Summary Basis of Decision for Fycompa

Clinical Pharmacology

Perampanel, the active ingredient of Fycompa, is an apparent first-in-class selective, non-competitive antagonist of the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal overexcitation. Although the mechanism of action of perampanel is unknown, AMPA antagonists could potentially reduce excessive excitatory activity and excitotoxicity.

The clinical pharmacology program included reports on the human pharmacodynamic and pharmacokinetic studies, including drug interactions studies and studies in special populations.

Fycompa demonstrated rapid absorption after oral administration with no evidence of first-pass metabolism. The medicinal ingredient, perampanel, has a long half-life at an average of 105 hours, such that steady-state is reached in 2-3 weeks. The half-life decreased to 25 hours when dosed in combination with the strong cytochrome P450 (CYP) 3A inducers carbamazepine, oxcarbazepine, and phenytoin, consistent with the substantially increased clearance. The most significant known interactions with Fycompa are: a) potent CYP inducers, including the concomitant anti-epileptic drugs (carbamazepine, oxcarbazepine, phenytoin) which substantially decreased Fycompa blood levels; b) oral contraceptives containing levonorgestrel which resulted in deceased levonorgestrel exposure by approximately 40%; and c) alcohol, which is additive to Fycompa in terms of negative effects on tasks involving alertness, and in terms of anger and depressed mood. Appropriate warnings and precautions are in place in the Fycompa Product Monograph.

The submitted comparative bioavailability studies were reviewed and are considered acceptable. These studies were performed to confirm the equivalence of the in vivo performance of the 6 mg and 12 mg strengths to that of the 2 mg strength at equivalent doses. Dissolution profiles demonstrated comparable in vitro drug-release between all of the product strengths (2 mg through 12 mg) and supported the waiver from performing in vivo bioequivalence studies on the 8 mg and 10 mg strengths.

Overall, the clinical pharmacological data support the use of Fycompa for the specified indication. For further details, please refer to the Fycompa Product Monograph approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Fycompa (perampanel) in partial-onset seizures, with or without secondary generalization,was studied in patients who were not adequately controlled with 1 to 3 concomitant anti-epileptic drugs (AEDs) in three Phase III, randomized, double-blind, placebo-controlled, multicentre studies (Studies 304, 305 and 306).

The total number of Fycompa-treated patients was 1,038. All studies had an initial 6-week baseline period, during which patients were required to have more than five seizures in order to be randomized. The baseline period was followed by a 19-week double-blind treatment period, consisting of a 6-week titration phase and a 13-week maintenance phase.

Patients in the three pivotal studies had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9 to 14 seizures per 28 days. During the studies, more than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation. Approximately 60% were on at least one of three AEDs known to substantially lower Fycompa blood levels [that is (i.e.), by increasing the activity of cytochrome P450 (CYP) 3A, or CYP3A, an enzyme family central to the metabolism of Fycompa]; these three enzyme-inducing AEDs (EI-AEDs) are: carbamazepine, oxcarbazepine, phenytoin. Overall, concomitant AEDs taken by at least 10% of the patients in the total placebo and Fycompa group were: carbamazepine (34%); lamotrigine (32%); valproic acid (31%); levetiracetam (30%); topiramate (20%); oxcarbazepine (18%); and clobazam (11%).

Studies 304 and 305 compared doses of Fycompa 8 mg/day and 12 mg/day with placebo. Study 306 compared doses of Fycompa 2 mg/day, 4 mg/day, and 8 mg/day with placebo. During the titration phase in all three studies, patients on Fycompa received an initial 2 mg once daily dose, which was subsequently increased by 2 mg at weekly increments to reach the final target dose. Patients who experienced intolerable adverse reactions with the dose increases were permitted to remain in the study at a reduced dose.

The primary endpoint in Studies 304, 305, and 306 was the percent change in seizure frequency per 28 days during the treatment period as compared to the baseline period. The key secondary endpoint was the 50% responder rate.

Fycompa was statistically significantly superior to placebo in the reduction of seizure frequency at daily doses of 4 mg (Study 306), and 8 mg (Studies 306, 304 and 305) and 12 mg (Studies 304 and 305). When the outcome data were reviewed with the two patient populations separated, i.e., with or without CYP3A EI-AEDs, efficacy rates were lower in patients on concomitant EI-AEDs than patients not on EI-AEDs. Results of the 50% responder rates were also lower in patients on concomitant EI-AEDs.

The considerable difference in treatment effect between the patients on concomitant EI-AEDs and those not on EI-AEDs resulted in separate dosing instructions for these two patient populations, including a higher starting dose and more frequent dose increases for those on concomitant EI-AEDs (i.e. with lower mean Fycompa blood levels).

There was a relatively smaller increase in efficacy from 8 mg/day to 12 mg/day, compared to a substantial increase in adverse events, including aggression-related events. However, in the open-label extensions, benefit of the 12 mg dose was observed in patients who received and tolerated the 8 mg dose, but who did not show a satisfactory clinical response. Over 90% of the patients were titrated to the 10 mg or 12 mg doses, and achieved benefits greater than those provided by the 8 mg dose (with an increase of the 50% responder rate from 38.5% to 48.3%). This resulted in dosing instructions in the Fycompa Product Monograph that only patients who tolerate 8 mg/day, and who require additional efficacy, should be titrated up to 12 mg/day. This recommendation is limited to the population not on EI-AEDs.

For more information, refer to the Fycompa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety evaluation was based on data from the three Phase III, placebo-controlled studies (described in the Clinical Efficacy section), several Phase I and Phase II studies as well as three open-label extension studies.

In the controlled Phase III studies, adverse reactions reported in ≥5% of patients treated with Fycompa (perampanel) were:dizziness; somnolence; fatigue; irritability; nausea; ataxia; and fall. Most events in all treatment groups were considered mild or moderate.

In addition to the typical adverse events (AEs) associated with anti-epileptic medications [for example (e.g.) dizziness; somnolence; coordination difficulties; neuropsychiatric; and vision-related AEs], Fycompa demonstrated a more extreme version of the hostility/aggression related subset of neuropsychiatric adverse drug reactions than other AEDs, in both frequency and severity in the Phase III studies  (21% drug vs. 8% placebo in the absence of EI-AEDs; 10% vs. 4% in the presence of EI-AEDs), and in terms of appearing in healthy volunteers, and in non-epilepsy studies. The effect was dose-related, and most commonly appeared within 6 weeks. A dose-related higher rate of falls was also seen (e.g., 18% at the highest dose in the absence of EI-AEDs, vs. 4% placebo). As expected, many of these events were reported at greater rates in the absence of concomitant EI-AEDs, reflecting the greater mean Fycompa blood levels in this population, compared to those patients taking EI-AEDs. Discontinuations due to AEs were also dose-related (3%, 8%, 19% at doses of 4, 8, and 12 mg/day respectively, vs. 5% in placebo) and reflected the common AEs above. The safety profile of Fycompa in the three open-label extension studies (extensions of six Phase II and Phase III studies) was consistent with the AE profile in the controlled studies. No new safety concerns arose.

Safety Topics of Special Interest

Fycompa with concomitant CYP3A enzyme-inducing anti-epileptic drugs

Carbamazepine, oxcarbazepine, and phenytoin (all strong CYP3A inducers) decrease mean Fycompa plasma concentrations in patients at any given dose by approximately 50-70% compared to patients not on these AEDs, and efficacy is generally reduced accordingly. While it can be anticipated that prescribers may therefore push Fycompa dosing in this patient population beyond the recommended maximum dose of 12 mg/day in order to compensate for the decreased blood levels, the problem is that Fycompa doses above 12 mg/day have not been studied, with the consequence that there are inadequate data regarding the maximal effective dosing of Fycompa in this segment of the population.

Furthermore, the unknowns about Fycompa safety in this circumstance are magnified due to insufficient characterization of Fycompa metabolism. Uncertainty around the enzymes responsible for the metabolism of Fycompa precludes knowledge of the potential for drug-drug interactions that may lead to either unexpected increases in Fycompa exposure, unexpected effects on the pharmacokinetics of other AEDs, or increased formation of reactive metabolites, which have been linked to idiosyncratic immune-related adverse drug reactions. In addition, the long half-life of Fycompa may magnify the potential for mortality from serious skin reactions with AEDs.

Information regarding the substantial decrease in Fycompa blood levels that occur in the presence of EI-AEDs and the lack of data and the uncertainties regarding doses beyond the recommended maximum dose of 12 mg/day has been added to the warnings and precautions section of the Fycompa Product Monograph.

Because of the significant decrease in mean Fycompa blood levels in the presence of EI-AEDs, and the resulting difference in adverse events (primarily the incidence rates), separate adverse event tables were provided for each of the two mutually-exclusive populations (presence or absence of EI-AEDs), both for the 2% threshold adverse event Table, and for the Table showing totality of rates within the following three specific categories of pooled events: hostility/aggression related; coordination/gait disturbance related; and somnolence/weakness related.

Psychiatric Disorders

In the Phase III placebo-controlled studies, dose-related hostility/aggression symptoms were associated with Fycompa in both populations (presence and absence of EI-AEDs), but, not unexpectedly, were greater in the latter population with higher mean Fycompa blood levels. The greatest increase in rates was between patients that were administered 8 mg/day to 12 mg/day. The rates and severity are markedly greater for Fycompa than for other AEDs; reports include homicidal ideation and/or threats. Review of these cases does not reveal a clear/discernible pattern to predict risk factors, time-to-onset, etc. A bold warning is placed in the Fycompa Product Monograph telling prescribers to inform patients that Fycompa can cause life-threatening psychiatric and behavioural reactions related to aggression, to avoid alcohol, and that a healthcare provider should be contacted immediately if these symptoms are experienced.

For more information, refer to the Fycompa Product Monograph, approved by Health Canada and available through the Drug Product Database.