Perampanel is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes (see Pharmacology: Pharmacokinetics under Actions).
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 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 (see Precautions).
Interactions between perampanel and other anti-epileptic medicinal products:
Potential interactions between perampanel (up to 12 mg once daily) and other anti-epileptic drugs (AEDs) were assessed in clinical studies and evaluated in the population PK analysis of four pooled Phase 3 studies including patients with partial-onset seizures and primary generalised tonic-clonic seizures. The effect of these interactions on average steady state concentration is summarised in the following table. (See Table 2.)
Click on icon to see table/diagram/image
Some anti-epileptic drugs known as enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel.
Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two-thirds in a study performed on healthy subjects.
A similar result was seen in a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day and patients with primary generalised tonic-clonic seizures receiving perampanel up to 8 mg/day in placebo-controlled clinical trials. The total clearance of perampanel was increased when administered with carbamazepine (2.75-fold), phenytoin (1.7-fold) and oxcarbazepine (1.9-fold), which are known inducers of enzymes of metabolism (see Pharmacology: Pharmacokinetics under Actions). This effect should be taken into account and managed when adding or withdrawing these anti-epileptic drugs from a patient's treatment regimen.
In a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day in placebo-controlled clinical trials, 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).
In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolised by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is not known.
Perampanel is dosed to clinical effect regardless of other AEDs.
Effect of Perampanel on CYP3A substrates:
In healthy subjects, perampanel (6 mg once daily for 20 days) decreased midazolam AUC by 13%. A larger decrease in exposure of midazolam (or other sensitive CYP3A 4 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. Felbamate has been shown to decrease the concentrations of some drugs and may also reduce perampanel concentrations.
Effect of cytochrome P450 inhibitors on perampanel pharmacokinetics:
In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased perampanel AUC by 20%, and prolonged perampanel half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when perampanel is combined with a CYP3A inhibitor with longer half-life than ketoconazole or when the inhibitor is given for a longer treatment duration. Strong inhibitors of other cytochrome P450 isoforms could potentially also increase perampanel concentrations.
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 (see Pharmacology: Pharmacodynamics under Actions). 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 in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.