Felbamate Oxcarbazepine

Carbamazepine, phenytoin, phenobarbital and primidone, felbamate, oxcarbazepine, and topiramate stimulate the metabolism of oral contraceptive steroids. 

The last few years has seen an explosion in AEDs. Some of those mentioned above may fall by the wayside and others appear. At the time of writing, we could include felbamate, zonisamide oxcarbazepine and topiramate. They all appear to have a phenytoin-like action on sodium channels, although topiramate appears to also potentiate the action of GABA on GABAa receptors like the benzodiazepines but through a different site. 

The newer AEDs were first approved as adjunctive therapy for patients with refractory partial seizures. To date, lamotrigine, topiramate, and oxcarbazepine have received FDA approval for use in monotherapy in patients with partial seizures. Felbamate has monotherapy approval but causes significant side effects. 

Sodium channel blockers oxcarbazepine, carba-mazepine, felbamate, valproic acid... 

Type I Block SRF by enhancing sodium channel inactivation Phenytoin Carbamazepine Oxcarbazepine Lamotrigine Felbamate ... 

Partial seizures Carbamazepine Phenytoin Lamotrigine Valproic acid Oxcarbazepine Gabapentin Topiramate Levetiracetam Zonisamide Tiagabine Primidone, phenobarbital Felbamate... 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

Therefore, plasma concentrations for drugs metabolized by these isoforms will be affected (see Chapter 10). Thus, the addition of phenytoin to an AED regimen can reduce their plasma levels by inducing their CYP3A4 metabolism for carbamazepine, felbamate, lamotrigine, oxcarbazepine, tiagabine, valproate, and zonisamide. Other drugs for which metabolism is induced by phenytoin include methadone, theophylline, warfarin, and oral contraceptives. On the other hand, plasma phenytoin levels are increased by carbamazepine, felbamate, cimetidine, warfarin, chloramphenicol, isoniazid, and disulfiram. Plasma phenytoin levels are decreased by rifampin, antacids, and valproate (free phenytoin levels remain the same). 

Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiseizure drugs in pediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine, and felbamate. Clin Pharmacokinet 1995 29 341-369. 

Battino, D., Estienne, M., and Avanzini, G., Chnical pharmacokinetics of antiepUeptic drugs in paediatric patients. Part II. Phenytoin, carhamazepine, sulthiame, lamotrig-ine, vigabatrin, oxcarbazepine and felbamate, Clin. Pharmacokinet., 29 341-369,... 

Felbamate has no clinically relevant effect on the pharmacokinetics of oxcarbazepine, but concurrent use appears to increase the incidence of adverse effects. 

A double-blind, randomised study in 8 healthy subjects found that oxcarbazepine 300 to 600 mg every 12 hours, given with felbamate 600 to 1200 mg every 12 hours for 10 days had no effect on the plasma levels of the major aetive metabolite of oxcarbazepine (monohydroxyoxcar-bazepine). However, the levels of dihydroxyoxcarbazepine (a minor, inactive metabolite) were reduced, and the maximum serum levels of oxearbazepine were reduced, by about 20%. Although these changes were eonsidered to be elinically irrelevant, the incidence of some adverse ef-feets (dizziness, somnolence, nausea, diplopia) rose during concurrent use. ... 

Hulsman JARJ, Rentmeester TW, Banfield CR, Reidenberg P, Colucci RD, Meehan JW, Rad-wanskiE, MojaverianP, LinC-C, Nezamis J, Affrime MB, Glue P. Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine. Clin Pharmacol Ther( 995) 58,383-9. 

Any changes in the pharmacokinetics of oxcarbazepine brought about by other antiepileptics seem to be of minimal clinical relevance. However, the clinical relevance of the increase in the active metabolite monohydroxyoxcarbazepine with lamotrigine requires further study. In addition, there is the theoretical risk that monohydroxyoxcarbazepine levels might rise to toxic levels if carbamazepine or phenytoin were withdrawn. For mention that there may be an increase in adverse effects if oxcarbazepine is used with felbamate, see Oxcarbazepine +Felbamate , p.545. 

Carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, topiramate, zonisamide... 

A method for the analysis of the basic antiepileptic compounds felbamate, lamotrigine, carbamazepine, carbamazepine-10,11-epoxide, gabapentin, pregabalin, levetiracetam, and oxcarbazepine monohydroxy derivative (oxcarb MHD) in human plasma is described. This protocol incorporates a simplified sample preparation step followed by quantitative high performance chromatography-tandem mass spectrometry detection of commonly prescribed and monitored anticonvulsant drugs. Since polytherapy is common in epilepsy patients, use of a multiconstituent assay can improve laboratory efficiency and reduce required analytical time. 

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