Perampanel is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes.
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 Fycompa 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of progestative containing oral contraceptives should be considered for women needing perampanel 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used.
Interactions between perampanel and other anti-epileptic drugs:
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.
|Influence of AED on
|Influence of Perampanel
on AED concentration
|35% decrease 1)
|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. 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 CYP3A4 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 CYP3A4 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 drugs and may also reduce perampanel concentrations.
Effect of cytochrome P450 inhibitors on perampanel pharmacokinetics
In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased perampanel AUC by 20% and prolonged perampanel half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when perampanel is combined with a CYP3A inhibitor with longer half-life than ketoconazole or when the inhibitor is given for a longer treatment duration.
In healthy subjects, perampanel (4 mg once daily for 19 days) had no effect on Cmax or AUC of levodopa.
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 pharmacodynamics 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.
Interaction studies have only been performed in adults. In a population pharmacokinetic analysis of the adolescent patients age ≥ 12 years and children age 4 to 11 years, there were no notable differences compared to the adult population.