Eisai Submits Supplemental Application to FDA for Use of its Antiepileptic Drug FYCOMPA® (perampanel) as Monotherapy for the Treatment of Partial Onset Seizures

Application Based on New FDA Communication Supporting Use as Monotherapy for the Treatment of Partial Onset Seizures Based on Extrapolation

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Eisai Inc.

Sep 26, 2016, 01:30 ET

WOODCLIFF LAKE, N.J., Sept. 26, 2016 /PRNewswire/ -- Eisai Inc. announced today that it has submitted a supplemental application to the U.S. Food and Drug Administration (FDA) for a proposed label change for its antiepileptic drug FYCOMPA^® (perampanel) CIII which would include use as monotherapy for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older.

FYCOMPA is approved as an adjunctive therapy, or an add-on treatment, in combination with another antiepileptic drug (AED), for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures, and primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy 12 years of age and older. Please see Important Safety Information for FYCOMPA, including Boxed WARNING for Serious Psychiatric and Behavioral Reactions, below.

Eisai submitted its application based on a new FDA communication which states that it is "acceptable to extrapolate the efficacy and safety of drugs approved as adjunctive therapy for the treatment of partial onset seizures (POS) to their use as monotherapy for the treatment of POS" as long as adequate information is provided on pharmacokinetics and possible drug-drug interactions (inhibition or induction) that may alter the metabolism of the drug. Eisai has submitted such data along with the proposed new label.

"Eisai is pleased to submit this new application, which may lead to an additional treatment option for those suffering from partial onset seizures," said Lynn Kramer, M.D., Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. "As a company, we are committed to advancing treatments that will make a difference to those who are affected by epilepsy, and we're looking forward to the potential for FYCOMPA as a single agent to help more patients suffering from these types of seizures."

This release discusses a non-approved use for FYCOMPA. It is not intended to convey conclusions about efficacy or safety for such use. There is no guarantee that the proposed use discussed in this release will gain FDA approval.

About Epilepsy

Epilepsy is a medical condition that produces seizures affecting a variety of mental and physical functions. According to the Institute of Medicine, epilepsy is one of the most common neurological disorders, which affects 2.9 million people in the United States. Partial-onset seizures are the most common type of seizure seen in people with epilepsy, accounting for 60 percent of all seizures. Generalized seizures account for approximately 40 percent of all epilepsy, with primary generalized tonic-clonic seizures being one of the most common and severe forms of generalized seizures.

About FYCOMPA (perampanel)

FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

FYCOMPA is an oral medication and the first and only FDA-approved non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist. The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans has not been fully elucidated.

FYCOMPA is supplied as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg film-coated tablets, and also in an oral suspension formulation. FYCOMPA has been designated by the U.S. Drug Enforcement Administration as a federally-controlled substance (CIII).

Important Safety Information for FYCOMPA (perampanel) CIII


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. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with FYCOMPA. 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

Antiepileptic 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 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 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.

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.

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 Common Adverse Reactions

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

Drug Interactions

FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel.

Plasma levels of FYCOMPA were decreased when administered with carbamazepine, phenytoin, or oxcarbazepine. Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John's wort) should be avoided. 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 seen when FYCOMPA is used in combination with other CNS depressants.

Pregnancy and Lactation

Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll 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 Dependence

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

Please see accompanying Full Prescribing Information for FYCOMPA (perampanel), including Boxed WARNING.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‑800‑FDA‑1088.

About Eisai Inc.

At Eisai Inc., human health care (hhc) is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US.