Hi, I’m Jim Wheless. I am Professor and Chief of pediatric neurology at the University of Tennessee Health Science Center & Director of the Le Bonheur Comprehensive Epilepsy Program; in Memphis, Tennessee.

Today, I am pleased to share an epilepsy case study from my clinical practice.

Throughout this video, I will be posing a series of questions for consideration. The questions will appear on screen with a series of answers to choose from. Simply select an answer option from the choices onscreen. The presentation will proceed after an option is selected.

This real-world case describes the adjunctive use of FYCOMPA in a patient with convulsive seizures—specifically, a patient with primarily generalized tonic-clonic seizures.

Note that FYCOMPA is indicated for the treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy age 4 years and older.

FYCOMPA is also indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

Please stay tuned for additional Important Safety Information, including a Boxed WARNING relating to serious or life-threatening psychiatric and behavioral adverse reactions.

Now let’s take a look at my patient, Meghan.

When I started seeing her, she was a 17-year-old high school student.

Meghan first began experiencing seizures at age 12, when she presented with infrequent myoclonic seizures. About a year later, she began having primary generalized tonic-clonic seizures.

Her MRI was normal, and her EEG showed generalized 3.5-4.5Hz and spike and wave complexes. There was no photoparoxysmal response, and the background was otherwise normal.

She had no other significant medical history.

At our first visit, Meghan appeared to be very frustrated. She indicated that she was not having myoclonic seizures, but was continuing to experience PGTC seizures about once every 4-6 weeks. She really wanted to get a driver’s license, but understood that would not be possible if the seizures continued.

She also indicated that she wanted to go to college after her senior year, but she was very nervous about experiencing a PGTC seizure in class or in front of her peers, and her parents were very anxious about her living away at college.

She wanted to know what she could do to improve her seizure control.

When I first saw her, her current medications included levetiracetam XR 1500 mg BID, and lamotrigine XR 200 mg BID.

She had received no other AEDs in the past, and was taking no other medications.

I planned to start her at a dose of 2 mg once daily. We would slowly increase the FYCOMPA dose, by about 2 mg every 4 weeks, understanding that the recommended target dose for FYCOMPA in PGTC seizures is 8 mg once daily.

Lamotrigine XR was tapered and discontinued; she remained on levetiracetam XR.

By the 10-week visit, Meghan was tolerating a dose of FYCOMPA 6 mg/day and had reached a clinical response.

Meghan did not report any adverse events during the FYCOMPA treatment, although we did carefully evaluate her for these events. She was monitored clinically, and at every follow-up visit I asked Meghan if she was experiencing any side-effects that she thought might be related to her medications.

I should note that although Meghan did not report any adverse events with FYCOMPA, every patient is different, and I continuously monitor my patients for efficacy and tolerability.

Although Meghan received a dose of 6 mg/day, the recommended maintenance dose of FYCOMPA in primary generalized tonic-clonic seizures is 8 mg once daily, taken at bedtime.

The treatment plan and these results are specific to Meghan. Other patients may respond differently.

Lamotrigine XR was tapered off over a period of 2 months.

After 8 months, Meghan was still taking FYCOMPA 6 mg/day and extended-release levetiracetam. She had been seizure free for 5 months at this point.

Meghan did admit to occasional nonadherence with her bedtime dose of FYCOMPA. I reinforced the importance of AED adherence and suggested she keep a reminder by her bed to prompt her to take her a dose.

I also recommended she set an alarm on her phone to go off at bedtime to help remind her to take her medication.

If you were seeing Meghan for the first time, what would you ask her about first?

While all of those are important to address, I started by looking at Meghan’s medications and assessing her medication adherence.

As I noted before, when Meghan was first diagnosed, she was started on levetiracetam XR 1500 mg BID. While this controlled her myoclonic seizures, she was still experiencing PGTC seizures despite adhering to her medication regimen. At that point, lamotrigine XR was added and titrated to her maximum tolerated dose of 200 mg BID.

Meghan admitted to me that it was sometimes difficult to remember to take her medications. She asked about treatment options that involved less frequent dosing.

Let’s pause again for a question.

What are your greatest clinical challenges when treating patients like Meghan?

In this case, there were multiple challenges. Meghan was still experiencing PGTC seizures despite receiving two AEDs. Although she was very motivated to achieve seizure freedom, she sometimes struggled to adhere to her medication regimen.

Meghan was focused on convulsive seizure freedom so she could get her driver’s license and avoid seizures in front of her friends, and I was focused on the importance of controlling her seizures in general.

But Meghan was like many of my adolescent and young adult patients, who struggle with medication adherence. I find that younger children tend to have a structured schedule and their parents are diligent about making sure they take their medication. As these kids enter high school and college, their schedules become much less predictable. At the same time, they are beginning to take on the responsibility for administering their medications.

After some discussion, Meghan and I decided on three critical goals:

1. First, we wanted Meghan to achieve PGTC seizure freedom
2. Then, we wanted to make sure we were balancing medication safety and efficacy
3. Finally, we hoped to simplify Meghan’s AED dosing regimen

Here is another question to think about.

What type of information might have the strongest influence on your selection of an AED for a patient like Meghan?

For PGTC seizures, there are limited treatment options based on this patient’s profile.

When considering treatment options, I would begin by ruling out any medications that might be contraindicated. Then I look at the efficacy data in PGTC seizures and assess the safety information. For patients like Meghan who are challenged with adherence, I also look at the dosing and administration to ensure the dosing will fit into their lifestyle. Pharmacokinetic data help me understand what might happen to drug levels if patients miss a dose of the AED.

FYCOMPA (perampanel) is one option I discuss.

Let’s look at some of the data for FYCOMPA in patients with PGTC seizures.

The use of FYCOMPA as adjunctive treatment for PGTC seizures was evaluated in a randomized, double-blind, placebo-controlled multicenter trial.

The trial included 162 patients in the intent-to-treat population. All patients were age 12 years or older and had experienced at least 3 seizures over the 8-week baseline period. The two groups were evenly divided in terms of the number of patients.

The trial included a 4-week titration period in which patients were titrated to a dose of 8 mg FYCOMPA per day or the highest tolerated dose (not to exceed 8 mg per day).

Following the titration period, patients entered the 13-week maintenance period.

I would like to point out that 307 patients were originally screened for this study. Of the 143 screen failures, 81.8%, or 117 patients were due to failure to meet the inclusion criteria. 1.4% of the screen failures, or 2 patients, were due to adverse events.

All patients in this trial were receiving a stable dose of 1 to 3 concomitant AEDs.

There were 5 different AEDs used during the trial by at least 10% of the total safety population (N=163).

17% of the trial population received enzyme-inducing AEDs, including carbamazepine, oxcarbazepine, or phenytoin.

The primary endpoint in this Phase III trial was the median percent reduction in PGTC seizure frequency per 28 days during the treatment period as compared to the baseline period.

Note that in this trial median baseline PGTC seizure frequency per 28 days was 2.6 in the FYCOMPA group and 2.5 in the placebo group (based on the full analysis set).

Patients treated with FYCOMPA experienced a median percent reduction in PGTC seizure frequency of 76% at the end of the maintenance period compared with a median percent reduction of 38% in the placebo group. The difference between the two groups was statistically significant.

A secondary endpoint in the trial was the percent of patients experiencing at least a 50% reduction in PGTC seizure frequency during the maintenance period of the trial compared to baseline.

64% of patients achieved a 50% or greater reduction in PGTC seizure frequency in the FYCOMPA group compared with 40% of patients in the placebo group.

When we look at the data for changes in PGTC seizure frequency during the maintenance phase of the trial we can see that the large majority of patients experienced improvements. Nearly half of all FYCOMPA-treated patients (48%) experienced a reduction in PGTC seizure frequency ranging from 75% to 100%, compared to 24% of those receiving placebo.

It is important to note that seizure frequency increased in 10% of FYCOMPA-treated patients (n=8), and in 28% of patients receiving placebo (n=23).

This study prespecified an exploratory endpoint. Investigators looked at the percentage of patients who achieved PGTC seizure freedom during the 13-week maintenance period.

What they found was that 31% of FYCOMPA treated patients, nearly 1 in 3, achieved PGTC seizure freedom during this period compared to 12% in the placebo group.

As previously stated, this was an exploratory endpoint. No adjustments were made for multiple comparisons, which is a study limitation.

I shared this efficacy data with Meghan and her parents to help set expectations for PGTC seizure reduction. They were interested in trying FYCOMPA, but wanted to learn more about FYCOMPA safety.

Again, our shared goal was for her to achieve seizure freedom.

Let’s pause here for another question.

When initiating FYCOMPA for a patient like Meghan, how might you begin your discussion of FYCOMPA’s safety information?

Before initiating FYCOMPA, it is very important that we carefully review the Medication Guide and Instructions for Use with patients and their caregivers. We must make sure patients are aware of all warnings and precautions, including the boxed warning associated with FYCOMPA.

Let’s take a closer look at FYCOMPA safety information.

In the PGTC seizure trial, the safety analysis set included 81 patients who received at least one dose of FYCOMPA.

Adverse events reported in at least 5% of patients receiving FYCOMPA 8 mg per day and more frequently than placebo are shown here.

In this trial, discontinuations due to adverse events occurred in 11% of patients receiving FYCOMPA and 6% of patients receiving placebo.

The most common adverse events responsible for these discontinuations were vomiting and dizziness.

Now let’s discuss the Important Safety Information that should be reviewed with all patients prior to initiating FYCOMPA.

FYCOMPA has a boxed warning for serious psychiatric and behavioral reactions.

Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA, irrespective of prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.

Monitor patients for these reactions as well as for changes in mood, behavior, or personality that are not typical for the patient, particularly during the titration period and at higher doses.

FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening.

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 mg and 12 mg per day, respectively, 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.

The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients should avoid the use of alcohol.

Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events.

Patients should be monitored during treatment with FYCOMPA, especially when taking higher doses.

Antiepileptic drugs, including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients.

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 or 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.

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 (CNS) depression when FYCOMPA is used with other drugs with sedative properties because of potential additive effects.

Falls were more common in patients taking FYCOMPA at doses of 8 mg and 12 mg versus placebo.

Drug reaction with eosinophilia and systemic symptoms, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA. DRESS may be fatal or life-threatening.

Evaluate your patients if these signs or symptoms are present.

A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency.

The most common adverse reactions include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety.

FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel.

Plasma levels of FYCOMPA were decreased when administered with moderate and 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 CNS depressants.

Caution should be exercised when FYCOMPA is administered to pregnant or nursing women.

Use in patients with severe hepatic or severe renal 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.

FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms.

Please see the Full Prescribing Information for FYCOMPA, including the Boxed Warning regarding SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS.

You can also visit the FYCOMPA website for health care professionals.

Now let’s get back to our case.

I carefully reviewed all of this safety information with Meghan and her parents and made sure to answer their questions. I explained that I like to titrate the dose of FYCOMPA slowly, and frequently assess for adverse events.

Meghan and her parents both wanted to better understand how often Meghan would have to take FYCOMPA and what would happen if she missed a dose.

In your practice, what strategy do you find most effective when patients are nonadherent to their medication regimen?

For young adults like Meghan, I use a variety of strategies, like counseling on the risks of missed doses and the importance of taking their medication as prescribed.

I also recommend the use of technology such as smartphones to set medication alerts or reminders.

Despite all of these strategies, I assume patients such as Meghan will miss doses of their AED medication.

I try to keep AED regimens as simple as possible by using once daily medications when possible.

I explained to Meghan that FYCOMPA is taken as one tablet, once daily at bedtime.

Since she was not receiving an enzyme inducing AED, I planned to start her at a dose of 2 mg once daily. We would slowly increase the FYCOMPA dose, by about 2 mg every 4 weeks, understanding that the recommended target dose for FYCOMPA in PGTC seizures in 8 mg once daily.

Here you can see the dosing information for FYCOMPA. Please take a moment to review FYCOMPA’s recommended dosing.

If you need more time, feel free to pause the presentation or see FYCOMPA’s prescribing information provided with this presentation.

For Meghan, I elected to taper her off of lamotrigine XR. She remained on levetiracetam XR.

We made a plan to touch base every 2 weeks to assess seizure frequency and monitor for adverse events, including psychiatric and behavioral reactions.

I reminded both Meghan and her parents to monitor for seizures, any behavioral changes or adverse events, and encouraged them to contact the office should these occur.

Although we were simplifying Meghan’s medication regimen, I still assumed that she would miss occasional AED doses.

An additional reason I consider FYCOMPA is its long half-life. With a long half-life, stable plasma concentrations are maintained in the event of a missed dose.

A PK model was constructed to explore the effects of a missed dose on FYCOMPA steady-state plasma concentrations.

A nonlinear mixed-effects program was used for PK modeling. PK simulations were done for adult patients receiving 8 mg/day FYCOMPA, and PK parameters were derived based on data from 19 Phase I FYCOMPA trials (N=606).

The results of this study are limited because the PK model is based on simulations and not on prospective clinical studies in humans. Further studies are needed to replicate the findings.

These simulated concentration time profiles were based on 8 mg once daily dosing in adults.

This graph on the left demonstrates modeled FYCOMPA plasma exposure in a patient not on concomitant enzyme-inducing AEDs who has missed a dose at day 15 and resumed regular dosing the following day.

On day 15, the trough concentration declined by 18% and the peak concentration declined by 12%.

Within 6 to 7 days of the missed dose, modeled FYCOMPA exposure was very close to that of a patient who did not miss a dose.

The graph on the right demonstrates modeled FYCOMPA plasma exposure in a patient on concomitant carbamazepine who has missed a dose of FYCOMPA at day 15 and resumed regular dosing the following day.

On day 15, the trough concentration declined by 44% and the peak concentration declined by 15%.

Within 3 to 4 days of the missed dose, modeled FYCOMPA exposure was very close to that of a patient who did not miss a dose.

Back to Meghan.

I told her that if she misses a dose of FYCOMPA, she should resume dosing the following day at the prescribed dose, and she should not try to make up for the missed dose. I told her to call the office if she misses more than 1 day of FYCOMPA.

By the 10 week visit, Meghan was tolerating a dose of FYCOMPA 6 mg/day and had reached a clinical response.

Note that the recommended maintenance dose of FYCOMPA for PGTC seizures is 8 mg once daily at bedtime, but since Meghan was responding, I chose to continue her on 6 mg/day and monitor her seizure frequency.

Lamotrigine XR had been tapered off over a period of 2 months.

I continued to follow Meghan regularly, and as of her 8-month visit, she was still taking FYCOMPA 6 mg/day and extended-release levetiracetam. She had been seizure free for 5 months, and was hoping to be able to start driving soon. She had also started to look at junior colleges.

Meghan did admit to occasional nonadherence with her bedtime dose of FYCOMPA. I reinforced the importance of AED adherence and suggested she keep a reminder by her bed to prompt her to take her dose. I also recommended she set an alarm on her phone to go off at bedtime to help remind her to take her medication.

As I mentioned earlier, Meghan was monitored carefully and did not report any adverse events during her treatment with FYCOMPA.

Again, although this particular patient did not report any adverse events with FYCOMPA, every patient is different, and it will be important to continue to monitor efficacy and tolerability throughout the course of treatment.

I hope this case study has prompted you to think about how FYCOMPA might be used in your patients with PGTC seizures.

I have been using FYCOMPA in my patients with convulsive seizures for several years. My increasing experience with FYCOMPA has made me very comfortable prescribing it for my patients.

If you would like additional information about FYCOMPA, please review the other materials on this website and also visit the FYCOMPA website for health care professionals, listed here.

Thanks for watching.

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