Role of Extended-Release Formulations in Epilepsy

Rodney A. Radtke, MD: In addition to the multiple new AEDs [antiepileptic drugs] that we have, we also have new formulations that enhance the administration and hopefully adherence of some of these agents. In general, I like to use the extended-release formulations. The advantages are usually 2-fold. First, many times they get around postdose adverse effects such as with carbamazepine. Postdose adverse effects are very common. With the extended-release carbamazepine, they’re much less common. In addition, rather than taking the drug 2 or 3 times a day, we’re able to take the drug once or twice per day, and the evidence in the literature clearly demonstrates that 3 times a day is a lot harder to take than 2, and 4 times a day is almost impossible to be compliant with on a consistent basis. So the 2 advantages are seemingly fewer adverse effects and definitely hope for improved adherence by virtue of less frequent administration of the drug.

In general, I always prefer to use the extended-release formulation because of the advantages of maybe fewer adverse effects and improved compliance. The only time that I really don’t go that route is if a third-party payer won’t support it and the cost is too much, and we end up using an immediate-release product. I don’t always give the extended-release product. I don’t always give the extended-release products once a day if that’s the design, particularly if you get to a large dose with the extended-release product. Say with lamotrigine, the patient is taking 800 or 900 mg a day, I may divide that up to spread it out. As long as they’re consistently able to comply and take the drug twice a day, it’s a little bit advantageous to spread it out and lower the peaks and raise the troughs, so that that effective blood level is maintained as close to level as possible.

The first extended-release product that really had an impact on patient adherence and patient tolerability of medication is the extended-release carbamazepine. That was a product that needed to be taken 3 times a day and also was really problematic for postdose adverse effects an hour or 2 after taking the medicine, particularly in the morning. With the extended-release formulation, we’re able to take it twice a day, and it really blunts that postdose adverse effect. And so it markedly enhanced the tolerability. A few of the other drugs, like oxcarbazepine, which is now available on a once-a-day product, also have some of those same advantages. It goes from twice a day to once a day and also blunts any postdose adverse effects.

Some of the other products are a little bit less important, like levetiracetam extended release. Postdose adverse effects aren’t a concern, but certainly taking it once a day as opposed to twice a day offers a distinct advantage. We have extended-release topiramate available. I was skeptical that it really changed anything in tolerability, but it seems to have. So I do have patients using that who could tolerate a higher dose of the extended release as opposed to the immediate release. And then with lamotrigine, that molecule does have some postdose adverse effects, so it lends itself to improved tolerability with the extended release. And obviously, the once-a-day product is going to be more consistently complied with.

The indication for the various agents, including the extended-release agents, are quite variable with respect to age. I think most pediatric neurologists have to go outside the package insert or off label to use the products. Many times, the studies haven’t been done. More and more, the studies are being done in the pediatric age group, or at least they’re allowing extrapolation from adult pharmacokinetic data to get the drug approved in a pediatric population. And certainly, a drug like extended-release oxcarbazepine that’s approved down to age 6 certainly is an advantage because that’s about the age that children are going to consistently swallow pills. And so now you have a once-a-day product that allows you to adequately treat the patient without having to get them to comply 2 or 3 times a day with many other products.