FAYCOMPA film-coated tablets 2 mg No. 7

FAYCOMPA film-coated tablets 2 mg No. 7

Fycompa is not a potent inducer or inhibitor of cytochrome P450 isoenzymes or the UGT isoenzyme involved in glucuronidation reactions. Oral contraceptives At a dose of 12 mg/day (but not 4 or 8 mg/day), perampanel reduced the Cmax and AUC of levonorgestrel by approximately 40%. Perampanel at a daily dose of 12 mg has no effect on the AUC of ethinyl estradiol, but reduces its Cmax by 18%. Patients taking Fycompa should be aware of the possibility of reduced effectiveness of contraceptives containing levonorgestrel and use additional methods of contraception (intrauterine devices or condoms). Interaction with other antiepileptic drugs (AEDs) The potential interaction of Fycompa (with a single daily dose of up to 12 mg) and other AEDs was assessed based on clinical trial data and population pharmacokinetic analysis of pooled data from three phase III studies. The effect of this interaction on the equilibrium concentrations of AEDs is shown in the table: Table Co-administered AEDs The effect of AEDs on the concentration of the drug Faicompa The effect of the drug Faicompa on the concentration of AEDs Carbamazepine Reduction by "70% Reduction by less than 10% Clobazam No effect Reduction by less than 10% Clonazepam No effect No effect Lamotrigine No effect Reduction by less than 10 % Levetiracetam No effect No effect Oxcarbazepine Reduction by » 50% Increase by 35% * Phenobarbital No effect No effect Phenytoin » 50% reduction No effect Topiramate 20% reduction No effect Valproic acid No effect Less than 10% decrease Zonisamide No effect No effect * Excluding the active metabolite monohydroxycarbazepine. Some AEDs that are enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) increase the overall clearance of perampanel and accordingly reduce its plasma concentrations. In a study involving healthy volunteers, carbamazepine, a known potent enzyme inducer, reduced perampanel concentrations by 2/3 (3-fold). A similar result was obtained in a population pharmacokinetic analysis in patients with partial-onset seizures treated with Fycompa at doses up to 12 mg/day in placebo-controlled clinical trials. Taking Fycompa did not have a clinically significant effect on the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest dose of perampanel (12 mg/day). When taking the drug perampanel simultaneously with oxcarbazepine, the clearance of the latter decreased by 26%. Oxcarbazepine is rapidly metabolized by cytosolic reductase to the active metabolite monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is unknown. The dose of perampanel is adjusted until a clinical effect is achieved, regardless of concomitant AEDs. Effect of perampanel on substrates of the CYP3A isoenzyme In healthy volunteers, Fycompa (daily dose 6 mg for 20 days) reduced the AUC of midazolam by 13%. A greater reduction in exposure to midazolam (and other sensitive CYP3A substrates) when taking higher doses of Fycompa cannot be excluded. Effect of inducers of cytochrome P450 isoenzymes on the pharmacokinetics of perampanel It is expected that potent inducers of cytochrome P450 isoenzymes, such as rifampicin and St. John's wort, may also reduce the plasma concentration of perampanel. Felbamate may also decrease plasma concentrations of perampanel. The effect of inhibitors of cytochrome P450 isoenzymes on the pharmacokinetics of perampanel In healthy volunteers, taking ketoconazole (at a daily dose of 400 mg for 10 days), which is an inhibitor of the CYP3A4 isoenzyme, increased the AUC of perampanel by 20% and prolonged its T1/2 by 15% (67.8 versus 58 ,4 hours). When perampanel is combined with another inhibitor of the CYP3A4 isoenzyme with a half-life longer than that of ketoconazole or with a longer administration of the inhibitor, an enhanced effect cannot be ruled out. Potent inhibitors of other cytochrome P450 isoenzymes may also potentially increase perampanel concentrations. Interaction with levodopa In healthy volunteers, administration of Fycompa (at a daily dose of 4 mg for 19 days) had no effect on the AUC or Cmax of levodopa. Interaction with alcohol In a pharmacodynamic interaction study in healthy volunteers, the effect of perampanel on alertness and reaction time, such as driving, was enhanced by alcohol intake. Repeated administration of perampanel at a daily dose of 12 mg increased the severity of irritability, confusion and depression. This effect has also been observed when Fycompa is taken in combination with other CNS depressants. Use in Adolescents Drug interaction studies have been conducted only in adults. In a population pharmacokinetic analysis, adolescents participating in phase III clinical trials showed no significant differences from the general study population.

Fycompa

Fycompa is not a potent inducer or inhibitor of cytochrome P450 or UGT.

TlepopaibHbie contraceptives At a dose of 12 mg (but not 4 or 8 mg) per day, perampanel reduced the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of levonorgestrel by approximately 40%. Perampanel at a daily dose of 12 mg has no effect

on the AUC of ethinyl estradiol, but reduces its Cmax by 18%. Patients taking Faicompa at a daily dose of 12 mg should take into account the possibility of a decrease in the effectiveness of progestogen-containing contraceptives and use additional methods of contraception (intrauterine devices or condoms).

Interaction with other AEDs

The potential interaction of Fycompa (at a single daily dose of up to 12 mg) and other AEDs was assessed based on clinical trial data and population pharmacokinetic analysis of pooled data from four phase III studies that included patients with partial and primary generalized tonic-clonic seizures. The effect of this interaction on the equilibrium concentrations of PEP is given in the table:

Some AEDs that are enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) increase the overall clearance of perampanel and accordingly reduce its plasma concentrations.
In a study involving healthy volunteers, carbamazepine, a known potent enzyme inducer, reduced perampanel concentrations by 2/3.

A similar result was obtained in a population pharmacokinetic analysis in patients with partial seizures receiving Fycompa in doses up to 12 mg and in patients with primary generalized tonic-clonic seizures receiving Fycompa in doses up to 8 mg per day during placebo-controlled studies. clinical trials. The clearance of the drug Fycompa increased when taken simultaneously with carbamazepine (2.75 times), phenytoin (1.7 times) and oxcarbazenin (1.9 times), which are inducers of liver enzyme metabolism. This effect should be taken into account when prescribing or canceling these NEPs.

In a population pharmacokinetic analysis of patients with partial seizures receiving Fycompa in doses up to 12 mg and in patients with primary generalized tonic-clonic seizures receiving Fycompa in doses up to 8 mg per day in placebo-controlled clinical trials, Fycompa had no clinically significant effect on the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest dose of perampanel (8 or 12 mg per day).

When taking the drug perampanel simultaneously with oxcarbazepine, the clearance of the latter decreased by 26%. Oxcarbazepine is rapidly metabolized by cytosolic reductase to the active metabolite monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is unknown. Perampanel is titrated until clinical effect is achieved, regardless of concomitant AEDs.

Effect of perampanel on CYP3A substrates

In healthy volunteers, Fycompa (at a daily dose of 6 mg for 20 days) reduced the AUC of midazolam by 13%. A greater reduction in exposure to midazolam (and other sensitive CYP3A substrates) with higher doses of Fycompa cannot be excluded. Effect of cytochrome P450 inducers on the pharmacokinetics of perampanel It is expected that potent inducers of cytochrome 1450 isoenzymes, such as rifampicin and St. John's wort, may also reduce the plasma concentration of perampanel. Felbamate may also decrease plasma concentrations of perampanel.

Effect of itochrome P450 inhibitors on the pharmacokinetics of perampanel

In healthy volunteers, taking ketoconazole (at a daily dose of 400 mg for 10 days), which is an inhibitor of the CYP3A4 isoenzyme, increased the AUC of perampanel by 20% and prolonged its T1/2 by 15% (67.8 hours versus 58.4 hours). When perampanel is combined with another inhibitor of the CYP3A4 isoenzyme with a half-life greater than that of ketoconazole or with a longer administration of the inhibitor, an enhanced effect cannot be ruled out. Potent inhibitors of other cytochrome P450 isoenzymes may also potentially increase perampanel concentrations. Interaction with levodopa In healthy volunteers, administration of Fycompa (at a daily dose of 4 mg for 19 days) had no effect on the AUC or Cmax of levodopa. Interaction with alcohol

In a pharmacodynamic interaction study in healthy volunteers, the effect of perampanel on alertness and reaction time, such as driving, was enhanced by alcohol intake. Repeated administration of perampanel at a daily dose of 12 mg increased the severity of irritability, confusion and depression. This effect has also been observed when Fycompa is taken in combination with other central nervous system (CNS) depressants.

Use in adolescents

Drug interaction studies were conducted in adults only. In a population pharmacokinetic analysis, adolescents participating in phase III clinical trials showed no significant differences from the general study population.

FICOMPA allows achieving better seizure control in patients with epilepsy

Two new subgroup analyzes of pivotal data presented at the first European Academy of Neurology (EAN) Congress show that FYCOMPA® (perampanel), a new class of drug, achieves better seizure control in patients with idiopathic generalized epilepsy .

Hatfield, UK, 22 June 2015 – Important new information about the once-daily drug Fycompa® (perampanel[1],[2] was presented today at the first European Academy of Neurology (EAN) Congress in Berlin, Germany One subgroup analysis assessed the effectiveness of perampanel as an adjuvant treatment for absence seizures and myoclonic seizures in patients with idiopathic generalized epilepsy.2 The second analysis showed that it reduced the incidence of primary generalized tonic-clonic (PGTC) seizures. observed in the phase III study was independent of patient age, gender, and race1.

Perampanel is an oral drug with a simple dosage regimen. It is currently used as an adjuvant treatment for partial seizures with or without secondary generalization in patients with epilepsy aged 12 years and older.[3] On May 27, 2015, a positive decision was received from the Committee on Medicinal Products for Human Use (CPMP) regarding the use of perampanel for the treatment of OHTC seizures. Perampanel is the only registered antiepileptic drug (AED) that selectively targets AMPA receptors, proteins in the brain that play an important role in the generalization of seizures.[4] This mechanism of action differs from that of other available AEDs.

“The treatment arsenal for uncontrolled OHTC seizures is limited, and perampanel is the first of a new class of drugs that has a unique mechanism of action and is well tolerated,” said Bernhard Steinhoff, medical director and chief executive officer of the Kork Center for Epilepsy Study, Germany.

Generalized tonic-clonic seizures can be a dangerous form of epilepsy.[5] They begin with loss of consciousness and sudden muscle contraction, which can cause the person to fall (tonic phase). Severe cramps then appear (clonic phase), after which the muscles relax.[6] Approximately 20–40% of patients with newly diagnosed epilepsy experience or develop refractoriness to treatment over time,[7] which can impair quality of life.[8]

These subgroup analyzes were conducted as part of the first phase III, randomized, double-blind, placebo-controlled study examining the efficacy and safety of perampanel as an adjuvant treatment for OHTC seizures in patients with idiopathic generalized epilepsy aged 12 years or older. A total of 164 patients were randomized to participate in the study, with 81 patients receiving perampanel and 81 patients receiving placebo.9 Study 332 results show that the perampanel group had a greater reduction in the incidence of OGTC seizures than the placebo group (76.5% vs. 38.4%, respectively; P < 0.0001).9 The proportion of patients with OHTC seizures who had a 50% response to treatment was also higher in the perampanel group than in the placebo group (64.2 % versus 39.5%, respectively; P = 0.0019).[9] We use both of these indicators as primary endpoints. In addition, the proportion of patients who were seizure-free during the 13-week maintenance period was 31% in the perampanel group and 12% in the placebo group.2 Patients receiving perampanel also reported improvements in quality of life across all measures assessed. including activities of daily living, cognition, and functional impairment.9 The adverse event profile observed in this study was comparable to that in other studies of perampanel. The majority of adverse events in both groups were classified as mild or moderate in severity. The most common symptoms were dizziness, fatigue, headache, drowsiness and irritability.9

The complete data set for analysis included data from 162 patients (81 patients receiving placebo and 81 patients receiving perampanel). Before randomization, absence seizures occurred in 37.0% of patients (n = 60), and myoclonic seizures in 29.0% of patients (n = 47). The study was not powered to detect differences between these seizure types, but there was a reduction in the number of absence seizures in the perampanel group compared with the placebo group. The frequency of myoclonic seizures decreased in both treatment groups, however, in the placebo group this decrease was more pronounced than in the perampanel group (-52.54% versus -24.47%). The proportion of patients who experienced an increase in the frequency of myoclonic seizures was comparable in the perampanel and placebo groups (30.4% versus 29.2%, respectively). In general, perampanel did not aggravate myoclonic seizures. The proportion of patients who did not have any seizures was 23.5% in the perampanel group and 4.9% in the placebo group.

The development of perampanel underscores Eisai's commitment to finding treatments for epilepsy. The company's work in this area is another example of how the company strives to address the diverse needs of patients and their families and provide them with even greater benefits, as reflected in the company's mission of human health care (hhc).

Notes to editors

About the drug Fycompa® (perampanel)

Perampanel is used as an adjunct drug for the treatment of partial seizures with or without secondary generalization in patients 12 years of age and older.3

Perampanel is a highly selective, noncompetitive AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor antagonist that has demonstrated the ability to reduce the frequency of partial seizures in phase II and III studies. AMPA receptors, present in large numbers in almost all excitatory neurons, transmit signals for the excitatory neurotransmitter glutamate in the brain. They are thought to be involved in the pathogenesis of diseases of the central nervous system characterized by excessive transmission of excitatory signals, including epilepsy.8

Further information is available on the website: www.fycompa.eu

About a phase III study examining the use of perampanel as an adjuvant treatment for idiopathic generalized epilepsy in patients with treatment-resistant primary generalized tonic-clonic seizures, stratified by age, sex, and race1

The study included patients aged 12 years or older with idiopathic generalized epilepsy (IGE) who had received one to three antiepileptic drugs for at least 30 days before the baseline period and had at least three OHTC seizures in the 8 weeks before. randomization. The diagnosis of IGE was confirmed by specialists from the Epilepsy Research Association, who did not participate in the study. The study had two phases: a pre-randomization phase (4-week screening, 4-8 week baseline period) and a post-randomization phase (4-week dose titration period, 13-week maintenance period, 4-week follow-up period). ). The dose of perampanel was increased by 2 mg weekly until a dose of 8 mg/day or the optimal individual dose was reached. The median percent change in seizure frequency from baseline and the proportion of patients with a 50% response to treatment were assessed, taking into account age, sex, and race.

The complete data set for analysis included data from 162 patients (81 patients receiving placebo and 81 patients receiving perampanel). The majority of patients were Caucasian (n = 87) or Asian Pacific (n = 68) and aged 18 years or older (n = 139). The number of men and women was comparable. The median percent change in OGTC seizure frequency from baseline was higher in the perampanel group than in the placebo group (–76.47% vs. –38.38%; P < 0.0001). Compared with placebo groups, all groups of patients receiving perampanel, regardless of age, sex and race, had a greater reduction in median attack frequency (percentage) from baseline and a greater increase in the proportion of patients with a 50% response for treatment. The proportion of patients with a 50% response to treatment was 39.5% in the placebo group and 64.2% in the perampanel group.

On a phase III study of perampanel as an adjuvant in the treatment of idiopathic generalized epilepsy: analysis of a subgroup of patients with absence and myoclonic seizures2

The study included patients aged 12 years or older who had had at least three OHTC seizures in the 8 weeks before randomization and had received one to three antiepileptic drugs for at least 30 days before the start of the baseline period. The study had two phases: a pre-randomization phase (4-week screening, 4-8 week baseline period) and a post-randomization phase (4-week dose titration period, 13-week maintenance period, 4-week follow-up period). ). The dose of perampanel was increased by 2 mg weekly until a dose of 8 mg/day or the optimal individual dose was reached. Secondary endpoints were the median percentage change in seizure frequency from baseline and the proportion of patients with a 50% response to treatment as assessed by the frequency of absence seizures and myoclonic seizures.

About Study 3329

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III study examining the efficacy and safety of perampanel versus placebo as an adjuvant treatment for treatment-refractory tonic-clonic seizures in a group of 164 elderly patients with OHTC seizures. 12 years and older receiving one to three antiepileptic drugs. The study was conducted at research centers in the USA, Europe, Japan and Asia.

Patients received perampanel tablets orally once a day at a dose of up to 8 mg/day (dose selection period), and then at the maximum tolerated dose (maintenance therapy period). The study had two phases: a pre-randomization phase (screening and baseline period) (maximum 12 weeks) and a post-randomization phase (4-week dose titration period, 13-week maintenance period) (17 weeks).

The results showed that, compared with placebo, perampanel therapy showed a significant improvement in the study's primary outcome measure—a reduction in the frequency of OGTC seizures over the 28-day maintenance period by at least 50% compared with baseline). In general, patients tolerated perampanel well. The most common adverse events (the incidence of which was 10% in the perampanel group and higher than in the placebo group) were dizziness, fatigue, headache, irritability and drowsiness. Adverse events observed in this study were similar to those reported in other studies of perampanel.

About epilepsy

Epilepsy is one of the most common diseases of the nervous system in the world. In Europe, epilepsy affects approximately 8 in 1000 people, and there are 50 million sufferers worldwide.[10],[11] Epilepsy is a chronic brain disorder that can occur at any age. It manifests itself in the form of seizures caused by excessive neuronal activity. Seizures vary in severity, from brief absence seizures or muscle cramps to intense, prolonged convulsions. Depending on the type, seizures may be limited to one part of the body or spread to the entire body. In addition, the frequency of occurrence of attacks also varies - the intervals between attacks can range from several hours to more than a year. Epilepsy is a polyetiological disease, but in many cases its genesis is unclear.

About the activities of Eisai EMEA in the field of epilepsy treatment

Eisai is committed to developing and distributing new drugs with a high degree of therapeutic efficacy to improve the quality of life of patients suffering from epilepsy. The development of antiepileptic drugs (AEDs) is the main strategic direction of Eisai's activities in Europe, the Middle East, Africa (EMEA), as well as in Russia and Oceania.

Eisai currently markets four drugs in Europe, the Middle East, and Africa, including:

Exalief (eslicarbazepine acetate) is a drug for the adjunctive treatment of partial seizures with or without secondary generalization in adult patients (Exalief licensed from BIAL);

Faicompa® (perampanel) is a drug for the adjunctive treatment of partial epileptic seizures with or without secondary generalization in adults and children over 12 years of age;

Inovelon® (rufinamide) is a drug for adjunctive treatment of attacks associated with Lennox-Gastaut syndrome in children over 4 years of age (rufinamide was developed by Novartis);

Zonegran® (zonisamide) is a drug for the monotherapy of partial seizures with or without secondary generalization in adults with newly diagnosed epilepsy and is a drug for the adjunctive treatment of partial seizures with or without generalization in adults, adolescents and children over 6 years of age (a license for Zonegran has been acquired from Dainippon Sumitomo Pharma, the company that developed this drug).

About Eisai Co., Ltd.

Eisai Co., Ltd. is one of the world's leading pharmaceutical research and development companies, headquartered in Japan. Eisai's mission is to focus on patients and their loved ones, improving healthcare efficiency through a human health care (HHC) approach. With more than 10,000 employees worldwide in R&D, manufacturing and marketing subsidiaries, Eisai strives to implement the hhc approach by creating innovative products in a variety of therapeutic areas with high unmet medical needs, including oncology and neuroscience.

As a global pharmaceutical company, Eisai's mission reaches patients everywhere through investments and partnerships focused on improving access to medicines in developing countries.

Additional information about Eisai Co., Ltd. presented on the website www.eisai.com.

Media Call Center: Eisai, Cressida Robson/Ben Speller, +44(0)7908 314 155/+44(0) 7908 409416, , ; Tonic Life Communications, Elisabeth Neal/Deepa Patel, +44(0)7896 954 865/+44 (0)7725 440 867, ,

Date of compilation: June 2015

Project code: Perampanel-UK2193g

Links

[1] Steinhoff B et al. Efficacy of adjunctive perampanel in idiopathic generalized epilepsy patients with drug-resistant primary tonic-clonic seizures by age, sex, race: double-blind PBO-controlled Phase 3 trial. European Academy of Neurology annual meeting 2015; Abstract #393