4.1. Therapeutic indications

Perampanel G.L. Pharma 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).

4.2. Posology and method of administration

Posology

Perampanel 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

Titration (incremental steps)

2 mg/day

2 mg/day

(no more frequently than weekly intervals)

2 mg/day

1 mg/day

1 mg/day

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 perampanel 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 perampanel 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 perampanel 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 perampanel 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 perampanel 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 perampanel 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 perampanel 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 perampanel 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 perampanel 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

Perampanel G.L. Pharma is for oral use. It 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.

4.3. Contraindications

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

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 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 perampanel.

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 perampanel may decrease the effectiveness of progestative-containing hormonal contraceptives; in this circumstance additional non-hormonal forms of contraception are recommended when using perampanel (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

Perampanel G.L. Pharma contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Perampanel 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, perampanel was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by perampanel 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 12 mg perampanel per day and an additional reliable method (intra-uterine device (IUD), condom) is to be used (see section 4.4).

Interactions between perampanel and other anti-epileptic medicinal products

Potential interactions between perampanel 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 perampanel (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 perampanel 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 perampanel 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 co-administered

Influence of AED on perampanel concentration

Influence of perampanel 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 perampanel 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 perampanel.

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential and contraception in males and females

Perampanel is not recommended in women of childbearing potential not using contraception unless clearly necessary. Perampanel 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). Perampanel 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 perampanel 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.

4.7. Effects on ability to drive and use machines

Perampanel 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).

4.8. Undesirable effects

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 perampanel 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

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There have been post-marketing cases of intentional and accidental overdose in paediatric patients with doses of perampanel up to 36 mg and in adult patients with doses up to 300 mg. The adverse reactions observed included altered mental status, agitation, aggressive behaviour, 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.