Pharmacology Update

Clobazam Tablets (ONFI™) CIV

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A new benzodiazepine anticonvulsant was recently approved for the treatment of a difficult-to-treat childhood epilepsy (Lennox-Gastaut syndrome [LGS]). Clobazam is manufactured by Catalent Pharma Solutions and marketed as ONFI.

Indications

Clobazam is indicated as an adjunct treatment for seizures associated with LGS in children (2 years of age or older).1

Dosage

Dosing is based on body weight. For patients weighing 30 kg or less, the initial dose is 5 mg daily and may be titrated up to 20 mg daily based on tolerability. For those weighing more than 30 kg, the initial dose is 10 mg daily up to 40 mg daily. Doses greater than 5 mg daily should be taken in two divided doses. The tablets may be taken whole or crushed and mixed with applesauce and can be taken without regard to meals. No dose adjustment is required in patients with mild or moderate renal impairment. For patients with mild-to-moderate hepatic impairment, the dose should be started at 5 mg daily for both weight groups and titrated to half the recommended dose for patients with normal hepatic function. For patients who are poor CYP2C19 metabolizers, the dose should be started at 5 mg and titrated to half the recommended dose.

Clobazam is available as 5 mg, 10 mg, and 20 mg tablets.

Potential Advantages

Clobazam provides another option for LGS, a condition that is difficult to manage.

Potential Disadvantages

Antiepileptic drugs, including clobazam, may increase the risk of suicidal thoughts or behavior.1 The incidence rate was 0.43% compared to 0.24% for placebo. Common adverse events include somnolence or sedation (26%), pyrexia (13%), upper respiratory infection (12%), and lethargy (10%). Clobazam may reduce the effectiveness of hormonal contraceptives metabolized by CYP3A4 (e.g., desogrestrel). Strong or moderate inhibitors of CYP3A4 may increase the exposure to the active metabolite (N-desmethylclobazam). Drugs metabolized by CYP2D6 may require dose reduction.

Comments

The efficacy and safety of clobazam was shown in two randomized, controlled studies.1,2 Subjects were patients with a clinical diagnosis of LGS with an onset before 11 years of age. Diagnosis was confirmed by one or more generalized seizures (including drop seizures [atonic, tonic, or myotonic]) for 6 months or longer. Study 1 included a 4-week baseline, 3-week titration, and 12-week maintenance period at which time the patient either continued on clobazam or was tapered over 2 or 3 weeks. Patients (n = 238) were randomized to placebo, low dose (0.25 mg/kg/day), medium dose (0.5 mg/kg/day), or high dose (1 mg/kg/day). The dose was titrated every 7 days up to a maximum of 10 mg, 20 mg, and 40 mg, respectively. The primary efficacy endpoint was percentage decrease in the average weekly rate of drop seizures from the baseline period as recorded by patients' parents/caregivers daily diaries. Mean percent reduction for the four study groups were 12.1%, 41.2%, 49.4%, and 68.3% from mean baseline rates of 96, 100, 61, and 105, respectively. All reductions were statistically significant for the clobazam arms. The effects appeared to be dose dependent with the high-dose patients achieving the greatest reduction (close to 60% of patients achieving an 80-100% reduction). In study 2, patients were randomized to a low-dose or high-dose group (5 mg if ≤ 30 kg or 10 mg if > 30 kg) or 20 mg to 40 mg. The study included a 4-week baseline, 3-week titration, and 4-week maintenance period. The reduction of seizures was 29% for the low-dose group and 93% for the high-dose group. Adverse events that resulted in the discontinuation of the drug increased with increased dose, 3.5% (2/57), 7.5% (4/53), 13.9% (8/58), and 27% (13/48).2 The most common adverse effects that led to discontinuation were lethargy, somnolence, aggressiveness, ataxia, insomnia, and fatigue. Fifteen patients in the high-dose group had their dose reduced. Currently, there are no head-to-head comparisons of different antiepileptics for this condition.3

Clinical Implications

LGS is a severe childhood epileptic encephalopathy with poor response to currently approved antiepileptic drugs, which include lamotrigine, topiramate, felbamate, and rufinamide. Clobazam offers another option for this difficult-to-treat condition.

References

1. ONFI Prescribing Information. Somerset, NJ: Catalent Pharma Solutions; October 2011.

2. Ng YT, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology 2011; 77:1473-1481.

3. Montouris GD. Rational approach to treatment options for Lennox-Gastaut syndrome. Epilepsia 2011;52(Suppl 5):10-20.