Perampanel

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.

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.

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. These effects may also be seen when perampanel is used in combination with other central nervous system (CNS) depressants.

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.

Use in patients with moderate or severe renal impairment or patients undergoing haemodialysis is not recommended.

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.

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 C_max and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by perampanel 12 mg whereas C_max was decreased by 18%. Therefore, the possibility of decreased efficacy of hormonal progestative-containing contraceptives should be considered for women needing perampanel 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used.

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. 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.

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.

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

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. Perampanel is not recommended during pregnancy.

Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk. 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.

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.

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. The effect of perampanel on human fertility has not been established.

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.

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.

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.

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.