Expert Commentary on a Broad-Spectrum Treatment Option Which May Offer Convulsive Seizure Freedom for Patients With Partial-Onset Seizures

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Hello and welcome.

 

My name is Sarah and today I'm joined by two national experts,

Dr. Selim Benbadis, Professor of Neurology at the University of South Florida, and Director of the University of South Florida/Tampa General Hospital Comprehensive Epilepsy Program,

and Dr. Matthew Holtzman, Neurologist at Wayne Neurology, PLC in Wayne, Michigan.

 

In this video, we will review broad-spectrum treatment with FYCOMPA^® (perampanel)

which may offer convulsive seizure freedom for patients with partial-onset seizures.

 

Welcome, both of you. So happy you could join us today.

 

-Thank you.

 

-Glad to be here.

 

Before we begin, let's take a moment to review

some important safety information about FYCOMPA.

 

INDICATION.

FYCOMPA (perampanel) is indicated in patients with epilepsy aged four years and older

for partial-onset seizures (POS) with or without secondarily generalized seizures

and adjunctive therapy for patients aged 12 years and older

for primary generalized tonic-clonic (PGTC) seizures.

 

IMPORTANT SAFETY INFORMATION.

WARNING: 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.

 

These reactions occurred in patients with and without prior psychiatric history,

prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.

 

Advise patients and caregivers to contact a healthcare provider immediately

if any of these reactions or changes in mood, behavior, or personality

that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA.

 

Closely monitor patients, 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.

 

Please see full important safety information at the end of this video.

 

- Dr. Holtzman, would you like to begin by reviewing our patient case?

 

- Yes, thank you.

This case is based on an actual patient from my practice, but identifying details have been changed.

 

Sarah is a 42-year-old female who works in sales.

 

Her first seizure occurred at age 29, and she initially presented to the emergency room with an episode of lost time.

 

She had been taking a shower and then woke up on her bed with her dog licking her.

She had no recollection of any events.

 

Brain magnetic resonance imaging and electroencephalogram were normal

and no treatment was implemented at that time.

 

A year later, she had a witnessed generalized tonic-clonic seizure.

 

Based on this event, Sarah was diagnosed with epilepsy.

 

Sarah was started on lamotrigine extended-release, titrated to 300 mg once daily.

 

Several years later, Sarah had another witnessed generalized tonic-clonic seizure

that included biting of the left side of the tongue.

 

She believed she had forgotten to take at least one day of medication.

 

Her verified level of lamotrigine in the emergency room was 0.8.

 

Her baseline level had been 5.4.

 

Sarah was devastated by this seizure because she lost her ability to drive for 6 months

and ultimately lost her job because of it.

 

Although at the time she was motivated to get her seizures under control, she was reluctant to add a second medication to her regimen.

 

Ultimately, she chose to continue on lamotrigine extended-release 300 mg once daily.

 

A year later, she experienced another witnessed generalized tonic-clonic seizure with a verified lamotrigine level of 1.8.

 

She reported she was certain she had not missed any doses of lamotrigine.

 

Together, we discussed her treatment goals.

 

For Sarah, these included seizure freedom and ability to drive and work normally, especially because she needed to turn down a job offer due to her inability to drive.

 

This is one of the most common challenges I see patients with seizures struggling with in their daily lives.

Sarah was ready to add a second medication to her treatment regimen.

Because she experienced breakthrough seizures on lamotrigine and was nonadherent to treatment in the past,

I recommended FYCOMPA due to its long half-life.

 

We discussed the clinical attributes of FYCOMPA, including data for seizure freedom, and reviewed the Boxed Warning and the adverse event profile.

 

FYCOMPA was added to Sarah's treatment regimen, starting with 2 mg once daily over 2 weeks,then increasing to 4mg once daily at night.

 

Sarah has remained seizure free and adverse event free on FYCOMPA 4 mg and lamotrigine extended-release 300 mg once daily.

 

She has had no further seizure events and is working and driving again.

 

She follows up every 6 months for documentation and refills.

 

- Thank you, Dr. Holtzman.

Would you like to share anything else about your clinical decision-making in this patient case?

 

- Yes, there are a few considerations I'd like to point out.

 

First, based on the literature, I was confident that using FYCOMPA as a first adjunctive therapy

I would have a high likelihood of getting her seizure-free.

 

Based on the FAME data, which we will discuss shortly, I knew that 4 mg would likely be an effective dose and I could always go up to 6 mg if I needed to.

 

Second, given her busy lifestyle and history of having missed a dose, it is very important that Sarah be on a medication that is not only dosed once daily, but also has a long half-life in case she missed a dose again.

 

Finally, Sarah did not complain of cognitive symptoms.

 

However, because she was young and working, I didn't want to prescribe a drug that could harm her performance at work or otherwise limit her.

 

She was already having enough challenges with losing her ability to drive.

 

- Thank you for that excellent review.

 

Dr. Benbadis, what would you like to add from your perspective?

 

- I agree with the addition of FYCOMPA to Sarah's treatment plan.

 

It is surprising that even when she was adherent to 300 mg/day of lamotrigine, her levels were so low.

 

As often seen in cases like Sarah's, she responded to FYCOMPA.

 

The advantage of a broad-spectrum medication like FYCOMPA is that regardless of whether she has focal epilepsy or idiopathic generalized epilepsy, FYCOMPA is indicated and it works.

 

As Dr. Holtzman noted, FYCOMPA was a good choice in terms of Sarah's cognition.

 

I personally prescribe FYCOMPA frequently when appropriate in students and patients in various professions where cognitive symptoms would cause challenges.

 

- Thank you for those insights.

 

Let's continue by reviewing the pivotal data for FYCOMPA in partial-onset seizures.

 

Dr. Benbadis, could you please summarize the data in the 3 FYCOMPA pivotal trials?

 

- Certainly.

 

The patient demographics of the pivotal trials were typical of what we would expect to see in a refractory focal epilepsy trial.

 

Patients in the studies were titrated every week over a 6-week titration period; doses were 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg.

 

The primary endpoint was median percent reduction in partial-onset seizure frequency per 28 days.

 

FYCOMPA achieved proven reductions in partial-onset seizure frequency at doses of 4 mg/day, 8 mg/day, and 12 mg/day,with inducer and non-inducer anti-seizure medications.

 

The secondary endpoint was 50% or greater reduction in partial-onset seizure frequency.

 

In the pivotal studies, up to 54% of patients experienced a 50% or greater reduction in partial-onset seizure frequency with FYCOMPA.

 

There was a prespecified exploratory endpoint of median percent reduction in secondarily generalized seizure frequency per 28 days.

 

Up to a 75% frequency reduction in secondarily generalized seizures with FYCOMPA was reported.

 

Seizure freedom in secondarily generalized seizures was a post hoc exploratory endpoint.

 

In the studies, up to 36% of patients with secondarily generalized seizures were convulsive seizure free during the 13-week maintenance phase.

 

The most common adverse reactions included dizziness and disturbances in gait or coordination, including ataxia, gait disturbance, balance disorder, and abnormal coordination; somnolence and fatigue-related events including fatigue, asthenia, and lethargy.

 

Finally, discontinuations due to adverse reactions occurred in 5% of participants taking placebo, 3% of participants taking FYCOMPA 4 mg, 8% of participants on FYCOMPA 8 mg, and 19% of participants on FYCOMPA 12 mg.

 

 

- Thank you, Dr. Benbadis.

 

Dr. Holtzman, you mentioned that data from the FAME study informed your treatment choice for our case patient, Sarah.

 

Would you please begin by reviewing the FAME study design and efficacy results?

 

- Of course.

 

The efficacy and safety of FYCOMPA as a first adjunctive therapy after anti-seizure medication monotherapy failure were evaluated in FAME, a 24-week maintenance, multicenter, open-label prospective trial.

 

FAME included patients aged greater than or equal to 12 years with partial-onset seizures, with or without secondarily generalized tonic-clonic seizures.

 

During the Titration Period of this Phase 4 study,patients received FYCOMPA 2 mg once daily at bedtime.

 

The daily dose was increased incrementally at greater than or equal to 2 week intervals by 2 mg,depending on clinical response and tolerability.

 

Patients who were enrolled in the study had greater than or equal to 2 partial-onset seizures at intervals of greater than or equal to 24 hours during the 8 weeks prior to week 0, and had been taking anti-seizure medication monotherapy administered at a stable dose for 8 weeks prior to week 0.

 

Treatment-emergent adverse events, withdrawal from treatment, and clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis) were assessed.

 

The primary endpoint was the percentage of patients with a greater than or equal to 50% reduction in total seizure frequency during the Maintenance Period as compared to baseline, or the 50% responder rate.

 

Secondary endpoints included the percentage of patients with greater than or equal to 75% reduction in total seizure frequency (the 75% responder rate); the percentage of patients with a 100% reduction in total seizure frequency (the 100% responder rate); and 50%, 75%, and 100% responder rates for secondarily generalized tonic-clonic seizures.

 

- FAME was original because it was a study of first adjunctive treatment in a less-refractory patient population.

 

It provides compelling data, especially in a more general neurology population.

 

- As Dr. Benbadis mentions, the FAME study was unique and the data it provides are valuable.It gives us evidence-based support to potentially use lower doses, which my patients appreciate.

 

As we see here, the primary endpoint of greater than or equal to 50% responder rate at Week 24 was achieved by 80% of patients with partial-onset seizures, and 88% of patients with secondarily generalized seizures, which was a secondary endpoint.

 

The secondary endpoint of greater than or equal to 75% responder rate at week 24 was achieved by 72% of patients with partial-onset seizures and 88% of patients with secondarily generalized seizures.

 

Finally, the secondary endpoint of seizure freedom was reached by 47% of patients with partial-onset seizures and 75% of patients with secondarily generalized seizures.

 

The numbers of patients with reductions in seizure frequency are shown in the table.

 

Of patients with partial-onset seizures, 68 of 85 achieved greater than or equal to 50% reduction,

61 of 85 achieved greater than or equal to 75% reduction,

and 40 of 85 achieved 100% reduction.

 

Of patients with secondarily generalized seizures, 14 of 16 achieved greater than or equal to 50% reduction, the same number achieved 75% reduction, and 12 of 16 achieved 100% reduction.

 

The FAME study had several limitations.

 

The study was open-label and did not include a control arm.

 

Appropriate multiplicity adjustments were not applied.

 

This information is descriptive.

 

And finally, the study included a relatively small number of patients.

 

Here we can see the number of patients with partial-onset seizures at each final maintenance dose.

 

As shown here, the majority of patients had a final maintenance dose of FYCOMPA 4 mg or 6 mg.

 

This includes 37 patients taking moderate and strong CYP3A4 inducers, which can cause a reduction in FYCOMPA plasma levels and may require higher doses of FYCOMPA.

 

The study was not designed to evaluate the effect of concomitant inducer/non-inducer anti-seizure medication.

 

I like to reach for FYCOMPA early because the FAME data showing that we can get a large percentage of patients with focal onset epilepsy seizure-free at a dose as low as 4 mg.

 

Based on the FAME data, I believed 4 mg of FYCOMPA once daily would likely be an effective dose to control Sarah's seizures, and I could always go up if I needed to.

 

Based on the literature, I was confident that using FYCOMPA as a first adjunctive therapy I would have a high likelihood of getting her seizure-free at a low dose.

 

- Based on these data from FAME, I agree with the addition of FYCOMPA to Sarah's treatment plan.

 

- Thank you so much, Dr. Holtzman.

Dr. Benbadis, would you please continue by reviewing the safety profile of FYCOMPA in the FAME study?

 

- Yes, of course.

 

The table shown here depicts the adverse reactions at 24 weeks from the FAME study.

Among the 102 patients in the FAME study safety set, 75.5% reported treatment-emergent adverse events.

 

The most common adverse events included dizziness, somnolence, and headache.

 

Treatment discontinuation occurred in 24.5% of patients during the study, with 13.2% of these due to adverse events.

 

Beyond these data, now more than half a million patients have been prescribed FYCOMPA.

 

It has been on the market long enough that we can use it with confidence.

 

- Thanks to both of you for that excellent review of the data.

Now, let's discuss how the pharmacokinetic profile of FYCOMPA comes into consideration when making treatment choices.

 

Dr. Holtzman, could you please begin?

 

- I'd be happy to.

 

FYCOMPA has a long half-life of up to 105 hours.

 

In the event of a missed dose, plasma levels of FYCOMPA remain relatively stable.

 

The long half-life of FYCOMPA means that when a patient misses a dose, their plasma levels remain unchanged.

 

Patients who miss a dose should resume dosing the following day at their prescribed dose.

 

Instruct patients to contact their healthcare provider if more than 1 day of dosing is missed.

 

The time to maximum serum concentration of FYCOMPA ranges between 0.5 to 2.5 hours under fasted conditions.

 

Steady state is reached in about 2-3 weeks.

 

Finally, we know that, pharmacokinetically, FYCOMPA works quite well alongside other drugs.

 

- That is correct.

FYCOMPA has a different mechanism of action from other anti-seizure medications.

 

It is helpful to have an option that we can combine with so many other drugs.

 

- Thank you both, for your excellent insights so far.

 

Let's wrap up this roundtable by discussing the dosing recommendations for FYCOMPA and their implications for patient treatment.

 

Dr. Benbadis, would you please begin?

 

- I'd be happy to.

FYCOMPA should be administered once daily at bedtime.

 

This once-daily dosing of FYCOMPA is an advantage for young, active, working patients that I see in my practice.

 

The titration is short and easy: start patients at 2 mg and titrate slowly, increasing to 4 mg at one to two weeks.

 

Then, assess at 4 mg and adjust as necessary, modifying the dose as needed based on clinical response and tolerability.

 

The dose can be increased based on clinical response and tolerability by increments of 2 mg once daily, no more frequently than at weekly intervals.

 

Most of my patients end up taking between 4 and 10 mg, which speaks to the efficacy of FYCOMPA.

 

- I was an early adopter of FYCOMPA.

When it first became available we were titrating up quickly.

 

But, as Dr. Benbadis explains, we now know that slower is better and it takes about 3 weeks to get into steady state.

 

I make sure to have patients reach steady state before I titrate higher.

 

When I do that, I have great results.

 

- This has been fantastic.

I can't thank you both enough for joining me today to discuss FYCOMPA.

 

And I would like to thank those of you watching, as well.

 

But before we end, please stay tuned, and let's review some additional important safety information.

 

- IMPORTANT SAFETY INFORMATION.

 

WARNING: 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.

 

These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression.

 

Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA.

 

Closely monitor patients, 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.

 

SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS.

 

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 in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients.

 

Homicidal ideation and/or threat have also been reported postmarketing in patients treated with FYCOMPA.

 

The combination of alcohol and FYCOMPA significantly worsened mood and increased anger.

 

Patients taking FYCOMPA 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 and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases.

 

Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic (PGTC) seizure clinical trial.

 

SUICIDAL BEHAVIOR AND IDEATION.

 

Anti-epileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients.

Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

 

Epilepsy and many other illnesses for which AEDs are prescribed, are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

 

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.

 

Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

 

DIZZINESS AND GAIT DISTURBANCE.

 

FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination.

 

Dizziness and vertigo were reported in 35% and 47% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients.

 

Gait disturbance related events were reported in 12% and 16% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients.

 

These adverse reactions occurred mostly during the titration phase.

 

These adverse reactions were also observed in the PGTC seizure clinical trial.

 

SOMNOLENCE AND FATIGUE.

 

FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events.

 

Somnolence was reported in 16% and 18% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 7% of placebo-treated patients.

 

Fatigue-related events were reported in 12% and 15% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 5% of placebo-treated patients.

 

These adverse reactions occurred mostly during the titration phase.

 

These adverse reactions were also observed in the PGTC seizure clinical trial.

 

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.

 

Falls were reported in 5% and 10% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively,compared to 3% of placebo-treated patients.

 

DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS).

 

DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA.

 

DRESS may be fatal or life-threatening.

 

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement.

 

If signs or symptoms are present, immediately evaluate the patient and discontinue FYCOMPA if an alternative etiology for signs or symptoms cannot be established.

 

WITHDRAWAL OF AEDs.

 

A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.

 

MOST COMMONN ADVERSE REACTIONS.

 

The most common adverse reactions in patients age 12 years and older receiving FYCOMPA (greater than or equal to 5%,and greater than or equal to 1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls,nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety.

 

Adverse reactions in patients 4 to less than 12 years were generally similar to patients aged 12 years and older.

 

DRUG INTERACTIONS.

 

FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel.

 

Plasma levels of perampanel were decreased when administered with known moderate and strong CYP3A4 inducers,including, carbamazepine, phenytoin, or oxcarbazepine.

 

Multiple dosing of FYCOMPA 12 mg per day enhanced the effects of alcohol on vigilance and alertness and increased levels of anger, confusion, and depression.

 

These effects may also be seenvwhen FYCOMPA is used in combinationv with other CNS depressants.

 

PREGNANCY AND LACTATION.

 

Physicians are advised to recommend that pregnant patients taking FYCOMPA enrolled in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.

 

Caution should be exercised when FYCOMPA is administered to pregnant or nursing women as there are no adequate data on the developmental risk associated with use in pregnant women, and no data on the presence of perampanel in human milk, the effects on the breastfed child, or the effects of the drug on milk production.

 

HEPATIC AND RENAL IMPAIRMENT.

 

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.

 

DRUG ABUSE AND DEPENCENCE.

 

FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms including anxiety, nervousness, irritability,fatigue, asthenia, mood swings, and insomnia.

 

INDICATION.

 

FYCOMPA (perampanel) is indicated in patients with epilepsy aged 4 years and older for partial-onset seizures (POS) with or without secondarily generalized seizures,and adjunctive therapy for patients aged 12 years and older for primary generalized tonic-clonic (PGTC) seizures.

 

View the prescribing information linked on this site.

 

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