological function have been reported in rodents following prenatal exposure to benzodiazepines
Neonatal flaccidity, respiratory and feeding difficulties, hypothermia, and withdrawal symptoms have been reported in infants born to mothers who received benzodiazepines, including clobazam, late in pregnancy
Lactation: Excreted in breast milk; effects of exposure on infants unknown
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of ONFI (clobazam)
Mechanism of action
A 1,5-benzodiazepine, exact mechanism of action not fully understood; thought to potentiate GABAergic neurotransmission resulting from binding to GABA-A receptor
Pharmacokinetics
Bioavailability: 100%
Peak Plasma Time: 0.5-4 hr
Peak Plasma Concentration: Dose-proportional (linear)
AUC: Dose-proportional (linear)
Protein Bound: 80-90% (clobazam); 70% (N-desmethylclobazam)
Vd: 100 L
Half-life: 36-42 hr (clobazam); 72-82 hr (N-desmethylclobazam)
Dialyzable: Unknown
Excretion: 11% as metabolites feces (1% unchanged drug), 82% as metabolites urine (2% unchanged drug)
Metabolism
- Metabolized extensively by N-demethylation in the liver, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6; active metabolite is extensively metabolized by CYP2C19
- Metabolites: N-desmethylclobazam is the major circulating active metabolite; at therapeutic doses, plasma concentration is 3-5 times higher than those of clobazam
- Enzyme substrate: CYP2C19 (active metabolite)
- Inhibitor: CYP2D6
- Inducer: Weak inhibitor of CYP3A4
Pharmacogenomics
Polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active metabolite N-desmethylclobazam
Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3-5 times higher in poor metabolizers (eg, subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (eg, subjects with *1/*2 genotype)
The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background
Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted
Systemic exposure for the parent drug, clobazam, is similar for both CYP2C19 poor and extensive metabolizers
