Abstracts

Felbatol[reg] (felbamate, FBM) was approved for US marketing in July 1993 as monotherapy and adjunctive treatment of partial seizures with and without secondary generalization in adults and as adjunctive therapy for partial and generalized seizures associated with Lennox-Gastaut syndrome in children after trials demonstrated significant seizure reductions in these populations. Before launch, about 3300 patients were exposed with [gt]900 receiving FBM for [ge]6 months. Six months after launch a single aplastic anemia (AA) case was reported in a FBM and carbamazepine treated patient. Additional case reports led in August 1994 to nearly 250,000 physicians receiving letters alerting them to the risk and recommending discontinuation in most patients. About 110,000 patients had been FBM treated. Of the 34 reported AA cases only one has been since 1994. Epidemiological analysis of AA cases indicated risk was greatest for adult, Caucasian, females with a prior history of serious antiepileptic drug (AED) allergy or toxicity and blood dyscrasias. Median time to onset was 145 days. Hepatic failure was also reported in 18 cases. True incidence, while difficult to ascertain, has been estimated for AA at 300/million and hepatic failure at 1/26,000-34,000 exposures.
In 1997 a HLA typing and urine metabolic screening registry was established to see if at risk patients could be identified.
The registry was stopped in 2003 with 1250 enrolled patients. Urinalysis testing indicated a 2:1 ratio of monocarbamate to mercapturate appears to be normal and a ratio [gt]3-4 standard deviations from mean may indicate risk. Mercapturates are detoxified products of an extremely electrophilic and cytotoxic alpha, beta unsaturated aldehyde, atropaldehyde, resulting from FBM metabolism and hypothesized to cause the idiosyncratic toxicities. Another theory stems from analysis of 7 FBM associated AA patients who demonstrated lower erythrocyte glutathione peroxidase, superoxide dismutase and glutathione reductase activities compared to age-matched controls, suggesting lower capability to handle toxins. As a result of the atropaldehyde sequestering glutathione, which is required for detoxification, excess free radical generation is postulated. Reduced quantities of glutathione, from lower enzyme levels, could also result in atropaldehyde build up. Whether metabolite ratios or enzyme levels can predict patient risk will require more FBM patients.
Clinically FBM is highly effective for refractory seizure treatment, still an unmet need despite new AEDs. In 1999 the American Academy of Neurology found sufficient evidence to recommend FBM for patients with intractable partial seizures [gt]18 years who have failed therapeutic levels of standard AEDs and in patients [gt]4 years with Lennox-Gastaut syndrome unresponsive to primary AEDs. Now 6000-8000 patients continue FBM treatment. By combining careful clinical history and baseline hematological and metabolic screening the FBM risk-benefit ratio can be better defined. FBM[apos]s efficacy warrants reexploration as a viable therapeutic option in refractory epilepsy.
[Supported by: MedPointe Pharmaceuticals]