New Add-on Therapy for Partial-onset Epilepsy

New Add-on Therapy for Partial-onset Epilepsy

Ko David Y , Levine Reed Loring
Published: US Neurology - Volume 4 - Issue I
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Adequate control of partial-onset epilepsy often requires polypharmacy, either due the to less than ideal efficacy of one antiepileptic drug (AED) (see Table 1) or due to side effects caused by the initial AED (see Table 2). Up to one-third of patients with partial-onset epilepsy will require treatment with more than one AED.

The ideal medical management of epilepsy is based on tailoring each patient’s regimen to his or her seizure type, comorbidities, lifestyle, and history of medication side effects. Therefore, a greater number of potential treatments offers greater options for any given patient to be treated with the best combination of medications. In recent years, many new AEDs have become available for add-on therapy for partial-onset epilepsy.

Of the newer AEDs, those that are US Food and Drug Administration (FDA)-approved for the adjunctive treatment of partial-onset epilepsy include felbamate tigabine, lamotrigine, pregabalin, gabapentin, topiramate, oxcarbazapine, zonisamide, and levetiracetam. An add-on AED should ideally have a clean pharmodynamic and phamcokinetic profile to minimize drug interactions and side effect profile. The newer AEDs are generally safer than the first-generation AEDs and, with the exception of Felbamate, do not require routine blood monitoring. All of the newer AEDs are category C in terms of use in females who want to have children, although a patient who is planning a pregnancy should aim for the lowest number of AEDs given at the lowest dose.

Rational polypharmacy has long been a goal, but unfortunately this has not been well studied in this age of evidence-based medicine. With so many different possible combinations, one rule of thumb of rational polypharmacy is to use medications with different mechanisms of action. Of the newer AEDs, one combination that would not be ‘rational’ would be neurontin and pregabalin, as they have exactly the same mechanism of action. One rational combination is valproic acid and lamotrigine, as lamotrigine’s half-life is prolonged, resulting in the patient requiring significantly lower doses.

Felbamate
Felbamate is recommended to patients with severe partial epilepsy or Lennox-Gastaut syndrome who fail other treatments. It is a potent blocker of N-methyl D-aspartate (NMDA) receptors and voltage-gated calcium (Ca) channels, and modulates sodium (Na+)-channel conductance. It is approximately 25% bound to plasma proteins and undergoes hepatic metabolism. In monotherapy, its elimination half-life may be as long as 30 hours, but when given with P450-inducing agents its half-life decreases to roughly 14 hours.1,2 The co-administration of valproate leads to increased plasma concentrations of felbamate. This medication will notably increase phenytoin levels and decrease carbamazepine levels.2,3 In both the adult and pediatric population, concomitant AEDs should be reduced by a minimum of 20% when starting felbamate, and may be reduced further if levels are high.1

Felbamate is generally well tolerated, with the most common adverse effects being insomnia, dizziness, fatigue, decreased appetite, weight loss, nausea, ataxia, and lethargy.2–5 In 110,000 patients, there were 10 cases of fatal aplastic anemia and 14 cases of fatal hepatic failure. The labeling was changed to advise that it be utilized in a limited subset of patients along with bi-weekly blood monitoring. Due to the risk for aplastic anemia and hepatic failure, it should be used when the benefits outweigh the risks.

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