Fycompa, pills 6mg, 28pcs

Composition

Active ingredient:  perampanel 6.0 mg (in terms of anhydrous substance). Auxiliary substances: lactose monohydrate 151.0 mg, hyprolose low-substituted 18.0 mg, povidone 10.0 mg, microcrystalline cellulose 14.0 mg, magnesium stearate 1.0 mg. Film shell:  opadray pink 10.0 mg (hypromellose 2910 56.0%, talc 25.0%, macrogol-8000 10.0%, titanium dioxide 8.6%, iron oxide red dye 0.4%).

Pharmacological action

Faykompa has an antiepileptic effect.

Pharmacodynamics

Mechanism of action. Perampanel is the first in its class selective non-competitive antagonist of ionotropic α-amino-3-hydroxy-5-methyl-4 – isoxazolpropionate – (AMPA) glutamate receptors on postsynaptic neurons.

Glutamate is the main excitatory neurotransmitter in the central nervous system, which plays an important role in the pathogenesis of a number of neurological diseases caused by overexcitation of neurons.

It is assumed that activation of AMPA receptors by glutamate is responsible for the fastest excitatory synaptic transmission in the brain.

In vitro studies, perampanel did not compete with AMPA for binding to the AMPA receptor, but it was displaced from binding by non-competitive AMPA receptor antagonists. This indicates that perampanel is a non-competitive AMPA receptor antagonist.

In vitro studies, perampanel inhibited AMPA-induced (but not N-methyl-D-aspartate (NMDA)-induced) increases in intracellular calcium concentrations. Perampanel significantly increased the latency period in an AMPA-induced in vivo model of an epileptic seizure.

The exact mechanism of development of the anticonvulsant effect of perampanel in humans is subject to further study.

Pharmacodynamic effects.

The pharmacokinetics and Pharmacodynamics of perampanel were analyzed based on the combined data of three efficacy studies conducted in partial epileptic seizures. The magnitude of perampanel exposure correlated with the severity of the reduction in seizure frequency.

Influence on psychomotor functions. At doses of 8 and 12 mg, perampanel, when administered once or repeatedly, dose-dependently worsened psychomotor functions in healthy volunteers. The effect of perampanel on complex psychomotor functions, such as driving, was enhanced by alcohol intake. Characteristics of psychomotor functions returned to baseline values within 2 weeks after discontinuation of perampanel.

Influence on cognitive function. When evaluating the effect of perampanel on the reaction rate to external influences and memory in healthy volunteers in a series of standard tests, no effect was observed with either a single or multiple dose of the drug at doses up to 12 mg/day.

Influence on mood and speed of reaction to external influences. The rate of response to external stimuli (arousal) in healthy volunteers who received perampanel at doses from 4 to 12 mg/day decreased dose-dependently. Mood deterioration in the volunteers was noted only against the background of taking 12 mg / day, mood changes were insignificant and reflected a general decrease in the reaction rate to external influences.

Repeated use of perampanel in a daily dose of 12 mg increased the worsening effect of alcohol on mindfulness and speed of reaction to external influences and increased the severity of irritability, confusion and depression according to the results of a 5-point scale for assessing the Mood Profile.

Influence on electrophysiological parameters of the heart. Perampanel in daily doses up to 12 mg did not prolong the QTc interval and did not have any dose-dependent or clinically significant effect on the duration of QRS complexes.

Clinical efficacy and safety. The efficacy of Faikompa® in partial seizures was established in three 19-week randomized, double-blind, placebo-controlled multicenter studies in adults and adolescents with partial seizures in the presence or absence of secondary generalization, not adequately controlled by other (from one to a combination of three) antiepileptic drugs (AEDs). During the 6-week baseline period, patients should have more than 5 seizures, and the non-seizure period should not exceed 25 days. In all three studies, patients had an average disease duration of 21.06 years. 85.3% to 89.1% of patients received 2 or 3 AEDs with or without concomitant vagus nerve stimulation.

In the first two trials, Faicompa® was compared to placebo in daily doses of 8 and 12 mg, and in the third — in daily doses of 2,4 and 8 mg.

In all three studies, after a 6-week baseline period prior to randomization, which is necessary to establish the baseline frequency of epileptic seizures, patients were randomized and received matched to randomized dose values. During the dose adjustment period in all three studies, treatment was started with a dose of 2 mg / day, which was increased weekly by 2 mg / day until the target dose was reached. Patients with intolerable side effects could remain on the same dose or their dose was reduced to a previously well-tolerated dose. In all three studies, the dose adjustment period was followed by a maintenance period of 13 weeks, during which patients were required to receive a constant dose of Faycompa.

According to the combined results of the three studies, the 50% response rate was 19% for the placebo group,29% for the 4 mg dose,35% for the 8 mg dose, and 35% for the 12 mg dose, respectively. A statistically significant reduction in the frequency of seizures over 28 days compared to placebo was shown for doses from 4 to 12 mg / day with a single dose.

These results show that taking perampanel in doses from 4 to 12 mg once a day as an additional therapy in this group of patients is significantly more effective than placebo.

Clinically significant improvement in seizure control was observed with a single dose of 4 mg/day of Faycompa, and increased with an increase in the daily dose to 8 mg. When the daily dose was increased to 12 mg, there was no additional increase in the effectiveness of the drug compared to the dose of 8 mg for the entire patient population. An increase in the effectiveness of the drug Faycompa at a dose of 12 mg was observed only in patients resistant to a dose of 8 mg.

A clinically significant reduction in the frequency of seizures relative to placebo was achieved as early as 2 weeks after reaching the daily dose of 4 mg.

Open extended study

97% (1186) of patients who completed randomized trials were recruited to participate in an open extended study in which they took perampanel for at least 1 year at an average daily dose of 10.05 mg.

These three baseline, double-blind, placebo-controlled phase III studies included 143 adolescents aged 12 to 18 years. The results obtained in adolescents were similar to those of adult patients.

Pharmacokinetics

The pharmacokinetics of perampanel were studied in healthy volunteers aged 18 to 79 years, in adults and adolescents with partial epileptic seizures, in adults with Parkinson’s disease, diabetic nephropathy and multiple sclerosis, as well as in patients with hepatic insufficiency.

Suction. When taken orally, perampanel is rapidly and completely absorbed, the effect of the first passage through the liver is insignificant. Food intake does not affect the degree of absorption, but slows down its speed. In comparison with fasting intake with concomitant use of the drug with food, the Cmax of perampanel in plasma decreases, and the time to reach it increases by 2 hours.

Distribution. In vitro data indicate that perampanel is approximately 95% bound to plasma proteins. In vitro, it was shown that perampanel is neither a substrate nor a significant inhibitor of organic anion transport peptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1,2,3 and 4, organic cation transporters (OCT) 1,2 and 3, as well as P-glycoprotein and breast cancer resistance protein (BCRP).

Metabolism. Perampanel is largely metabolized by primary oxidation and subsequent glucuronidation.

According to the results of in vitro studies with recombinant cytochrome P450 in human liver microsomes, primary oxidative metabolism is mediated by CYP3A4 isoenzymes. However, the metabolism of perampanel is not fully understood, and its other pathways are not excluded.

After the use of radioactively labeled perampanel, only trace amounts of its metabolites are detected in plasma.

Output. After use of radioactively labeled perampanel to healthy elderly volunteers,30% of the radioactivity label was detected in the urine and 70% in the feces. The isolated radioactive label was mainly a mixture of oxidized and conjugated metabolites. In a population pharmacokinetic analysis of summary data from 19 phase I clinical trials, the average T1 / 2 of perampanel was 105 hours. When administered concomitantly with carbamazepine, which is a potent inducer of the CYP3A4 isoenzyme, the T1/2 of perampanel was 25 hours.

Linearity/Non-Linearity. In healthy volunteers, the plasma concentration of perampanel increases in direct proportion to the dose in the range from 2 to 12 mg. In a population pharmacokinetic analysis of patients with partial seizures treated with perampanel at doses up to 12 mg/day in placebo-controlled clinical trials, a linear relationship was established between the dose value and the concentration of perampanel in plasma.

Use in special patient groups

Patients with hepatic insufficiency.The pharmacokinetics of perampanel after a single dose of 1 mg were evaluated in 12 patients with mild to moderate hepatic insufficiency (classes A and B on the Child-Pugh scale) and demographically corresponding 12 healthy volunteers. The mean apparent clearance of unbound perampanel in mild hepatic insufficiency was 188 ml / min versus 338 ml / min in healthy volunteers and 120 ml/min (versus 392 ml/min). – with a moderate degree. T1 / 2 in patients with hepatic insufficiency was prolonged: in mild cases-up to 306 hours versus 125 hours in healthy volunteers, in moderate cases – up to 295 hours versus 139 hours.

Patients with renal insufficiency. The pharmacokinetics of perampanel in patients with renal insufficiency have not been studied separately. Elimination of perampanel occurs almost exclusively through the formation of metabolites followed by their rapid excretion. Only trace amounts of perampanel metabolites are detected in plasma. In a population pharmacokinetic analysis of patients with partial seizures and a creatinine clearance of 39-160 ml / min who received perampanel at doses up to 12 mg / day in placebo-controlled studies, there was no relationship between perampanel clearance and creatinine clearance.

Influence of gender. In a population pharmacokinetic analysis of patients with partial seizures who received perampanel at doses up to 12 mg/day in placebo-controlled trials, the clearance of perampanel in women (0.605 l / h) was 17% lower than in men (0.73 l/h).

Elderly patients (≥65 years). In a population pharmacokinetic analysis of patients aged 12 to 74 years with partial seizures who received perampanel at doses up to 12 mg/day in placebo-controlled studies, no significant effect of age on perampanel clearance was found.

Children’s patients. In a population pharmacokinetic analysis of adolescent patients participating in phase III clinical trials, no significant differences were found from the general population.

Drug interaction studies

In vitro drug interaction assessment

Inhibition of enzymes involved in drug metabolism. Among the main cytochromes and UDP-glucuronyltransferases of the liver, perampanel (30 mmol/L) in experiments on human liver microsomes weakly inhibited the isoenzymes CYP2C8 and UGT1A9 in vitro.

Induction of enzymes involved in drug metabolism. Compared to the positive control (including phenobarbital and rifampicin), among the main cytochromes and UDP-glucuronyltransferases in human hepatocyte culture, perampanel weakly induced the isoenzymes CYP2 B 6 (30 mmol/L) and CYP3 A 4/5 (≥3 mmol/L).

Indications

Faikompa is indicated as an adjunct to the treatment of partial seizures in patients with epilepsy aged 12 years and older with or without secondary generalized seizures.

Use during pregnancy and lactation

For women with preserved childbearing potential who do not use contraceptive methods, taking the drug Faykompa is recommended only if absolutely necessary.

Data on the use of perampanel in pregnant women are significantly limited ( No direct or indirect toxic effects were found in animal reproductive toxicity studies. As a precautionary measure, it is recommended to avoid using the drug Faykompa during pregnancy.

Animal studies have shown that perampanel and/or its metabolites are excreted in breast milk. It is not known whether perampanel is excreted in human breast milk, so the risk to the child cannot be excluded.

Considering the benefits of both breast-feeding for the child and therapy for the woman, it is necessary to either stop breastfeeding, or refrain from taking / discontinue taking Faycompa during breastfeeding.

Impact on fertility

Animal studies have shown that high doses (30 mg/kg) of perampanel prolong and disrupt the regularity of the estrous cycle, but these changes did not affect fertility and early fetal development. No effect on male fertility was found. The effect of perampanel on human fertility has not been studied.

Contraindications

Hypersensitivity to perampanel or any of the excipients of the drug. Pregnancy and lactation. Severe renal or hepatic insufficiency; patients undergoing hemodialysis. Children under 12 years of age (no efficacy or safety data available). Galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Side effects

Among patients with partial seizures who received perampanel in all clinical trials,72% took the drug for 6 months and 43% – for more than 12 months. Adverse reactions leading to withdrawal of patients from controlled phase III trials were observed in 1.7,4.2, and 13.7% of patients treated with perampanel, respectively, at doses of 4,8, and 12 mg per day, and in 1.4% of patients treated with placebo. The most common reasons for withdrawal from studies were dizziness and drowsiness (≥1% in the combined perampanel group than in the placebo group). The following lists the adverse events (AES) reported with perampanel, according to the organ-system classes and frequency of their occurrence. To assess the frequency of adverse events, the following classification is used: very common (≥1/10); common (≥1/100, <1/10); infrequent (≥1/1000, <1/100); rare (≥1/10 000, Eating and metabolic disorders: often-decreased appetite, increased appetite. Mental disorders: often-aggression, anger, anxiety, confusion. Nervous system disorders: very often – dizziness, drowsiness; often-ataxia, dysarthria, balance disorders, increased irritability. Visual disorders: often – diplopia, blurred vision. Hearing disorders and labyrinthine disorders: often-central vertigo. Disorders of the gastrointestinal tract: often-nausea. Musculoskeletal and connective tissue disorders: often-back pain. General disorders: often-gait disorders, fatigue. Laboratory and instrumental data: often-increased body weight. Injuries, intoxications, and manipulation complications: often-falls. Based on the data of clinical studies, it can be expected that the frequency, nature and severity of adverse reactions in adolescents are the same as in adults.

Interaction

Oral contraceptives At a dose of 12 mg per day, perampanel reduced the maximum concentration (Cmax) and area under the concentration-time curve (AUC) of levonorgestrel by approximately 40%. Patients taking Faycompa should consider the possibility of reducing the effectiveness of contraceptives containing levonorgestrel, and use additional methods of contraception (intrauterine devices or condoms). Ketoconazol E in healthy volunteers with repeated use of ketoconazole, an inhibitor of the CYP3A4 isoenzyme, after a single dose of 1 mg of perampanel, the half-life of the latter increased by 15%, and AUC0 -∞ – by 20%. Cytochrome P 450 It is believed that perampanel is neither a potent inhibitor nor a potent inducer of cytochrome P 450 isoenzymes. A drug interaction study in healthy volunteers showed a threefold increase in the clearance of perampanel when co-administered with carbamazepine. A population pharmacokinetic analysis of patients with partial seizures who received perampanel in daily doses up to 12 mg in placebo-controlled clinical trials showed a similar result. The total clearance of perampanel increases when used concomitantly with carbamazepine (3 times), phenytoin (2 times) and oxcarbazepine (2 times) – inducers of the CYP3A4 isoenzyme. This effect should be taken into account when adding or removing these AEDs during treatment. Other potent inducers of cytochrome P450 isoenzymes, such as rifampicin and St. John’s wort, are also able to reduce the concentration of perampanel in plasma. Felbamate may also reduce the plasma concentration of perampanel. Effect of perampanel on concomitant use of AEDs in a population pharmacokinetic analysis in patients with partial seizures who received Faicompa at doses up to 12 mg per day in placebo-controlled clinical trials, perampanel use had little effect on the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate and zonisamide. There was a statistically significant effect of perampanel on the clearance of carbamazepine, clobazam, lamotrigine and valproic acid, but its value at the highest dose of perampanel (12 mg per day) did not reach 10%. Concomitant use of Faicompa with oxcarbazepine resulted in a 26% reduction in clearance of the latter. In healthy volunteers, Faicompa reduced the AUC of midazolam by 13% and had no effect on the AUC or Cmax of levodopa. Use in adolescents Drug interaction studies were conducted only in adults. In the population pharmacokinetic analysis of adolescents participating in phase III clinical trials, there were no significant differences from the general study population.

How to take it, course of use and dosage

Use in adults and adolescents Perampanel is taken orally 1 time a day before bedtime, regardless of food intake. The tablet should be swallowed whole, washed down with 1 glass of water. The tablet should not be chewed, crumbled or broken, because the tablet cannot be neatly divided, as there is no risk on it. It has been shown that the drug Faykompa in daily doses from 4 to 12 mg is effective in the treatment of partial epileptic seizures.Taking the drug Faykompa should begin with a dose of 2 mg per day. The dose can be increased depending on the clinical response and tolerability in increments of 2 mg no more than once a week to 4-8 mg per day. Depending on the individual clinical response and tolerability of the drug at a dose of 8 mg per day, it is possible to further increase the dose of Faycomp to 12 mg per day in 2 mg increments no more than once a week. Despite the fact that perampanel has a long half-life, it is recommended, as with other AEDs, to cancel it gradually in order to minimize the likelihood of an increase in the frequency of attacks. Single dose skipping: due to the fact that perampanel has a fairly long half-life, the patient should wait and take the next scheduled dose in accordance with the agreed schedule of taking the drug. If more than 1 dose is missed (the total duration without the drug is less than 5 half-lives: 3 weeks for patients not receiving PEP that changes the metabolism of perampanel and 1 week for patients receiving PEP that changes the metabolism of perampanel), you should consider resuming the drug at the last dose taken. If the patient has stopped taking the drug for more than 5 half-lives, follow the recommendations as at the initiation of treatment. Use in children under 12 years of age. The safety and efficacy of perampanel in children under 12 years of age has not been established (see section “Contraindications”). Use in elderly patients (over 65 years of age)In clinical trials of Faycompa, there were not enough patients with epilepsy older than 65 years to assess the differences with younger patients. Analysis of safety information in patients treated with perampanel did not reveal any differences in the safety profile depending on age. These data confirm that no age-dependent dose adjustment of perampanel is required. In elderly patients, perampanel should be used with caution (see “Interaction with other medicinal products”, “Special instructions”). Use in patients with renal insufficiencyin mild renal insufficiency, no dose adjustment of perampanel is required. The use of Faikompa in patients with moderate to severe renal insufficiency or patients undergoing hemodialysis is not recommended (see the section “Contraindications”). Use in patients with hepatic insufficiencyincrease the dose in patients with mild to moderate hepatic insufficiency, as in other patients, is made depending on the clinical response and tolerability. Since the elimination half-life of perampanel is prolonged in patients with mild to moderate hepatic insufficiency, the minimum time interval before each dose increase should be two weeks, and the maximum dose should not exceed 8 mg per day. Use in severe hepatic insufficiency is not recommended (see section “Contraindications”).

Overdose

Clinical experience with perampanel overdose in humans is limited. In the report of a deliberate overdose that could have resulted in a dose of up to 264 mg, the patient showed a change in consciousness, agitation and aggressive behavior; recovery was without consequences. There is no specific antidote. General maintenance therapy is indicated, including monitoring of vital signs and clinical status of the patient. Given the long half-life of perampanel, its effects may have a longer duration in time. Due to the low renal clearance of perampanel, special procedures such as forced diuresis, hemodialysis or hemoperfusion are ineffective.

Special instructions

Suicidal alertness Cases of suicidal thinking and behavior have been reported in patients taking PEP for various indications. A meta-analysis of randomized placebo-controlled studies of PEP also showed a small increase in the risk of suicidal thinking and behavior. The mechanism of increased risk is unknown, and at present it is impossible to exclude the possibility of an increase in this risk when using the drug Faykompa. As a result, patients should be monitored for signs of suicidal thinking and behavior, and appropriate treatment should be provided. Patients or their caregivers should be informed about the need to seek medical attention if signs of suicidal thinking or behavior appear. Contraception with childbearing function during the use of perampanel and at least for 1 month after its completion, adequate methods of contraception should be used. While taking the drug Faycompa at a dose of 12 mg/day, the effectiveness of hormonal contraceptives containing levonorgestrel may be reduced due to the likelihood of drug interaction (see the section “Interaction with other drugs”). In these cases, it is necessary to provide for the use of additional non-hormonal methods of contraception. Completion of therapy It is recommended to complete therapy with Faycompa gradually in order to minimize the likelihood of an increase in the frequency of seizures. In extreme cases, abrupt discontinuation of the drug is possible, given its long elimination period and a relatively slow decrease in its plasma concentration after discontinuation. Falls There was a tendency, the cause of which is not known, to increase the number of falls, especially in elderly patients; aggression Cases of aggression were registered, and their frequency was higher in patients taking higher doses of the drug Faycompa. Most of these adverse events were mild to moderate in severity and resolved either independently or with a reduced dose. In severe cases of aggressive behavior, treatment had to be discontinued. Thus, the dose titration rule should be strictly observed and reduced while maintaining the patient’s symptoms of aggression. Development of addiction Caution should be exercised when prescribing Fycompa to patients with a history of drug dependence. Such patients should be monitored for timely detection of possible addiction to perampanel. Concomitant therapy with AEDS (CYP 3A inducers)The efficacy of perampanel in fixed doses was lower in those patients who received concomitant antiepileptic therapy with CYP 3A inducers (carbamazepine, phenytoin, oxcarbazepine) than in patients receiving enzyme-inactive AEDs. The 50% response rate to 4 mg,8 mg, and 12 mg perampanel was 23%,31.5%, and 30%, respectively, in patients treated with CYP 3A inducers, and 33.3%,46.5%, and 50.0%, respectively, in patients treated with enzyme-inactive AEDs. The effect of perampanel therapy should be carefully monitored when replacing or adding concomitant AEDs. Depending on the individual clinical response to treatment and tolerability of the drug, the dose may be increased or decreased in 2 mg increments. Influence on the ability to drive vehicles and work with mechanicsmi Faycompa has a moderate effect on the ability to drive vehicles and work with mechanisms. Perampanel can cause dizziness and drowsiness and thus affect the ability to drive vehicles and use machinery. Patients are advised not to drive vehicles, operate complex equipment, or engage in other potentially dangerous activities until it is determined whether the perampanel affects their ability to perform these activities.

Form of production

Film-coated tablets

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

2 years

Active ingredient

Perampanel

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Children over 12 years of age, For adults as prescribed by a doctor

Indications

Epilepsy