The most significant known interactions with FYCOMPA are with: Potent CYP3A inducer anti-epileptic drugs (AEDs) carbamazepine, phenytoin and oxcarbazepine; Alcohol; Hormonal contraceptives containing levonorgestrel.
Interactions between FYCOMPA and other anti-epileptic drugs (AEDs): Potential interactions between FYCOMPA (up to 12 mg once daily) and other 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.
Potent CYP3A enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to substantially increase FYCOMPA clearance and consequently to decrease plasma concentrations of FYCOMPA by 50-70%. Starting dose and frequency of titration increase are altered accordingly in the presence of these three AEDS, but there is a lack of data to support dose corrections at the high end of dosing. Conversely, withdrawal of a concomitant CYP3A enzyme inducer can be expected to increase plasma concentrations of FYCOMPA and dose reduction may be required. This effect should also be taken into account and managed when adding or withdrawing these anti-epileptic drugs from a patient's treatment regimen.
The consequences of these interactions on average steady state concentrations are summarized in the following Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Oxcarbazepine is rapidly metabolised by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of FYCOMPA on monohydroxycarbazepine concentrations is not known.
Potential for Interaction with AEDs that Induce other than CYP3A4/5: The contributions of major CYP enzymes other than CYP3A4/5 to FYCOMPA metabolism have not been fully characterized, and thus the potential for adverse drug interaction with FYCOMPA cannot be excluded for other CYP450 strong inducers (see Pharmacology: Pharmacokinetics under Action). Felbamate has been shown to decrease the concentrations of some drugs and may also reduce FYCOMPA concentrations. In a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials (37 patients co-administered phenobarbital and 9 patients co-administered primidone) no effect on FYCOMPA AUC was found; however, a modest effect of phenobarbital and primidone to decrease FYCOMPA concentrations cannot be excluded.
Effect of other strong cytochrome P450 inducers on FYCOMPA (including rifampicin, St John's Wort): Strong inducers of cytochrome P450, such as rifampicin, hypericum (St. John's Wort) and some anti-retrovirals, are expected to decrease FYCOMPA concentrations and should be avoided.
Effect of strong cytochrome P450 inhibitors on FYCOMPA: Co-administration of single 1-mg dose of FYCOMPA with 400 mg once-daily doses of ketoconazole, a strong CYP3A4 inhibitor, for 8 days in healthy subjects increased FYCOMPA AUC by 20% and prolonged FYCOMPA half-life by 15% (68h vs 58h). The effect of ketoconazole on clinically effective doses of FYCOMPA 4 mg to 12 mg is not known. As well, 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. The potential for strong inhibitors of cytochrome P450 isoforms other than CYP3A4/5 to increase FYCOMPA concentrations cannot be excluded, as FYCOMPA metabolism has not yet been fully characterized.
Effect of on CYP3A substrates such as Midazolam: In healthy subjects, FYCOMPA (6 mg once daily for 20 days) decreased midazolam (4 mg single-dose) AUC by 13%. A larger decrease in exposure of midazolam (or other sensitive CYP3A substrates) at higher FYCOMPA doses cannot be excluded.
Hormonal contraceptives: In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive (single dose of 30 μg ethinylestradiol and 150 μg levonorgestrel), FYCOMPA was shown to decrease the levonorgestrel exposure by approximately 40% (mean Cmax and AUC values). Ethinylestradiol AUC was not affected by FYCOMPA 12 mg whereas Cmax was decreased by 18%. Therefore, use of FYCOMPA with oral or implant contraceptives containing levonorgestrel may render them less effective and an additional reliable non-hormonal method (intra-uterine device (IUD), condom) is to be used.
Alcohol and other CNS depressants: 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. Therefore, patients taking FYCOMPA should be advised to avoid the use of alcohol. These effects may also be seen when FYCOMPA is used in combination with other central nervous system (CNS) depressants (e.g., benzodiazepines, narcotics, barbiturates, sedating antihistamines).
Levodopa: In healthy subjects, FYCOMPA (4 mg once daily for 19 days) had no effect on Cmax or AUC of levodopa (100 mg single dose).
Drug-Food Interactions: FYCOMPA is almost completely absorbed after oral administration. Administration of FYCOMPA with food does not change the extent of absorption; however, administration with food slows drug absorption, resulting in a lower Cmax and later Tmax.
Drug-Herb Interactions: Interactions with herbal product have not been evaluated.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been observed.
Drug-Lifestyle Interactions: Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate heavy machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely affects their mental and/or motor performance.