Felbamate Today
March 1, 1998
Felbamate Today
ABSTRACT & COMMENTARY
Source: Kaufman D, et al. Evaluation of case reports of aplastic anemia among patients treated with felbamate. Epilepsia 1997;38:1265-1269.
Felbamate (fbm), with its unique mechanism of action, is an extremely effective antiepileptic drug (AED) in certain individuals (particularly in the Lennox-Gastaut syndrome). Cases of aplastic anemia associated with FBM, however, led to its withdrawal as a commonly used AED. Kaufman and associates now have reviewed carefully the aplastic anemia cases that led to the downfall of FBM. In an accompanying editorial, Pellock and Brodie (Epilepsia 1997;38:1261-1264) make recommendations for the current usage of this effective but risk-bearing agent.
Kaufman et al reviewed the 31 putative cases of aplastic anemia in patients treated with FBM reported to the U.S. FDA between January 1994 and January 1995. Immediately, they concluded that six cases should not be considered to have been caused by FBM due to pre-existing conditions (2 with SLE, 4 with long-standing hematological disorders). Two more putative cases did not have confirmatory bone marrow aspirates or blood counts. Thus, 23 cases of aplastic anemia were confirmed in the 110,000 patients treated with FBM in the first year it was on the market.
The authors classified the 23 cases according to the presence or absence of medical illnesses (viral infections, rheumatoid arthritis, etc.) and previous AED or other drug allergies, any of which may confound the attribution of aplastic anemia to FBM. In only three cases (13%) was confounding unlikely, with FBM as the only plausible etiologic agent. In 11 cases (48%), confounding was "possible," with FBM still as the most likely etiologic agent. In the remaining nine cases (39%), confounding was "probable," and FBM was only one of several possible causative agents for the aplastic anemia.
Seven patients (30%) died. The authors could not identify other potential risk factors associated with these aplastic anemia cases, such as age, sex, geographic region, etc. Overall, combining cases where confounding processes other than FBM were absent or unlikely, the authors estimated that FBM caused aplastic anemia at the rate of 127 cases per million exposures.
COMMENTARY
When approved by the FDA in 1992 and marketed in 1993, FBM, being the first new AED in the United States in 15 years, was warmly received by the neurological community. Its outstanding efficacy in some patients, lack of sedative qualities compared to older AEDs, and aggressive marketing to physicians and the public by Carter Wallace resulted in great popularity. Within one year, 110,000 patients had been exposed.
The above reviewed cases of aplastic anemia triggered a "Dear Doctor" letter to 250,000 physicians from FBM's manufacturer and the FDA. They recommended FBM's use be restricted to the most severe medication-resistant epilepsy cases and that physicians obtain written informed consent from all patients treated.
Pellock and Brodie make several important points in their editorial. Before marketing, FBM was administered to 4000 patients in clinical trials. Clearly, that number, although large, was insufficient to detect a rare event, such as aplastic anemia, occurring at a rate of 127 cases per million exposures. However, it is impractical to "test" a new agent before marketing on enough patients to identify such rare events. Rigorous post-marketing surveillance programs are required.
Pellock and Brodie estimate that FBM is associated with aplastic anemia 20 times more frequently than carbamazepine and that FBM produces hepatotoxicity at a rate similar to valproate. They make the following recommendations for the use of FBM:
1. FBM is highly beneficial for some patients (particularly those with the Lennox-Gastaut syndrome) and should not be withheld from needy patients.
2. FBM should be considered a third or fourth AED option, after old and new AEDs, such as gabapentin, lamotrigine, tiagabine, and topirimate.
3. Before FBM administration, the history should be reviewed for pre-existing hematologic, hepatic, or autoimmune disease.
4. Baseline hematologic and liver function tests should be performed.
5. The patients and their families should be informed fully about potential risks.
6. Written consent should be obtained.
7. Dose escalations should be made slowly.
8. The goal should be FBM monotherapy. -drl
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