What is the role of felbamate in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Felbamate is a potent anticonvulsant, very effective against multiple seizure types. Unfortunately, after the occurrence of aplastic anemia and hepatic failure, approval for general use was withdrawn. It is now available in the United States only for a very limited use, principally by neurologists in patients for whom potential benefit outweighs the risk. It blocks the NMDA receptors and voltage-gated calcium channels and also modulates sodium-channel conductance, but has no effect on gamma-aminobutyric acid (GABA) receptors. [68, 69, 70]

In addition to its activity against seizures, felbamate has been shown to have a neuroprotective effect on models of hypoxic-ischemic injuries. Wallis and Panizzon reported neuroprotection after treatment with felbamate in the rat hippocampal slice model following hypoxic exposure. [71] Wasterlain et al also demonstrated the neuroprotective effect of felbamate after bilateral carotid ligation in rat pups with a window of opportunity for neuroprotection of 1-4 hours after the ligation. [72]

After oral administration, felbamate is well absorbed, with a time to peak plasma concentration Tmax) of 1-4 hours after the dose. It is distributed rapidly throughout the body, including the brain. Lipid-mediated blood-brain barrier penetration of felbamate is similar to that of phenytoin (PHT) and phenobarbital (PHB). It is 20-25% bound to plasma proteins (mainly albumin).

The liver, via hydroxylation and conjugation, extensively metabolizes felbamate. The major identified metabolites of felbamate are p-hydroxy-felbamate, 2-hydroxy-felbamate, a monocarbonate, and a 3-carbamoyl oxy-2-phenylpropionic acid. Approximately 40-49% of a felbamate dose is recovered in the urine as the parent compound. The elimination half-life of felbamate ranges from 13 to 30 hours when the drug is administered as monotherapy.

Concomitant enzyme inducers decrease the half-life to 13-14 hours, and the concentration of felbamate is significantly higher than expected in the presence of valproate (VPA). Felbamate also increases PHT levels and reduces carbamazepine (CBZ) levels with increments in CBZ-epoxide levels.

Because of its potentially fatal toxic effects (in particular, the small but definitive risk of aplastic anemia and hepatic failure), use of felbamate is restricted to patients with severe partial epilepsy or Lennox-Gastaut syndrome who do not respond to other medications. The reported therapeutic serum level ranges from 30-100 mg/L. Initial dose of 1200 mg/d in 3 or 4 divided doses, with titration of 600 mg/wk up to a maximum of 2400-3600 mg/d, is recommended. Reducing the dosage of concomitant antiepileptic drugs (AEDs) can eliminate most adverse effects.

In children, recommended starting dose is 15 mg/kg/d, with weekly increments as high as 45 mg/kg/d. Again, concomitant AEDs should be reduced by 20% or more upon initiation of treatment and reduced further on the basis of symptoms and blood levels. Felbamate is available as 400 mg and 600 mg tablets and 600 mg/5 mL suspension.

Felbamate usually is well tolerated. Common adverse effects include insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue, ataxia, and lethargy. Polytherapy is associated with increases in adverse effects. Clinical trials have shown that approximately 12% of patients discontinue the drug because of adverse effects. Fatal hepatic failure has been reported in 14 of 110,000 treated patients. Besides polytherapy, no other risk factor has been found. Most of the deaths occurred within 6 months of initiation of therapy.


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