For new-onset epilepsy, there’s not yet strong enough evidence for the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) to recommend third-generation antiepileptic drugs (AEDs) in their new treatment guidelines.
But for treatment-resistant epilepsy, several recently approved AEDs may be winners.
“The update was prompted by the explosion of new antiepileptic drugs that have been approved since the time of the first guideline and the overwhelming amount of information available on each one,” Jacqueline French, MD, of the New York University Comprehensive Epilepsy Center, told MedPage Today.
Issued jointly by the two organizations and published online in Neurology, the updated guidance for new-onset and treatment-resistant epilepsy replace ones in effect since 2004. The FDA has approved six third-generation AEDs that were included in this review since that time — eslicarbazepine (Aptiom), ezogabine (Potiga, which has been discontinued), lacosamide (Vimpat), perampanel (Fycompa), pregabalin (Lyrica), and rufinamide (Banzel) — and two older AEDs for certain types of epileptic disorders, clobazam (Onfi) and vigabatrin (Sabril).
To develop the new guidelines, a joint AAN-AES subcommittee of experts systematically reviewed studies from January 2003 to November 2015, classifying them according to the AAN therapeutic rating scheme. Depending on the strength of the evidence for each drug, the subcommittee established recommendations labeled as Level A (effective and the recommendation should be considered), Level B (possibly effective and the recommendation may be considered), Level C (similar to Level B, but with different levels of evidence), or Level U (unproven or unknown).
The subcommittee had no Level A recommendations for new-onset epilepsy, but stated:
- Lamotrigine (Lamictal) should be considered for patients with new-onset focal epilepsy or unclassified generalized tonic-clonic seizures (Level B), and levetiracetam and zonisamide (Zonegran) may be considered (Level C)
- Pregabalin at 150 mg/d is possibly less efficacious than lamotrigine at 100 mg/d (Level C)
- For patients age 60 or older, lamotrigine should be considered (Level B) and gabapentin may be considered (Level C)
- Ethosuximide (Zarontin) or valproate should be considered before lamotrigine in childhood absence epilepsy, unless there are compelling reasons based on adverse events profile (Level B)
It’s incorrect to associate the strength of the evidence — which has to do with the adequacy of the trial design — with the effectiveness of the drug, noted French, who was a member of the subcommittee.
“Level A is usually achieved through two adequate and well-controlled trials with placebo comparator, which is a requirement for initial FDA approval,” she said. “Studies are downgraded for significant percent dropout, but not for degree of effectiveness, so for example a less effective, better tolerated drug with low dropout might fare better than a highly effective drug that some people do not tolerate.”
For newly diagnosed epilepsy, the subcommittee members decided there was not enough data to give third-generation AEDs Level A or B ratings, but “absence of evidence just means the trial has not yet been done in most cases,” French said.
“Notably, at the time of the last guideline publication in 2004, there was insufficient evidence to endorse levetiracetam (Keppra) yet even at that time it was — and still is — one of the most commonly used AEDs for treatment of newly diagnosed epilepsy,” she said.
For treatment-resistant epilepsy, the subcommittee recommended:
- Immediate-release pregabalin and perampanel for treatment-resistant adult focal epilepsy (Level A)
- Vigabatrin for treatment-resistant adult focal epilepsy, but not as first-line agents (Level A)
- Rufinamide for Lennox-Gastaut syndrome as add-on therapy (Level A)
The subcommittee also made several Level B and Level C recommendations for treatment-resistant adult and childhood focal epilepsy, treatment-resistant juvenile myoclonic epilepsy, and treatment-resistant generalized tonic-clonic seizures in adults.
“There is no single takeaway message from this update, as there might be for a guideline with a focused clinical question,” French stated. “Rather, the guidelines provide up-to-date information on a large number of available drugs for epilepsy, so that providers will know where the high quality evidence exists for use of these drugs in specific epilepsy syndromes.”
This guideline was developed with financial support from the American Academy of Neurology.
Subcommittee members disclosed relationships with Pfizer, UCB, GlaxoSmithKline, Valeant, Sunovion, Upsher-Smith, Cyberonics, SK Life Science, Eisai Pharmaceuticals, Lundbeck, Novartis, Supernus, Anavex Life Science, Marinus Pharmaceuticals, GW Pharmaceuticals, Takeda, Acorda, Impax, and Johnson & Johnson.