Felbamate

Abstract

Summary: Felbamate (FBM) was the first of the new antiepileptic drugs (AEDs) approved in the United States in 1993 with broad-spectrum efficacy against partial and generalized seizures of various types, and indicated for use as adjunctive and monotherapy. The identification of idiosyncratic aplastic anemia and hepatotoxicity, however, drastically curtailed its use. To update information concerning FBM and its idiosyncratic effects, case studies and literature reviews were undertaken. Thirty-four FBM-associated aplastic anemia patients have been reported, with 13 known fatalities. The overall FBM aplastic anemia risk is estimated at between 27 and 209 per million vs. 2 to 2.5 per million in the general population. Prior AED hypersensitivity, cytopenia, and immune disease significantly increase risk. FBM aplastic anemia has not been reported in children below the age of 13 years. Hepatic failure is much less common, occurring with an overall risk similar to that associated with valproate, but children below the age of 5 years have been affected. The recent identification of a reactive metabolite, atropaldehyde, and HLA studies suggest that high-risk patients can be identified. The efficacy profile of FBM should encourage further investigations to allow its better use, but at present FBM is not a first-line AED. Key Words: Felbamate-Idiosyncratic reactions-Atropaldehyde-Risk factors-Aplastic anemia.Felbamate (FBM) led the introduction of the new antiepileptic drugs (AEDs) and is truly unique. It has a broad spectrum of control on multiple seizure types, particular efficacy in refractory patients, a relative lack of central nervous system depressant effects, and a relative paucity of typical adverse events associated with its use (1,2). Despite the identification of rare but lifethreatening idiosyncratic reactions, FBM continues to be used, albeit with caution, in patients who are refractory to other medications. Moreover, with the failure of other therapies, FBM is again being considered as a therapeutic agent.FBM was the first of the new AEDs to be approved in the United States after a gap of nearly 15 years. Initially marketed in early 1993, FBM is indicated for monotherapy and adjunctive therapy in the treatment of partial seizures with or without generalization in adults, or as adjunctive therapy in the treatment of partial and generalized seizures associated with the Lennox-Gastaut syndrome in children (3). The identification of aplastic anemia and hepatotoxicity associated with FBM, however, drastically curtailed its use despite its broad spectrum of activity and particularly its efficacy in controlling encephalopathic epilepsy syndromes of childhood (4). It is now considered a third-or fourth-line drug and is prescribed primarily for those with truly intractable epilepsy (4).The clinical development program for FBM utilized novel study designs (3). These included rapid dose escalation and loading of FBM after withdrawal from other AEDs in patients undergoing presurgical evaluations and trials allowing FBM mo...

Use-Dependent Inhibition of the N-Methyl-D-aspartate Currents by Felbamate: a Gating Modifier with Selective Binding to the Desensitized Channels

“…Although serious complications such as aplastic anemia and hepatotoxicity have limited its use, FBM is an anticonvulsant which is too important to discard. With informed consent of the patients, FBM has remained as a useful anticonvulsant for Lennox-Gastaut syndrome in children and for a variety of complex partial seizures that are refractory to the other anticonvulsants in adults (Kaufman et al, 1997;Pellock, 1999).The intriguing pharmacological profile of FBM implies a unique mechanism of action. Just as for the other nonsedative anticonvulsants, any proposed mechanism underlying FBM action preferably should explain why seizure discharges are effectively inhibited but normal neuronal firings are relatively preserved.…”

“…Although serious complications such as aplastic anemia and hepatotoxicity have limited its use, FBM is an anticonvulsant which is too important to discard. With informed consent of the patients, FBM has remained as a useful anticonvulsant for Lennox-Gastaut syndrome in children and for a variety of complex partial seizures that are refractory to the other anticonvulsants in adults (Kaufman et al, 1997;Pellock, 1999).…”

AED Treatment through Different Ages: As Our Brains Change, Should Our Drug Choices Also?

“…We don't know whether these effects also occur in the setting of seizures, and to what extent naturally occurring apoptosis is modified by other factors, ameliorating these effects. Some data suggest that AEDs that antagonize AMPA receptor-mediated ion channels, such as topiramate, may actually have a neuroprotective and anticonvulsant effect (30). In general, infants and children are more susceptible to some adverse drug effects than adults, whereas they can be more tolerant of others.…”

“…Children are also at higher risk of developing Stevens-Johnson syndrome from lamotrigine, as well as hepatic injuries from the use of valproate in combination with enzyme-inducing AEDs. Yet, they are relatively resistant to the aplastic anemia caused by felbamate (30). Vigabatrin appears to adversely affect adults more often than children.…”

New generation anticonvulsants for the treatment of epilepsy in children

“…The incidence of aplastic anemia with felbamate may be as high as 1:8000. 16 Felbamate remains on the market in the United States but with a black box warning for aplastic anemia and hepatic failure and is not considered a first-line anticonvulsant medication. 17 Rather, this drug is restricted to only the most intractable patients with epilepsy and can be administered only by a neurologist.…”