Each film-coated tablet contains 2, 4, 8 mg perampanel.
Excipients/Inactive Ingredients: 2 mg tablet: Core: Perampanel, lactose monohydrate, low-substituted-hydroxypropyl cellulose, povidone, magnesium stearate.
Film coating: OPADRY ORANGE (containing): Hypromellose 2910, talc, Macrogol 8000, titanium dioxide, ferric oxide yellow, ferric oxide, red.
4 mg tablet: Core: Perampanel, lactose monohydrate, low-substituted-hydroxypropyl cellulose, povidone, magnesium stearate.
Film coating: OPADRY RED (containing): Hypromellose 2910, talc, Macrogol 8000, titanium dioxide, ferric oxide red.
8 mg tablet: Core: Perampanel, lactose monohydrate, low-substituted-hydroxypropyl cellulose, povidone, microcrystalline cellulose, magnesium stearate.
Film coating: OPADRY PURPLE (containing): Hypromellose 2910, talc, Macrogol 8000, titanium dioxide, ferric oxide red, ferric oxide, black.
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.
FYCOMPA is indicated for the adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in adult and adolescent patients from 12 years of age with epilepsy.
Fycompa is indicated for the adjunctive treatment of primary generalized tonic-clonic seizures in adult and adolescent patients from 12 years of age with idiopathic generalized epilepsy (see Pharmacology: Pharmacodynamics under Actions).
Dosing Considerations: Concomitant CYP3A Enzyme-Inducing AEDs Significantly Reduce Both Plasma Levels and Efficacy: Carbamazepine, oxcarbazepine and phenytoin all decrease mean FYCOMPA blood levels by approximately 50-70% and substantially decrease FYCOMPA efficacy. As there are no clinical trial data for FYCOMPA doses greater than 12 mg/day, there is insufficient information to recommend dose adjustments to correct for this.
Serious Aggression- and Hostility-Related Adverse Events: Closely monitor patients particularly during the titration period and at higher doses. FYCOMPA should be reduced if symptoms of aggression or hostility occur and should be discontinued immediately if symptoms are severe or worsening.
Recommended Dose and Dose Adjustment: Partial Onset Seizures: FYCOMPA at doses of 4 mg/day to 12 mg/day has been shown to be effective therapy in partial-onset seizures.
Treatment with FYCOMPA should be initiated with a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg to a maintenance dose of 4 mg/day to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased by increments of 2 mg/day to 12 mg/day.
In order to optimize the balance between efficacy and tolerability, FYCOMPA must always be titrated according to individual patient response.
FYCOMPA should be taken orally once daily at bedtime. The maximum recommended daily dose of FYCOMPA is 12 mg/day. Doses beyond 12 mg/day have not been studied in patients.
Primary Generalised Tonic-Clonic Seizures: FYCOMPA at a dose up to 8 mg/day has been shown to be effective in primary generalized tonic clonic seizures.
Treatment with FYCOMPA should be initiated at a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg (either weekly or every 2 weeks, as per half-life considerations described as follows) to a maintenance dose of up to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased up to 12 mg/day, which may be effective in some patients (see Precautions). Patients who are taking concomitant medicinal products that do not shorten the half-life of perampanel (see Interactions) should be titrated no more frequently than at 2-week intervals. Patients who are taking concomitant medicinal products that shorten the half-life of perampanel (see Interactions) should be titrated no more frequently than at 1-week intervals.
Adults: In the Presence of Enzyme-Inducing AEDs (EI-AEDs; carbamazapine, oxcarbazepine, phenytoin): The recommended starting dose of FYCOMPA in the presence of EI-AEDs, including carbamazepine, oxcarbazepine and phenytoin, is 4 mg/day. Based on clinical response and tolerability, the dose may be increased by increments of 2 mg to a maximum dose of 12 mg/day. Dose increases should occur no more frequently than at 1-week intervals.
Clinical trials revealed a lower efficacy in these patients at a given dose, compared to those not on enzyme-inducing AEDs. This is the result of lower FYCOMPA blood levels, suggesting that relatively higher doses would be needed in this patient population to achieve similar efficacy as those not on enzyme-inducing AEDs. However, there are no efficacy or safety data to support FYCOMPA doses beyond 12 mg/day, as they have not been studied in patients.
When these enzyme-inducing AEDs are introduced or withdrawn from a patient's treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.
In the Absence of Enzyme-Inducing AEDs: Treatment with FYCOMPA should be initiated with a dose of 2 mg/day. The dose may be increased, based on clinical response and tolerability, by increments of 2 mg up to a dose of 8 mg/day. Dose increases should occur no more frequently than at 2-week intervals.
If FYCOMPA is well tolerated at 8 mg/day but clinical response is lacking, the dose may be increased by increments of 2 mg to 12 mg/day, depending upon individual clinical response and tolerability. The maximum recommended daily dose is 12 mg/day. In these patients, there was little difference in efficacy between 8 and 12 mg/day, while the proportion of patients with adverse events, including aggression/hostility-related increased.
Paediatrics population (below 12 years of age): The safety and efficacy of FYCOMPA in children below 12 years of age have not been established yet. No data are available.
Elderly Patients (≥ 65 years of age): Clinical studies of FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA in the elderly population. Because of increased likelihood for adverse reactions in the elderly, dosage increases during titration are recommended no more frequently than every 2 weeks.
Patients with Renal Impairment: Dose adjustment is not required in patients with mild renal impairment. Use in patients with moderate or severe renal impairment or patients undergoing hemodialysis is not recommended.
Patients with Hepatic Impairment: Dosage adjustment is recommended in patients with mild and moderate hepatic impairment, based on higher exposure and the longer half-life of FYCOMPA. The maximum recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with moderate hepatic impairment. Starting dose should be 2 mg per day with increments of 2 mg every two weeks until target dose is achieved. Dose increases in patients with mild and moderate hepatic impairment, as with all patients, should be based on clinical response and tolerability. Use in patients with severe hepatic impairment is not recommended.
Missed Dose: Single missed dose: As FYCOMPA has a long half-life, the patient should wait and take their next dose as scheduled.
If more than 1 dose has been missed, for a continuous period of less than 5 half-lives (3 weeks for patients not taking FYCOMPA metabolism-inducing anti-epileptic drugs (AED), 1 week for patients taking FYCOMPA metabolism-inducing AEDs consideration should be given to restart treatment from the last dose level.
If a patient has discontinued FYCOMPA for a continuous period of more than 5 half-lives, it is recommended that initial dosing recommendations given in the previously mentioned text should be followed.
Discontinuing: When withdrawing, the dose should be gradually reduced. However, due to its long-half life and subsequent slow decline in plasma concentrations, FYCOMPA can be discontinued abruptly if absolutely needed.
There is limited clinical experience with FYCOMPA overdose in humans. In a report of an intentional overdose that could have resulted in a dose up to 264 mg, the patient experienced events of altered mental status, agitation and aggressive behaviour and recovered without sequelae.
There is no available specific antidote to the effects of FYCOMPA. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.
In view of its long half-life, the effects caused by FYCOMPA could be prolonged. Because of low renal clearance special interventions such as forced diuresis, dialysis or haemoperfusion are unlikely to be of value.
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Suicidal ideation: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents including FYCOMPA. A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for FYCOMPA.
Therefore patients should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.
Severe cutaneous adverse reactions (SCARs): Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown) in association with FYCOMPA treatment.
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.
Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target like lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes.
If signs and symptoms suggestive of these reactions appear, FYCOMPA should be withdrawn immediately and an alternative treatment considered (as appropriate).
If the patient has developed a serious reaction such as SJS or DRESS with the use of FYCOMPA, treatment with FYCOMPA must not be restarted in this patient at any time.
Neurologic effects: Dizziness, Disturbance in Gait and Coordination and Falls: FYCOMPA caused dose-related increases in events related to dizziness, disturbance in gait or coordination, and falls. In the absence of enzyme-inducing AEDS, the rate of coordination-related events at FYCOMPA doses of 8 to 12 mg/day was 54% for FYCOMPA vs 15% for placebo. In the presence of enzyme-inducing AEDs, the rates were 47% and 13% respectively.
These adverse reactions occurred mostly during the titration phase and led to discontinuation more frequently in FYCOMPA-treated patients than in placebo-treated. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures).
Somnolence- and Fatigue-Related Events: FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the absence of enzyme-inducing AEDS, the rate of somnolence/fatigue-related events at FYCOMPA doses of 8 to 12 mg/day was 39% for FYCOMPA vs 11% for placebo. In the presence of enzyme-inducing AEDs, the rates were 24% and 13% respectively.
Somnolence or fatigue-related events led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
Hormonal contraceptives: At doses of 12 mg/day FYCOMPA may decrease the effectiveness of progestative-containing hormonal contraceptives; in this circumstance additional non-hormonal forms of contraception are recommended when using FYCOMPA.
End of treatment: It is recommended that discontinuation be undertaken gradually to minimize the potential for rebound seizures. However, due to its long half life and subsequent slow decline in plasma concentrations, FYCOMPA can be discontinued abruptly if absolutely needed.
Falls: There appears to be an increased risk of falls, particularly in the elderly; the underlying reason is unclear and may in part be related to the underlying diseases studied.
Aggression: Aggressive and hostile behavior has been reported in patients receiving FYCOMPA therapy. In FYCOMPA-treated patients in clinical trials, aggression, anger and irritability were reported more frequently at higher doses. Most of the reported events were either mild or moderate and patients recovered either spontaneously or with dose adjustment. However, thoughts of harming others, physical assault or threatening behavior were observed in some patients (< 1% in FYCOMPA clinical studies). Patients and caregivers should be counseled to alert a health care professional immediately if significant changes in mood or patterns of behavior are noted. The dosage of FYCOMPA should be reduced if such symptoms occur and should be discontinued immediately if symptoms are severe.
Abuse potential: Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of FYCOMPA abuse.
Substantial Decrease in Mean FYCOMPA Blood Levels for Patients on Concomitant CYP3A Enzyme-Inducing AEDs (Carbamazepine, Oxcarbazepine, Phenytoin): Carbamazepine, oxcarbazepine, and phenytoin (all strong cytochrome P450 inducers) decrease FYCOMPA plasma concentrations and efficacy to a clinically significant extent, as compared to patients not on these AEDs. The rate of occurrence of adverse events in clinical trials was often greater in the absence of concomitant enzyme-inducing AEDs (EI-AEDs), apparently reflecting higher mean FYCOMPA blood levels in that condition of use.
Other concomitant (non-anti-epileptic) cytochrome P450 inducing or inhibiting medicinal products: Patients should be closely monitored for tolerability and clinical response when adding or removing cytochrome P450 inducers or inhibitors, since perampanel plasma levels can be decreased or increased; the dose of perampanel may need to be adjusted accordingly.
Endrocrine and Metabolism: FYCOMPA Film-coated Tablets contain lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take these medicines.
Hepatotoxicity: Cases of hepatotoxicity (mainly hepatic enzyme increased) with FYCOMPA in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.
Caution with Driving and Use of Machinery: FYCOMPA may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities requiring mental alertness, until the effect of FYCOMPA is known.
Women of childbearing potential and contraception in males and females: FYCOMPA is not recommended in women of childbearing potential not using contraception unless clearly necessary. FYCOMPA may decrease the effectiveness of progestative containing hormonal contraceptives. An additional non-hormonal form of contraception is, therefore recommended (see Precautions and Interactions).
Pregnancy: There are limited amounts of data (less than 300 pregnancy outcomes) from the use of FYCOMPA in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats at maternally toxic doses (see Pharmacology: Toxicology: Preclinical safety data under Actions). FYCOMPA is not recommended during pregnancy.
Breastfeeding: Studies in lactating rats have shown excretion of FYCOMPA and/or its metabolites in milk (see Pharmacology: Toxicology: Preclinical safety data under Actions). It is not known whether FYCOMPA is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from FYCOMPA therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility: In the fertility study in rats, prolonged and irregular estrous cycles were observed at high-dose (30 mg/kg) in females; however, these changes did not affect the fertility and early embryonic development. There were no effects on male fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions). The effect of FYCOMPA on human fertility has not been established.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 1,038 patients on FYCOMPA (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51% of patients were female and the mean age was 35 years.
Adverse Reactions Leading to Discontinuation:
In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomized to receive at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomized to receive placebo [see Pharmacology: Pharmacodynamics: Clinical Efficacy & Safety under Actions]. The adverse events most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria.
Most Common Adverse Reactions:
Table 1 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in ≥2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving at doses of 8 mg or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation. (See Table 1.)
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Weight gain has been observed with FYCOMPA use in adults.
In the controlled Phase 3 epilepsy clinical trials, FYCOMPA-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively.
Clinical monitoring of weight is recommended.
Comparison of Sex and Race:
No significant sex differences were noted in the incidence of adverse reactions.
Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.
The following adverse reactions have been identified during post approval use of FYCOMPA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS) (see Precautions).
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.)
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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.
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).
In healthy subjects, FYCOMPA (4 mg once daily for 19 days) had no effect on Cmax
or AUC of levodopa (100 mg single dose).
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
Interactions with herbal product have not been evaluated.
Interactions with laboratory tests have not been observed.
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.
Special precautions for disposal: No special requirements.
Incompatibilities: Not applicable.
This medicinal product is to be stored below 30°C.
Shelf-Life: 2 mg, 4 mg, 8 mg tablet: (60 months).
N03AX22 - perampanel ; Belongs to the class of other antiepileptics.
FC tab 2 mg (orange, round, biconvex, debossed with €275 on one side and '2' on the other side) x 28's. 4 mg (red, round, biconvex, debossed with €277 on one side and '4' on the other side) x 28's. 8 mg (purple, round, biconvex, debossed with €295 on one side and '8' on the other side) x 28's.