Case Study: 12-Year-Old Adolescent with Partial-Onset Seizures with Secondary Generalization

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’m going to present a case study from my clinical practice.

This real-world case describes the first-line use of FYCOMPA in a patient with partial onset secondarily generalized seizure.

Note that FYCOMPA is indicated in patients with epilepsy ages 4 years and older for partial-onset seizures with or without secondarily generalized seizures.

FYCOMPA is also indicated as adjunctive therapy for patients ages 12 years and older for primary generalized tonic-clonic seizures.

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

Now let’s take a look at our patient, Robert. He is a 12-year-old male in 6th grade, living with his parents and 2 siblings.

He has no family history of epilepsy and no personal history of meningitis, encephalitis, or febrile seizures.

Robert did have a closed head injury when he was 5 years old due to a motor vehicle accident.

He also has asthma, which was diagnosed at 7 years of age and is currently being treated with a nasal steroid (mometasone) and an anti-inflammatory (montelukast 5 mg) at night. He also has seasonal allergies and takes loratadine 10 mg at bedtime.

At 6 years of age, he was diagnosed with ADHD and takes 20 mg of a mixed salt of a single-entity extended release amphetamine in the morning; he has difficulty with math and reading.

Regarding his seizure history, the patient experienced new-onset focal seizures followed by bilateral convulsive activity at school, which prompted a school official to call the EMT and bring him to the local hospital.

While collecting patient history, he recollected having a probable partial seizure 2-3 weeks prior.

An EEG revealed multifocal epileptiform discharges and rare bilateral discharges. MRI showed evidence of multiple areas of hemosiderin on SWI images, and a couple of small areas of encephalomalacia related to the prior closed injury; no new abnormalities were noted.

He received a diagnosis of partial-onset seizures with secondarily generalized tonic-clonic seizures.

I discussed the need for AED therapy with Robert and his parents, and he stated that he wanted to be seizure-free. He also preferred a once-daily drug regimen; he did not want to take medication at school or in the morning as he eats breakfast at school.

Also, since he already takes multiple medications for asthma, allergies, and ADHD, he preferred to take fewer pills—once daily, if possible.

I presented several medication options to Robert and his parents, and we made a shared decision to start FYCOMPA.

I started him on FYCOMPA at 2 mg once daily at bedtime. After 4 weeks, his FYCOMPA dose was increased to 4 mg per day.

I also discussed the FYCOMPA safety information and potential side effects.

As part of the treatment plan, I monitored for efficacy and safety, and I counseled Robert’s parents to be alert for psychiatric and behavioral reactions.

Robert has been maintained on FYCOMPA 4 mg per day, and has been seizure free for 8 months.

Robert does miss occasional doses of his medication. I continue to emphasize to Robert and his family, the importance of adhering to his medication regimen, and work with him on strategies to improve adherence.

Robert did not report any adverse events during his FYCOMPA treatment, although we did carefully evaluate him for these events. He was monitored clinically, and at every follow-up visit I asked Robert if he was experiencing any side effects or problems that he thought might be related to his medications.

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

I should also note here that the treatment plan and results described in this case study are specific to this particular patient, and other patients may have different outcomes.

Here is a question to think about.

If you were evaluating Robert for the first time and developing a treatment program, what type of information might have the strongest influence on your selection of an AED?

When considering treatment options, I begin by excluding medications that might be contraindicated in a patient like Robert. Then I look at the efficacy data in partial-onset seizures and secondarily generalized seizures and assess the safety information.

For patients like Robert who is an adolescent and may be 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 considered.

Let us now review new study data that looked at FYCOMPA monotherapy in newly diagnosed or untreated patients, similar to Robert’s case.

The FREEDOM study is a 26-week, multicenter, uncontrolled, open-label study conducted in Japan and South Korea, which assessed the first-line use of FYCOMPA in newly diagnosed or untreated patients with epilepsy who have partial-onset seizures with or without secondary generalization.

The objective of this study was to evaluate the seizure-freedom rate during a 26-week maintenance phase. The evaluation criteria focused on the efficacy and safety of FYCOMPA used as monotherapy in new-onset or untreated patients with partial-onset seizures, including secondarily generalized seizures.

In this study, 96% of the patients were newly diagnosed with epilepsy. These patients presented with the seizure types seen here. The majority of patients presented with complex partial seizures with secondary generalization.

Seventy-three patients entered the 4-mg maintenance period and had at least 1 postdose primary efficacy measurement. These patients had experienced a median baseline seizure frequency of 2 seizures per 12 weeks.

Following a 28-day pretreatment phase, patients were started on 2 mg of FYCOMPA for 2 weeks, and then titrated to 4 mg of FYCOMPA for 4 weeks.

They then began a 26-week maintenance phase during which they were monitored for seizure freedom. If a seizure occurred during this 26-week maintenance phase, patients were titrated to 6 mg once daily, and then to 8 mg once daily.

During the 26-week maintenance phase, the majority of the newly diagnosed or untreated patients with partial-onset seizures were seizure free.

In the open-label analysis, 63% of patients with partial-onset seizures achieved seizure freedom with FYCOMPA 4 mg. Of the patients with secondarily generalized seizures at baseline, 65% achieved seizure freedom.

It’s important to note that this was an open-label study without blinding, randomization, or a control arm. Appropriate multiplicity adjustments were not applied and the information presented here is descriptive.

Here you see the adverse events at 26 weeks that occurred in at least 5% of patients taking 4 mg of FYCOMPA.

Psychiatric disorders reported at 4 mg/day included irritability (2.9%), affect lability (1.5%), depression (1.5%), and insomnia (1.5%).

It is important to note that of the 22 patients who discontinued treatment during the 4-mg treatment phase, 8 patients or 9% discontinued due to an adverse event.

Additional reasons for discontinuation can be seen here.

I’m encouraged to see additional data that supports why we may want to pause at 4 mg and assess for efficacy and safety in partial-onset seizure patients. It’s important to know that some patients may respond to 4 mg.

Let’s get back to our patient Robert.

So, I presented several medication options to Robert and his parents, and we made a shared decision to start FYCOMPA. We made this decision because FYCOMPA is administered once daily and has seizure freedom data for secondarily generalized seizures. In addition, it has a well-established safety profile. Its drug-drug interaction profile was also a factor in choosing FYCOMPA.

Let’s pause here for another question.

Before initiating FYCOMPA for a patient like Robert, 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’s safety information.

This is information I always discuss with my patients when 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 adjunctive 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 disturbances 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 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 perampanel 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.

Dose 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 or visit FYCOMPA.com/hcp

Now let’s get back to our case.

I educated Robert and his family on epilepsy and described the importance of long-term treatment given the age of onset and etiology. I also discussed seizure first aid and advised him to avoid unsupervised baths, swimming alone, or climbing to heights.

After reviewing FYCOMPA’s Medication Guide and discussing the Important Safety Information with Robert and his family, I started him on FYCOMPA at 2 mg once daily at bedtime and planned to follow-up with him 4 weeks later to assess how he was doing and then increase his dose to 4 mg once daily at bedtime if he was doing well.

I also discussed the FYCOMPA safety information and potential side effects, and asked his family to call the office in the event of a seizure, if they suspected he was having a side effect, or if they noticed any behavioral changes.

As part of the treatment plan, I monitored for efficacy and safety, including psychiatric and behavioral reactions.

I’d like to point out that the recommended maintenance dose range for FYCOMPA for partial-onset seizures is 8 mg to 12 mg once daily, although some patients with partial-onset seizures may respond to doses of 4 mg 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.

Robert and his parents returned to my office 4 weeks later for a follow-up visit. At this point, I increased his FYCOMPA dose to 4 mg once daily at bedtime.

During his follow-up, he noted that he missed a dose of his medication. Although this did not cause him a problem, we worked on strategies to improve adherence.

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

For adolescents like Robert, 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 like Robert will miss some doses of their AED medication. I try to keep AED dosing regimens as simple as possible by using once daily medications when possible.

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.

FYCOMPA has a long half-life of up to 105 hours based on a model of 4-mg daily treatment over a period of 4 weeks.

The long half-life of FYCOMPA was established in Phase I clinical trials with healthy adults. In pediatric patients ages 4-11, the half-life of FYCOMPA is long but is reduced by approximately half. In the presence of concomitant moderate or strong CYP3A4 inducers, FYCOMPA continues to have a long half-life but it is reduced by approximately half in both adults and pediatric patients.

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 QD dosing in adults.

The 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.

Let’s get back to our patient Robert and see how he is doing. I am pleased to report that this patient has been on FYCOMPA 4 mg once daily and has been seizure free for 8 months.

He continues to miss occasional doses of his medication once or twice a month and I continue to emphasize to Robert and his family, the importance of adherence to his medication regimen.

As I mentioned earlier, Robert was monitored carefully and did not report any adverse events during his 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.

Finally, the treatment plan and results I’ve just described are specific to this particular patient, and other patients may have different outcomes.

I hope this case study has prompted you to think about how FYCOMPA might be used in your patients with newly diagnosed partial-onset seizures with or without secondary generalization.

I have been using FYCOMPA in my patients with convulsive seizures for several years. My increasing experience with FYCOMPA in patients with partial-onset seizures with secondary generalization 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 healthcare professionals, listed here.

Thanks for watching.

[Music]