Extended Release Formulation's Role in Treating Epilepsy

Michael R. Sperling, MD: A number of drugs were available for us to prescribe that have been made into extended release formulations. These include oxcarbazepine, carbamazepine, lamotrigine, levetiracetam, topiramate, and divalproex. So we have a variety to use. How does one transition from either an oral solution or an oral tablet to the extended release tablet? Perhaps, Trevor, you would like to address that.

Trevor J. Resnick, MD: I think it’s important to differentiate between an extended release formulation where an immediate release drug, due to different technologies, has an extended release in terms of it being released, as opposed to a medication that has a long half-life and is used in an extended release fashion such as being once a day, or whatever the case may be. Because the variables for those 2 are going to be different. But as far as transitioning is concerned, I think most of us as treating neurologists, epileptologists, would prefer to have patients on once-a-day medication, mostly from the standpoint of compliance and adherence.

And we know that the more frequently you have to take a medication, the less adherent you’re going to be, and the more likely you are to have breakthrough seizures. That is obviously mitigated by the fact that there’s a differential cost for patients who are on extended release formulations. But on a level playing field, if we were able to, most of us would prefer to use standard release formulations.

Michael R. Sperling, MD: Eric, do you think there’s anything particular about the liquid oral solutions versus pill when shifting to an extended released preparation or are they fairly similar in your view?

Jesus E. Pina-Garza, MD: In most cases if we look at all the options on the menu, they’re very similar. There are situations where we have a 10% variation on the area under the curve with certain medications. But the concept that led to this is very simple. We have learned a lot from the very first anticonvulsants about the association of efficacy and toxicity levels. When we look at medications that have frequent peaks and troughs, we have the potential for having breakthrough when the trough is too low, and we have the potential for higher toxicity when the peak is too high. And this applies to many of the medications we know and to the post hoc analysis when we look at levels and the relation with efficacy and adverse effects.

So the concept is having medications where you have a very small difference between peak and trough, and also the advantages of taking the medications just once a day, which can help your adherence, is really significant to treat. Probably as significant, if not more, as developing a new mechanism of action. Because the only way the drug works is if you are able to keep it in the blood system, or in the brain.

So in most cases the transition is going to be a 1-to-1. And for most of my patients, if there is an adverse effect that is related to the small picture we have with the extended release formulation, I try to give them the dose in the evening. Or if the seizures tend to be mostly asleep-related seizures. If you’re able to tolerate it, and your seizures are mostly during the daytime, you may be better with a daytime dosage.

Michael R. Sperling, MD: Thank you. Kate, do any of the drugs differ in your perspective from that 1-to-1 transition that Eric was speaking of?

Kathryn A. Davis, MD, MS, FAES: So this is in patients where they’ve already been, for instance, on X-dose of lamotrigine or oxcarbazepine and we’re trying to switch them to extended release. No, I don’t; it’s actually quite simple. I think the biggest thing when I’m making the change is to make sure that they don’t miss any doses in that transition. So if you’re switching everything to night, that first day make sure you still take the immediate release in the morning, which could be a mistake that is easy to make if you don’t tell the patients to do that.

Michael R. Sperling, MD: All right. So for nearly all the drugs it’s 1-to-1. The 1 exception would be valproate where the extended release has about an 85% area under the curve, so you actually have to raise the dose of valproate by about that 15%.

Trevor J. Resnick, MD: Actually, so does oxcarbazepine.

Michael R. Sperling, MD: And then oxcarbazepine is the other 1 where also it does make a difference, where you have to raise the dose somewhat. These are the only 2 really, the oxcarbazepine and the divalproex. So those are the examples. The others you can do pretty much a 1-to-1.

Trevor J. Resnick, MD: One-to-1.

Michael R. Sperling, MD: And in fact, even though the area under the curve may be a little less with oxcarbazepine and divalproex, because the troughs are higher, you may often get away with using the same dose.