Felbamate
In 1993 the efficacy of felbamate (FBM) was documented in a double-blind, placebo-controlled trial.36 Seizure frequency was assessed by guardian report and by serial 4-hour EEG-video monitoring sessions during the course of the study. FBM significantly reduced the number of atonic seizures compared to placebo in both the treatment (p = 0.01) and the maintenance (p = 0.002) phases of the study. Of the 37 patients who received FBM, 3 were without atonic seizures during the treatment phase, and 5 had no atonic seizures during the maintenance phase. A dose-response relationship was demonstrated for reduction of atonic seizures, with a linear reduction in the number of atonic seizures per day with increasing plasma FBM levels. There was a statistically significant reduction in seizure frequency for all seizure types among the FBM-treated patients compared to those who received placebo (p = 0.002).
‘Global evaluations’ of patient functioning and neuropsychological tests were performed on all study subjects in order to assess non-seizure-related outcomes. The global evaluation scores during the maintenance period were significantly higher (p < 0.001) among the FBM group than the placebo group.
Dodson reported the 12-month open-label study of FBM that followed the clinical trial.37 Those who converted from placebo to FBM had the same degree of improvement on FBM as those who received FBM during the trial. At the end of the double-blind trial only 2 of the 22 subjects randomized to placebo had experienced a > 50% reduction in atonic seizure. However, during the first month that these patients from the placebo group were treated with FBM 12 of the 22 subjects (55%) had a > 50% reduction in atonic seizures. Combining both the groups of patients from the randomized double-blind trial in the follow-on study, 33 of 50 or approximately two-thirds had a > 50% reduction of atonic seizures 12 months after beginning the open-label study.
No pattern of serious adverse events due to FBM was apparent at the time of FDA approval in 1993. By the summer of 1994 120,000 patients had been exposed to FBM and reports of both aplastic anemia and hepatic failure had been reported to Wallace Laboratories and the FDA. After letters had been sent to over 200,000 physicians in the USA informing them of these new risks, most patients were withdrawn from FBM and the use of FBM in LGS declined.
Over the last four years analysis of the available data have led to a better estimate of the risk of FBM. Kaufman, et.al. reviewed all case reports of aplastic anemia among patients treated with FBM. The incidence of aplastic anemia among those treated with FBM was estimated to have a lower limit of 1 per 37,037 patients and an upper limit of 1 per 4784 patients, with a "most probable" incidence of 1 per 7874 patients treated.38
Pellock and Brodie estimated that the incidence of hepatotoxicity to be about 1 per 26,000–34,000 patients treated with FBM 39 – similar to the recently reported risk of hepatotoxicity for valproate (VPA).40 No children under the age of 13 years have been reported to have FBM-related aplastic anemia. Female sex, history of immune disorders (e.g., lupus), a history of prior blood dyscrasias, and allergic reactions to medications are probably associated with increased risk for FBM-associated aplastic anemia. These factors may later prove helpful in selecting patients for FBM treatment.
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