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Eisai Ltd

European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN
Telephone: +44 (0)845 676 1400
Fax: +44 (0)845 676 1486
WWW: http://www.eisai.co.uk
Medical Information e-mail: Lmedinfo@eisai.net
Out of Hours Telephone: +44 (0)845 676 1400

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Summary of Product Characteristics last updated on the eMC: 28/11/2013
SPC Fycompa 2mg,4mg,6mg,8mg,10mg,12mg film-coated tablets
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This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.



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1. Name of the medicinal product

2 mg: Fycompa 2 mg film-coated tablets

4 mg: Fycompa 4 mg film-coated tablets

6 mg: Fycompa 6 mg film-coated tablets

8 mg: Fycompa 8 mg film-coated tablets

10 mg: Fycompa 10 mg film-coated tablets

12 mg: Fycompa 12 mg film-coated tablets


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2. Qualitative and quantitative composition

2 mg: Each film-coated tablet contains 2 mg of perampanel.

4 mg: Each film-coated tablet contains 4 mg of perampanel.

6 mg: Each film-coated tablet contains 6 mg of perampanel.

8 mg: Each film-coated tablet contains 8 mg of perampanel.

10 mg: Each film-coated tablet contains 10 mg of perampanel.

12 mg: Each film-coated tablet contains 12 mg of perampanel.

Excipient with known effect:

Each 2 mg tablet contains 78.5 mg of lactose monohydrate.

Each 4 mg tablet contains 157.0 mg of lactose monohydrate.

Each 6 mg tablet contains 151.0 mg of lactose monohydrate.

Each 8 mg tablet contains 149.0 mg of lactose monohydrate.

Each 10 mg tablet contains 147.0 mg of lactose monohydrate.

Each 12 mg tablet contains 145.0 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.


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3. Pharmaceutical form

Film-coated tablet (tablet).

2 mg: Orange, round, biconvex tablet, engraved with E275 on one side and '2' on other side

4 mg: Red, round, biconvex tablet, engraved with E277 on one side and '4' on other side

6 mg: Pink, round, biconvex tablet, engraved with E294 on one side and '6' on other side

8 mg: Purple, round, biconvex tablet, engraved with E295 on one side and '8' on other side

10 mg: Green, round, biconvex tablet, engraved with E296 on one side and '10' on other side

12 mg: Blue, round, biconvex tablet, engraved with E297 on one side and '12' on other side


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4. Clinical particulars

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4.1 Therapeutic indications

Fycompa is indicated for the adjunctive treatment of partial-onset seizures with or without secondarily generalised seizures in patients with epilepsy aged 12 years and older.


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4.2 Posology and method of administration

Posology

Adults and adolescents

Fycompa must be titrated, according to individual patient response, in order to optimise the balance between efficacy and tolerability.

Perampanel should be taken orally once daily before bedtime.

Perampanel at doses of 4 mg/day to 12 mg/day has been shown to be effective therapy in partial-onset seizures.

Treatment with Fycompa should be initiated with a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg/day to a maintenance dose of 4 mg/day to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased by increments of 2 mg/day to 12 mg/day. Patients who are taking concomitant medicinal products that do not shorten the half-life of perampanel (see section 4.5) should be titrated no more frequently than at 2-week intervals. Patients who are taking concomitant medicinal products that shorten the half-life of perampanel (see section 4.5) should be titrated no more frequently than at 1-week intervals.

When withdrawing Fycompa, the dose should be gradually reduced (see section 4.4).

Single missed dose: As perampanel has a long half-life, the patient should wait and take their next dose as scheduled.

If more than 1 dose has been missed, for a continuous period of less than 5 half-lives (3 weeks for patients not taking perampanel metabolism-inducing anti-epileptic drugs (AED), 1 week for patients taking perampanel metabolism-inducing AEDs (see section 4.5)), consideration should be given to restart treatment from the last dose level.

If a patient has discontinued perampanel for a continuous period of more than 5 half-lives, it is recommended that initial dosing recommendations given above should be followed.

Elderly (65 years of age and above)

Clinical studies of Fycompa in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Analysis of safety information in 905 perampanel-treated elderly subjects (in double-blind studies conducted in non-epilepsy indications) revealed no age-related differences in the safety profile. In combination with the lack of age-related difference in perampanel exposure, the results indicate that dose adjustment in the elderly is not required. Perampanel should be used with caution in elderly taking into account the drug interaction potential in polymedicated patients (see section 4.4).

Renal impairment

Dose adjustment is not required in patients with mild renal impairment. Use in patients with moderate or severe renal impairment or patients undergoing haemodialysis is not recommended.

Hepatic impairment

Dose increases in patients with mild and moderate hepatic impairment should be based on clinical response and tolerability. For patients with mild or moderate hepatic impairment, dosing can be initiated at 2 mg. Patients should be up-titrated using 2 mg doses no faster than every 2 weeks based on tolerability and effectiveness.

Perampanel dosing for patients with mild and moderate impairment should not exceed 8 mg.

Use in patients with severe hepatic impairment is not recommended.

Paediatric population

The safety and efficacy of perampanel in children below 12 years of age have not been established yet. No data are available.

Method of administration

Fycompa should be taken as single oral dose at bedtime. It may be taken with or without food (see section 5.2). The tablet should be swallowed whole with a glass of water. It should not be chewed, crushed or split. The tablets cannot be split accurately as there is no break line. To ensure the patient receives the entire dose the tablets should be swallowed whole without chewing or crushing.


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4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.


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4.4 Special warnings and precautions for use

Suicidal ideation

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for perampanel.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Nervous system disorders

Perampanel may cause dizziness and somnolence and therefore may influence the ability to drive or use machines (see section 4.7).

Oral contraceptives

At doses of 12 mg/day Fycompa may decrease the effectiveness of progestative-containing hormonal contraceptives; in this circumstance additional non-hormonal forms of contraception are recommended when using Fycompa (see section 4.5).

End of treatment

It is recommended that discontinuation be undertaken gradually to minimise the potential for rebound seizures (see section 4.2). However, due to its long half-life and subsequent slow decline in plasma concentrations, perampanel can be discontinued abruptly if absolutely needed.

Falls

There appears to be an increased risk of falls, particularly in the elderly; the underlying reason is unclear.

Aggression

Aggressive and hostile behaviour has been reported in patients receiving perampanel therapy. In perampanel-treated patients in clinical trials, aggression, anger and irritability were reported more frequently at higher doses. Most of the reported events were either mild or moderate and patients recovered either spontaneously or with dose adjustment. However, thoughts of harming others, physical assault or threatening behaviour were observed in some patients (< 1% in perampanel clinical studies). Patients and caregivers should be counselled to alert a healthcare professional immediately if significant changes in mood or patterns of behaviour are noted. The dosage of perampanel should be reduced if such symptoms occur and should be discontinued immediately if symptoms are severe.

Abuse potential

Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of perampanel abuse.

Concomitant CYP 3A inducing anti-epileptic medicinal products

Response rates after addition of perampanel at fixed doses were less when patients received concomitant CYP3A enzyme-inducing anti-epileptic medicinal products (carbamazepine, phenytoin, oxcarbazepine) as compared to response rates in patient who received concomitant non-enzyme– inducing anti-epileptic medicinal products. The 50% responder rates in the 4 mg, 8 mg and 12 mg groups were respectively 23.0%, 31.5%, and 30.0% in combination with enzyme inducing antiepileptic medicinal products and were 33.3%, 46.5% and 50.0% when perampanel was given in combination with non-enzyme-inducing anti-epileptic medicinal products. Patient's response should be monitored when they are switching from concomitant non-inducer anti-epileptic medicinal products to enzyme inducing medicinal products and vice versa. Depending upon individual clinical response and tolerability, the dose may be increased or decreased 2 mg at a time (see section 4.2).

Other concomitant (non- anti-epileptic) cytochrome P450 inducing or inhibiting medicinal products

Patients should be closely monitored for tolerability and clinical response when adding or removing cytochrome P450 inducers or inhibitors, since perampanel plasma levels can be decreased or increased; the dose of perampanel may need to be adjusted accordingly.

Monotherapy

Two to 6.5% of the patients on perampanel in the clinical studies became seizure free during the last 28 days of treatment compared with 0% -1.7% on placebo. There are no data regarding the effects of withdrawal of concomitant anti-epileptic medicinal products to achieve monotherapy with perampanel.

Fycompa contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.


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4.5 Interaction with other medicinal products and other forms of interaction

Fycompa is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes (see section 5.2).

Oral contraceptives

In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, Fycompa was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by Fycompa 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of progestative-containing oral contraceptives should be considered for women needing Fycompa 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used (see 4.4).

Interactions between Fycompa and other anti-epileptic medicinal products

Potential interactions between Fycompa (up to 12 mg once daily) and other anti-epileptic drugs (AEDs) were assessed in clinical studies and evaluated in the population PK analysis of three pooled Phase 3 studies. The effect of these interactions on average steady state concentration is summarised in the following table.

AED coadministered

Influence of AED on Fycompa concentration

Influence of Fycompa on AED concentration

Carbamazepine

3 fold decrease

<10% decrease

Clobazam

No influence

<10% decrease

Clonazepam

No influence

No influence

Lamotrigine

No influence

<10% decrease

Levetiracetam

No influence

No influence

Oxcarbazepine

2 fold decrease

35% increase 1)

Phenobarbital

No influence

No influence

Phenytoin

2 fold decrease

No influence

Topiramate

20% decrease

No influence

Valproic Acid

No influence

<10% decrease

Zonisamide

No influence

No influence

1) Active metabolite monohydroxycarbazepine was not assessed.

Some anti-epileptic drugs known as enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel.

Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two-thirds in a study performed on healthy subjects.

A similar result was seen in a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials. The total clearance of Fycompa was increased when administered with carbamazepine (3-fold), phenytoin (2-fold) and oxcarbazepine (2-fold), which are known inducers of enzymes of metabolism (see section 5.2). This effect should be taken into account and managed when adding or withdrawing these anti-epileptic drugs from a patient's treatment regimen.

In a population pharmacokinetic analysis of patients with partial-onset seizures receiving Fycompa up to 12 mg/day in placebo-controlled clinical trials, Fycompa did not affect to a clinically relevant manner the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest perampanel dose evaluated (12 mg/day).

In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolised by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is not known.

Perampanel is dosed to clinical effect regardless of other AEDs.

Effect of perampanel on CYP3A substrates

In healthy subjects, Fycompa (6 mg once daily for 20 days) decreased midazolam AUC by 13%. A larger decrease in exposure of midazolam (or other sensitive CYP3A substrates) at higher Fycompa doses cannot be excluded.

Effect of cytochrome P450 inducers on perampanel pharmacokinetics

Strong inducers of cytochrome P450, such as rifampicin and hypericum, are expected to decrease perampanel concentrations. Felbamate has been shown to decrease the concentrations of some drugs and may also reduce perampanel concentrations.

Effect of cytochrome P450 inhibitors on perampanel pharmacokinetics

In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased perampanel AUC by 20% and prolonged perampanel half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when perampanel is combined with a CYP3A inhibitor with longer half-life than ketoconazole or when the inhibitor is given for a longer treatment duration. Strong inhibitors of other cytochrome P450 isoforms could potentially also increase perampanel concentrations.

Levodopa. In healthy subjects, Fycompa (4 mg once daily for 19 days) had no effect on Cmax or AUC of levodopa.

Alcohol

The effects of perampanel on tasks involving alertness and vigilance such as driving ability were additive or supra-additive to the effects of alcohol itself, as found in a pharmacodynamic interaction study in healthy subjects. Multiple dosing of perampanel 12 mg/day increased levels of anger, confusion, and depression as assessed using the Profile of Mood State 5-point rating scale (see section 5.1). These effects may also be seen when Fycompa is used in combination with other central nervous system (CNS) depressants.

Paediatric population

Interaction studies have only been performed in adults.

In a population pharmacokinetic analysis of the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.


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4.6 Fertility, pregnancy and lactation

Women of childbearing potential and contraception in males and females

Fycompa is not recommended in women of childbearing potential not using contraception unless clearly necessary.

Pregnancy

There are limited amounts of data (less than 300 pregnancy outcomes) from the use of perampanel in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats at maternally toxic doses (see section 5.3). Fycompa is not recommended during pregnancy.

Breastfeeding

Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk (for details see 5.3). It is not known whether perampanel is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Fycompa therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

In the fertility study in rats, prolonged and irregular estrous cycles were observed at high-dose (30 mg/kg) in females; however, these changes did not affect the fertility and early embryonic development. There were no effects on male fertility (see section 5.3). The effect of perampanel on human fertility has not been established.


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4.7 Effects on ability to drive and use machines

Fycompa has moderate influence on the ability to drive and use machines.

Perampanel may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether perampanel affects their ability to perform these tasks (see sections 4.4 and 4.5).


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4.8 Undesirable effects

Summary of safety profile

In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 subjects have received perampanel of whom 1,174 have been treated for 6 months and 703 for longer than 12 months.

Adverse reactions leading to discontinuation: In controlled Phase 3 clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7%, 4.2% and 13.7% in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% in patients randomised to receive placebo. The adverse reactions most commonly (≥1% in the total perampanel group and greater than placebo) leading to discontinuation were dizziness and somnolence.

Tabulated list of adverse reactions

In the table below, adverse reactions, which were identified based on review of the full Fycompa clinical studies safety database, are listed by System Organ Class and frequency. The initial review was done by considering all treatment emergent adverse events (TEAEs) in the double-blind Phase 3 epilepsy studies that occurred in ≥2% of patients in the total Fycompa group. The following were also considered: incidence rates higher than with placebo; severity, seriousness, and rates of discontinuation due to the events; analyses of exposure and dose-response; and consistency with Fycompa pharmacology. TEAEs that occurred in less frequency and met the same criteria as for the more frequent TEAEs were also considered. The following convention has been used for the classification of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000).

The dose of 2 mg/day was not included in this assessment because it is not considered to be an effective dose, and the rates of TEAEs in that dose group were generally comparable to, or lower than, those in the placebo group.

Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Very Common

Common

Metabolism and nutrition disorders

 

Decreased appetite

Increased appetite

Psychiatric Disorders

 

Aggression

Anger

Anxiety

Confusional state

Nervous system disorders

Dizziness

Somnolence

Ataxia

Dysarthria

Balance disorder

Irritability

Eye disorders

 

Diplopia

Vision blurred

Ear and labyrinth disorders

 

Vertigo

Gastrointestinal disorders

 

Nausea

Musculoskeletal and connective tissue disorders

 

Back pain

General disorders

 

Gait disturbance

Fatigue

Investigations

 

Weight increased

Injury, poisoning and procedural complications

 

Fall

Paediatric population

Based on the clinical trial database of 143 adolescents, the frequency, type and severity of adverse reactions in adolescents are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.


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4.9 Overdose

There is limited clinical experience with perampanel overdose in humans. In a report of an intentional overdose that could have resulted in a dose up to 264 mg, the patient experienced events of altered mental status, agitation and aggressive behaviour and recovered without sequelae. There is no available specific antidote to the effects of perampanel. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. In view of its long half-life, the effects caused by perampanel could be prolonged. Because of low renal clearance special interventions such as forced diuresis, dialysis or haemoperfusion are unlikely to be of value.


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5. Pharmacological properties

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX22

Mechanism of action

Perampanel is a first-in-class selective, non-competitive antagonist of the ionotropic α-amino-3- hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal overexcitation. Activation of AMPA receptors by glutamate is thought to be responsible for most fast excitatory synaptic transmission in the brain. In in vitro studies, perampanel did not compete with AMPA for binding to the AMPA receptor, but perampanel binding was displaced by noncompetitive AMPA receptor antagonists, indicating that perampanel is a noncompetitive AMPA receptor antagonist. In vitro, perampanel inhibited AMPA-induced (but not NMDA-induced) increase in intracellular calcium. In vivo, perampanel significantly prolonged seizure latency in an AMPA-induced seizure model.

The precise mechanism by which perampanel exerts its antiepileptic effects in humans remains to be fully elucidated.

Pharmacodynamic effects

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Perampanel exposure is correlated with reduction in seizure frequency.

Psychomotor performance. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in healthy volunteers in a dose-related manner. The effects of perampanel on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. Psychomotor performance testing returned to baseline within 2 weeks of cessation of perampanel dosing.

Cognitive function. In a healthy volunteer study to assess the effects of perampanel on alertness, alertness and memory using a standard battery of assessments, no effects of perampanel were found following single and multiple doses of perampanel up to 12 mg/day.

Alertness and mood. Levels of alertness (arousal) decreased in a dose-related manner in healthy subjects dosed with perampanel from 4 to 12 mg/day. Mood deteriorated following dosing of 12 mg/day only; the changes in mood were small and reflected a general lowering of alertness. Multiple dosing of perampanel 12 mg/day also enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion and depression as assessed using the Profile of Mood State 5-point rating scale.

Cardiac electrophysiology. Perampanel did not prolong the QTc interval when administered in daily doses up to 12 mg/day, and did not have a dose-related or clinically important effect on QRS duration.

Clinical efficacy and safety

The efficacy of Fycompa in partial-onset seizures was established in three adjunctive therapy 19 week, randomised, double-blind, placebo-controlled, multicentre trials in adult and adolescent patients. Subjects had partial-onset seizures with or without secondary generalisation and were not adequately controlled with one to three concomitant AEDs. During a 6-week baseline period, subjects were required to have more than five seizures with no seizure-free period exceeding 25 days. In these three trials, subjects had a mean duration of epilepsy of approximately 21.06 years. Between 85.3% and 89.1% of patients were taking two to three concomitant AEDs with or without concurrent vagal nerve stimulation.

Two studies (studies 304 and 305) compared doses of Fycompa 8 and 12 mg/day with placebo and the third study (study 306) compared doses of Fycompa 2, 4 and 8 mg/day with placebo. In all three trials, following a 6-week Baseline Phase to establish baseline seizure frequency prior to randomisation, subjects were randomised and titrated to the randomised dose. During the Titration Phase in all three trials, treatment was initiated at 2 mg/day and increased in weekly increments of 2 mg/day to the target dose. Subjects experiencing intolerable adverse events could remain on the same dose or have their dose decreased to the previously tolerated dose. In all three trials, the Titration Phase was followed by a Maintenance Phase that lasted 13 weeks, during which patients were to remain on a stable dose of Fycompa.

The pooled 50% responder rates were placebo 19%, 4 mg 29%, 8 mg 35% and 12 mg 35%. A statistically significant effect on the reduction in 28-day seizure frequency (Baseline to Treatment Phase) as compared to the placebo group was observed with Fycompa treatment at doses of 4 mg/day (Study 306), 8 mg/day (Studies 304, 305 and 306), and 12 mg/day (Studies 304 and 305). These studies show that once-daily administration of perampanel at doses of 4 mg to 12 mg was significantly more efficacious than placebo as adjunctive treatment in this population.

Data from placebo-controlled studies demonstrate that improvement in seizure control is observed with a once-daily Fycompa dose of 4 mg and this benefit is enhanced as the dose is increased to 8 mg/day. No efficacy benefit was observed at the dose of 12 mg as compared to the dose of 8 mg in the overall population. Benefit at the dose of 12 mg was observed in some patients who tolerate the dose of 8 mg and when the clinical response to that dose was insufficient. A clinically meaningful reduction in seizure frequency relative to placebo was achieved as early as the second week of dosing when patients reached a daily dose of 4 mg.

Open label extension study

Ninety-seven percent of the patients who completed the randomised trials were enrolled in the open label extension study (n=1186). Patients from the randomised trial were converted to perampanel over 16 weeks followed by a long term maintenance period (≥1 year). The mean average daily dose was 10.05 mg.

The three pivotal double-blind placebo-controlled phase 3 studies included 143 adolescents between the ages of 12 and 18. The results in these adolescents were similar to those seen in the adult population.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Fycompa in one or more subsets of the paediatric population in treatment-resistant epilepsies (localisation-related and age-related epilepsy syndromes) (see section 4.2 for information on adolescent use).


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5.2 Pharmacokinetic properties

The pharmacokinetics of perampanel have been studied in healthy adult subjects (age range 18 to 79), adults and adolescents with partial-onset seizures, adults with Parkinson's disease, adults with diabetic neuropathy, adults with multiple sclerosis, and subjects with hepatic impairment.

Absorption

Perampanel is readily absorbed after oral administration with no evidence of marked first-pass metabolism. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food, peak plasma concentrations are reduced and delayed by 2 hours compared with dosing in a fasted state.

Distribution

Data from in vitro studies indicate that perampanel is approximately 95% bound to plasma proteins.

In vitro studies show that perampanel is not a substrate or significant inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1, 2, 3, and 4, organic cation transporters (OCT) 1, 2, and 3, and the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP).

Biotransformation

Perampanel is extensively metabolised via primary oxidation and sequential glucuronidation. Primary oxidative metabolism is mediated by CYP3A based on results of in vitro studies using recombinant human CYPs and human liver microsomes. However, the metabolism has not been completely elucidated and other pathways cannot be excluded.

Following administration of radiolabeled perampanel, only trace amounts of perampanel metabolites were observed in plasma.

Elimination

Following administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 30% of recovered radioactivity was found in the urine and 70% in the faeces. In urine and faeces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of perampanel was 105 hours. When dosed in combination with the strong CYP3A inducer carbamazepine, the average t1/2 was 25 hours.

Linearity/non-linearity

In healthy subjects, plasma concentrations of perampanel increased in direct proportion to administered doses over the range of 2 to 12 mg. In a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, a linear relationship was found between dose and perampanel plasma concentrations.

Special populations

Hepatic impairment

The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 healthy, demographically matched subjects. The mean apparent clearance of unbound perampanel in mildly impaired subjects was 188 ml/min vs. 338 ml/min in matched controls, and in moderately impaired subjects was 120 ml/min vs. 392 ml/min in matched controls. The t1/2 was longer in mildly impaired (306 h vs. 125 h) and moderately impaired (295 h vs. 139 h) subjects compared to matched healthy subjects.

Renal impairment

The pharmacokinetics of perampanel have not been formally evaluated in patients with renal impairment. Perampanel is eliminated almost exclusively by metabolism followed by rapid excretion of metabolites; only trace amounts of perampanel metabolites are observed in plasma. In a population pharmacokinetic analysis of patients with partial-onset seizures having creatinine clearances ranging from 39 to 160 mL/min and receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, perampanel clearance was not influenced by creatinine clearance.

Gender

In a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, perampanel clearance in females (0.605 l/h) was 17% lower than in males (0.730 l/h).

Elderly (65 years of age and above)

In a population pharmacokinetic analysis of patients with partial-onset seizures ranging in age from 12 to 74 years, and receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, no significant effect of age on perampanel clearance was found.

Paediatric population

In a population pharmacokinetic analysis of the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.

Drug interaction studies

In vitro assessment of drug interactions

Drug metabolising enzyme inhibition

In human liver microsomes, perampanel (30 μmol/l) had a weak inhibitory effect on CYP2C8 and UGT1A9 among major hepatic CYPs and UGTs.

Drug metabolising enzyme induction

Compared with positive controls (including phenobarbital, rifampicin), perampanel was found to weakly induce CYP2B6 (30 μmol/l) and CYP3A4/5 (≥3 μmol/l) among major hepatic CYPs and UGTs in cultured human hepatocytes.


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5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In the fertility study in rats, prolonged and irregular oestrous cycles were observed at the maximum tolerated dose (30 mg/kg) in females; however, these changes did not affect fertility and early embryonic development. There were no effects on male fertility.

The excretion into breast milk was measured in rats at 10 days post-partum. Levels peaked at one hour and were 3.65 times the levels in plasma.

In a pre- and postnatal development toxicity study in rats, abnormal delivery and nursing conditions were observed at maternally toxic doses, and the number of stillbirths was increased in offspring. Behavioural and reproductive development of the offspring was not affected, but some parameters of physical development showed some delay, which is probably secondary to the pharmacology-based CNS effects of perampanel. The placental transfer was relatively low; 0.09% or less of administered dose was detected in the foetus.

Nonclinical data reveal that perampanel was not genotoxic and had no carcinogenic potential. The administration of maximum tolerated doses to rats and monkeys resulted in pharmacologically-based CNS clinical signs and decreased terminal body weight. There were no changes directly attributable to perampanel in clinical pathology or histopathology.


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6. Pharmaceutical particulars

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6.1 List of excipients

Core

Lactose monohydrate

Low-substituted hydroxypropyl cellulose

Povidone K-29/32

Magnesium stearate (E470b)

Additional excipient in: 6mg, 8mg, 10mg, 12mg tablet

Microcrystalline cellulose

Film coating

Hypromellose 2910

Talc

Macrogol 8000

Titanium dioxide (E171)

Additional excipient(s) in:

2mg tablet

Ferric oxide, yellow (E172)

Ferric oxide, red (E172)

4mg, 6mg tablet

Ferric oxide, red (E172)

8mg tablet

Ferric oxide, red (E172)

Ferric oxide, black (E172)

10mg tablet

Ferric oxide, yellow (E172)

FD&C Blue #2 Indigo carmine aluminium lake (E132)

12mg tablet

FD&C Blue #2 Indigo carmine aluminium lake (E132)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

2mg, 4mg tablet: 4 years

6mg, 8mg, 10mg, 12mg tablet: 3 years


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6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.


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6.5 Nature and contents of container

PVC/aluminium blisters

2 mg – pack of 7 only for first week of dosing, 28 and 98

4 mg – packs of 7, 28, 84 and 98

6 mg – packs of 7, 28, 84 and 98

8 mg – packs of 7, 28, 84 and 98

10 mg – packs of 7, 28, 84 and 98

12 mg – packs of 7, 28, 84 and 98

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. Marketing authorisation holder

Eisai Europe Limited

European Knowledge Centre

Mosquito Way

Hatfield

Hertfordshire AL10 9SN

United Kingdom

tel: +44 (0)208 600 1400

fax: +44 (0)208 600 1401

e-mail: EUmedinfo@eisai.net


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8. Marketing authorisation number(s)

2 mg

2 mg

2 mg

4 mg

4 mg

4 mg

4 mg

6 mg

6 mg

6 mg

6 mg

8 mg

8 mg

8 mg

8 mg

10 mg

10 mg

10 mg

10 mg

12 mg

12 mg

12 mg

12 mg

7 film-coated tablets:

28 film-coated tablets:

98 film-coated tablets:

7 film-coated tablets:

28 film-coated tablets:

84 film-coated tablets:

98 film-coated tablets:

7 film-coated tablets:

28 film-coated tablets:

84 film-coated tablets:

98 film-coated tablets:

7 film-coated tablets:

28 film-coated tablets:

84 film-coated tablets:

98 film-coated tablets:

7 film-coated tablets:

28 film-coated tablets:

84 film-coated tablets:

98 film-coated tablets:

7 film-coated tablets:

28 film-coated tablets:

84 film-coated tablets:

98 film-coated tablets:

EU/1/12/776/001

EU/1/12/776/017

EU/1/12/776/018

EU/1/12/776/002

EU/1/12/776/003

EU/1/12/776/004

EU/1/12/776/019

EU/1/12/776/005

EU/1/12/776/006

EU/1/12/776/007

EU/1/12/776/020

EU/1/12/776/008

EU/1/12/776/009

EU/1/12/776/010

EU/1/12/776/021

EU/1/12/776/011

EU/1/12/776/012

EU/1/12/776/013

EU/1/12/776/022

EU/1/12/776/014

EU/1/12/776/015

EU/1/12/776/016

EU/1/12/776/023


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9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 23/07/2012


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10. Date of revision of the text

13 November 2013


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11. Legal category

POM - Medicinal product subject to medical prescription

Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu



More information about this product

Link to this document from your website: http://www.medicines.org.uk/emc/medicine/26951/SPC/


Active Ingredients/Generics