Onfi (Clobazam tablets)

January 31, 2013

New molecular entity: A benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients age 2 years or older.

A benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years or older

At the annual meeting of the American Epilepsy Society in December 2012, data from a long-term, open-label extension (OLE) study evaluating clobazam (Onfi, Lundbeck) for the adjunctive treatment of drop seizures associated with Lennox-Gastaut syndrome (LGS) were presented as a late-breaking poster. Of 306 patients previously enrolled in 2 earlier studies, 267 entered the OLE and approximately 70% (188 of 267) remained in the study until its conclusion on March 23, 2012. Clobazam tablets were granted orphan drug status and approved by FDA in late 2011 for use as an adjunctive treatment for seizures associated with LGS in adults and children aged 2 years and older. LGS usually begins before 4 years of age and can be caused by a number of conditions, including brain malformations, severe head injuries, central nervous system infections, and inherited degenerative or metabolic conditions. In 30% to 35% of patients, no cause can be found. Patients commonly have frequent seizures of a wide variety, including tonic (stiffening of the body, upward deviation of the eyes, dilation of the pupils, and altered respiratory patterns), atonic (brief loss of muscle tone and consciousness, causing abrupt falls), atypical absence (staring spells), and myoclonic (sudden muscle jerks).

According to the study authors, there is no quick fix for LGS; therefore “It’s important to collect long-term data because these challenging seizures associated with LGS typically continue throughout the patient’s life.”

Efficacy. The effectiveness of clobazam tablets as adjunctive therapy was established in 2 multicenter controlled studies of patients aged 2 years and older. The reductions in weekly frequency of drop seizures (atonic, tonic, or myoclonic seizures resulting in a fall or loss of posture) from the 4-week baseline period to a maintenance period was tested. The first trial enrolled 238 patients aged 2 to 54 years and randomly assigned to 3 doses of clobazam daily (5 mg, 10 mg, 20 mg) stratified by weight. When compared to placebo, all doses significantly reduced the frequency of drop seizures by 41.8 to 68.3% from the baseline to 12-week maintenance period. The second trial randomized 68 patients aged 2 to 54 years to either high or low-dose clobazam. A significant reduction in drop seizure frequency from baseline to the 4-week maintenance period was found in the high-dose group (93%) compared to the low-dose group (29%).

Safety. Clobazam was administered to 333 healthy volunteers and 300 patients with current or prior LGS during development, including 197 patients treated for 12 months or longer. Great variability in conditions and exposure were noted with only 1 randomized placebo-controlled trial, allowing for adverse event comparison with multiple clobazam doses. In this study, clobazam 5 mg, 10 mg, and 20 mg were compared to placebo. The adverse reactions associated with clobazam treatment discontinuation in  ≥1% patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia. Adverse reactions that occurred in ≥5% of clobazam-treated patients (at any dose), and at a rate greater than placebo treated patients in this trial included vomiting, pyrexia, irritability, upper respiratory tract infection, somnolence or sedation, lethargy, drooling, ataxia, aggression, insomnia, and cough. Just as with other antiepileptic drugs, clobazam may increase the risk of suicidal thoughts or behaviors in a very small number of people taking the drug. Patients taking antiepileptic drugs should be monitored for depression, suicidal thoughts or behavior, and unusual changes in mood or behavior. Clobazam may slow thinking and impair motor skills; therefore it is important that people taking the drug not drive, operate heavy machinery, or engage in other dangerous activities until they know how the drug affects them. Clobazam has been categorized as a Schedule IV drug under the Controlled Substances Act. Clobazam should not be discontinued suddenly. People using the drug should talk with their healthcare professional about slowly stopping the drug to avoid withdrawal symptoms. FDA is requiring that a Medication Guide be given to patients and caregivers when clobazam is dispensed. The Medication Guide describes the risks and adverse reactions people should be mindful of when using the product.

Dosing. The starting dose in patients weighing ≤30 kg is 5 mg daily, titrated as tolerated up to 20 mg daily. In patients weighing >30 kg body weight, the starting dose of 10mg daily is recommended and titrated as tolerated up to 40 mg daily. Doses above 5 mg/day should be administered in 2 divided doses. Clobazam tablets can be administered whole or crushed and mixed in applesauce. As with all antiepileptic drugs and benzodiazepines, clobazam should be withdrawn gradually and a taper decreasing the total daily dose by 5 mg/day to 10 mg/day on a weekly basis until discontinued is recommended. Dosage adjustment for clobazam is recommended in the geriatric population, in patients who are known CYP2C19 poor metabolizers or concurrently taking strong or moderate CYP2C19 inhibitors, and in patients with hepatic impairment. No dose adjustment is required for patients with mild and moderate renal impairment. Patients concurrently taking drugs metabolized by CYP2C9 may require lower doses of the drug while taking clobazam. Lastly, blood concentrations of clobazam are increased by approximately 50% when alcohol is consumed.