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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 Precautions).
Interactions between Fycompa and other anti-epileptic medicinal products: Potential interactions between Fycompa (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 generalized 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/imageSome anti-epileptic drugs known as CYP450 3A enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase Fycompa clearance and consequently to decrease plasma concentrations of Fycompa. Conversely, withdrawal of a concomitant CYP450 3A enzyme inducer can be expected to increase plasma concentrations of Fycompa and dose reduction may be required.
Carbamazepine, a known potent enzyme inducer, reduced Fycompa 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 Fycompa up to 12 mg/day and patients with primary generalised tonic-clonic seizures receiving Fycompa up to 8 mg/day in placebo-controlled clinical trials. The total clearance of Fycompa 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 Fycompa up to 12 mg/day in placebo-controlled clinical trials, 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 Fycompa dose evaluated (12 mg/day).
In the epilepsy population pharmacokinetic analysis, Fycompa 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 Fycompa on monohydroxycarbazepine concentrations is not known.
Fycompa is dosed to clinical effect regardless of other AEDs.
Effect of Fycompa 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 Fycompa pharmacokinetics: Strong inducers of cytochrome P450, such as rifampicin and hypericum, are expected to decrease Fycompa 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 Fycompa concentrations.
Effect of cytochrome P450 inhibitors on Fycompa pharmacokinetics: In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased Fycompa AUC by 20% and prolonged Fycompa half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when Fycompa 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 Fycompa 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 Fycompa 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 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 the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.
