Felbamate

Mechanism of action

Felbamate has been proposed to have a unique dual mechanism of action as a positive modulator of GABAA receptors and as a blocker of NMDA receptors, particularly isoforms containing the NR2B subunit.{{Cite journal

Approval history

United States

• August 1993. Felbamate was approved for partial seizures with and without secondary generalization in adults and for Lennox–Gastaut Syndrome, a serious form of childhood epilepsy. Over the following year 150,000 people were started on felbamate therapy and a third of these became established.
• August 1, 1994. It was urgently withdrawn after 10 cases of aplastic anemia. A "Dear Doctor" letter was sent to 240,000 physicians.
• September 27, 1994. Felbamate had a limited redemption in another "Dear Doctor" letter sent to 260,000 physicians. It was recommended that the drug remain available only for patients with severe epilepsy for whom the benefits outweigh the risks, and that changes be made to the product's labelling to reflect the newly recognized risk. This redemption came with an additional warning since there had been 10 cases acute liver failure (4 of which were fatal). At this point, 10,000 to 12,000 people remained on the drug.

United Kingdom

• The drug is only available on a limited named-patient basis.

Indications and usage

• Adults: Monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization.
• Children: Adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome.

Dosing

Felbamate is available in tablets (400 mg and 600 mg) and as a peach-coloured oral suspension (600 mg/5 mL).

• Adults (≥ 14 years): begin with 1,200 mg daily given every 6 to 8 hours
• Children (2–14 years): 15 to 45 mg per kg per day given every 6 to 8 hours

Side effects

Adverse reactions include decreased appetite, vomiting, insomnia, nausea, dizziness, somnolence, and headache. Many patients report increased alertness with the drug. Two rare but very serious effects include aplastic anemia and serious liver damage. The risk of aplastic anemia is between 1:3,600 and 1:5,000, of which 30% of cases are fatal. The risk of liver damage is between 1:24,000 to 1:34,000, of which 40% of cases are fatal.

Drug interactions

Felbamate is an inhibitor of CYP2C19 - an enzyme involved in the metabolism of several commonly used medications. Felbamate interacts with several other AEDs, including phenytoin, valproate, and carbamazepine; dosage adjustments may be necessary to avoid adverse effects. Concomitant administration of felbamate and carbamazepine decreases blood levels of both drugs, while increasing the level of carbamazepine-10,11 epoxide, the active metabolite of carbamazepine.

History

Felbamate was discovered by Frank Berger at Wallace Laboratories.

References

References

1. (March 1997). "Barbiturate-Like Actions of the Propanediol Dicarbamates Felbamate and Meprobamate". J. Pharmacol. Exp. Ther..
2. (November 1991). "Felbamate for Partial Seizures: Results of a Controlled Clinical Trial". Neurology.
3. (March 1995). "Efficacy of Felbamate Monotherapy in Patients Undergoing Presurgical Evaluation of Partial Seizures". Epilepsy Res..
4. (Feb 1994). "Mechanism of Action of the Anticonvulsant Felbamate: Opposing Effects on ''N''-Methyl-D-aspartate and Gamma-Aminobutyric Acid A Receptors". Annals of Neurology.
5. (June 1996). "Felbamate Inhibits [³H]''t''-Butylbicycloorthobenzoate (TBOB) Binding and Enhances Cl^– Current at the Gamma-Aminobutyric Acid A (GABAA) Receptor". J. Pharmacol. Exp. Ther..
6. (May 1995). "Felbamate Block of the ''N''-Methyl-D-aspartate Receptor". [[The Journal of Pharmacology and Experimental Therapeutics]].
7. (May 1999). "Subtype-Selective Antagonism of ''N''-Methyl-D-aspartate Receptors by Felbamate: Insights into the Mechanism of Action". [[The Journal of Pharmacology and Experimental Therapeutics]].
8. (March 2008). "Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor". [[Journal of Medicinal Chemistry]].
9. Rogawski MA. (March 2011). "Revisiting AMPA Receptors as an Antiepileptic Drug Target". [[Epilepsy Currents]].
10. "www.fda.gov".
11. "www.fda.gov".
12. Flockhart DA. (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". [[Indiana University School of Medicine]].
13. (February 1998). "Newer Antiepileptic Drugs: Gabapentin, Lamotrigine, Felbamate, Topiramate and Fosphenytoin". [[American Family Physician.
14. (2008-04-07). "Frank Berger". Daily Telegraph.