Antiepileptic Therapy Half-Life, Dosing & Black Box Warning

Amit Verma, MD: Perampanel is an appropriate choice for a patient like her. What we would be most concerned about in a patient for whom we’re starting antiepileptic medications is this: We want the drug to be effective. We want the drug to be effective at a low dose to minimize adverse-effect profile, and we want the medication to have a long enough half-life so that, if somebody misses their dose of medication, their serum levels are not going to drop enough that might put the patient at risk for having a seizure.

In an ideal world, we would want to take something that’s got a long half-life, so the plasma levels stay stable. We want to pick a medication that has the fewest adverse effects, and we want to try to have the patient on as small a dose as possible.

There have been many studies done with perampanel, the so-called registration trials, which led to perampanel’s approval in the United States. Then there was a more recent study called the FREEDOM study, which looked at low doses of perampanel looking for efficacy with 4 mg, and it was found to be effective even at 4 mg per day of perampanel. Given that we already had these registration data from the original studies that led to its approval in the United States and now the FREEDOM data, most people feel fairly comfortable aiming for 4 mg per day and then seeing how the patient does. Aiming for 4 mg a day can help with trying to keep the patient at a low dose, so the adverse-effect profile is cleaner and so the patient is not being exposed to as many adverse effects as would occur if the patient was on a higher dose of perampanel.

Whenever we discuss using perampanel with a patient, we always discuss the black box warning because it’s part of the package insert, and there is an adverse effect, we need to make sure the patient and their family are aware about. The black box warning refers to the fact that perampanel was associated in studies with the risk of mood disorders. More specifically, the 1 that was referred to in that black box is the risk of homicidal ideation. We have to discuss that with the patient because if we don’t, they’re going to read about it anyway, and that’s something they’re going to be concerned about.

The way we discuss the black box warning with the patients is that the number of patients who had this homicidal ideation adverse effect was about 6 patients of 4000-plus patients in their study. It was a small percentage of patients who experienced this adverse effect. The adverse effect occurred at a range of doses that were prescribed for those patients, and the adverse effect occurred at a range of timelines. In some patients it occurred early, and in some patients it occurred late. One of the things that was common was that all the patients who had that adverse effect had an underlying psychiatric history. When we address the black box warning, I talk them through the issue, and I talk them through the potential adverse effects that can occur. I ask the family members and the patient to watch out for any changes in mood or behavior on the part of the patient. If they have any changes in mood or behavior, we ask them to call us. If they report something of concern, then we can make changes to the dosing of the medication or potentially take them off it.

For the most part, patients tolerate the medication quite well. Of course, we never want to downplay the black box warning because it’s obviously quite prominent in the package insert, but it’s important to discuss the context of that adverse effect with the patient and the caregivers to encourage them to report any of those adverse effects if they do occur, so we can then make corrective measures.

Taking the medication once at bedtime helps some of the adverse effects. In addition to the black box warning, the medication is associated with other adverse effects such as somnolence, which is sleepiness, tiredness, and so on. We typically ask the patients to take the medication at night, so if they feel tired or sleepy, then they’re just going to be sleeping at that point anyway. Oftentimes, taking their medication once a day at bedtime is much better than having that patient take the medication several times per day.