Pharmacotherapeutic Group: antiepileptics, other antiepileptics. ATC Code: N03AX22.
Pharmacology: Pharmacodynamics: Mechanism of action: FYCOMPA is a selective, non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor 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. Activation of AMPA receptors by glutamate is thought to be responsible for most fast excitatory synaptic transmission in the brain. In in vitro studies, FYCOMPA did not compete with AMPA for binding to the AMPA receptor, but FYCOMPA binding was displaced by noncompetitive AMPA receptor antagonists, indicating that FYCOMPA is a noncompetitive AMPA receptor antagonist. In vitro, FYCOMPA inhibited AMPA-induced (but not NMDA-induced) increase in intracellular calcium. In vivo, FYCOMPA significantly prolonged seizure latency in an AMPA-induced seizure model.
The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans remains to be fully elucidated.
Pharmacodynamic effects: A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. In addition, a pharmacokinetic-pharmacodynamic (efficacy) analysis was performed in one efficacy trial for primary generalized tonic clonic seizures. In both analysis, FYCOMPA exposure is correlated with reduction in seizure frequency.
Psychomotor performance. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in healthy volunteers in a dose-related manner. The effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. Psychomotor performance testing returned to baseline within 2 weeks of cessation of FYCOMPA dosing.
Cognitive function: In a healthy volunteer study to assess the effects of FYCOMPA on alertness, and memory using a standard battery of assessments, no effects of FYCOMPA were found following single and multiple doses of FYCOMPA up to 12 mg/day.
Alertness and Mood: Levels of alertness (arousal) decreased in a dose-related manner in healthy subjects dosed with FYCOMPA from 4 to 12 mg/day. Mood deteriorated following dosing of 12 mg/day only; the changes in mood were small and reflected a general lowering of alertness. Multiple dosing of FYCOMPA 12 mg/day also enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion and depression as assessed using the Profile of Mood State 5-point rating scale.
Cardiac Electrophysiology: FYCOMPA did not prolong the QTc interval when administered in daily doses up to 12 mg/day, and did not have a dose-related or clinically important effect on QRS duration.
Clinical Efficacy and Safety: Partial Onset Seizures: The efficacy of FYCOMPA in partial-onset seizures was established in three adjunctive therapy 19-week, randomised, double-blind, placebo-controlled, multicentre trials in adult and adolescent patients. Subjects had partial-onset seizures with or without secondary generalisation and were not adequately controlled with one to three concomitant AEDs. During a 6-week baseline period, subjects were required to have more than five seizures with no seizure-free period exceeding 25 days. In these three trials, subjects had a mean duration of epilepsy of approximately 21.06 years. Between 85.3% and 89.1% of patients were taking two to three concomitant AEDs with or without concurrent vagal nerve stimulation.
Two studies (studies 304 and 305) compared doses of FYCOMPA 8 and 12 mg/day with placebo and the third study (study 306) compared doses of FYCOMPA 2, 4 and 8 mg/day with placebo. In all three trials, following a 6-week Baseline Period to establish baseline seizure frequency prior to randomisation, subjects were randomised and titrated to the randomised dose. During the Titration Period in all three trials, treatment was initiated at 2 mg/day and increased in weekly increments of 2 mg/day to the target dose. Subjects experiencing intolerable adverse events could remain on the same dose or have their dose reduced to the previously tolerated dose. In all three trials, the Titration Period was followed by a Maintenance Period that lasted 13 weeks, during which patients were to remain on a stable dose of FYCOMPA. The pooled 50% responder rates were placebo 19%, 4 mg 29%, 8 mg 35% and 12 mg 35%. A statistically significant effect on the reduction in 28-day seizure frequency (Baseline to Treatment Phase) as compared to the placebo group was observed with FYCOMPA treatment at doses of 4 mg/day (Study 306), 8 mg/day (Studies 304, 305 and 306), and 12 mg/day (Studies 304 and 305). The 50% responder rates in the 4 mg, 8 mg and 12 mg groups were respectively 23.0%, 31.5%, and 30.0% in combination with enzyme inducing anti-epileptic medicinal products and were 33.3%, 46.5% and 50.0% when FYCOMPA was given in combination with non-enzyme-inducing anti-epileptic medicinal products. These studies show that once-daily administration of FYCOMPA at doses of 4 mg to 12 mg was significantly more efficacious than placebo as adjunctive treatment in this population.
Data from placebo-controlled studies demonstrate that improvement in seizure control is observed with a once-daily FYCOMPA dose of 4 mg and this benefit is enhanced as the dose is increased to 8 mg/day. No efficacy benefit was observed at the dose of 12 mg as compared to the dose of 8 mg in the overall population. Benefit at the dose of 12 mg was observed in some patients who tolerate the dose of 8 mg and when the clinical response to that dose was insufficient. A clinically meaningful reduction in seizure frequency relative to placebo was achieved as early as the second week of dosing when patients reached a daily dose of 4 mg. 1.7 to 5.8% of the patients on FYCOMPA in the clinical studies became seizure free during the 3 month maintenance period compared with 0% - 1.0% on placebo.
Open label extension study: Ninety-seven percent of the patients who completed the randomised trials were enrolled in the open label extension study (n=1186). Patients from the randomised trial were converted to FYCOMPA over 16 weeks followed by a long term maintenance period (≥1 year). The mean average daily dose was 10.05 mg.
Primary Tonic-Clonic Seizures: FYCOMPA as adjunctive therapy in patients 12 years of age and older with idiopathic generalised epilepsy experiencing primary generalised tonic-clonic seizures was established in a multicenter, randomized, double-blind, placebo-controlled study (Study 332). Eligible patients on a stable dose of 1 to 3 AEDs experiencing at least 3 primary generalised tonic-clonic seizures during the 8-week baseline period were randomized to either Fycompa or placebo. The population included 164 patients (Fycompa N=82, placebo N=82). Patients were titrated over four weeks to a target dose of 8 mg per day or the highest tolerated dose and treated for an additional 13 weeks on the last dose level achieved at the end of the titration period. The total treatment period was 17 weeks. Study drug was given once per day.
The 50% primary generalised tonic-clonic seizures responder rate during the Maintenance Period was significantly higher in the FYCOMPA group (58.0%) than in the placebo group (35.8%), P=0.0059. The 50% responder rate was 22.2% in combination with enzyme inducing anti-epileptic medicinal products and was 69.4% when FYCOMPA was given in combination with non-enzyme-inducing anti-epileptic medicinal products. The number of FYCOMPA subjects taking enzyme inducing anti-epileptic medicinal products was small (n = 9). The median percent change in primary generalised tonic-clonic seizure frequency per 28 days during the Titration and Maintenance Periods (combined) relative to Prerandomization was greater with FYCOMPA (-76.5%) than with placebo (-38.4%), P<0.0001. During the 3 months maintenance period, 30.9% (25/81) of the patients on FYCOMPA in the clinical studies became free of PGTC seizures compared with 12.3% (10/81) on placebo.
Other subtypes of idiopathic generalized seizure: The efficacy and safety of FYCOMPA in patients with myoclonic seizures have not been established. The available data are insufficient to reach any conclusions.
The efficacy of FYCOMPA in the treatment of absence seizures has not been demonstrated.
In Study 332, in patients with PGTC seizures who also had concomitant myoclonic seizures, freedom from seizures was achieved in 16.7% (4/24) on FYCOMPA compared to 13.0% (3/23) in those on placebo. In patients with concomitant absence seizures, freedom from seizures was achieved in 22.2% (6/27) on FYCOMPA compared to 12.1% (4/33) on placebo. Freedom from all seizures was achieved in 23.5% (19/81) of patients on FYCOMPA compared to 4.9% (4/81) of patients on placebo.
Open label extension phase: Of the 140 subjects who completed the Study 332 114 subjects (81.4%) had entered the Extension phase. Patients from the randomised trial were converted to FYCOMPA over 6 weeks followed by a long term maintenance period (≥ 1 year). In the Extension Phase, 73.7% of subjects have a modal daily FYCOMPA dose of greater than 4 to 8 mg/day and 16.7% had a modal daily dose of greater than 8 to 12 mg/day. A decrease in PGTC seizure frequency of at least 50% was seen in 65.9% of subjects after 1 year of treatment during the Extension Phase (relative to their pre-FYCOMPA baseline seizure frequency). These data were consistent with those for percent change in seizure frequency and showed that the PGTC 50% responder rate was generally stable across time from about week 26 through the end of year 2 Similar results were seen when all seizures and absence vs. myoclonic seizures were evaluated over time.
Conversion to monotherapy: In a retrospective study of clinical practice, 51 patients with epilepsy who received perampanel as adjunctive treatment converted to perampanel monotherapy. The majority of these patients had a history of partial onset seizures. Of these, 14 patients (27%) reverted to adjunctive therapy in the following months. Thirty four (34) patients were followed up for at least 6 months and, of these, 24 patients (71%) remained on perampanel monotherapy for at least 6 months. Ten (10) patients were followed up for at least 18 months and, of these, 3 patients (30%) remained on perampanel monotherapy for at least 18 months.
Paediatric population: The three pivotal double-blind placebo-controlled phase 3 studies included 143 adolescents between the ages of 12 and 18. The results in these adolescents were similar to those seen in the adult population.
Study 332 included 22 adolescents between the ages of 12 and 18.
The results in these adolescents were similar to those seen in the adult population.
Paediatrics (< 12 years of age): The safety and efficacy of FYCOMPA in paediatric patients have not been established and its use in this patient population is not indicated.
Pharmacokinetics: The pharmacokinetics of FYCOMPA have been studied in healthy adult subjects (age range 18 to 79), adults and adolescents with partial-onset seizures and primary generalized tonic-clonic seizures, adults with Parkinson's disease, adults with diabetic neuropathy, adults with multiple sclerosis, and subjects with hepatic impairment.
Absorption: FYCOMPA is rapidly and completely absorbed after oral administration with no evidence of marked first class metabolism. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food, peak plasma concentrations are reduced and delayed by 2 hours compared with dosing in a fasted state.
Distribution: Data from in vitro studies indicate that FYCOMPA is approximately 95% bound to plasma proteins.
In vitro studies show that FYCOMPA is not a substrate or significant inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1, 2, 3, and 4, organic cation transporters (OCT) 1, 2, and 3, and the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP).
Biotransformation: FYCOMPA is extensively metabolised via primary oxidation and sequential glucuronidation. Primary oxidative metabolism is mediated by CYP3A4 based on results of in vitro studies using recombinant human CYPs and human liver microsomes. However, the metabolism has not been completely elucidated and other pathways cannot be excluded.
Following administration of radiolabeled FYCOMPA, only trace amounts of FYCOMPA metabolites were observed in plasma.
Elimination: Following administration of a radiolabeled FYCOMPA dose to 8 healthy elderly subjects, 30% of recovered radioactivity was found in the urine and 70% in the faeces. In urine and faeces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of FYCOMPA was 105 hours. When dosed in combination with the strong CYP3A inducer carbamazepine, the average t1/2 was 25 hours.
Linearity/non-linearity: In healthy subjects, plasma concentrations of FYCOMPA increased in direct proportion to administered doses over the range of 2 to 12 mg. In a population pharmacokinetic analysis of patients with partial-onset seizures receiving FYCOMPA up to 12 mg/day and patients with primary generalized tonic clonic seizures receiving FYCOMPA up to 8 mg/day in placebo-controlled clinical trials, a linear relationship was found between dose and FYCOMPA plasma concentrations.
Special Populations: Hepatic impairment: The pharmacokinetics of FYCOMPA following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 healthy, demographically matched subjects. The mean apparent clearance of unbound FYCOMPA in mildly impaired subjects was 188 mL/min vs. 338 ml/min in matched controls, and in moderately impaired subjects was 120 mL/min vs. 392 mL/min in matched controls. The t1/2 was longer in mildly impaired (306 h vs 125 h) and moderately impaired (295 h vs 139 h) subjects compared to matched healthy subjects.
Renal impairment: The pharmacokinetics of FYCOMPA have not been formally evaluated in patients with renal impairment. FYCOMPA is eliminated almost exclusively by metabolism followed by rapid excretion of metabolites; only trace amounts of FYCOMPA metabolites are observed in plasma. In a population pharmacokinetic analysis of patients with partial-onset seizures having creatinine clearances ranging from 39 to 160 mL/min and receiving FYCOMPA up to 12 mg/day in placebo controlled clinical trials, FYCOMPA clearance was not influenced by creatinine clearance. In a population pharmacokinetic analysis of patients with primary generalized tonic-clonic seizures receiving FYCOMPA up to 8 mg/day in a placebo-controlled clinical study, FYCOMPA clearance was not influenced by baseline creatinine clearance.
Gender: In a population pharmacokinetic analysis of patients with partial-onset seizures receiving FYCOMPA up to 12 mg/day and patients with primary generalized tonic-clonic seizures receiving FYCOMPA up to 8 mg/day in placebo-controlled clinical trials, FYCOMPA clearance in females (0.54 L/h) was 18% lower than in males (0.66 L/h).
Elderly (65 years of age and above): In a population pharmacokinetic analysis of patients with partial-onset seizures (age range: 12 to 74 years) and primary generalized tonic-clonic seizures (age range 12 to 58 years), and receiving FYCOMPA up to 8 or 12 mg/day in placebo-controlled clinical trials, no significant effect of age on FYCOMPA clearance was found. A dose adjustment in the elderly is not considered to be necessary (see Dosage & Administration).
Paediatric population: 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.
Drug Interaction Studies: In Vitro Assessment of Drug Interactions: Drug Metabolising Enzyme Inhibition: In human liver microsomes, FYCOMPA (30 μmol/L) had a weak inhibitory effect on CYP2C8 and UGT1A9 among major hepatic CYPs and UGTs.
Drug Metabolising Enzyme Induction: Compared with positive controls (including phenobarbital, rifampicin), FYCOMPA was found to weakly induce CYP2B6 (30 μmol/L) and CYP3A4/5 (≥3 μmol/L) among major hepatic CYPs and UGTs in cultured human hepatocytes.
Toxicology: Preclinical safety data: Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: In the fertility study in rats, prolonged and irregular oestrous cycles were observed at the maximum tolerated dose (30 mg/kg) in females; however, these changes did not affect fertility and early embryonic development. There were no effects on male fertility.
The excretion into breast milk was measured in rats at 10 days post-partum. Levels peaked at one hour and were 3.65-times the levels in plasma.
In a pre- and postnatal development toxicity study in rats, abnormal delivery and nursing conditions were observed at maternally toxic doses, and the number of stillbirths was increased in offspring. Behavioral and reproductive development of the offspring was not affected, but some parameters of physical development showed some delay, which is probably secondary to the pharmacology-based CNS effects of FYCOMPA. The placental transfer was relatively low; 0.09% or less of administered dose was detected in the foetus.
Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenic potential. The administration of maximum tolerated doses to rats and monkeys resulted in pharmacologically-based CNS clinical signs and decreased terminal body weight. There were no changes directly attributable to FYCOMPA in clinical pathology or histopathology.