Ficompa, 8 mg 28 pcs

Epilepsy, Seizures

The drug Faicompa is indicated as an adjunctive treatment for partial seizures in patients with epilepsy aged 12 years and older with or without secondary generalized seizures.

Active ingredient

Composition

1 film-coated tablet contains:

the active substance:

Perampanel (in terms of anhydrous substance) 8 mg.

How to take, the dosage

Ingestion,before sleep, regardless of meals.

Application in adults and adolescents.Perampanel is taken once a day. The tablet must be swallowed whole with 1 cup of water, and must not be chewed, crumbled or broken because the tablet cannot be neatly divided because there is no risk on it.

Faicompa in daily doses of 4 to 12 mg has been shown to be effective in the treatment of partial epileptic seizures. Administration of Ficompa should be started with a dose of 2 mg/day. The dose may be increased depending on clinical response and tolerability, in increments of 2 mg no more than once a week, to 4-8 mg/day. Depending on individual clinical response and tolerability, a dose of 8 mg/day may be further increased to 12 mg/day, in 2 mg increments no more than once a week. In patients concomitantly receiving PEPs that do not reduce the half-life of perampanel, the dose of perampanel should be adjusted at two-week intervals. In patients concomitantly receiving PEPs that decrease the half-life of perampanel, the dose of perampanel should be increased once a week.

The drug should be withdrawn gradually.

Single missed doses: Because peppanel has a relatively long T1/2, the patient should wait and take the next planned dose according to the agreed dosing schedule.

If more than 1 dose is missed (total duration without the drug is less than 5T1/2: 3 weeks for patients not receiving PEPs that modify perampanel metabolism and 1 week for patients receiving PEPs that modify perampanel metabolism), consideration should be given to resuming the drug at the last dose taken.

If the patient has interrupted the drug for more than 5T1/2, the recommendations should be followed as when initiating treatment.

Use in children younger than 12 years.The safety and effectiveness of perampanel in children younger than 12 years has not been established.

Perampanel use in elderly patients (≥65 years). Clinical studies of Ficompa have not included enough epilepsy patients over 65 years of age to evaluate differences with younger patients. An analysis of safety information in 905 elderly patients taking perampanel showed no differences in safety profile by age. These data confirm that there is no need to adjust the dose of perampanel according to age. In elderly patients, perampanel should be used with caution.

Application in patients with renal insufficiency.In mild renal insufficiency, correction of the dose of perampanel is not required. Use of Ficompa in patients with moderate to severe renal impairment or patients on hemodialysis is not recommended.

Application in patients with hepatic insufficiency.Dose escalation in patients with mild to moderate hepatic insufficiency, as in other patients, is based on clinical response and tolerability. Since in mild to moderate hepatic insufficiency the T1/2 of perampanel is prolonged, the minimum time interval before each dose increase should be 2 weeks and the maximum dose should not exceed 8 mg/day. Use in severe hepatic impairment is not recommended.

Interaction

The drug Ficompa is not a potent inducer or inhibitor of cytochrome P450 isoenzymes or UGT isoenzymes involved in glucuronidation reactions.

Oral contraceptives

At a dose of 12 mg/day (but not 4 or 8 mg/day), perampanel reduced the Cmax and AUC of levonorgestrel by approximately 40%. Perampanel at a daily dose of 12 mg had no effect on the AUC of ethinylestradiol, but reduced its Cmax by 18%. Patients taking Ficompa should consider the possibility of decreased effectiveness of contraceptives containing levonorgestrel and use additional methods of contraception (intrauterine devices or condoms).

Interaction with other antiepileptic drugs (PEP)

Potential interactions between Ficompa (with a single daily dose up to 12 mg) and other PEPs were evaluated based on data from clinical trials and population pharmacokinetic analysis of pooled data from three phase III studies. The effect of this interaction on equilibrium concentrations of PEPs is shown in the table:

Table

. Co-administered PEPEffect of PEP on Ficomp drug concentrationFicomp drug effect on PEP concentrationCarbamazepineDecrease by “70%Decrease by less than 10%ClobazamNo effectDecrease by less than 10%ClonazepamNo effectNo effectLamotrigineNo effectDecrease by less than 10%LevetiracetamNo effectNo effectOxcarbazepineNo effectDecrease by “50% Increase by 35% *PhenobarbitalNo effectPhenytoinNo effectDecrease by “50%No effectTopiramateDecrease by 20%No effectValproic acidNo effectDecrease by less than 10%ZonisamideNo effect

* Excluding the active metabolite monohydroxycarbazepine.

Some PEDs that are enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) increase total clearance of perampanel and decrease its plasma concentrations accordingly.

In a study involving healthy volunteers, carbamazepine, a known potent enzyme inducer, reduced perampanel concentrations by 2/3 (3-fold).

A similar result was obtained in a population-based pharmacokinetic analysis in patients with partial seizures receiving Ficompa at doses up to 12 mg/day in placebo-controlled clinical trials. Administration of Ficompa had no clinically significant effect on the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest dose of perampanel (12 mg/day).

When perampanel was taken concomitantly with oxcarbazepine, the latter’s clearance was decreased by 26%. Oxcarbazepine is rapidly metabolized with cytosolic reductase to the active metabolite monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is unknown.

The dose of perampanel is adjusted until clinical effect is achieved, regardless of concomitant PEPs.

Effects of perampanel on CYP3A isoenzyme substrates

In healthy volunteers, Ficompa (at a daily dose of 6 mg for 20 days) reduced the AUC of midazolam by 13%. A greater reduction in exposure to midazolam (and other sensitive CYP3A isoenzyme substrates) cannot be excluded with higher doses of Ficompa.

Influence of cytochrome P450 isoenzyme inducers on the pharmacokinetics of perampanel

. It is expected that potent inducers of cytochrome P450 isoenzymes, such as rifampicin and St. John’s wort, may also decrease the plasma concentration of perampanel. Felbamate can also decrease the plasma concentration of perampanel.

Influence of cytochrome P450 isoenzyme inhibitors on the pharmacokinetics of perampanel

. In healthy volunteers, administration of ketoconazole (daily dose of 400 mg for 10 days), a CYP3A4 isoenzyme inhibitor, increased the AUC of perampanel by 20% prolonged its T1/2 by 15% (67.8 vs 58.4 h). When combining perampanel with another CYP3A4 isoenzyme inhibitor with a longer half-life than ketoconazole or when taking the inhibitor for a longer time, an increased effect cannot be excluded. Powerful inhibitors of other cytochrome P450 isoenzymes can also potentially increase the concentration of perampanel.

Interaction with levodopa

In healthy volunteers, administration of Ficompa (daily dose of 4 mg for 19 days) had no effect on the AUC or Cmax of levodopa.

Interaction with alcohol

In a pharmacodynamic interaction study on healthy volunteers, the effect of perampanel on attention and responsiveness, such as driving, was enhanced by alcohol intake. Repeated administration of perampanel at a daily dose of 12 mg and increased the severity of irritability, confusion and depression. This effect was also observed when taking Ficompa in combination with other CNS depressants.

Application in adolescents

Drug interaction studies have only been conducted in adults. In population pharmacokinetic analyses, there were no notable differences from the general study population in adolescents who participated in phase III clinical trials.

Special Instructions

Suicidal alertness

Suicidal thinking and behavior have been reported in patients taking PEPs for various indications. A meta-analysis of randomized placebo-controlled trials of PEPs also showed a small increase in the risk of suicidal thinking and behavior. The mechanism of the increased risk is unknown; at this time, the possibility of an increase in this risk cannot be ruled out with Ficomp as well. As a consequence, patients should be monitored for symptoms of suicidal thinking and behavior; appropriate treatment should be prescribed.

Patients or their caregivers should be informed to seek medical attention when signs of suicidal thinking or behavior occur.

Nervous system disorders

Perampanel may cause dizziness and drowsiness and thereby affect the ability to drive and use machinery.

Oral contraceptives

The effectiveness of progestagen-containing hormonal contraceptives may be reduced while taking Ficompa at a dose of 12 mg/day (see section “Interaction with other medicinal products”). In these cases, the use of additional non-hormonal contraceptive methods should be considered.

Cessation of therapy

It is recommended that therapy with Ficompa be ended gradually to minimize the likelihood of increased seizure frequency. In extreme cases, abrupt discontinuation of the drug may be possible, given its long elimination period and relatively slow decline in plasma concentrations after discontinuation.

Falls

There has been a tendency for an increase in falls, especially in elderly patients, the cause of which is unknown.

Aggression

There have been reported cases of aggressive and hostile behavior in patients receiving perampanel therapy. In clinical trials of perampanel, aggression, anger, and irritability occurred more frequently when it was used at higher doses. Most of these adverse events were mild to moderate in severity and went away either on their own or when the dose was reduced. However, thoughts of harming others, physical aggression or threatening behavior were seen in some patients (

Dependence

Cautious use of Ficomp should be made in patients with a history of drug dependence. These patients should be monitored for the timely detection of possible perampanel dependence.

Companion therapy with PEPs inducing CYP3A isoenzyme

The fixed-dose efficacy of perampanel was lower in those patients who received concomitant antiepileptic therapy with CYP3A isoenzyme inducers (carbamazepine, phenytoin, oxcarbazepine) than in patients who received PEPs that do not affect enzyme activity. 50% response on perampanel therapy in doses of 4, 8 and 12 mg was achieved in 23, 31.5 and 30% of patients receiving PEPs inducing CYP3A isoenzyme and in 33.3, 46.5 and 50% of patients receiving PEPs without influence on enzyme activity, respectively. The effect of perampanel therapy should be closely monitored when concomitant PEPs are replaced or added. Depending on individual clinical response to treatment and tolerability of the drug, the dose may be increased or decreased in 2 mg increments.

Companion therapy with other cytochrome P450 isoenzyme inducers or inhibitors that are not PEPs

Tolerability and effects of perampanel therapy should be closely monitored when adding or withdrawing cytochrome P450 isoenzyme inducers or inhibitors, asas this may alter the plasma concentration of perampanel and dosage adjustment may be required.

Monotherapy

At 28 days, no seizures occurred in 2-6.5% of those taking perampanel in clinical trials (0-1.7% in the placebo group). There are no data on the effect of withdrawal of concomitant anticonvulsant therapy.

Influence on the ability to drive vehicles and operate machinery Perampanel has a moderate effect on the ability to drive vehicles and operate machinery. Perampanel may cause dizziness and somnolence and thereby affect the ability to drive vehicles and operate mechanisms. Patients are advised not to drive vehicles, operate complex equipment, or engage in other potentially hazardous activities until it is determined whether perampanel affects their ability to perform these activities.

Contraindications

Side effects

Among the 1,639 patients with partial seizures who received perampanel in all of the clinical trials conducted, 1,174 took the drug for 6 months and 703 for more than 12 months.

The adverse reactions leading to patient withdrawal from controlled phase III trials were reported in 1.7, 4.2, and 13.7% in patients receiving perampanel at doses of 4, 8, and 12 mg/day, respectively, and in 1.4% in patients receiving placebo. Dizziness and somnolence were the most frequent reasons for withdrawal from the studies (≥1% in the combined group receiving perampanel and more than in the placebo group).

The adverse events reported with perampanel are listed below according to systemic organ class and frequency of occurrence. The following classification is used to estimate the incidence of adverse events: very common (≥1/10); common (≥1/100,

Eating and metabolic disorders: common – decreased appetite, increased appetite.

Mental disorders:often – aggression, anger, anxiety, confusion.

Nervous system disorders:very often – dizziness, somnolence; often – ataxia, dysarthria, impaired balance, increased irritability.

Visual disorders:often – diplopia, blurred vision.

Hearing organ and labyrinth disorders:often – central vertigo.

Gastrointestinal disorders:often – nausea.

Disorders of the musculoskeletal system and connective tissue:often – back pain.

General disorders:often – gait disturbance, fatigue.

Laboratory and instrumental findings:often – increased body weight.

Injuries, intoxications and complications of manipulations:often – falls.

Adolescents.Based on clinical trial data, the frequency, nature, and severity of adverse reactions in adolescents can be expected to be the same as in adults.

Overdose

Symptoms: Clinical experience with perampanel overdose in humans is limited. In a report of an intentional overdose that may have resulted in a dose of up to 264 mg, the patient experienced altered consciousness, agitation, and aggressive behavior; recovery was without consequence.

Treatment:There is no specific antidote. General supportive therapy, including monitoring of vital signs and clinical status of the patient, is indicated. Given the long T1/2 of perampanel, its effects may have a long duration in time. Because of the low renal clearance of perampanel, special procedures such as forced diuresis, hemodialysis or hemoperfusion are ineffective.

Pregnancy use

Women of preserved childbearing potential who are not using contraceptive methods are advised to take Ficompa only if absolutely necessary.

The data on the use of perampanel in pregnant women are considerably limited (

In animal studies, it has been shown that perampanel and/or its metabolites are excreted with breast milk. It is not known whether perampanel is excreted with breast milk in humans, so the risk to the baby cannot be ruled out.

With the benefits of both breastfeeding for the baby and therapy for the woman, it is necessary to either stop breastfeeding or to refrain from taking/stop taking Ficomp while breastfeeding.

Effects on fertility

In animal studies, perampanel has been shown to prolong and disrupt the regularity of the estrous cycle at high doses (30 mg/kg), but these changes had no effect on fertility or early fetal development. No effect on male fertility was found. The effect of perampanel on human fertility has not been studied.