RIVIERA BEACH, FLORIDA—The efficacy of newer antiepileptic drugs (AEDs) may not be greater than that of older drugs, according to an update presented at the 41st Annual Meeting of the Southern Clinical Neurological Society. Many AEDs appear to be safer, although in some cases it is too soon to tell.
Drawing from both clinical trials and empirical evidence, Richard H. Mattson, MD, Professor of Neurology and Epilepsy Fellowship Director at Yale University in New Haven, Connecticut, reviewed the benefits and risks of the six newest AEDs on the market.
Clobazam
Clobazam, a benzodiazepine that was used in other countries for 35 years, received FDA approval in late 2011.
Although other benzodiazepines have nitrogen in the 1, 4 positions on the B ring of the molecule, clobazam has a 1, 5 structure. Its unique formulation makes it less sedating and less likely to lead to tolerance.
Benzodiazepines as a class are safe, noted Dr. Mattson, but the FDA recently issued a warning about Stevens Johnson syndrome (SJS) in patients who take clobazam. Of 20 known cases, six have occurred in the United States.
One of Dr. Mattson’s patients developed a rash suggestive of SJS. While he is careful to warn patients of the risk, Dr. Mattson continues to prescribe the drug. About half of his patients have a positive response, and about half develop tolerance by six months. For the others, he said, “It can be dramatically effective.”
Eslicarbazepine
Eslicarbazepine acetate, a monohydroxy derivative of oxcarbazepine that received FDA approval late last year, was developed in an attempt to avoid the side effects of carbamazepine and oxcarbazepine.
Clinicians initially hoped that eslicarbazepine would have no inductive effect, but it has been found to increase clearance of oral contraceptives, for example, and to affect bone biomarkers. Eslicarbazepine does appear to be better tolerated, however. In a study comparing oxcarbazepine twice a day with once-daily dosing of eslicarbazepine, those on oxcarbazepine were three times more likely to have side effects.
Carbamazepine remains the gold standard for partial (focal) seizures, based on clinical evidence. However, noting that carbamazepine, once hailed as a “shining new star,” was later found to have “horrendous pharmacokinetics and poor tolerability,” Dr. Mattson cautioned that it is too soon to draw conclusions about eslicarbazepine.
Ezogabine
Ezogabine has a novel mechanism of action. It facilitates potassium channel opening, thereby aiding repolarization of neurons and inhibiting repetitive firing. The drug had modest efficacy in clinical trials.
Two adverse effects have been reported—a bluish skin discoloration and visual disturbances. The FDA recently issued an advisory about both and called for patients on ezogabine to be monitored for visual problems. Although it is too early to know whether the visual problems are reversible, Dr. Mattson said he would not prescribe this drug.
Vigabatrin
Visual field disturbances have also been associated with vigabatrin, an AED synthesized to inhibit gamma-aminobutyric acid (GABA) transaminase. Although the drug is otherwise well tolerated and reasonably effective, rates of visual disturbances are reported to be as high as 30%.
But that figure is suspect, according to Dr. Mattson. Tests of visual field disturbances are often inaccurate, particularly in patients with epilepsy. In addition, a committee engaged in a second prospective review has found the risk of visual problems to be much lower thus far.
Lacosamide
Lacosamide is another novel compound, with a mechanism of action that involves slow sodium channel inactivation. The drug has excellent pharmacokinetics and is safe, according to Dr. Mattson.
“If something bad were going to happen with lacosamide, it should have appeared by now,” he said. “I think it’s a keeper.”
Perampanel
Perampanel, a first-in-class selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is effective, with no serious toxicity reported to date. It does, however, have a boxed warning about the risk of serious neuropsychiatric events, the significance of which is not yet known.
Gains in Safety, If Not in Efficacy
Twenty-one AEDs are now available, Dr. Mattson said, including some entirely new drugs and others that are refinements of older agents. Many newer drugs have improved pharmacokinetics, fewer interactions, and greater safety than older AEDs.
The same is not true of efficacy, however. Two trials of AEDs, 15 years apart—the latter studying second-generation agents—found virtually identical response rates: In both trials, close to half of those studied were well controlled for a year. “We don’t have data for all the newer drugs,” Dr. Mattson noted, “but what evidence we do have indicates that we really have not made a lot of progress in finding a drug with greater efficacy.