Although there have been important improvements in antiepileptic drug (AED) therapy options in recent years, many patients with epilepsy still have disease refractory to certain therapies. A survey of the newest AEDs shows clinical progress and improved outcomes, but also room for improvement.
“The 4 newest AEDs have possible advantages over previously approved drugs. However, at this point, none is clearly better or considered suitable for first-line therapy,” said Carl W. Bazil, MD, PhD, Director, Comprehensive Epilepsy Center, Columbia University, New York, at the 2016 American Academy of Neurology annual meeting.
Clobazam (Onfi) has been available in many developed countries for decades. It was approved by the FDA in 2011 as an orphan drug for the adjunctive treatment of seizures associated with the Lennox-Gastaut syndrome based on its significant reduction of atonic seizures in 2 multicenter controlled clinical trials. But it has also been associated with serious adverse events and subsequent warnings from the FDA.
In other countries, however, clobazam is widely used as a broad-spectrum AED; one study of patients with refractory focal epilepsy had a seizure-free rate of 11% at 6 months, Dr Bazil said.
“Clobazam differs from other benzodiazepines in that tolerance, especially to the anticonvulsant effect, seems much less common. It is also less sedating than other drugs in this class, although this is the most common adverse effect,” he emphasized.
Clobazam's half-life of 70 to 80 hours is relatively long, so once-daily dosing is typical, usually at bedtime. Of note, cannabidiol may alter the metabolism of clobazam, leading to higher concentrations of the active metabolite and possibly resulting in increased efficacy. Insurers may make this agent prohibitively difficult or expensive to obtain, Dr Bazil suggested.
Initially approved by the FDA in 2012 for the treatment of patients with seizures, perampanel (Fycompa) tablets received a new indication from the FDA in 2015 for the adjunctive treatment of primary generalized tonic-clonic seizures in patients aged ≥12 years. And in May 2016, the FDA approved a new formulation of perampanel as oral suspension for the adjunctive treatment of patients with seizures, offering a new treatment option for patients who are unable to use oral tablets.
“Perampanel is a first-in-class AED that acts through noncompetitive AMPA receptor inhibition. It therefore likely has its anticonvulsant action through decreased excitation of overactive neurons,” said Dr Bazil.
The efficacy of perampanel in focal seizures was shown in 3 randomized, double-blind, placebo-controlled clinical trials, demonstrating an effective dose of 4 mg to 12 mg daily.
As with clobazam, perampanel has a very long half-life (70-100 hours) and is therefore suitable for once-daily dosing.
The most common adverse effects associated with perampanel include dizziness, somnolence, headache, and fatigue, but there are also concerns for adverse psychiatric effects, including aggression, irritability, and homicidal ideation. The drug has a boxed warning about these psychiatric effects, although they are rare, said Dr Bazil.
“Despite its distinct mechanism, perampanel is not definitely more effective than other agents, and there are psychiatric concerns,” Dr Bazil concluded.
The FDA approved ezogabine (Potiga) in 2011 as adjunctive therapy for the treatment of adults (aged ≥18 years) with partial-onset seizures that responded inadequately to several alternative treatments. Ezogabine is a first-in-class drug with a mechanism of action that activates voltage-gated potassium channels. The efficacy of ezogabine in focal seizures was demonstrated in 3 randomized, double-blind, placebo-controlled clinical trials. The effective dose is 600 mg to 1200 mg daily given in 3 doses.
Urinary retention was a known and expected adverse effect of ezogabine, and occurred in approximately 2% of patients, said Dr Bazil. More concerning, however, was the “postmarketing recognition of bluish discoloration caused by accumulation of a metabolite,” he said.
“Discoloration is typically rather subtle, but may be seen in the skin, especially fingers and lips. It can also occur in the retina, leading to the recommendation for ophthalmological examinations every 6 months on the drug,” Dr Bazil explained.
Although reports suggest that discoloration will gradually resolve with time after the drug is stopped, this complication and the need for monitoring have greatly limited the use of ezogabine in clinical practice.
Eslicarbazepine (Aptiom), which is structurally related to carbamazepine (Tegretol) and oxcarbazepine (Trileptal), was initially approved by the FDA in 2013 as adjunctive therapy; in 2015 it received a new indication as monotherapy for the treatment of patients with partial-onset seizures.
The initial approval of eslicarbazepine for partial-onset seizures was based on 3 randomized, double-blind, placebo-controlled clinical trials in patients with refractory focal seizures. The efficacy of eslicarbazepine as monotherapy was subsequently established in 2 historical control clinical trials and used for the FDA approval of the new indication as monotherapy. The adverse effects of the drug are qualitatively similar to the related compounds, Dr Bazil said.
Eslicarbazepine is dosed at 400 mg to 800 mg daily, which can be increased to 1200 mg daily.
“Eslicarbazepine is similar to oxcarbazepine, but with a longer half-life. Although there are theoretical advantages, no comparative clinical trials have been performed,” said Dr Bazil.