Q: How do you incorporate the newer, third-generation AEDs in clinical practice?

The US Food and Drug Administration (FDA) decision to allow for the extrapolation of AED efficacy data for the same seizure type (and the same presumed pathophysiology) from adults to children ages 4 years and older was huge. This has been of great benefit to those of us who treat children. Now, with AEDs already approved in adults for seizure types that also affect children, such as focal seizures, all we have to do for pediatric studies is to figure out what dose produces the same effective serum levels. Persistence has paid off, and this change has been a long time coming. The background is that adults will almost always be studied first, owing to many factors, the chief factor being that they can consent for themselves. In the past, pediatric clinicians had no choice but to use their best clinical judgment (with little or no pediatric information to go on). Pediatric studies were conducted, but they were slow to recruit patients and the ethics were challenging, since, historically, children with refractory seizures might have been exposed to placebo. This is a much better path and is a win for the FDA, physicians, and families.

With respect to the newest agents, I think that there are 3 significant advantages over the older agents. In general, they are better tolerated by patients, they have fewer interactions with other drugs, and several of them only have to be taken once daily. These are substantial advantages that relate to patient adherence. Further, while simply lowering the patient’s total pill burden might be overlooked by some, most patients appreciate it and view this as a big improvement. As doctors, we often do not think about that, but when patients have to buy 2 pill containers because their medicines for the week do not fit in 1, they appreciate a lowered pill burden. In summary, the FDA decision to allow data extrapolation from partial seizure studies in adults to children has been hugely beneficial to those of us who treat children. In general, the newer AEDs are better tolerated and have fewer drug-drug interactions, and several of them have the additional advantages of once-daily dosing and a low pill burden.

Other than cost, differences that govern the choice of a third-generation AED over a first- or second-generation drug primarily come down to issues of pharmacokinetics, tolerability, ease of use, drug-drug interactions, and adverse events. Indeed, in a patient with a new diagnosis of epilepsy, the newer, third-generation AEDs, such as eslicarbazepine and perampanel, have not demonstrated significantly greater efficacy than first- or second-generation AEDs. For the adult patient with new-onset seizures, many appropriate generic options are available for first-line treatment, such as levetiracetam, oxcarbazepine, and lamotrigine. The pharmacokinetics of the newer agents tend to be more favorable, with greater tolerability and fewer drug-drug interactions, than the older AEDs. Eslicarbazepine, for instance, does not have a new mechanism of action like perampanel does, but it is an improved version of medications that we have been using for many years (eg, oxcarbazepine, carbamazepine). I say “improved” because it is taken once daily and likely has fewer side effects, partly because it has a long half-life. Perampanel is also dosed once daily and has a half-life of 105 hours, which is one of the longest. Perampanel and eslicarbazepine are likely the most appropriate in patients who are not necessarily medically intractable but are having difficulty with tolerability or drug-drug interactions. Indeed, these are among the major reasons to stay away from the first-generation AEDs, which may decrease the efficacy of other drugs, such as contraceptives, antihypertensives, HIV drugs, and statins. But, as far as efficacy is concerned, there are no significant differences between early and later-generation AEDs.

We have been fortunate with the introduction of several agents in recent years, including brivaracetam, eslicarbazepine, and perampanel. Historically, there have been many challenges associated with trial design and new AED approvals. However, the new licensing pathway for focal (also known as partial) onset seizures allows that, under certain conditions, a monotherapy approval can be granted based on an analysis of efficacy and safety data obtained in add‐on trials (provided that serum equivalence in those on other AEDs and those on no additional AEDs can be demonstrated). Therapies such as perampanel and brivaracetam were approved using this new design. This is a good move, as very few AEDs in our collective experience have been effective only as adjunctive therapy and not as monotherapy for focal onset seizures; an exception would be a scenario in which a therapy is only effective as an adjunct because of a drug interaction with the first AED that results in an increase in the serum level of the new AED. However, the FDA addresses this concern by requiring drug level data in both contexts.

Unfortunately, you frequently need to take into account the patient’s insurance and financial situation. The FDA approval of newer AEDs as monotherapy will allow payers to cover these drugs. Still, many insurance companies may try to limit when these new AEDs can be prescribed. Even with the monotherapy approval, certain health plans require the demonstration of failure of their preferred sequence of AEDs before allowing you to prescribe the newer branded drugs. Government health plans vary from state to state. Interestingly, some patients with certain state Medicaid plans may actually have the best access to some of the newer branded AEDs, while those with Medicare plans may have difficulty. Additionally, patients with very low incomes may qualify for assistance programs from companies that make these newer branded drugs, and they may be able to access them for little-to-no cost.