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Najm: Hello. I am Imad Najm. I’m the director of the Epilepsy Center at the Cleveland Clinic in Cleveland, Ohio.
I am joined by Dr. Amir Arain, Professor of Neurology and head of the epilepsy division at the University of Utah, and Dr. Trevor Resnick, a pediatric epileptologist in the Comprehensive Epilepsy Program at Nicklaus Children’s Hospital in Miami, Florida.
Najm: In this second chapter of a 3-part video series, both of my colleagues will be sharing an overview of a case drawn from their clinics. In each case, initial antiepileptic monotherapy failed, and perampanel, a schedule III controlled substance, was chosen as a first adjunctive therapy.
Before watching this video, be sure to familiarize yourself with the safety and efficacy data for perampanel by watching Chapter 1 of this series.
To start, Dr. Arain, would you please remind our viewers of the indication and Boxed WARNING for perampanel?
Arain: Certainly. FYCOMPA, or perampanel, is indicated for partial-onset seizures with or without secondarily generalized seizures in patients aged 4 and older with epilepsy.
FYCOMPA is also indicated as adjunctive therapy for patients aged 12 and older for primary generalized tonic-clonic seizures.
FYCOMPA has a Boxed WARNING for serious psychiatric and behavioral reactions. Serious or life-threatening psychiatric and behavioral adverse reactions, including aggression, hostility, or irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA.
These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.
We need to advise our patients and their caregivers to contact a health care provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical of the patients are observed while taking FYCOMPA or after discontinuing FYCOMPA.
We should also closely monitor patients, particularly during the titration period and at higher doses of FYCOMPA. FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening.
I would ask that you please note important safety information about FYCOMPA within this video and please refer to the full prescribing information for FYCOMPA, as well.
Najm: Thank you, Dr. Arain, for that important information.
To begin our discussion of patient cases, Dr. Resnick, will you please tell us about your patient, R.B.?
Resnick: Thank you, Dr. Najm.
R.B. is a developmentally normal 14-year-old adolescent. At the age of 13, he started having nocturnal generalized seizures about once a month, but in other respects he had no complaints.
His MRI was normal. His EEG showed right frontal spikes. He was started on levetiracetam by his original physician, and the levetiracetam was increased over a period of months. But despite maximization of the dose, he continued having seizures approximately once a month.
Resnick: By the time I took over R.B’s care, despite 8 months of therapy and maximization of the levetiracetam, he continued to experience seizures at a rate of about once per month.
So the goal in terms of changing therapy—and the goal for all of us as neurologists and epileptologists—is seizure freedom. And there were a number of other considerations for updating his treatment regimen.
In reviewing the issues with the patient and his family, once-daily dosing was desired, and we also reviewed the safety and efficacy profile of AEDs that we might consider as first adjunctive therapy. In addition to FYCOMPA, the other antiepileptic drugs that were considered for first adjunctive therapy included oxcarbazepine, lacosamide, and lamotrigine.
The most compelling reason that the family, and at my suggestion, decided on FYCOMPA was because of the fact that R.B.’s seizure type was specifically secondarily generalized seizures at night.
Resnick: I added FYCOMPA 2 milligrams daily as first adjunctive therapy, with no dose adjustments to levetiracetam. After 2 weeks, the dose of FYCOMPA was increased to 4 milligrams daily. R.B. was reevaluated every 6 weeks. While on 4 milligrams FYCOMPA once daily, R.B.’s seizures decreased in frequency to about once every 3 months. However, following that last seizure, FYCOMPA was increased to 6 milligrams per day.
R.B. now has been on levetiracetam and adjunctive FYCOMPA 6 milligrams per day for 1 year, and he is currently seizure free. I should note that while R.B. did not report any adverse events with this regimen, every patient is different, and I continuously monitor my patients for efficacy and tolerability, as I continue to do for R.B.
Najm: Thank you very much, Dr. Resnick. The most important thing that I have learned from this case is what Dr. Resnick showed us: Perampanel could be a good option for those patients who failed the first antiepileptic medication and those with a history of generalized convulsive seizures, and it could be quite effective.
The second thing that is as important here is, when we start the medication at a low dose of 2 milligrams per day, for example, and go to 4 milligrams, and we see some improvement in seizure control, but not 100% seizure control, this would be an indication that probably we should continue to go up slowly to 6 or 8 milligrams, where we might achieve the seizure freedom that R.B. achieved under Dr. Resnick’s care.
Najm: Now Dr. Arain, you also have an interesting case to share with us that is relevant to the first adjunctive therapy setting.
Arain: Yes, Dr. Najm, I do have one and I’ll share that with you.
This is the case of a 21-year-old male college student. M.W. is the name, and he has a history of febrile seizures, one at age 3 and one at age 4.
When he came to me in the epilepsy clinic in August 2019, he presented with focal impaired awareness seizure, where he would not get an aura, he would stare, lip smack, be unresponsive, would have left-hand dystonic posturing, and right-hand motor automatisms.
And these focal impaired awareness seizures were happening about once per week. And they at times evolved into bilateral tonic-clonic activity, about once per month.
Arain: M.W. was seen initially in the emergency department after his first secondarily generalized tonic-clonic seizure. That was about 9 months prior to seeing me. His MRI showed right hippocampal sclerosis and EEG showed right anterior temporal sharps. At that point, he was started on lamotrigine 25 milligrams a day and increased every 2 weeks to a target dose of 100 milligrams twice a day.
Upon starting lamotrigine, his focal impaired awareness seizures decreased from 3 or 4 per week to 1 per week, and his secondarily generalized tonic-clonic seizures decreased from 2 per month to 1 per month. Lamotrigine was increased to a target of 300 milligrams twice a day.
But still the seizures continued. After about 6 months of therapy, M.W. was still experiencing seizures despite continuing lamotrigine, and his driver’s license had been suspended. He had not been very compliant at times and seizures happened because of poor compliance.
So is FYCOMPA an option for this patient?
Arain: Certainly. My primary goals in changing therapy for this patient were controlling his seizures, minimizing pill burden, and addressing barriers to re-qualify for his driver’s license.
Considerations for updating the treatment regimen were the goals of finding a balance between safety and efficacy; minimizing drug-drug interactions; again, decreasing the pill burden; and once-a-day dosing.
Another AED that I considered was levetiracetam. In most cases, we have to take it twice a day, so my compelling reason for choosing FYCOMPA was that FYCOMPA is a long-acting seizure medication and once-a-day dosing is possible.
Arain: After we reviewed the medication guide, M.W. was started on FYCOMPA 2 milligrams per day, and no adjustments were made to lamotrigine. Initially, for the first week or so, he complained of some sleepiness. That resolved on its own, and after a month of being on 2 milligrams per day, I increased it to 4 milligrams per day at bedtime.
And at 4 milligrams, the patient has been seizure free for more than 6 months now. And no dose adjustments were made to FYCOMPA or lamotrigine. And we are continuing to monitor for efficacy and tolerability and also for any seizure recurrence.
Najm: Very nice case, Dr. Arain. Thank you for sharing that case with us. Now, Dr. Resnick, will you please review the Select Safety Information for perampanel?
Resnick: Of course. In the partial-onset seizures clinical trials, hostility and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 and 12 milligrams per day, respectively. This is compared to 6% of patients in the placebo group.
These effects were dose related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects led to dose reduction, interruption, and discontinuation.
Now, the combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Therefore, patients should avoid the use of alcohol while taking FYCOMPA.
Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events, and patients should be monitored during treatment with FYCOMPA, especially when taking higher doses of the medication.
Antiepileptic drugs, including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients with epilepsy.
Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts and behavior, thoughts about self-harm, and/or any unusual changes in mood or behavior.
FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination, especially during the titration phase, which is the most important phase of starting a medication.
Resnick: FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events, especially during the titration phase.
Patients should be advised against engaging in hazardous activities requiring mental alertness such as operating motor vehicles or dangerous machinery until the effect of FYCOMPA is known.
Patients should be carefully observed for signs of central nervous system depression when FYCOMPA is used with other drugs with sedative properties because of the potential additive effects.
Falls were more common in patients taking FYCOMPA at doses of 8 and 12 milligrams versus placebo, which as we know are the higher doses of FYCOMPA.
Drug reaction with eosinophilia and systemic symptoms, also known as DRESS or multiorgan hypersensitivity, has been reported in patients taking AEDs including FYCOMPA. DRESS may be fatal or life-threatening. We should always evaluate our patients if these signs or symptoms are present.
A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency.
Now, the most common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, weight gain, nausea, vertigo, headache, ataxia, vomiting, contusion, abdominal pain, and anxiety.
FYCOMPA may also decrease the efficacy of contraceptives containing levonorgestrel.
Plasma levels of FYCOMPA were decreased when administered with moderate or strong CYP3A4 inducers.
FYCOMPA may enhance the effects of alcohol on vigilance, alertness, anger, confusion, and depression.
These effects may also be seen when FYCOMPA is used in combination with other central nervous system depressants.
Therefore, caution should be exercised when FYCOMPA is administered to pregnant or nursing women.
Resnick: Use in patients with severe hepatic or severe impairment is not recommended.
Dosage adjustments are recommended in patients with mild or moderate hepatic impairment.
Use with caution in patients with moderate renal impairment.
Finally, FYCOMPA is a schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms.
And again, we encourage you to review the FYCOMPA full prescribing information, including Boxed WARNING.
Najm: Thank you, Dr. Resnick and Dr. Arain, for sharing all of this valuable information.
I would like to close by encouraging viewers to watch the final chapter in this video series, in which Dr. Arain and Dr. Resnick discuss the dosing and pharmacokinetics data for perampanel.
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