Perampanel: prescribing information – dosing, contraindications, interactions, side effects

Fycompa (perampanel) is indicated for the adjunctive treatment of:
- partial-onset seizures (POS) with or without secondarily generalised seizures in patients from 4 years of age and older.
- primary generalised tonic-clonic (PGTC) seizures in patients from 7 years of age and older with idiopathic generalised epilepsy (IGE).

Fycompa (perampanel) is indicated for the adjunctive treatment of
- partial-onset seizures (POS) with or without secondarily generalised seizures in patients from 4 years of age and older.
- primary generalised tonic-clonic (PGTC) seizures in patients from 7 years of age and older with idiopathic generalised epilepsy (IGE).

Posology

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 at bedtime.
The physician should prescribe the most appropriate formulation and strength according to weight and dose. Alternate formulations of perampanel are available, including oral suspension.

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

The following table summarises the recommended posology for adults, adolescents and children from 4 years of age. More details are provided below the table.

Adult/adolescent
(12 years and older)
Children (4 – 11 years); weighing:
≥ 30 kg
20 - < 30 kg
< 20 kg
Recommended starting dose
2 mg/day
2 mg/day
1 mg/day
1 mg/day
Titration
(incremental steps)
2 mg/day
(no more frequently than weekly intervals)
2 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
Recommended maintenance dose
4 – 8 mg/day
4 – 8 mg/day
4 – 6 mg/day
2 – 4 mg/day
Titration
(incremental steps)
2 mg/day
(no more frequently than weekly intervals)
2 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
0.5 mg/day
(no more frequently than weekly intervals)
Recommended maximum dose
12 mg/day
12 mg/day
8 mg/day
6 mg/day

Adults, adolescents age ≥ 12 years
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 (either weekly or every 2 weeks as per half-life considerations described below) 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.

Children (from 4 to 11 years) weighing ≥ 30 kg
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 (either weekly or every 2 weeks as per half-life considerations described below) 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.

Children (from 4 to 11 years of age) weighing 20 kg and < 30 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day. The dose may be increased based on clinical response and tolerability by increments of 1 mg (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day to 6 mg/day.
Depending upon individual clinical response and tolerability at a dose of 6 mg/day, the dose may be increased by increments of 1 mg/day to 8 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.

Children (from 4 to 11 years of age) weighing < 20 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day. The dose may be increased based on clinical response and tolerability by increments of 1 mg (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 2 mg/day to 4 mg/day.
Depending upon individual clinical response and tolerability at a dose of 4 mg/day, the dose may be

increased by increments of 0.5 mg/day to 6 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.

Primary Generalised Tonic-Clonic Seizures
Perampanel at a dose up to 8 mg/day has been shown to be effective in primary generalised tonic-clonic seizures.

The following table summarises the recommended posology for adults, adolescents and children from 7 years of age. More details are provided below the table.

Adult/adolescent
(12 years and older)
Children (7 – 11 years); weighing:
≥ 30 kg
20 - < 30 kg
< 20 kg
Recommended starting dose
2 mg/day
2 mg/day
1 mg/day
1 mg/day
Titration
(incremental steps)
2 mg/day
(no more frequently than weekly intervals)
2 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
Recommended maintenance dose Up to 8 mg/day
4 – 8 mg/day
4 – 6 mg/day
2 – 4 mg/day
Titration
(incremental steps)
2 mg/day
(no more frequently than weekly intervals)
2 mg/day
(no more frequently than weekly intervals)
1 mg/day
(no more frequently than weekly intervals)
0.5 mg/day
(no more frequently than weekly intervals)
Recommended maximum dose
12 mg/day
12 mg/day
8 mg/day
6 mg/day

Adults, adolescents age ≥ 12 years
Treatment with Fycompa should be initiated at a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg (either weekly or every 2 weeks, as per half-life considerations described below) to a maintenance dose of up to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased up to 12 mg/day, which may be effective in some patients (see section 4.4). 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.

Children (from 7 to 11 years) weighing ≥ 30 kg
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 (either weekly or every 2 weeks as per half-life considerations described below) 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.

Children (from 7 to 11 years of age) weighing 20 kg and < 30 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day. The dose may be increased based on clinical response and tolerability by increments of 1 mg (either weekly or every 2 weeks as

per half-life considerations described below) to a maintenance dose of 4 mg/day to 6 mg/day.
Depending upon individual clinical response and tolerability at a dose of 6 mg/day, the dose may be increased by increments of 1 mg/day to 8 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.

Children (from 7 to 11 years of age) weighing < 20 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day. The dose may be increased based on clinical response and tolerability by increments of 1 mg (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 2 mg/day to 4 mg/day.
Depending upon individual clinical response and tolerability at a dose of 4 mg/day, the dose may be increased by increments of 0.5 mg/day to 6 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.

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

Missed doses
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 re-start 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 patients aged 65 and over to determine whether they respond differently from younger patients. Analysis of safety information in 905 perampanel-treated elderly patients (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 have not yet been established in children below 4 years of age in the POS indication or in children below 7 years of age in the PGTCS indication.

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.

Posology

Fycompa must be titrated, according to individual patient response, in order to optimise the balance between efficacy and tolerability.
Perampanel suspension should be taken orally once daily at bedtime.
It may be taken with or without food, but preferably always under the same conditions. Switching between the tablet and suspension formulation should be done with caution (see section 5.2).
The physician should prescribe the most appropriate formulation and strength according to weight and dose.

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

The following table summarises the recommended posology for adults, adolescents and children from 4 years of age. More details are provided below the table.

Adult/adolescent
(12 years and older)
Children (4 – 11 years); weighing:
≥ 30 kg
20 - < 30 kg
< 20 kg
Recommended starting dose
2 mg/day
(4 ml/day)
2 mg/day
(4 ml/day)
1 mg/day
(2 ml/day)
1 mg/day
(2 ml/day)
Titration
(incremental steps)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
Recommended maintenance dose
4 – 8 mg/day
(8 – 16 ml/day)
4 – 8 mg/day
(8 – 16 ml/day)
4 – 6 mg/day
(8 – 12 ml/day)
2 – 4 mg/day
(4 – 8 ml/day)
Titration
(incremental steps)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
0.5 mg/day
(1 ml/day)
(no more frequently than weekly intervals)
Recommended maximum dose
12 mg/day
(24 ml/day)
12 mg/day
(24 ml/day)
8 mg/day
(16 ml/day)
6 mg/day
(12 ml/day)

Adults, adolescents age ≥ 12 years
Treatment with Fycompa should be initiated with a dose of 2 mg/day (4 ml/day). The dose may be increased based on clinical response and tolerability by increments of 2 mg (4 ml) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day (8 ml/day) to 8 mg/day (16 ml/day). Depending upon individual clinical response and tolerability at a dose of 8 mg/day (16 ml/day), the dose may be increased by increments of 2 mg/day (4 ml/day) to 12 mg/day (24 ml/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.

Children (from 4 to 11 years) weighing ≥ 30 kg
Treatment with Fycompa should be initiated with a dose of 2 mg/day (4 ml/day). The dose may be increased based on clinical response and tolerability by increments of 2 mg (4 ml/day) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day (8 ml/day) to 8 mg/day (16 ml/day). Depending upon individual clinical response and tolerability at a dose of 8 mg/day (16 ml/day), the dose may be increased by increments of 2 mg/day (4 ml/day) to 12 mg/day (24 ml/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.

Children (from 4 to 11 years of age) weighing 20 kg and < 30 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day (2 ml/day). The dose may be increased based on clinical response and tolerability by increments of 1 mg (2 ml/day) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day (8 ml/day) to 6 mg/day (12 ml/day). Depending upon individual clinical response and tolerability at a dose of 6 mg/day (12 ml/day), the dose may be increased by increments of 1 mg/day (2 ml/day) to 8 mg/day (16 ml/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.

Children (from 4 to 11 years of age) weighing < 20 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day (2 ml/day). The dose may be increased based on clinical response and tolerability by increments of 1 mg (2 ml/day) (either weekly

or every 2 weeks as per half-life considerations described below) to a maintenance dose of 2 mg/day (4 ml/day) to 4 mg/day (8 ml/day). Depending upon individual clinical response and tolerability at a dose of 4 mg/day (8 ml/day), the dose may be increased by increments of 0.5 mg/day (1 ml/day) to 6 mg/day (12 ml/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.

Primary Generalised Tonic-Clonic Seizures
Perampanel at a dose up to 8 mg/day has been shown to be effective in primary generalised tonic-clonic seizures.

The following table summarises the recommended posology for adults, adolescents and children from 7 years of age. More details are provided below the table.

Adult/adolescent
(12 years and older)
Children (7 – 11 years); weighing:
≥ 30 kg
20 - < 30 kg
< 20 kg
Recommended starting dose
2 mg/day
(4 ml/day)
2 mg/day
(4 ml/day)
1 mg/day
(2 ml/day)
1 mg/day
(2 ml/day)
Titration
(incremental steps)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
Recommended maintenance dose
Up to 8 mg/day
(Up to 16 ml/day)
4 – 8 mg/day
(8 – 16 ml/day)
4 – 6 mg/day
(8 – 12 ml/day)
2 – 4 mg/day
(4 – 8 ml/day)
Titration
(incremental steps)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
2 mg/day
(4 ml/day)
(no more frequently than weekly intervals)
1 mg/day
(2 ml/day)
(no more frequently than weekly intervals)
0.5 mg/day
(1 ml/day)
(no more frequently than weekly intervals)
Recommended maximum dose
12 mg/day
(24 ml/day)
12 mg/day
(24 ml/day)
8 mg/day
(16 ml/day)
6 mg/day
(12 ml/day)

Adults, adolescents age ≥ 12 years
Treatment with Fycompa should be initiated at a dose of 2 mg/day (4 ml/day). The dose may be increased based on clinical response and tolerability by increments of 2 mg (4 ml/day) (either weekly or every 2 weeks, as per half-life considerations described below) to a maintenance dose of up to 8 mg/day (16 ml/day). Depending upon individual clinical response and tolerability at a dose of 8 mg/day (16 ml/day), the dose may be increased up to 12 mg/day (24 ml/day), which may be effective in some patients (see section 4.4). 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.

Children (from 7 to 11 years) weighing ≥ 30 kg
Treatment with Fycompa should be initiated with a dose of 2 mg/day (4 ml/day). The dose may be increased based on clinical response and tolerability by increments of 2 mg (4 ml) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day (8 ml/day) to 8 mg/day (16 ml/day). Depending upon individual clinical response and tolerability at a dose of 8 mg/day (16 ml/day), the dose may be increased by increments of 2 mg/day (4 ml/day) to 12 mg/day (24 ml/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.

Children (from 7 to 11 years of age) weighing 20 kg and < 30 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day (2 ml/day). The dose may be increased based on clinical response and tolerability by increments of 1 mg (2 ml) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day (8 ml/day) to 6 mg/day (12 ml/day). Depending upon individual clinical response and tolerability at a dose of 6 mg/day, the dose may be increased by increments of 1 mg/day (2 ml/day) to 8 mg/day (16 ml/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.

Children (from 7 to 11 years of age) weighing < 20 kg
Treatment with Fycompa should be initiated with a dose of 1 mg/day (2 ml/day). The dose may be increased based on clinical response and tolerability by increments of 1 mg (2 ml) (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 2 mg/day (4 ml/day) to 4 mg/day (8 ml/day). Depending upon individual clinical response and tolerability at a dose of 4 mg/day (8 ml/day), the dose may be increased by increments of 0.5 mg/day (1 ml/day) to 6 mg/day (12 ml/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.

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

Missed doses
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 re-start 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 patients aged 65 and over to determine whether they respond differently from younger patients. Analysis of safety information in 905 perampanel-treated elderly patients (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 (4 ml). Patients should be up-titrated using 2 mg (4 ml) 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 have not yet been established in children below 4 years of age in the POS indication or in children below 7 years of age in the PGTCS indication.

Method of administration

Fycompa is for oral use.

Preparation: The press-in-bottle adapter (PIBA) which is supplied in the product carton should be inserted firmly into the neck of the bottle before use and remain in place for the duration of the usage of the bottle. The oral syringe should be inserted into the PIBA and the dose withdrawn from the inverted bottle. The cap should be replaced after each use. The cap fits properly when the PIBA is in place.

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

Summary of the safety profile

In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 patients have received perampanel of whom 1,147 have been treated for 6 months and 703 for longer than 12 months.

In the controlled and uncontrolled study in patients with primary generalised tonic-clonic seizures, 114 patients have received perampanel of whom 68 have been treated for 6 months and 36 for longer than 12 months.

Adverse reactions leading to discontinuation:
In the controlled Phase 3 partial-onset seizures clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7% (3/172), 4.2% (18/431) and 13.7% (35/255) in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% (6/442) 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.

In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the rate of discontinuation as a result of an adverse reaction was 4.9% (4/81) in patients randomised to receive perampanel 8 mg, and 1.2% (1/82) in patients randomised to receive placebo. The adverse reaction most commonly leading to discontinuation (≥ 2% in the perampanel group and greater than placebo) was dizziness.

Post-marketing use

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with perampanel treatment (see section 4.4).

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 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), not known (cannot be estimated from the available data).

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

System Organ Class
Very common
Common
Uncommon
Not known
Metabolism and nutrition disorders

Decreased appetite
Increased appetite

Psychiatric disorders

Aggression
Anger
Anxiety
Confusional state
Suicidal ideation
Suicide attempt
Hallucinations
Psychotic disorder

Nervous system disorders
Dizziness
Somnolence
Ataxia
Dysarthria
Balance disorder
Irritability

Eye disorders

Diplopia
Vision blurred

Ear and labyrinth disorders

Vertigo

Gastrointestinal disorders

Nausea

Skin and subcutaneous tissue disorders

Drug Reaction with Eosinophilia and Systemic
Symptoms
(DRESS)*
Stevens - Johnson
Syndrome (SJS)*
Musculoskeletal and connective tissue disorders

Back pain

General disorders

Gait disturbance
Fatigue

Investigations

Weight increased

System Organ Class
Very common
Common
Uncommon
Not known
Injury, poisoning and procedural complications

Fall

*
See section 4.4

Paediatric population

Based on the clinical trial database of 196 adolescents exposed to perampanel from double-blind studies for partial-onset seizures and primary generalised tonic-clonic seizures, the overall safety profile in adolescents was similar to that of adults, except for aggression, which was observed more frequently in adolescents than in adults.

Based on the clinical trial database of 180 paediatric patients exposed to perampanel from a multicentre, open label study, the overall safety profile in children was similar to that established for adolescents and adults, except for somnolence, irritability, aggression, and agitation which were observed more frequently in the paediatric study compared to studies in adolescents and adults.

Available data in children did not suggest any clinically significant effects of perampanel on growth and development parameters including body weight, height, thyroid function, insulin-like growth factor-1 (IGF-1) level, cognition (as assessed by Aldenkamp-Baker neuropsychological assessment schedule [ABNAS]), behaviour (as assessed by Child Behavior Checklist [CBCL]), and dexterity (as assessed by Lafayette Grooved Pegboard Test [LGPT]). However, long term effects [greater than 1 year] on learning, intelligence, growth, endocrine function, and puberty in children remain unknown.

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 the national reporting system listed in Appendix V.

Summary of the safety profile

In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 patients have received perampanel of whom 1,147 have been treated for 6 months and 703 for longer than 12 months.

In the controlled and uncontrolled study in patients with primary generalised tonic-clonic seizures, 114 patients have received perampanel of whom 68 have been treated for 6 months and 36 for longer than 12 months.

Adverse reactions leading to discontinuation:
In the controlled Phase 3 partial-onset seizures clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7% (3/172), 4.2% (18/431) and 13.7% (35/255) in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% (6/442) 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.

In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the rate of discontinuation as a result of an adverse reaction was 4.9% (4/81) in patients randomised to receive perampanel 8 mg, and 1.2% (1/82) in patients randomised to receive placebo. The adverse reaction most commonly leading to discontinuation (≥ 2% in the perampanel group and greater than placebo) was dizziness.

Post-marketing use

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with perampanel treatment (see section 4.4).

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 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), not known (cannot be estimated from the available data).

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

System Organ Class
Very common
Common
Uncommon
Not known
Metabolism and nutrition disorders

Decreased appetite
Increased appetite

Psychiatric disorders

Aggression
Anger
Anxiety
Confusional state
Suicidal ideation
Suicide attempt
Hallucinations
Psychotic disorder

Nervous system disorders
Dizziness
Somnolence
Ataxia
Dysarthria
Balance disorder
Irritability

Eye disorders

Diplopia
Vision blurred

System Organ Class
Very common
Common
Uncommon
Not known
Ear and labyrinth disorders

Vertigo

Gastrointestinal disorders

Nausea

Skin and subcutaneous tissue disorders

Drug Reaction with Eosinophilia and Systemic
Symptoms
(DRESS)*
Stevens - Johnson
Syndrome (SJS)*
Musculoskeletal and connective tissue disorders

Back pain

General disorders

Gait disturbance
Fatigue

Investigations

Weight increased

Injury, poisoning and procedural complications

Fall

*
See section 4.4

Paediatric population

Based on the clinical trial database of 196 adolescents exposed to perampanel from double-blind studies for partial-onset seizures and primary generalised tonic-clonic seizures, the overall safety profile in adolescents was similar to that of adults, except for aggression, which was observed more frequently in adolescents than in adults.

Based on the clinical trial database of 180 paediatric patients exposed to perampanel from a multicentre, open label study, the overall safety profile in children was similar to that established for adolescents and adults, except for somnolence, irritability, aggression, and agitation, which were observed more frequently in the paediatric study compared to studies in adolescents and adults.

Available data in children did not suggest any clinically significant effects of perampanel on growth and development parameters including body weight, height, thyroid function, insulin-like growth factor-1 (IGF-1) level, cognition (as assessed by Aldenkamp-Baker neuropsychological assessment schedule [ABNAS]), behaviour (as assessed by Child Behavior Checklist [CBCL]), and dexterity (as assessed by Lafayette Grooved Pegboard Test [LGPT]). However, long term effects [greater than 1 year] on learning, intelligence, growth, endocrine function, and puberty in children remain unknown.

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 the national reporting system listed in Appendix V.

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 anti-epileptic 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 (children, adolescents, and adults) 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.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens - Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown; see section 4.8) in association with perampanel treatment.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target-like lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes.

If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate).

If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time.

Absence and myoclonic seizures

Absence and myoclonic seizures are two common generalised seizure types that frequently occur in IGE patients. Other AEDs are known to induce or aggravate these seizure types. Patients with myoclonic seizures and absence seizures should be monitored while on Fycompa.

Nervous system disorders

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

Hormonal 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 sections 4.5 and 4.6).

Falls

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

Aggression,psychotic disorder

Aggressive, hostile, and abnormal behaviours have been reported in patients receiving perampanel therapy. In perampanel-treated patients in clinical trials, aggression, anger, irritability, and psychotic disorder 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 trials). Homicidal ideation has been reported in patients. 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 discontinuation should be considered if symptoms are severe (see section 4.2).

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. Patients’ 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.

Hepatotoxicity

Cases of hepatotoxicity (mainly hepatic enzyme increased) with perampanel in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.

Excipients

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

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 anti-epileptic 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 (children, adolescents, and adults) 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.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens - Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown; see section 4.8) in association with perampanel treatment.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target-like

lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes.

If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate).

If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time.

Absence and myoclonic seizures

Absence and myoclonic seizures are two common generalised seizure types that frequently occur in IGE patients. Other AEDs are known to induce or aggravate these seizure types. Patients with myoclonic seizures and absence seizures should be monitored while on Fycompa.

Nervous system disorders

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

Hormonal 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 sections 4.5 and 4.6).

Falls

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

Aggression, psychotic disorder

Aggressive, hostile, and abnormal behaviours have been reported in patients receiving perampanel therapy. In perampanel-treated patients in clinical trials, aggression, anger, irritability, and psychotic disorder 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 trials). Homicidal ideation has been reported in patients. 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 discontinuation should be considered if symptoms are severe (see section 4.2).

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. Patients’ 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.

Hepatotoxicity

Cases of hepatotoxicity (mainly hepatic enzyme increased) with perampanel in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.

Excipients

Fructose intolerance
Fycompa contains sorbitol (E420), each mL of Fycompa contains 175 mg sorbitol.

Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Caution should be exercised when combining Fycompa oral suspension with other antiepileptic medications containing sorbitol, since a combined intake of over 1 gram of sorbitol may affect absorption of some drugs.

Benzoic Acid (E210) and Sodium Benzoate (E211)
Fycompa contains benzoic acid (E210) and sodium benzoate (E211), each mL of Fycompa contains <0.005 mg benzoic acid and 1.1 mg sodium benzoate.

Benzoic acid and benzoates can displace bilirubin from albumin. Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus.

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

Hormonal 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 hormonal progestative-containing 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 section 4.4).

Interactions between Fycompa and other anti-epileptic medicinal products

Potential interactions between Fycompa and other anti-epileptic drugs (AEDs) were assessed in clinical studies. A population PK analysis of three pooled Phase 3 studies in adolescent and adult patients with partial-onset seizures evaluated the effect of Fycompa (up to 12 mg once daily) on the PK of other AEDs. In another population PK analysis of pooled data from twenty Phase 1 studies in healthy subjects, with Fycompa up to 36 mg, and one Phase 2 and six Phase 3 studies in paediatric, adolescent, and adult patients with partial-onset seizures or primary generalised tonic-clonic seizures, with Fycompa up to 16 mg once daily, evaluated the effect of concomitant AEDs of perampanel clearance. 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
20% decrease
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.

Based on the results from the population pharmacokinetic analysis of patients with partial-onset seizures and patients with primary generalised tonic-clonic seizures the total clearance of Fycompa was increased when co-administered with carbamazepine (3-fold), and phenytoin or 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. Clonazepam, levetiracetam, phenobarbital, topiramate, zonisamide, clobazam, lamotrigine and valproic acid did not affect to a clinically relevant manner the clearance of Fycompa.

In a population pharmacokinetic analysis of patients with partial-onset seizures, 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).

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 and the potential for higher plasma concentrations of reactive metabolites in their presence has not been excluded. Felbamate has been shown to decrease the concentrations of some medicinal products 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.

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 adolescent patients age ≥ 12 years and children age 4 to 11 years, there were no notable differences compared to the adult population.

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

Hormonal 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 hormonal progestative-containing 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 section 4.4).

Interactions between Fycompa and other anti-epileptic medicinal products

Potential interactions between Fycompa and other anti-epileptic drugs (AEDs) were assessed in clinical studies. A population PK analysis of three pooled Phase 3 studies in adolescent and adult patients with partial-onset seizures evaluated the effect of Fycompa (up to 12 mg once daily) on the PK of other AEDs. In another population PK analysis of pooled data from twenty Phase 1 studies in healthy subjects, with Fycompa up to 36 mg, and one Phase 2 and six Phase 3 studies in paediatric, adolescent and adult patients with partial-onset seizures or primary generalised tonic-clonic seizures, with Fycompa up to 16 mg once daily, evaluated the effect of concomitant AEDs of perampanel clearance. 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
20% decrease
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.

Based on the results from the population pharmacokinetic analysis of patients with partial-onset seizures and patients with primary generalised tonic-clonic seizures the total clearance of Fycompa was increased when co-administered with carbamazepine (3-fold), and phenytoin or 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. Clonazepam, levetiracetam, phenobarbital, topiramate, zonisamide, clobazam, lamotrigine and valproic acid did not affect to a clinically relevant manner the clearance of Fycompa.

In a population pharmacokinetic analysis of patients with partial-onset seizures, 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).

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 and the potential for higher plasma concentrations of reactive metabolites in their presence has not been excluded. Felbamate has been shown to decrease the concentrations of some medicinal products 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.

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 adolescent patients age ≥ 12 years and children age 4 to 11 years, there were no notable differences compared to the adult population.

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. Fycompa may decrease the effectiveness of progestative-containing hormonal contraceptives. An additional non-hormonal form of contraception is, therefore recommended (see sections 4.4 and 4.5).

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.

Breast-feeding

Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk (for details see section 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 breast-feeding or to discontinue/abstain from Fycompa therapy taking into account the benefit of breast--feeding for the child and the benefit of therapy for the woman.

Fertility

In the fertility study in rats, prolonged and irregular oestrous 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.

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).

There have been post-marketing cases of intentional and accidental overdose. Reported doses of perampanel were up to approximately 50 mg in paediatric patients and up to 300 mg in adult patients.
The adverse reactions observed included altered mental status, agitation, aggressive behaviour, vomiting, coma, and depressed level of consciousness. The patients 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.

5.
PHARMACOLOGICAL 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-isoxazolepropionic 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. In addition, a pharmacokinetic-pharmacodynamic (efficacy) analysis was performed in one efficacy trial for primary generalised tonic-clonic seizures. In both analyses, 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, 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.

In a placebo-controlled study conducted in adolescent patients, no significant changes in cognition relative to placebo as measured by Cognitive Drug Research (CDR) System Global Cognition Score were observed for perampanel. In the open label extension, no significant changes were observed in global CDR system score after 52 weeks of perampanel treatment (see section 5.1 Paediatric population).

In an open-label uncontrolled study conducted in paediatric patients, no clinically important changes in cognition relative to baseline as measured by ABNAS were observed following adjunctive perampanel therapy (see section 5.1 Paediatric population).

Alertness and mood

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-isoxazolepropionic 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. In addition, a pharmacokinetic-pharmacodynamic (efficacy) analysis was performed in one efficacy trial for primary generalised tonic-clonic seizures. In both analyses, 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, 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.

In a placebo-controlled study conducted in adolescent patients, no significant changes in cognition relative to placebo as measured by Cognitive Drug Research (CDR) System Global Cognition Score were observed for perampanel. In the open label extension, no significant changes were observed in global CDR system score after 52 weeks of perampanel treatment (see section 5.1 Paediatric population).

In an open-label uncontrolled study conducted in paediatric patients, no clinically important changes in cognition relative to baseline as measured by ABNAS were observed following adjunctive perampanel (see section 5.1 Paediatric population).

Alertness and mood

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

Absorption

Perampanel is readily absorbed after oral administration with no evidence of marked first--pass metabolism. Co-administration of perampanel tablets with a high fat meal had no impact on the peak plasma exposure (Cmax) or total exposure (AUC0-inf) of perampanel. The tmax was delayed by approximately 1 hour compared to that under fasted conditions.

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. The metabolism of perampanel is mediated primarily by CYP3A based on clinical study results in healthy subjects administered radiolabelled perampanel and supported by in vitro studies using recombinant human CYPs and human liver microsomes.

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

Elimination

Following administration of a radiolabelled perampanel dose to either 8 healthy adults or elderly subjects, approximately 30% of recovered radioactivity was found in the urine and 70% in the faeces.

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

Absorption

Perampanel is readily absorbed after oral administration with no evidence of marked first-pass metabolism.

Perampanel oral suspension is bioequivalent on a mg per mg basis to perampanel tablets under fasted conditions. When a single 12-mg dose of both formulations was administered with a high fat meal, perampanel oral suspension achieves equivalent AUC0-inf and approximately 23 % lower Cmax and 2 hours delay in time to peak exposure (tmax) compared to the tablet formulation. However, population pharmacokinetic analysis demonstrated that under simulated steady state exposure conditions, Cmax and AUC(0-24h), of perampanel oral suspension were bioequivalent to the tablet formulation under both fasted and fed conditions.

When coadministered with a high fat meal, Cmax and AUC0-inf of a single 12-mg dose of perampanel oral suspension were approximately 22% and 13%, respectively, lower compared to fasted conditions.

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. The metabolism of perampanel is mediated primarily by CYP3A based on clinical study results in healthy