Fikcom - instructions for use, dose, side effects, contraindications

Active substancePerampanelPerampanel

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Dosage form: & nbspfilm coated tablets

Composition:

Each tablet, film-coated, with a dosage of 2 mg contains: Active substance: perrampanel 2.0 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 78.5 mg, low-substituted giprolose 14.0 mg, povidone 5.0 mg, magnesium stearate 0.5 mg.

Film sheath: opadrai orange 5 mg (hypromellose 2910 56.0%, talc 28.0%, macrogol-8000 10.0%, titanium dioxide 4.0%, iron dye oxide yellow 1.8%, iron dye oxide red 0 , 2%).

Each tablet, film-coated, with a dosage of 4 mg contains: Active substance: perrampanel 4.0 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 157.0 mg, low-substituted giprolose 28.0 mg, povidone 10.0 mg, magnesium stearate 1.0 mg.

Film sheath: opadray red 10 mg (hypromellose 2910 56.0%, talc 28.0%, macrogol-8000 10.0%, titanium dioxide 4.0%, iron dye oxide red 2.0%).

Each tablet, film-coated, with a dosage of 6 mg contains:

Active substance: perimpanel 6.0 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 151.0 mg, low-viscosity giprolose 18.0 mg, povidone 10.0 mg, microcrystalline cellulose 14.0 mg, magnesium stearate 1.0 mg.Sheath Film: Opadry pink 10.0 mg (56.0% Hypromellose 2910, 25.0% talc, Macrogol 8000, 10.0%, 8.6% titanium dioxide, iron red dye 0.4% oxide).

Each tablet, film-coated, with a dosage of 8 mg contains: Active substance: 8.8 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 149.0 mg, low-substituted giprolose 18.0 mg, povidone 10.0 mg, microcrystalline cellulose 14.0 mg, magnesium stearate 1.0 mg. Sheath Film: Opadry Purple 10.0 mg (56.0% Hypromellose 2910, 29.4% talc, Macrogol 8000, 10.0%, 4.0% titanium dioxide, iron oxide red dye 0.4% iron oxide colorant black 0.2%).

Each tablet, film-coated, with a dosage of 10 mg contains: Active substance: perrampanel 10.0 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 147.0 mg, low-substituted giprolose 18.0 mg, povidone 10.0 mg, microcrystalline cellulose 14.0 mg, magnesium stearate 1.0 mg. Sheath Film: Opadry green 10.0 mg (50.9% Hypromellose 2910, 24.0% talc, Macrogol 8000, 9.1%, 8.0% titanium dioxide, iron oxide yellow colorant 1.5% indigo carmine 6 5 %).

Each tablet, film-coated, with a dosage of 12 mg contains: Active substance: 12.8 mg (in terms of anhydrous substance). Excipients: lactose monohydrate 145.0 mg, low-substituted giprolose 18.0 mg, povidone 10.0 mg, microcrystalline cellulose 14.0 mg, magnesium stearate 1.0 mg. Film sheath: opadrai blue 10.0 mg (hypromellose 2910 50.9%, talc 25.5%, macrogol-8000 9.1%, titanium dioxide 8.0%, indigo carmine 6.5%).

Description:

Dosage 2 mg: orange round biconvex tablets, film-coated, engraved "£ 275" on one side and "2" on the other side.

Dosage 4 mg: red-orange round biconvex tablets, film-coated, with engraving "£ 277" on one side and "4" on the other side.

Dosage 6 mg: pink round biconvex tablets, film-coated, with engraving "€ 294" on one side and "6" on the other side.

Dosage 8 mg: gray-pink round biconvex tablets coated with a film sheath, with engraving "€ 295" on one side and "8" on the other side.

Dosage of 10 mg: gray-green round biconvex tablets covered with a film sheath, with engraving "€ 296" on one side and "10" on the other side.

Dosage 12 mg: blue round biconvex tablets, film-coated, with engraving "€ 297" on one side and "12" on the other side.

Pharmacotherapeutic group:antiepileptic agent.

ATX: & nbsp

N.03.A.X.22 Perampanel

Pharmacodynamics:

Mechanism of action

Perampanel is the first in its class selective non-competitive

antagonist of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-

(AMPA) of glutamate receptors on postsynaptic neurons.

Glutamate is the main stimulant neuromediator in the central nervous

system (CNS), which plays an important role in the pathogenesis of a number of neurological

diseases caused by overexcitation of neurons.

It is assumed that the activation of AMPA-receptor glutamate is responsible for the fastest exciting synaptic transmission in the brain.

In studies in vitro, Perampanel did not compete with AMPA for binding to the AMPA receptor, but it was displaced from binding by non-competitive AMPA receptor antagonists. The ego indicates that perampanel is a noncompetitive antagonist of AMPA receptors.

In studies in vitro Perrampanel inhibited AMPA-induced (but not M-methyl-E-aspartate (NMDA) induced) increase in intracellular calcium concentration. In vivo Perrampanel significantly increased the latent period in the AMPA-induced model of epileptic seizure.

The exact mechanism of development of the anticonvulsant effect of the perampapel in humans is subject to further study. Pharmacodynamic effects Based on the summary of the three efficacy studies conducted with partial epileptic seizures, the pharmacokinetics and pharmacodynamics of the perampapel were analyzed. The analysis of pharmacokinetics and pharmacodynamics

nonramipanel based on efficacy studies in primary-generalized tonic-clonic seizures. According to the results of two analyzes, the magnitude of the non-stimulan effect correlated with the severity of the decrease in the frequency of seizures.

Impact on psychomotor functions. In doses of 8 and 12 mg perampanel at a single and multiple admission dose-dependent worsened psychomotor functions in healthy volunteers. The effect of the panel on complex psychomotor functions, such as driving, was enhanced by the intake of alcohol.The characteristics of the psychomotor functions returned to the baseline values within 2 weeks after discontinuation of the non-stimulan. Impact on cognitive function. When assessing a series of standard tests of the impact of the panampanel on mindfulness and memory in healthy volunteers, there was no effect, either with single or repeated administration of the drug at doses up to 12 mg / day.

Influence on mood and speed of reaction to external influence. The speed of response to external influences (excitability) in healthy volunteers. who received perampanel in doses from 4 mg to 12 mg per day, dose-dependent decrease. Deterioration mood in volunteers was noted only against the background of taking 12 mg / day, changes moods were insignificant and reflected a general decrease in the reaction rate to the external effect.

Multiple admission of perampane in a daily dose of 12 mg increased the worsening effect of alcohol on vigilance and the reaction rate to the external action and increased the intensity irritation, confusion and depression based on the results of the 5-point rating scale of the Emotional State Profile. Influence on the electrophysiological parameters of the heart.

Perrampanel in daily doses up to 12 mg did not extend the interval QTc and ns had any dose-dependent or clinically significant effect on the duration of the complexes QRS.

Clinical efficacy and safety

Partial epileptic seizures The effectiveness of the preparation of Ficcom during partial attacks was established during the course of 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, adequately controlled others (from one to a combination of three) with anti-epileptic drugs (PEP). During the 6-week baseline period, patients were required to have more than 5 seizures, a period without seizures, should not exceed 25 days. In three of these studies, patients had an average duration of 21.06 dying. From 85.3 to 89.1% of patients took 2 or 3 PEP with or without concomitant vagal stimulation.

In the first two studies, the preparation Fikcom in daily doses of 8 and 12 mg, and in the third - in daily doses of 2, 4 and 8 mg was compared with placebo.

In all three studies, after a 6-week baseline period prior to randomization and necessary to establish a baseline frequency of epileptic seizures, patients were randomized and received titrated before randomized dose values. During the titration period, in all three studies, treatment started with a dose of 2 mg / day, which was increased weekly by 2 mg / day until reaching the target dose. Patients with intolerable side effects could remain at the same dose or their the dose was reduced to a previously well tolerated dose. In all three studies, the titration period was followed by a supportive period that lasted 13 weeks and during which patients were to receive a constant dose of the Ficcomp drug.

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

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

Clinically significant improvement in control over seizures was observed with a single admission of 4 mg of Fikcom drug per day, and increased with an increase in the daily dose to 8 mg. With an increase in the daily dose to 12 mg, no additional increase in drug efficacy was observed, but compared with a dose of 8 mg for the entire patient population. Increase the effectiveness of the drug Ficompa in a dose of 12 mg was noted only in patients resistant to a dose of 8 mg.

A clinically significant reduction in the frequency of seizures with placebo was achieved as early as the second week after reaching a daily dose of 4 mg.

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

In these three basic double-blind placebo-controlled Phase III trials, 143 adolescents aged 12 to 18 years old participated. The results obtained in adolescents were similar to the results of adult patients. Primary genistisation tonic-clonic seizures The effectiveness of the drug Fikcom as an additionaltreatment of primary generalized tonic-clonic seizures in 164 patients aged 12 years and older with idiopathic generalized epilepsy was established during a multicenter, randomized double blind placebo-control and research. Patients were included in the study, who took stable doses from 1 to 3 PEN and had at least 3 primary-generalized tonic-clonic seizures throughout the 8-week baseline period. Selection of the dose to the target value of 8 mg / day or to the highest tolerated dose was carried out for 4 weeks. The maintenance period was 13 weeks at the level of the last dose reached at the end of the titration period. The total treatment period was 17 weeks. The study drug was taken once a day. The proportion of the 50% response in the primary generalized tonic-clonic seizures was 64.2% in the group of perampanel and 39.5% in the placebo group. The median decrease in the frequency of primary generalized tonic-clonic seizures in 28 days was 76.47% in the group of the penrampanel and 38.38% in the placebo group. The estimated difference in treatment efficacy in the perampanel group and placebo was 30.81%which indicates a significant improvement in the reduction in the incidence of primary generalized tonic-clonic seizures in the perampanel group compared to the placebo group.

Open extended study

Of 140 patients who completed the main study, 114 (81.4%) within 6 pedel were transferred to a daily dose of 4-8 mg (73.7% of patients) or more than 8-12 mg (16.7% of patients) for at least 1 year.

The study involved 22 teenagers aged 12 to 18 years. The results obtained in adolescents were similar to those obtained in the adult population.

Pharmacokinetics:

The pharmacokinetics of the penrampanel were studied in healthy volunteers aged 18 to 79, in adults and adolescents with partial epileptic seizures and primary-generalized tonic-clonic seizures, in adults with Parkinson's disease, diabetic nephropathy and multiple sclerosis, as well as in patients from hepatic insufficiency.

Suction

Ingestion perampanel quickly and completely absorbed, the effect of "first passage" through the liver is negligible.Eating does not affect the degree of absorption, but slows its speed. Compared to fasting with simultaneous administration of the drug with food, the maximum concentration of the plasma in the plasma is reduced, and the time its achievement is increased by 2 h. Distribution

Research data in vitro point to the fact that perampanel approximately 95% binds to plasma proteins. In vitro it was shown that perampanel is not a pi substrate, nor a significant inhibitor of transport peptides of organic anions (OATP) 1B1 and 1B3, carriers of organic anions (OAT) 1, 2. 3 and 4. carriers of organic cations (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 glucuronation.

According to the research results in vitro with recombinant cytochrome P450 in human liver microsomes, the primary oxidative metabolism is mediated by isoenzymes CYP3A. However, the metabolism of the penrampanel is not yet fully understood, and its other pathways can not be ruled out.

After the application of a radio-labeled perampanel, only trace amounts of its metabolites are detected in the plasma.

Excretion

After receiving the radioactively labeled perampanel by eight healthy elderly volunteers, 30% of the radioactive label were detected in urine and 70% in feces. The radioactive label isolated was mainly a mixture of oxidized and conjugated metabolites. In the population pharmacokinetic analysis of the summary data of 19 Phase I clinical trials, the mean half-life (T1/2) perampanela was 105 hours. When used simultaneously with carbamazepine, which is a powerful isoenzyme inducer CYP3A, average T1/2 the spanpan was 25 h. Linearity / Nonlinearity In healthy volunteers, the concentration of the penrampanel in the plasma increases in direct proportion to the dose in the range of 2 to 12 mg. In a population pharmacokinetic analysis in patients with partial seizures who received perampanel in doses up to 12 mg / day and in patients with primary generalized tonic-clonic seizures who received perampanel in doses up to 8 mg / day in placebo-controlled clinical studies, between the dose value and the concentration of plasma in the plasma

Use in special patient groups

Patients with hepatic insufficiency

Pharmacokinetics of perampanel after a single dose of 1 mg was evaluated in 12 patients with mild to moderate hepatic insufficiency (classes A and B for Child-Pugh scale) and demographically corresponding to them 12 healthy volunteers. The average apparent clearance of an unbound band at hepatic insufficiency of mild degree was 188 ml / min against 338 ml / min in healthy volunteers, and 120 ml / min (vs. 392 ml / min) - at moderate degree. A \ a in patients with hepatic insufficiency was prolonged: at mild degree - up to 306 h against 125 h in healthy volunteers, with moderate degree - up to 295 h against 139 h.

Patients with renal insufficiency

Pharmacokinetics of the penrampanel the patients with renal failure were not studied separately. Elimination of the perampanel is carried out almost exclusively by the formation of metabolites followed by their rapid excretion. In the plasma, only trace amounts of metabolites of the penampanel are detected. In population pharmacokinetic analysis in patients with partial seizures and creatinine clearance of 39-160 ml / min, received during placebo-controlled research perampanel in doses up to 12 mg per day, there was no relationship between the clearance of the penrampanel and the clearance of creatinine.

Effect of sex

In a population pharmacokinetic analysis in patients with partial seizures who received perampanel in doses up to 12 mg / day and in patients with primary generalized tonic-clonic seizures who received perampanel in doses up to 8 mg / day, in the course of placebo-controlled studies, the clearance of the penrampanel in women (0.54 l / h) was on 18 % lower than that of men (0.66 l / h).

Patients of advanced age (> 65 years) In a population pharmacokinetic analysis in patients aged 12 to 74 years with partial seizures, received during placebo-controlled research perampanel in doses up to 12 mg and in patients with primary generalized tonic-clonic attacks, who received perampanel up to 8 mg per day, There was no significant effect of age on the clearance of the peripanel. Patients of childhood In population pharmacokinetic analysis in adolescent patients who participated in phase III clinical trials. there were no noticeable differences from the general population.

Drug Interactions Studies

Evaluation of drug interactions in vitro

Inhibition of enzymes involved in the metabolism of drugs In microsomes of human liver perampanel (at a concentration of 30 μmol / L) had a weak inhibitory effect on CYP2C8 and UGT1A9 among other hepatic enzymes and UDP-glucuronyltransferases (CGT).

Induction of enzymes involved in the metabolism of drugs In comparison with control preparations (including phenobarbital and rifampicin), provided weak inducing effect on CYP2B6 (at concentration 30 μmol / l) CYP3A4/5 (at concentration of at least 3 μmol / l) among major hepatic enzymes and UGTs in cultured human hepatocytes.

Indications:

In the complementary therapy for treatment of partial seizures in

patients with epilepsy at the age of 12 years and older with or without presence

secondary generalized seizures.

In the complementary therapy for the treatment of primary generalized tonic-clonic seizures in patients with epilepsy aged 12 years and older.

Contraindications:

Hypersensitivity to the perampanel or any of the excipients of the drug.

Pregnancy and lactation.

Severe renal or hepatic insufficiency; patients on hemodialysis.

Children under 12 years of age (no data on efficacy and safety). Intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption.

Pregnancy and lactation:

Pregnancy

Data on the use of perampanel in pregnant women are significantly limited (less than 300 cases). In studies of reproductive toxicity, no direct or indirect toxic effects were detected in animals. As a precaution, it is recommended to avoid the use of the preparation Fikcom during pregnancy.

Breastfeeding period

In animal studies, it was shown that perampanel and / or its metabolites are excreted in breast milk. It is not known whether perampanel with human breast milk, so the risk to the child can not be ruled out.

Given the benefits of both breastfeeding for a child and therapy for a woman, it is necessary either to stop breastfeeding,or refrain from taking / stop taking the drug Ficcom during breastfeeding.

Dosing and Administration:

Application v adults and teenagers

Perampanel taken orally 1 time per day before bed, regardless of food intake.

The tablet should be swallowed with a glass of water.

Tablets can not be chewed, crumbled or to break. A tablet can not be

neatly divided, because it is not on it risks.

Partial seizures

It was shown that the preparation Ficompa in daily doses of 4 to 12 mg effective in the treatment of partial epileptic seizures. Fiscal drug reception should be started with a dose of 2 mg / day. Dose can be increased depending on the clinical response and tolerability in 2 mg increments (once a week or once every two weeks, taking into account the half-life of the drug) to 4-8 mg / day. Depending on the individual clinical response and the tolerability of the drug at a dose of 8 mg / day, it is possible to further increase the dose of the drug Fai-room up to 12 mg / day in 2 mg increments no more often than once a week. In patients who simultaneously receive PEP, which do not reduce the half-life of the penampanel, titration of the dose of the panampanel should occur at two-week intervals.In patients who simultaneously receive PEP, which reduce the half-life of the penampanel, one should titrate (increase) the dose of perampanel once a week (see "Interaction with other drugs").

Primary-generalized tonic-clonic seizures

It was shown that the preparation Fikomia in daily doses up to 8 mg is effective in the treatment of primary generalized tonic-clonic seizures. Some patients may be given higher doses (up to 12 mg / day). The drug should be taken at a dose of 2 mg / day. The dose may be increased depending on the clinical response and tolerability in 2 mg increments (once in week or once every two weeks, taking into account the half-life of the drug) to 8 mg / day. Depending on the individual clinical response and tolerability of the drug at a dose of 8 mg / day, a further dose increase of up to 12 mg / day is possible. In patients who simultaneously receive PEP. not decreasing the half-life of the peripanel, titration of the dose of the panampanel should occur at two-week intervals. In patients who simultaneously receive PEP. which reduce the half-life of the penampanel, one should titrate (increase) the dose of the penampanel once a week (see "Interaction with other drugs").In spite of the fact that the penumbence has a long half-life, it is recommended, as for other PEPs, to cancel it gradually in order to minimize the likelihood of an increased frequency of seizures.

Single admission pass: Due to the fact that the patient has a sufficiently long half-life, the patient should wait and take the next planned dose in accordance with the agreed schedule of taking the drug.

If more than one dose is missed, (total duration without preparation less than 5 half-lives:

weeks for patients not receiving PEP, altering the metabolism of the penrampanel and 1 week for patients receiving PEP. which alter the metabolism of the penrampanel), consideration should be given to resuming the administration of the drug at the last dose taken.

If the patient interrupts the intake of the drug for a period of more than 5 half-lives, it is necessary to follow the recommendations as when initiating treatment.

Application the children under 12 years. Safety and efficacy of perampanel in children younger than 12 years of age are established (see "Contraindications"),

Application the patients of the old age (over 65 years)

In clinical trials of the Ficcom drug, an insufficient number of patients with epilepsy older than 65 years participated to assess differences with younger patients. Analysis of safety information in patients taking perampanel, ns revealed differences in the safety profile depending on age. These data confirm that correction of the dose of the pepampanel according to age is not required. In elderly patients perampanel Use with caution (see "Interaction from other medicines "," Special instructions ").

Application v patients with renal insufficiency

In case of mild renal insufficiency, correction of the dose of the ponampanel is not required. The use of Fay kom pa in patients with moderate to severe and severe renal failure or patients on hemodialysis is not recommended (see "Contraindications").

Application the patients with hepatic insufficiency

Dose increase in patients with mild to moderate hepatic insufficiency, as in other patients, is performed depending on the clinical response and tolerability.Since with a mild to moderate hepatic insufficiency, the half-life of the penampanel is prolonged, the minimum time interval before each dose increase should be two weeks, and the maximum dose should not exceed 8 mg / day. Use in severe hepatic insufficiency is not recommended (see section "Contraindications")

Side effects:

Among 1639 patients with partial seizures who received perampanel in all clinical trials conducted, 1147 took the drug for 6 months. and 703 - more than 12 months. In controlled and uncontrolled trials involving patients with primary generalized tonic-clonic seizures, 68 patients received perampanel for 6 months and 36 patients for more than 12 months. Partialities with seizures Unwanted reactions leading to patients with partial seizures from controlled studies of the 111 phase, were observed in 1.7%, 4.2%, and 13,7% in patients who received perampanel. respectively, in doses of 4 mg, 8 mg and 12 mg per day, and in 1,4% - in patients receiving a placebo. Most often, the reasons for getting out of the research were dizziness and drowsiness. Пррвичпо-геператповаиныс tonic-clonic seizures In a controlled Phase III clinical trial involving patients with primary generalized tonic-clonic seizures The undesirable reactions that led to the exit of patients from the study were noted in 4.9% of patients in the group of perampanel. and 1.2% in the placebo group.

Unwanted reaction, the most often leading to the exit from the study, was dizziness. The following undesirable phenomena (AEs) observed during application perampanela, according to the system-organ classes and the frequency of their occurrence. For rate frequencies emergence

the following classification is applied: very often (> 1/10); often (> 1/100, <1/10).

Disorders from the metabolism and nutrition: often - decreased appetite, increased appetite.

Disorders of the psyche: often - aggression, anger, anxiety, confusion.

Impaired nervous system: very often - dizziness, drowsiness; often - ataxia, dysarthria, imbalance, increased irritability.

Disorders from the side of the organ of vision: often - diplopia, blurred vision. Hearing disorders and labyrinthine disturbances: often - central dizziness.

Disturbances from the gastrointestinal tract: often - nausea. Disturbances from the musculoskeletal and connective tissue: often - pain in the back.

Common violations: often - gait disturbance, fatigue. Laboratory and instrumental data: often - weight gain. Trauma, intoxication and complications of manipulation: often - falls.

Teens

Based on data from clinical trials on 165 teenagers can expect that the frequency, nature and severity of adverse reactions they have the same as in adults. Announcement of unwanted reactions It is extremely important to notify of undesirable reactions that arose during the post-registration applications medicinal product. This will allow you to control the benefit / risk ratio when using it. Please inform medical workers of any undesired reactions to the address given in this manual.

Overdose:

The clinical experience of perepoznelov perepanelom in humans is limited. In a report of a deliberate overdose that could lead to a dose of up to 264 mg, the patient experienced a change in consciousness,agitation and aggressive behavior; restoration took place without consequences.

There is no specific antidote. General supportive therapy is shown, which includes monitoring of vital signs and clinical status of the patient. Considering the long half-life of the membrane, its effects can have a long duration in time. Because of low renal clearance of the transplant, special procedures, such as forced diuresis, hemodialysis or hemoperfusion, are ineffective.

Interaction:

The preparation of Ficompact is not a potent inducer or inhibitor of cytochrome P450 or CGT.

TlepopaibHbie contraceptive means At a dose of 12 mg (but not 4 or 8 mg) per day perampanel reduced the maximum concentration (C_max) and the area under the concentration-time curve (AUC) levonorgestrel by approximately 40%. Perampanel in a daily dose of 12 mg does not affect

on AUC ethinyl estradiol, but reduces it FROM_max on 18%. Patients taking the preparation of Faikcom at a daily dose of 12 mg should consider the likelihood of a decrease in the effectiveness of progestogen-containing contraceptives and use additional methods of contraception (intrauterine devices or condoms).

Interaction with other PEPs

Potential interaction of the preparation Fikcom (with a single intake of a daily dose of up to 12 mg) and other PEPs was evaluated based on clinical data research and population pharmacokinetic analysis of summary data four Phase III studies, including patients with partial and primary generalized tonic-clonic seizures. Effect- of this interaction at equilibrium concentrations of PES is given in the table:

Together

applicable

PEP

Effect of NEP on the concentration of the drug

Effect of the Fikcom drug on the concentration of PEP

Karbamazsnin

Decrease of 2.75 times

Decrease of less than 10%

Clobazam

11c influences

Decrease of less than 10%

Clonazepam	Does not affect	Does not affect
Lamotrillin	Does not affect	Decrease of less than 10%
Levetiracetam	Does not affect	11e is affected
Occarbazepia	Decrease in 1,9 times	Increase by 35%
Phenobarbital	Does not affect	Does not affect
Phenytoin	Decrease in 1,7 times	Does not affect
Topiramate	Decrease by 19%	Does not affect
Valproic acid	Does not affect	Decrease of less than 10%
Zonisamide	Does not affect	Does not affect

* Excluding the active metabolite of monohydroxycarbazepine.

Some PEP, which are inducers of enzymes (carbamazepine, phenytoin, oxcarbazepia) increase the overall clearance of the penrampanel and, accordingly, reduce its plasma concentrations.

In a study involving healthy volunteers, carbamazepine, a well-known potent inducer of enzymes, reduced the concentration of the penampanel by 2/3.

A similar result was obtained in a population pharmacokinetic analysis in patients with partial seizures who received the preparation Fikcom in doses up to 12 mg and in patients with primary generalized tonic-clonic seizures who received the preparation Fikcom in doses up to 8 mg per day during placebo-controlled clinical trials. Clearance of the preparation Fikcom increased with simultaneous admission with carbamazepine (2.75 times), phenytoin (1.7 times) and oxcarbazenin (1.9 times), which are inducers of the metabolism of liver enzymes. This effect should be taken into account when assigning or canceling NES data.

In a population pharmacokinetic analysis in patients with partial seizures who received Fikcom drug in doses up to 12 mg and in patients with primary generalized tonic-clonic seizures who received Fikcom drug in doses up to 8 mg per day during placebo-controlled clinical trials, the use of Fikcom was clinically significant in influencing the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest dose perampanela (8 or 12 mg per day).

At simultaneous reception of a preparation perrampanela with okkarbazepinom, the clearance of the last decreased on 26%. Oxcarbazepine metabolized with the participation of the cytosolic reductase to the active metabolite of monohydroxycarbazepine. The effect of the concentration monohydroxycarbazepine is unknown. Perampanel titrate until the clinical effect is achieved, regardless of the associated PEP.

Influence of the spandex on substrates CYP3A

In healthy volunteers, the preparation Fikcom (in a daily dose of 6 mg for 20 days) reduced AUC midazolam by 13%. It can not be ruled out that the exposure of midazolam (and other sensitive substrates CYP3A) when taking higher doses of the drug Ficomp. Influence of inducers of i-thichrome P450 on pharmacokinetics of the panpanel It is expected that powerful inducers of cytochrome 1450 isoenzymes such as rifampicin and St. John's wort, also can reduce the concentration of the penampanel in the plasma. Felbamate can also reduce the concentration of the plasma in the plasma.

Effect of inhibitors of i-tochrome P450 on the pharmacokinetics of the perampanel

In healthy volunteers, taking ketoconazole (in a daily dose of 400 mg for 10 days), which is an inhibitor of the isoenzyme CYP3A4, increased AUC perrampanela by 20% prolonged its T1/2 by 15% (67.8 hours vs. 58.4 hours). When a combination of perampanel with another inhibitor of isoenzyme CYP3A4 with a half-life period greater than that of ketoconazole or with a longer intake of an inhibitor, the enhancement of the effect can not be ruled out. Powerful inhibitors of other cytochrome P450 isoenzymes also potentially may increase the concentration of the ponampanel. Interaction with levodopa In healthy volunteers, the administration of the preparation Fikcom (at a daily dose of 4 mg for 19 days) had no effect on AUC or with_max levodopa. Interaction with alcohol

In the study of pharmacodynamic interaction on healthy volunteers Effect, The response to attention and quickness of response, such as driving, was enhanced by the use of alcohol.Multiple reception of the perampane in a daily dose of 12 mg increased the intensity of irritation, confusion and depression. This effect is also observed with the use of the preparation Ficompa in combination with other central nervous system depressants (CNS).

Application the teenagers

Research drug interactions were conducted only in adults. AT population pharmacokinetic analysis in adolescents who participated in phase III clinical trials, there were no noticeable differences from the general study population.

Special instructions:

Suicidal alertness

Patients receiving PEP but with different indications had cases of suicidal thinking and behavior. A meta-analysis of randomized ilazepo-controlled trials of PEP also showed a slight increase in the risk of suicidal thinking and behavior. The mechanism of increasing the risk is unknown, it is not possible to exclude the possibility of an increase in this risk with the use of the drug Ficomp. As a consequence, patients should be monitored to identify symptoms of suicidal thinking and behavior; appropriate treatment should be prescribed.Patients or caregivers should be informed of the need to seek medical help when signs of suicidal thinking or behavior appear.

Disturbances from the nervous system

The periapiael may cause dizziness and drowsiness and, thereby, affect the ability to drive and use mechanisms.

Oral contraceptives

Against the background of the preparation of Fikcom in dose of 12 mg / day, the effectiveness of progestogen-containing hormonal contraceptives could be reduced (see "Interactions with Other Drugs"). In these cases, the use of additional non-hormonal methods of contraception.

Completion of therapy

It is recommended to complete therapy with Fikcom drug gradually in order to minimize the likelihood of an increase in the frequency of seizures (see section "Method of administration and dose"). In extreme cases, a sharp discontinuation of the drug may occur, given its long elimination period and a relatively slow decrease in plasma concentration after discontinuation.

Falls

There is a trend towards an increase in the number of falls, especially in elderly patients, whose cause is unknown.

Aggression

There have been recorded cases of aggressive and hostile behavior in patients receiving perampanel therapy. In clinical studies of non-stimulant aggression, anger and irritability were more common when applied at higher doses. Most of these adverse events were mild or

of moderate severity and passed either alone or with a lower dose. However, thoughts of harm to others, physical attacks or threatening behavior have been observed in some patients (< 1 % at clinical research perampanela). Patients and carers should be advised to report immediately to the doctor if there is a significant change in mood or behavior. The dose of perampanel should be reduced, if such symptoms appear, treatment should be stopped immediately if the symptoms are severe. The development of dependence Care must be taken when administering the preparation Ficompactpatients who have a history of drug dependence.Such patients need to be observed in order to detect the development of a possible dependence on the perimpanel in a timely manner. Accompanying therapy CYP3A inducing PES Partial seizures Efficiency in the fixed doses were less for Czech patients, which were given concomitant antiepileptic therapy inducers CYP3A (carbamazepine, phenytoin, oxcarbazepine), than in patients who did not affect the activity of PEP enzymes. A 50% response to treatment with a 4 mg, 8 mg and 12 mg dose was achieved in 23%, 31.5% and 30% of patients, respectively CYP3A inducing PEP, and, respectively, in 33.3 %, 46.5% and 50.0 % patients who took no effect on the activity of enzymes PEP. The effect of the therapy with the panpanel should be carefully monitored when replacing or adding concomitant PEPs. Depending on the individual clinical response to treatment and the tolerability of the drug, the dose may be increased or decreased in 2 mg increments (see section "Dosage and Administration").

Primary-generalized tonic-cuff attacks

The efficacy of the pancipene at fixed doses of 8 mg was less in those patients,who received concomitant counter-antiepiletic therapy inductors CYP3A (carbamazepine, phenytoin, oxcarbazepine) than in patients receiving PEP. not affecting the activity of liver enzymes. A 50% response to treatment with the scaffold was achieved in 22.2 % patients on admission CYP3A inducing PEP, and in 69.4% of patients, which did not affect the activity of NEP enzymes. Number of patients taking perampanel in combination with NEP-inducers of enzymes, was small (n = 9). Depending on the individual clinical response to treatment and the tolerability of the drug, the dose may be increased or decreased in 2 mg increments to 12 mg / day.

Concomitant therapy with other inducers or inhibitors of cytochrome 1450

The tolerability and effect of therapy with the panampanel should be carefully monitored by the addition or removal of inducers or inhibitors of cytochrome P450, ego can change the concentration of the plasma in the plasma and it may be necessary to correct its dose. Monotherapy Partial seizures From 2 to 6.5% who took perampanel in clinical trials were free of seizures for 28 days (compared with 0-1.7% in the placebo group).Data on the effect of withdrawal of concomitant therapy with PEG1 are absent.

Primary-generalized tonic-clinical seizures 49.3% of patients taking perampanel in clinical trials, were free of seizures during 28 days (compared with 26.3% in the placebo group). Data on the effect of cancellation of concomitant therapy NEP are absent.

Effect on the ability to drive transp. cf. and fur:

Fikcom has a moderate impact on the ability to manage vehicles and work with mechanisms. Pereampapel can cause dizziness and drowsiness and, thereby affecting the ability of transport management and use mechanisms. Patients are not recommended manage vehicles, work with complex equipment or engage in other potentially dangerous activities before pores, until it turns out, does on their ability to perform these actions (see the sections " action "and" Special instructions ").

Form release / dosage:

Film-coated tablets.

2 mg, 4 mg, 6 mg. 8 mg, 10 mg, 12 mg.

Dosage 2 mg: 7 tablets each in a blister pack of PVC / aluminum foil. 1 blister each together with instructions for use placed in a cardboard box.

Dosages 4-6-8-10-12 mg: but 14 tablets in blister of PVC / aluminum foil. By 2 blisters with instruction on the application is placed in a cardboard box.

The places of opening of the cardboard pack are glued two transparent protective stickers.

Packaging:(14) - blisters (2) - packs cardboard

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years (for dosages of 2 and 4 mg) or 3 year (for dosages of 6-8-10-12 mg).

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002200

Date of registration:23.08.2013

The owner of the registration certificate:Eysay Europe LimitedEysay Europe Limited United Kingdom

Manufacturer: & nbsp

EISAI MANUFACTURING, Ltd. United Kingdom

Representation: & nbspRAYFARM, LLCRAYFARM, LLC

Information update date: & nbsp26.08.2015

Illustrated instructions

Instructions

Ficomcom (Fycompa)