clobazam: A New (Old) Drug Approved to Treat Seizures

Clobazam: A New (Old) Drug Approved to Treat Seizures

On October 21, 2011, the US Food and Drug Administration (FDA) approved clobazam (Onfi^®)* as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in adults and children aged 2 and older.^[1] This is good news for people with Lennox-Gastaut syndrome, and their families and physicians, because successful treatment of seizures associated with Lennox-Gastaut syndrome has been an elusive goal.

Lennox-Gastaut Syndrome

People with Lennox-Gastaut syndrome typically have mixed seizure types, developmental delay, and a specific pattern of slow spike and wave (< 2.5 Hz) on the electroencephalogram (EEG). Seizures usually begin in childhood before the age of 8 years and may follow infantile spasms. In Lennox-Gastaut syndrome, multiple seizure types such as atypical absence seizures, drop attacks, and nocturnal tonic seizures are often accompanied by disabilities such as blindness, cerebral palsy, hearing impairment, and mental retardation, culminating in its designation as a "catastrophic epilepsy." Many etiologies may be responsible, including anoxic, cryptogenic, infectious, malformations of cortical development, metabolic, and post-traumatic. Although Lennox-Gastaut syndrome accounts for only about 4% of cases of childhood epilepsy, affected children are overrepresented in neurology clinics because of treatment-resistant seizures, behavioral problems, and multiple comorbidities. Drop attacks, which occur in at least 50% of patients, are particularly problematic because the sudden falls may result in facial and head injuries, often requiring the child to wear a protective, but stigmatizing helmet.^[2] Episodes of status epilepticus require frequent visits to the emergency department.

A Look at Clobazam

Clobazam, a 1,5-benzodiazepine, was approved for adjunctive therapy of epilepsy in children over 3 years old in Europe in 1975^[3] and is available in over 100 countries.^[1] Clobazam is a benzodiazepine, the same family that includes familiar drugs used for acute seizure control such as diazepam (Valium^®) and lorazepam (Ativan^®). Clobazam acts as a gamma-aminobutyric acid alpha (GABA_A)receptor agonist. It is primarily metabolized in the liver by cytochrome P450 (CYP)3A4, which produces an active metabolite, N-desmethylclobazam. N-desmethylclobazam has a long half-life of 30-65 hours and is metabolized by CYP2C19.^[3]

Clinical Trials and Clinical Role

The FDA approval of clobazam was based on 2 recent studies.^[4,5] In the first study, 68 patients (2-26 years) with Lennox-Gastaut syndrome received open-label low dose (0.25 mg/kg/day) or high dose (1.0 mg/kg/day) clobazam for a 3-week titration, 4-week maintenance, and 3-week taper in addition to their usual treatment.^[4] Both doses significantly reduced the frequency of drop attacks, the low dose (P = .01) and the high dose (P < .0001). The high dose also significantly reduced nondrop seizures (P < .0001).

The second study was a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of 238 patients (aged 2-60 years) with childhood onset of Lennox-Gastaut syndrome.^[5] After a 4-week baseline, patients were titrated for 3 weeks, maintained on treatment for 12 weeks (placebo, low dose (0.25 mg/kg/day), medium dose, (0.5 mg/kg/day) or high dose (1.0 mg/kg/day), and then tapered off treatment over 2-3 weeks or entered into the extension phase. The mean percentage decrease in average weekly drop seizures from baseline to the maintenance period was 12.1% for placebo vs 41.2% for low dose (P = .01), 49.4% for medium dose (P = .0015), and 68.3% for high dose (P < .0001), demonstrating increasing efficacy with dose. Decreases in nondrop seizures were not significant. Adverse events that occurred notably more often with clobazam than placebo were somnolence, pyrexia, lethargy, drooling, and constipation.

Conclusions

Clobazam joins 5 other FDA-approved antiepileptic drugs for the treatment of Lennox-Gastaut syndrome: clonazepam, felbamate, lamotrigine, topiramate, and more recently, rufinamide. Valproate is traditionally used as well. However, despite multiple medications and attempts at seizure control with the ketogenic diet, vagus nerve stimulator, and epilepsy surgery, patients rarely become seizure free.^[4,6] The long experience of clobazam use outside the United States suggests that this drug harbors no unpleasant surprises regarding safety or side effects. The FDA approval of clobazam represents a valuable additional tool for physicians to decrease drop attacks in their patients with Lennox-Gastaut syndrome. Clobazam is now available at retail pharmacies in the US.