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Felbamate

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Felbamate
Clinical data
Trade namesFelbatol
AHFS/Drugs.comMonograph
MedlinePlusa606011
Routes of
administration		By mouth(tablets,oralsuspension)
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability>90%
MetabolismHepatic
Eliminationhalf-life20–23 hours
Identifiers
  • (3-carbamoyloxy-2-phenylpropyl) carbamate
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.042.714Edit this at Wikidata
Chemical and physical data
FormulaC11H14N2O4
Molar mass238.243g·mol−1
3D model (JSmol)
  • O=C(N)OCC(c1ccccc1)COC(N)=O
  • InChI=1S/C11H14N2O4/c12-10(14)16-6-9(7-17-11(13)15)8-4-2-1-3-5-8/h1-5,9H,6-7H2,(H2,12,14)(H2,13,15)checkY
  • Key:WKGXYQFOCVYPAC-UHFFFAOYSA-NcheckY
(verify)

Felbamate(marketed under the brand nameFelbatolbyMedPointe) is ananticonvulsant[2]used in the treatment ofepilepsy.It is used to treatpartial seizures[3][4](with and without generalization) in adults and partial and generalized seizures associated withLennox–Gastaut syndromein children. However, an increased risk of potentially fatalaplastic anemiaand/orliver failurelimit the drug's usage to severe refractory epilepsy.

Mechanism of action

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Felbamate has been proposed to have a unique dual mechanism of action as a positive modulator ofGABAAreceptors[5][6]and as a blocker ofNMDA receptors,particularly isoforms containing theNR2Bsubunit.[7][8][9][10]Although it is clear that felbamate does cause pharmacological inhibition of NMDA receptors, the relevance of NMDA receptor blockade as a strategy for the treatment of human epilepsy has been questioned.[11]Therefore, the importance of the effects of felbamate on NMDA receptors to its therapeutic action in epilepsy is uncertain.

Approval history

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United States

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  • 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  • August 1, 1994.It was urgently withdrawn after 10 cases of aplastic anemia.[12]A "Dear Doctor" letter was sent to 240,000 physicians.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.[13]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

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

Indications and usage

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  • 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

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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

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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 includeaplastic anemiaand 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.[citation needed]

Drug interactions

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Felbamate is aninhibitorofCYP2C19- an enzyme involved in themetabolismof several commonly used medications.[14]Felbamate interacts with several other AEDs, includingphenytoin,valproate,andcarbamazepine;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 ofcarbamazepine-10,11 epoxide,the activemetaboliteof carbamazepine.[15]

History

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Felbamate was discovered byFrank BergeratWallace Laboratories.[16]

References

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  1. ^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)".nctr-crs.fda.gov.FDA.Retrieved22 Oct2023.
  2. ^Rho JM, Donevan SD, Rogawski MA (March 1997)."Barbiturate-Like Actions of the Propanediol Dicarbamates Felbamate and Meprobamate".J. Pharmacol. Exp. Ther.280(3): 1383–91.PMID9067327.
  3. ^Leppik IE, Dreifuss FE, Pledger GW, et al. (November 1991). "Felbamate for Partial Seizures: Results of a Controlled Clinical Trial".Neurology.41(11): 1785–9.doi:10.1212/wnl.41.11.1785.PMID1944909.S2CID25245002.
  4. ^Devinsky O, Faught RE, Wilder BJ, et al. (March 1995)."Efficacy of Felbamate Monotherapy in Patients Undergoing Presurgical Evaluation of Partial Seizures".Epilepsy Res.20(3): 241–6.doi:10.1016/0920-1211(94)00084-A.PMID7796796.S2CID21915205.
  5. ^Rho JM, Donevan SD, Rogawski MA (Feb 1994). "Mechanism of Action of the Anticonvulsant Felbamate: Opposing Effects onN-Methyl-D-aspartate and Gamma-Aminobutyric Acid A Receptors ".Annals of Neurology.35(2): 229–34.doi:10.1002/ana.410350216.PMID8109904.S2CID33913077.
  6. ^Kume A, Greenfield LJ, Macdonald RL, Albin RL (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.277(3): 1784–92.PMID8667250.
  7. ^Subramaniam S, Rho JM, Penix L, Donevan SD, Fielding RP, Rogawski MA (May 1995). "Felbamate Block of theN-Methyl-D-aspartate Receptor ".The Journal of Pharmacology and Experimental Therapeutics.273(2): 878–86.PMID7752093.
  8. ^Kleckner NW, Glazewski JC, Chen CC, Moscrip TD (May 1999). "Subtype-Selective Antagonism ofN-Methyl-D-aspartate Receptors by Felbamate: Insights into the Mechanism of Action ".The Journal of Pharmacology and Experimental Therapeutics.289(2): 886–894.PMID10215667.
  9. ^Harty TP, Rogawski MA (March 2000)."Felbamate Block of RecombinantN-Methyl-D-aspartate Receptors: Selectivity for the NR2B Subunit ".Epilepsy Research.39(1): 47–55.doi:10.1016/s0920-1211(99)00108-4.PMID10690753.S2CID25467576.
  10. ^Chang HR, Chung-Chin Kuo CC (March 2008). "Molecular determinants of the anticonvulsant felbamate binding site in the N-methyl-D-aspartate receptor".Journal of Medicinal Chemistry.51(6): 1534–45.doi:10.1021/jm0706618.PMID18311896.
  11. ^Rogawski MA (March 2011)."Revisiting AMPA Receptors as an Antiepileptic Drug Target".Epilepsy Currents.11(2): 56–63.doi:10.5698/1535-7511-11.2.56.PMC3117497.PMID21686307.
  12. ^"www.fda.gov".Food and Drug Administration.Archived fromthe originalon November 2, 2008.Retrieved2008-11-15.
  13. ^"www.fda.gov".Food and Drug Administration.Archived fromthe originalon September 29, 2007.Retrieved2008-11-15.
  14. ^Flockhart DA (2007)."Drug Interactions: Cytochrome P450 Drug Interaction Table".Indiana University School of Medicine.Retrieved on December 25, 2008.
  15. ^Curry WJ, Kulling DL (February 1998)."Newer Antiepileptic Drugs: Gabapentin, Lamotrigine, Felbamate, Topiramate and Fosphenytoin".Am Fam Physician.57(3): 513–20.PMID9475899.Archived fromthe originalon 2011-09-27.Retrieved2005-12-06.
  16. ^"Frank Berger".Daily Telegraph.2008-04-07.ISSN0307-1235.Retrieved2018-09-22.
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