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Felbamate is currently being developed as an antiepileptic agent. Although its mechanism of action has yet to be fully elucidated, felbamate appears to inhibit both the spread of seizures and increase seizure threshold in animal models. Data available in the clinical setting provide evidence that, at doses of up to 3600 mg/day as an adjunct to existing antiepileptic therapy or as monotherapy following substitution for other medications, the drug reduces the frequency of partial onset seizures in adult patients refractory to conventional antiepileptic treatments. Felbamate is also effective in the treatment of Lennox-Gastaut syndrome in children, a severe epilepsy which is usually refractory to antiepileptic agents. The effect of felbamate in the treatment of generalised tonic-clonic seizures in adults with partial onset seizures which are secondarily generalised is promising but requires clarification in large-scale trials.
The most common adverse effects occurring during administration of felbamate are mild to moderate gastrointestinal (nausea, vomiting and anorexia) and central nervous system (headache, somnolence, diplopia, dizziness and insomnia) disturbances. Drug interactions with other antiepileptic agents may prove problematic in terms of adverse effects.
Thus, at this stage of its development, the antiepileptic efficacy of felbamate in treatmentrefractory patients with partial onset seizures and Lennox-Gastaut syndrome has been proven but efficacy in generalised tonic-clonic seizures requires further substantiation in large well controlled and well designed clinical trials. In addition, a more comprehensive base of comparative clinical trials data is necessary to further clarify issues of relative efficacy and tolerability compared with other antiepileptic agents. The clinical implications of the drug interactions associated with felbamate also require more detailed investigation. These data will be awaited with interest and when available will help to place felbamate in perspective in the management of epilepsy.
Felbamate has anticonvulsant activity in a number of animal models. The most pronounced activity is observed in the mouse maximal electroshock seizure model in which felbamate inhibits hindlimb tonic extension, indicating an inhibition of seizure spread. The drug also confers protection against pentylenetetrazol-, picrotoxin- and isoniazid-induced seizures but is less effective in preventing seizures induced by bicuculline and ineffective against strychnine-induced seizures. These data suggest that felbamate may increase seizure threshold. Felbamate also suppresses N-methyl-D-aspartate- (NMDA) and quisqualic acid-induced seizures. Inhibition of seizures in the corneal-kindled rat model of complex partial onset seizures has also been demonstrated with felbamate.
The mechanism of action of felbamate has yet to be fully elucidated but, unlike some antiepileptic drugs, it does not appear to involve the stimulation of the central γ-aminobutyric acid (GABA) system since radioligand binding studies have demonstrated that the drug has little or no affinity for components of the benzodiazepine/GABAA/chloride channel ionophore. Similarly, the drug has little affinity for the NMDA receptor as a whole but appears to have some affinity for the glycine recognition site of the NMDA receptor.
Felbamate possess some neuroprotective activity against hypoxic-ischaemic damage at plasma concentrations achieved during clinical use.
Felbamate exhibits linear pharmacokinetics with dose-related increases in plasma concentrations and area under the plasma concentration-time curve values. Following administration of a single dose of 100 to 1200mg in healthy volunteers, maximum plasma felbamate concentrations of 2.0 to 21.2 mg/L were achieved, while following 28 days of treatment (400 to 1200 mg/day) maximum plasma felbamate concentrations were 2.5 to 3 times higher than those achieved after the first dose. Clinical trials have found no difference in the pharmacokinetic behaviour of felbamate in paediatric and adult populations. The presence of food does not appear to affect absorption of felbamate.
Felbamate is equally distributed between the plasma and red blood cells and shows a low plasma protein binding (22 to 36). The apparent volume of distribution after a single oral dose of 200 or 1200mg or repeated administration of 1600 mg/day ranged from 0.74 to 0.85 L/kg and there does not appear to be any systemic accumulation following repeated administration since the area under the plasma concentration-time curve values are the same on the first and last days of administration. The elimination half-life of a single dose (100 to 1200mg) and repeated doses (400 to 1600 mg/day) of felbamate ranged from 13.5 to 23.1 hours. The value for apparent clearance was approximately 25 ml/h/kg after a single dose of 1200mg to healthy volunteers. In patients with epilepsy who were receiving phenytoin or carbamazepine, administration of a single dose of felbamate 200mg or repeated administration of 1600 mg/day resulted in apparent clearance values of 44.5 and 35.7 ml/h/kg, respectively.
Felbamate is metabolised to 2-hydroxy, p-hydroxy and monocarbamate metabolites plus a number of unidentified polar metabolites and conjugates, none of which have significant anticonvulsant activity in the mouse maximal electroshock model. Following oral administration approximately 90% of radiolabelled felbamate was eliminated in the urine and <4% in the faeces, with the majority being in the form of the unchanged parent compound. The low recovery of radioactivity in the faeces suggests good oral absorption.
Felbamate interacts with other antiepileptic agents, changing the pharmacokinetic parameters of both felbamate and other antiepileptic agents. Plasma concentrations of felbamate are increased during coadministration with valproic acid and decreased with phenytoin and carbamazepine. Furthermore, plasma concentrations of phenytoin and valproic acid are increased during coadministration with felbamate, while those of carbamazepine are decreased and those of the epoxide metabolite of carbamazepine are increased.
The efficacy of felbamate as an antiepileptic agent has been assessed in 7 major clinical trials involving a total of 370 patients. At present there are no data regarding the effect of felbamate in newly diagnosed patients or comparing its efficacy with that of standard antiepileptic agents. Available data indicate that felbamate (up to 3600 mg/day) is effective in suppressing partial onset seizures in patients whose epilepsy is poorly controlled by other antiepileptic medications, when administered as an adjunct or as monotherapy. A reduction in generalised tonic-clonic seizures has been observed in patients with partial onset seizures which were secondarily generalised. Seizures associated with the Lennox-Gastaut syndrome in children and adults are also suppressed by felbamate.
The most common effects associated with felbamate therapy are mild to moderate in severity, with gastrointestinal (nausea, vomiting, anorexia) and central nervous system (dizziness, insomnia, somnolence, headache, diplopia) disturbances being the most frequently reported. Adverse effects are more frequent during the use of felbamate as an adjunct than as a monotherapy.
Dosage and Administration
Felbamate is administered as a tablet or suspension at a dosage of up to 3600 mg/day in adults and up to 45 mg/kg/day or 3600 mg/day, whichever is less, in children (<14 years old). The daily dosage can be divided into 3 or 4 administrations. Due to the presence of drug interactions between felbamate and other antiepileptic medications, initiation of felbamate as an adjunct therapy may necessitate downward adjustment of the dosage of phenytoin and valproic acid, based on clinical observations and steady-state plasma concentrations. It is recommended that the dosage of carbamazepine be reduced by one-third on addition of felbamate therapy.
KeywordsCarbamazepine Valproic Acid Seizure Frequency Felbamate Antiepileptic Agent
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- Burdette DE, Zheng C, Tornow MA, Olson LD, Sackellares JC. Felbamate reduces atypical generalized spike wave discharges in patients with Lennox-Gastaut Syndrome. Abstract. Neurology 42: 330, 1992Google Scholar
- Dix R, Raymond R, Kamin M, Rosenberg A, Perhach J. Dose and concentration-effect relationship of felbamate (felbatol™) in Lennox-Gastaut syndrome. Journal of Neurology 239 (Suppl. 2): 571, 1992Google Scholar
- Fuerst RH, Graves NM, Leppik IE, Remmel RP, Rosenfeld WE, et al. A preliminary report on alteration of carbamazepine and phenytoin metabolism by felbamate. Abstract. Drug Intelligence and Clinical Pharmacy 20: 465, 1986Google Scholar
- Garofalo EA, Olson LD, Sackellars JC, Komarynski MA, Tornow MA, et al. Lennox-Gastaut Syndrome: treatment of seizures with felbamate. Abstract. Annals of Neurology 30: 492, 1991Google Scholar
- Gordon R, Diamantis W, Sofia RD. Enhancement of the anticonvulsant activities of diazepam, muscimol and phenobarbital by felbamate in the mouse. Abstract. FASEB Journal 2:105, 1988Google Scholar
- Graves NM, Leppik PIE. Antiepileptic medications in development. DICP, The Annals of Pharmacotherapy 25: 978–986, 1991Google Scholar
- Graves NM, Remmel RP, Miller S, Rathbun RC, Miller ML, et al. The effect of felbamate on the major metabolites of carbamazepine. Abstract. Pharmacotherapy 9: 196, 1989bGoogle Scholar
- Gudipati RM, Raymond RH, Ward DL, Shumaker RC, Perhach JL. Effect of food on the absorption of felbamate in healthy male volunteers. Abstract. Neurology 42 (Suppl. 3): 332, 1992Google Scholar
- Leppik IE, Kramer LD, Bourgois B, Graves N, Campbell J, et al. Felbamate after withdrawal from other antiepileptic drugs. Abstract. Neurology 40 (Suppl. 1): 158, 1990Google Scholar
- Milne KL, Pledger GW. Drug interactions in a controlled trial: problems in design and implementation. Abstract. Epilepsia 28: 615, 1987Google Scholar
- Murphy JV, Schallert GS, Bednarczyk M. Use of felbamate in intractable, pediatric-onset epilepsies. Abstract. Epilepsia 32: 24, 1991Google Scholar
- Patrias J, Espe-Lillo J, Ritter FJ. Felbamate-methsuximide interaction. Abstract. Epilepsia 33 (Suppl. 3): 84, 1992Google Scholar
- Penix LP, Morin AM, Wasterlain CG. Effect of felbamate on MK-801 binding. Abstract. Epilepsia 31: 642, 1990Google Scholar
- Sachdeo RC, Fraught E, Kamin M, Rosenberg A. Maintenance of seizure control with felbamate monotherapy. Abstract. Neurology 42 (Suppl. 3): 330, 1992aGoogle Scholar
- Shumaker RC, Fantel C, Kelton E, Wong K, Weliky I. Evaluation of the elimination of [14C] felbamate in healthy men. Abstract. Epilepsia 31: 642, 1990Google Scholar
- Sofia R, Kramer I, Perhach JL, Rosenberg A. Felbamate. In Pisani F, et al. (Eds) Antiepileptic drugs (Epilepsy Research Suppl. 3), Elsevier Science Publishers, 1991Google Scholar
- Wagner ML, Leppik IE, Graves NM, Remme RP, Campbell JI. Felbamate serum concentrations: effect of valproate, carbamazepine, phenytoin and phenobarbital. Abstract. Epilepsia 31: 642, 1990Google Scholar
- Wagner ML, Graves NM, Leppik IE, Remmel RP, Ward DL, et al. The effect of felbamate on valproate disposition. Abstract. Epilepsia 32: 15, 1991aGoogle Scholar
- Ward DL, Shumaker RC. Comparative bioavailability of felbamate in healthy men. Abstract. Epilepsia 31: 642, 1990Google Scholar
- Ward DL, Wagner ML, Perhach JL, Kramer L, Graves N, et al. Felbamate steady-state pharmacokinetics during coadministration of valproate. Abstract. Epilepsia 32 (Suppl. 30): 8, 1991Google Scholar