A comprehensive outline of factors that can inform the selection of therapy for patients with epilepsy given approved agents.
Michael R. Sperling, MD; Jesus E. Pina-Garza, MD; Trevor J. Resnick, MD; Kathryn A. Davis, MD, MS, FAES
PUBLISHED March 01, 2019
Michael R. Sperling, MD: When we talk about best practices in prescribing drugs, what does that mean to you?
Jesus E. Pina-Garza, MD: Best practices in prescribing drugs to me would be putting ourselves in the patient’s shoes and selecting the best option for them. There are other ways to look at that and some of that is the objective data, the guidelines. To me, since efficacy is very hard to differentiate, that’s one of the reasons the FDA, the industry actually, is unable to do head-to-head comparisons; the FDA criteria to approve a drug is to show superiority.
So it’s very hard to show superiority on efficacy, but some of the ones that have been done comparatively show superiority on adverse effects and tolerability, which is very important because in selecting a drug and doing good patient practice, safety is super important. It’s probably number 1. Assuming that all the medications work similarly regarding efficacy, safety is number 1, and tolerability is number 2.
Michael R. Sperling, MD: If someone develops an adverse effect when you put someone on medication, Trevor, do you think about the mechanism of action of that drug in forming your choice of next drug or not?
Trevor J. Resnick, MD: Depending on which drug, yes, I do. I think for a lot of us, sodium channel drugs have that similar list of adverse effects, and if that patient has that adverse effect and has it at a medium to low dose, I will probably avoid another sodium channel drug. So mechanism of action does play a role, but it’s 1 variable that I’ll look at.
Michael R. Sperling, MD: Yes, I think we all had the experience of having somebody on 1 sodium channel blocking drug, having it not work, then switching to another sodium channel drug and it works.
Trevor J. Resnick, MD: And it works, yes.
Michael R. Sperling, MD: Or the person who could not tolerate phenytoin, for example, tolerated carbamazepine or tolerated lacosamide. And I guess it makes it a challenge. Now you had also mentioned about single-day dosing. So are there certain things that you think about when you’re prescribing a drug? Do you tend to lean towards drugs that can be given once per day? Is that a more important or less important factor in your choice of medication?
Trevor J. Resnick, MD: Well, I think it’s 1 factor. And I think from a compliance standpoint we discussed that, that it’s important from that standpoint. I think for some of the extended-release formulations the peak/trough issue may be important for that patient. And in some patients, the standard release formulations also have fewer adverse effects because they don’t have the same bimodal peak pattern. So in those patients who are on drugs that they’re taking twice a day, some of them will say, “An hour and a half after taking my drug I feel drowsy and dizzy. Otherwise, I’m doing fine and I’m seizure-free.” And that would be a good scenario to switch them to extended release formulation to obviate those 2 peaks.
Michael R. Sperling, MD: And I must say, I’ve had that experience many times. And in theory, the extended release might be used once a day, but if the patient is comfortable taking it twice a day, and it eliminates the adverse effects, I may be happy in that circumstance. There are a number of agents that are available with extended release formulations, I suppose. And does the half-life of the agent make a difference when you think about that, or not really?
Kathryn A. Davis, MD, MS, FAES: It does for me, and I think this is a point that we may have differing opinions on. For a drug that is extended release but has a shorter half-life, I counsel patients extensively regarding avoiding missing medications. Because if you’re taking it once a day and miss that dose, your level of your drug will go down substantially. In contrast, with a once-a-day drug like zonisamide or perampanel that has a long half-life—where, of course, I’ll still counsel them not to miss their medications—if they miss 1 dose because of the very extended half-life, the level in their bloodstream is not going to substantially drop.
Michael R. Sperling, MD: … Your comment in this regard relates to adherence though, right?
Jesus E. Pina-Garza, MD: That’s correct. And I think the comment that Trevor made earlier, and Kate too, is really important. Because that makes me think about a population of patients, not with focal epilepsy, but with generalized epilepsy very common that we see in adolescents. And they fall into the category of being refractory because they’re still having seizures. However, when they are calm, the only time they have seizures is because they missed their medications, and even extended release has a short half-life. So that’s when the selection of longer half-lives may be a little more forgiving to those patients. So clearly if they take it all the time, that may not make a difference, but the human factor is hard to take away.
Michael R. Sperling, MD: And there were some data, there was a paper published a while back, by Ed Faught, MD, I think, about that.
Trevor J. Resnick, MD: That’s correct.
Michael R. Sperling, MD: And what did that show?
Jesus E. Pina-Garza, MD: So one of the dumbest questions I ever asked for about a decade was, how often do you miss your medication?
Michael R. Sperling, MD: Never.
Jesus E. Pina-Garza, MD: And people say never because it’s hard to report something you forgot. If you knew it, you would have taken it. But really when you ask people that, they say, “How do you know?” And if they have a diary that they mark their dosing, or they have at least…the date that they refilled the medication, they’ll know if they’re missing and how much they’re missing.
So Ed Faught looked at the possession ratios, how often you don’t have the medication in your hands, from the Medicare Pharmacy Registry. So when you have medications that we prescribe, number 30, once a day, is refilled every 33 days, which means 10% is not taken. When you have number 60 BID [twice a day], it lasts 36 days—20%. When you have 90 TID [3 times a day], it lasts like 42 days, that’s like 37%. I can’t test for the QID [4 times a day], I’m allergic to penicillin. And when I took erythromycin, my 10-day supply always lasted like 50 days. I clearly stopped like 10 days, like 16, because the compliance goes down to 54% on adherence. So clearly the once-a-day options are much better. The future would be to have injectables like we have in other areas of medicine, or pumps that take care of the human factor.