Syncopa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SYNCOPA

Composition:

Active substance: perampanel;

1 tablet contains 6 mg or 8 mg of perampanel;

Excipients: lactose monohydrate; low-substituted hydroxypropylcellulose; microcrystalline cellulose; povidone; magnesium stearate;

Coating mixture: titanium dioxide (E 171), polyethylene glycol (macrogol), hypromellose (hydroxypropylmethylcellulose), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• 6 mg tablets: film-coated tablets, light pink, round, biconvex;
• 8 mg tablets: film-coated tablets, white-pink, round, biconvex.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Perampanel. ATC code N03AX22.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Perampanel is the first in its class of selective non-competitive antagonists of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors on postsynaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), playing a key role in the pathogenesis of several neurological disorders caused by neuronal overexcitation. Activation of AMPA receptors by glutamate is believed to mediate the fastest synaptic transmission of excitation in the brain.

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

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

The exact mechanism of the anticonvulsant effect of perampanel in humans requires further investigation.

Pharmacodynamic effects

An analysis of the pharmacokinetics and pharmacodynamics of perampanel was conducted based on pooled data from three efficacy studies in partial epileptic seizures. Additionally, a pharmacokinetic/pharmacodynamic analysis of perampanel was performed using data from a study on efficacy in primary generalized tonic-clonic seizures. According to the results of both analyses, perampanel's effect correlates with a reduction in seizure frequency.

Effect on psychomotor function. Perampanel at doses of 8 mg and 12 mg, administered as single or multiple doses, dose-dependently impaired psychomotor function in healthy volunteers. The effect of perampanel on complex psychomotor functions, such as the ability to drive a vehicle, was enhanced by alcohol consumption. Psychomotor function parameters returned to baseline levels within 2 weeks after discontinuation of perampanel.

Effect on cognitive function. In a study involving healthy volunteers to assess the effect of perampanel on attention and memory using a series of standard tests, no effect of perampanel was observed either after single or multiple doses up to 12 mg/day.

In a placebo-controlled study conducted in adolescent patients, no significant changes in cognitive abilities were observed in the perampanel group compared to the placebo group according to the Global Cognition Score [Global Cognition Score] (Cognitive Drug Research [CDR]). In an open-label extension study, no significant changes in CDR scores were observed after 52 weeks of perampanel treatment (see section "Paediatric population" below).

In an open-label, uncontrolled study conducted in paediatric patients, no clinically relevant changes in cognitive abilities were observed after adjunctive therapy with perampanel compared to baseline, as measured by ABNAS [Attention-Based Neuropsychological Assessment System] (see section "Paediatric population" below).

Effect on mood and reaction to external stimuli. Reaction to external stimuli (arousal) in healthy volunteers receiving perampanel at doses of 4 to 12 mg/day decreased in a dose-dependent manner.

Mood deterioration occurred only after a dose of 12 mg/day. Mood changes were minor and reflected a general decrease in alertness.

Repeated administration of perampanel at a dose of 12 mg/day also enhanced the effect of alcohol on alertness and reaction time to external stimuli and increased the severity of irritability, confusion, and depression as assessed by a 5-point emotional profile rating scale.

Effect on cardiac electrophysiological properties. Perampanel did not prolong the QTc interval when administered at daily doses up to 12 mg/day and had no dose-dependent or clinically significant effect on QRS complex duration.

Clinical efficacy and safety

Partial epileptic seizures. The efficacy of perampanel in partial seizures was established in three randomized, double-blind, placebo-controlled, multicenter adjunctive therapy studies lasting 19 weeks involving adults and adolescents. Patients had partial seizures, with or without secondary generalization, that were not adequately controlled with one to three concomitant antiepileptic drugs (AEDs). During a 6-week baseline period, patients had to have more than five seizures, with a seizure-free interval not exceeding 25 days. In these three studies, patients had a mean duration of epilepsy of approximately 21.06 years. Between 85.3% and 89.1% of patients were concurrently taking two or three antiepileptic drugs, with or without vagus nerve stimulation.

In two studies (studies 304 and 305), perampanel doses of 8 mg and 12 mg/day were compared with placebo, while in the third study (study 306), perampanel doses of 2 mg, 4 mg, and 8 mg/day were compared with placebo. In all three studies, after a 6-week baseline period preceding randomization, required to establish baseline seizure frequency, patients were randomized to receive assigned doses. During the titration period in all three studies, treatment was initiated at 2 mg/day and increased weekly by 2 mg/day until the target dose was reached. Patients who experienced intolerable adverse events could remain at the same dose or reduce it to a previously well-tolerated dose. In all three studies, the dose titration period was followed by a 13-week maintenance period during which patients received a constant dose of perampanel.

According to pooled results from the three studies, the 50% response rate was 19% in the placebo group, 29% for the 4 mg dose, 35% for the 8 mg dose, and 35% for the 12 mg dose. A statistically significant effect on reducing seizure frequency over 28 days (from baseline to treatment period) compared to placebo was observed with perampanel 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% response rate in the 4 mg, 8 mg, and 12 mg perampanel groups was 23.0%, 31.5%, and 30.0%, respectively, when perampanel was combined with enzyme-inducing antiepileptic drugs, and 33.3%, 46.5%, and 50.0%, respectively, when combined with non-enzyme-inducing antiepileptic drugs. These studies demonstrate that perampanel, administered once daily at doses of 4 to 12 mg as adjunctive therapy, was significantly more effective than placebo.

Data from placebo-controlled studies show that improvement in seizure control occurs with perampanel at a dose of 4 mg once daily and increases with dose escalation to 8 mg/day. Increasing the daily dose to 12 mg did not result in additional efficacy compared to 8 mg for the overall patient population. Increased efficacy with perampanel at 12 mg was observed only in patients who did not respond to the 8 mg dose. Clinically significant reduction in seizure frequency compared to placebo was observed as early as the second week after reaching a daily dose of 4 mg.

Between 1.7% and 5.8% of patients receiving perampanel in clinical studies became seizure-free during the 3-month maintenance period compared to 0–1.0% of patients receiving placebo.

Open-label extension study. 97% of patients with partial seizures who completed the randomized study were enrolled in an open-label extension study (n = 1186). Patients from the randomized study were transitioned to perampanel over 16 weeks, followed by a long-term maintenance period (≥1 year). The mean daily dose was 10.05 mg.

Primary generalized tonic-clonic seizures. The efficacy of perampanel as adjunctive therapy for primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, placebo-controlled study (study 332) in patients aged 12 years and older with idiopathic generalized epilepsy. Patients included in the study were on stable doses of 1 to 3 antiepileptic drugs (AEDs) and had at least 3 primary generalized tonic-clonic seizures during an 8-week baseline period. The study population included 164 patients (perampanel N = 82, placebo N = 82). Dose titration to a target of 8 mg/day or the highest tolerated dose occurred over 4 weeks. The maintenance period lasted 13 weeks at the final dose achieved at the end of the titration period. The total treatment period was 17 weeks. The investigational drug was administered once daily.

The 50% response rate for primary generalized tonic-clonic seizures during the maintenance period was significantly higher in the perampanel group (58.0%) than in the placebo group (35.8%), P = 0.0059. A 50% response was observed in 22.2% of patients receiving perampanel in combination with enzyme-inducing antiepileptic drugs and in 69.4% of patients receiving perampanel in combination with non-enzyme-inducing antiepileptic drugs. The number of patients receiving perampanel and enzyme-inducing antiepileptic drugs was small (n = 9). The median reduction in frequency of primary generalized tonic-clonic seizures over 28 days during the titration and maintenance periods (combined) compared to the pre-randomization period was greater in the perampanel group (–76.5%) than in the placebo group (–38.4%), P < 0.0001. During the 3-month maintenance period, 30.9% (25/81) of patients receiving perampanel in clinical studies became free of primary generalized tonic-clonic seizures compared to 12.3% (10/81) of patients receiving placebo.

Other subtypes of idiopathic generalized seizures. The efficacy and safety of perampanel in patients with myoclonic seizures have not been established. Available data are insufficient to draw any conclusions.

The efficacy of perampanel in the treatment of absence seizures has not been demonstrated.

Among patients with primary generalized tonic-clonic seizures (study 332) who also had concomitant myoclonic seizures, seizure freedom was achieved in 16.7% (4/24) of patients receiving perampanel compared to 13.0% (3/23) in the placebo group. Among patients with concomitant absence seizures, seizures ceased in 22.2% (6/27) of patients receiving perampanel compared to 12.1% (4/33) of patients receiving placebo. Freedom from all seizures was achieved in 23.5% (19/81) of patients receiving perampanel compared to 4.9% (4/81) of patients receiving placebo.

Open-label extension study. Of the 140 patients who completed the core study (study 332), 114 patients (81.4%) entered the continuation phase. Patients from the randomized study were transitioned to perampanel over 6 weeks, followed by a long-term maintenance period (≥1 year). In the continuation phase, 73.7% (84/114) of patients received a modal daily dose of perampanel exceeding 4–8 mg/day, and 16.7% (19/114) received a modal daily dose exceeding 8–12 mg/day. A reduction in frequency of primary generalized tonic-clonic seizures by at least 50% was observed in 65.9% (29/44) of patients after 1 year of treatment during the continuation phase (compared to baseline seizure frequency, prior to perampanel administration). These results were consistent with data on the percentage change in seizure frequency and showed that 50% of patients with primary generalized tonic-clonic seizures remained stable for approximately 26 weeks to the end of the second year. Similar results were obtained when all seizures and absences were compared to myoclonic seizures over time.

Transition to monotherapy. In a retrospective study of clinical practice, 51 epilepsy patients receiving perampanel as adjunctive therapy were transitioned to perampanel monotherapy. Most of these patients had a history of partial seizures. Fourteen patients (27%) returned to adjunctive therapy within the following months. Thirty-four (34) patients were followed for at least 6 months, of whom 24 patients (71%) remained on perampanel monotherapy for at least 6 months. Ten (10) patients were followed for at least 18 months, of whom 3 patients (30%) remained on perampanel monotherapy for at least 18 months.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of perampanel studies in one or more subsets of the paediatric population with treatment-resistant epilepsy (epilepsy syndromes related to localization and age) (see section "Posology and method of administration").

In three pivotal phase III double-blind, placebo-controlled studies, 143 adolescents aged 12 to 18 years participated. Results in adolescents were similar to those in adult patients.

In study 332, 22 adolescents aged 12 to 18 years participated. The data obtained in adolescents were similar to those in the adult population.

A 19-week randomized, double-blind, placebo-controlled study with an open continuation phase (study 235) was conducted to evaluate the short-term effect of perampanel as adjunctive therapy (target dose range 8 to 12 mg once daily) on cognitive function in 133 adolescent patients aged 12 to 18 years with inadequately controlled partial seizures (perampanel n = 85, placebo n = 48). Cognitive function was assessed using the Global Cognition t-Score of the CDR system, which combines five categories: attention power, continuity of attention, quality of episodic secondary memory, quality of working memory, and memory speed. The mean change (standard deviation [SD]) in CDR t-Score from baseline to the end of double-blind treatment (19 weeks) was 1.1 (7.14) in the placebo group and –1.0 (8.86) in the perampanel group, with a least-squares mean difference between treatment groups (95% CI [confidence interval]) of –2.2 (–5.2; 0.8). There was no statistically significant difference between treatment groups (p = 0.145). CDR t-Scores in the placebo and perampanel groups were 41.2 (10.7) and 40.8 (13.0), respectively, at baseline. For patients receiving perampanel in the open continuation phase (n = 112), the mean change (SD) from baseline to the end of open-label treatment (52 weeks) in CDR t-Score was –1.0 (9.91). This was not statistically significant (p = 0.96). After 52 weeks of perampanel treatment (n = 114), no effect on bone growth was observed. No effect on body weight, height, or sexual development was observed after 104 weeks of treatment (n = 114).

An open-label, uncontrolled study (study 311) was conducted to evaluate the exposure-response relationship of perampanel as adjunctive therapy in 180 patients aged 4 to 11 years with inadequately controlled partial or primary generalized tonic-clonic seizures. Doses were titrated over 11 weeks to a target dose of 8 mg/day or the maximum tolerated dose (not exceeding 12 mg/day) for patients not taking concomitant CYP3A-inducing antiepileptic drugs (carbamazepine, oxcarbazepine, eslicarbazepine, and phenytoin), or to a target dose of 12 mg/day or the maximum tolerated dose (not exceeding 16 mg/day) for patients concurrently taking a CYP3A-inducing antiepileptic drug. The perampanel dose achieved at the end of titration was maintained for 12 weeks (total 23 weeks of exposure) after completion of the core study. Patients entering the continuation phase received treatment for an additional 29 weeks, with a total exposure duration of 52 weeks.

Among patients with partial seizures (n = 148), the median change in seizure frequency over 28 days, the proportion with at least 50% response, and the proportion of patients seizure-free after 23 weeks of perampanel treatment were –40.1%, 46.6% (n = 69/148), and 11.5% (n = 17/148), respectively, for partial seizures overall. The treatment effect on reduction in median seizure frequency (40–52 weeks: n = 108 patients, –69.4%), the 50% response rate (40–52 weeks: 62.0%, n = 67/108), and the proportion of patients seizure-free (40–52 weeks: 13.0%, n = 14/108) remained consistent after 52 weeks of perampanel treatment.

In the subgroup of patients with partial seizures and secondarily generalized seizures (n = 54 patients), the corresponding values were –58.7%, 64.8% (n = 35/54), and 18.5% (n = 10/54). The treatment effect on reduction in median seizure frequency (40–52 weeks: n = 41 patients, –73.8%), the 50% response rate (40–52 weeks: 80.5%, n = 33/41), and the proportion of patients seizure-free (40–52 weeks: 24.4%, n = 10/41) remained consistent after 52 weeks of perampanel treatment.

Among patients with primary generalized tonic-clonic seizures (n = 22, 19 patients aged 7 to <12 years and 3 patients aged 4 to <7 years), the median change in seizure frequency over 28 days, the proportion with at least 50% response, and the proportion of patients seizure-free were –69.2%, 63.6% (n = 14/22), and 54.5% (n = 12/22), respectively. The treatment effect on reduction in median seizure frequency (40–52 weeks: n = 13, –100.0%), the 50% response rate (40–52 weeks: 61.5%, n = 8/13), and the proportion of patients seizure-free (40–52 weeks: 38.5%, n = 5/13) was maintained after 52 weeks of perampanel treatment. These results should be interpreted with caution due to the small number of patients.

Similar results were obtained in the subgroup of patients with primary generalized tonic-clonic seizures in idiopathic generalized epilepsy (n = 19, 17 patients aged 7 to <12 years and 2 patients aged 4 to <7 years); corresponding values were 56.5%, 63.2% (n = 12/19), and 52.6% (n = 10/19). The treatment effect on reduction in median seizure frequency (weeks 40–52: n = 11, –100.0%), the 50% response rate (weeks 40–52: 54.5%, n = 6/11), and the proportion of patients seizure-free (40–52 weeks: 36.4%, n = 4/11) was maintained after 52 weeks of perampanel treatment. These results should be interpreted with caution due to the small number of patients.

Pharmacokinetics

The pharmacokinetics of perampanel were studied in healthy adult volunteers (aged 18 to 79 years), adults, adolescents, and children with partial and primary generalized tonic-clonic seizures, adults with Parkinson's disease, adults with diabetic neuropathy, adults with multiple sclerosis, and in patients with hepatic impairment.

Absorption

Perampanel is rapidly absorbed after oral administration with no evidence of significant first-pass metabolism.

Perampanel oral suspension is bioequivalent to perampanel tablets when administered at the same milligram doses under fasting conditions. When these formulations were administered as a single 12 mg dose with a high-fat meal, perampanel oral suspension achieved equivalent AUC0–∞ and approximately 23% lower Cmax with a 2-hour delay in time to maximum exposure (tmax) compared to tablets. However, population pharmacokinetic analysis demonstrated that under modeled steady-state conditions, Cmax and AUC(0–24 hours) of perampanel oral suspension corresponded to those of the tablet formulation both under fasting and fed conditions.

When administered with a high-fat meal, Cmax and AUC0–∞ of a single 12 mg dose of perampanel oral suspension were approximately 22% and 13% lower, respectively, compared to administration under fasting conditions.

Distribution

In vitro study data indicate that perampanel is approximately 95% bound to plasma proteins.

In vitro, perampanel has been shown not to be a substrate or significant inhibitor of organic anion transporting 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).

Biotransformation

Perampanel is extensively metabolized primarily via oxidation followed by glucuronidation. The metabolism of perampanel is mainly mediated by CYP3A isoenzymes, based on clinical studies in healthy volunteers administered radiolabeled perampanel and in vitro studies using recombinant human CYP and human liver microsomes.

After administration of radiolabeled perampanel, only trace amounts of perampanel metabolites were detected in plasma.

Elimination

After administration of a radiolabeled perampanel dose to eight elderly healthy volunteers, 30% of the radiolabel was recovered in urine and 70% in feces. The excreted radiolabel consisted primarily of a mixture of oxidized and conjugated metabolites. Based on population pharmacokinetic analysis of pooled data from 19 phase I studies, the mean t½ of perampanel was 105 hours. When co-administered with the strong CYP3A inducer carbamazepine, the mean t½ was 25 hours.

Linearity / non-linearity

In a population pharmacokinetic analysis based on pooled data from twenty phase I studies in healthy volunteers receiving perampanel at doses of 0.2 to 36 mg as single or multiple doses, one phase II study, and five phase III studies in patients with partial seizures receiving perampanel at doses of 2 to 16 mg/day, and two phase III studies in patients with primary generalized tonic-clonic seizures receiving perampanel at doses of 2 to 14 mg/day, a linear relationship between dose and perampanel plasma concentration was observed.

Special patient groups

Patients with hepatic impairment. The pharmacokinetics of perampanel after a single 1 mg dose were evaluated in 12 patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) compared to 12 healthy volunteers with matched population characteristics. The mean unbound perampanel clearance in patients with mild hepatic impairment was 188 mL/min versus 338 mL/min in healthy volunteers, and in patients with moderate hepatic impairment was 120 mL/min versus 392 mL/min in healthy volunteers. t½ was prolonged in patients with hepatic impairment: in mild impairment, to 306 hours versus 125 hours in healthy volunteers; in moderate impairment, to 295 hours versus 139 hours in healthy volunteers.

Patients with renal impairment. The pharmacokinetics of perampanel in patients with renal impairment have not been studied separately. Perampanel is eliminated almost exclusively via metabolite formation followed by rapid excretion. Only trace amounts of perampanel metabolites are detected in plasma. According to population pharmacokinetic analysis, in patients with partial seizures and creatinine clearance ranging from 39 to 160 mL/min receiving perampanel at doses up to 12 mg/day in placebo-controlled studies, creatinine clearance did not affect perampanel clearance. In patients with primary generalized tonic-clonic seizures receiving perampanel at doses up to 8 mg/day in a placebo-controlled clinical study, baseline creatinine clearance did not affect perampanel clearance.

Gender. According to population pharmacokinetic analysis, in patients with partial seizures receiving perampanel at doses up to 12 mg/day and patients with primary generalized tonic-clonic seizures receiving perampanel at doses up to 8 mg/day in placebo-controlled clinical studies, perampanel clearance in women (0.54 L/h) was 18% lower than in men (0.66 L/h).

Elderly patients (aged 65 years and older). In a population pharmacokinetic analysis in patients with partial seizures (aged 12 to 74 years) and primary generalized tonic-clonic seizures (aged 12 to 58 years) receiving perampanel up to 8 mg or up to 12 mg/day in placebo-controlled clinical studies, no significant effect of age on perampanel clearance was observed. Dose adjustment in elderly patients is considered unnecessary (see section "Posology and method of administration").

Paediatric patients. According to population pharmacokinetic analysis based on pooled data, perampanel clearance in children aged 4 to 11 years, adolescent patients aged ≥12 years, and adults increased with increasing body weight. Therefore, dose adjustment is required for children aged 4 to 11 years with body weight <30 kg (see section "Posology and method of administration").

Assessment of drug interactions in vitro

Inhibition of drug-metabolizing enzymes. In human liver microsomes, perampanel (at a concentration of 30 µmol/L) showed weak inhibitory effects on CYP2C8 and UGT1A9 among the major hepatic CYP and UGT enzymes.

Induction of drug-metabolizing enzymes. Compared to control drugs (including phenobarbital and rifampicin), perampanel was found to weakly induce CYP2B6 (at a concentration of 30 µmol/L) and CYP3A4/5 (at a concentration of at least 3 µmol/L) among the major hepatic CYP and UGT enzymes in cultured human hepatocytes.

Clinical characteristics

Indications

Perampanel is indicated as adjunctive therapy:

• for partial-onset seizures in patients with epilepsy aged 4 years and older (with body weight ≥ 30 kg), with or without secondary generalization;
• for primary generalized tonic-clonic seizures in patients aged 7 years and older (with body weight ≥ 30 kg) with idiopathic generalized epilepsy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").

Interaction with other medicinal products and other forms of interaction

Perampanel is not considered a strong inducer or inhibitor of cytochrome P450 enzymes or UGT (see section "Pharmacokinetics").

Hormonal contraceptives

In healthy women receiving 12 mg (but not 4 mg/day or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, perampanel reduced levonorgestrel exposure (mean Cmax and AUC decreased by 40%). Perampanel at a dose of 12 mg did not affect the AUC of ethinylestradiol, while Cmax was reduced by 18%. Therefore, a potential reduction in the efficacy of hormonal contraceptives containing progestogen should be considered for women requiring perampanel at a dose of 12 mg/day, and an additional reliable method of contraception (intrauterine device (IUD), condom) should be used (see section "Special precautions for use").

Interaction between perampanel and other antiepileptic drugs

Potential interactions between perampanel and other antiepileptic drugs (AEDs) were evaluated in clinical studies. A population pharmacokinetic analysis of three pooled phase III studies in adolescents and adult patients with partial-onset seizures assessed the effect of perampanel (at doses up to 12 mg once daily) on the pharmacokinetics of other antiepileptic drugs. Another population pharmacokinetic analysis of pooled data from twenty phase I studies in healthy volunteers receiving perampanel up to 36 mg, as well as one phase II study and six phase III studies in children, adolescents, and adults with partial-onset or primary generalized tonic-clonic seizures receiving perampanel up to 16 mg once daily, evaluated the effect of concomitant antiepileptic drugs on perampanel clearance. The impact of these interactions on mean steady-state concentrations is summarized in the table below.

• Without taking into account the active metabolite monohydroxycarbazepine.

According to results of population pharmacokinetic analysis in patients with partial seizures and patients with primary generalized tonic-clonic seizures, the total clearance of perampanel was increased when co-administered with carbamazepine (by 3-fold) and phenytoin or oxcarbazepine (by 2-fold), which are known inducers of metabolism enzymes (see section "Pharmacokinetics"). This effect should be taken into account and monitored when adding or removing these antiepileptic drugs from the patient's treatment regimen. Clonazepam, levetiracetam, phenobarbital, topiramate, zonisamide, clobazam, lamotrigine, and valproic acid did not clinically significantly affect the clearance of perampanel.

Based on population pharmacokinetic analysis, in patients with partial seizures, perampanel did not clinically significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine, and valproic acid at the highest perampanel dose (12 mg/day).

It has been established that perampanel reduces the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolized by cytosolic reductase to its active metabolite monohydroxycarbazepine. The effect of perampanel on the concentration of monohydroxycarbazepine is unknown.

Perampanel should be titrated to achieve clinical effect independently of other concomitant antiepileptic medications.

Effect of perampanel on CYP3A substrates

In healthy volunteers, perampanel (6 mg once daily for 20 days) reduced midazolam AUC by 13%. A greater reduction in midazolam exposure (or other sensitive CYP3A substrates) cannot be excluded when higher doses of perampanel are administered.

Effect of cytochrome P450 inducers on perampanel pharmacokinetics

Strong inducers of cytochrome P450 isoenzymes, such as rifampicin and St. John's wort, are expected to reduce perampanel concentrations, and an increased plasma concentration of reactive metabolites in their presence cannot be excluded. Felbamate has been shown to reduce the concentration of certain drugs and may also reduce perampanel concentrations.

Effect of cytochrome P450 inhibitors on perampanel pharmacokinetics

In healthy volunteers, administration of ketoconazole (400 mg once daily for 10 days), an inhibitor of the CYP3A4 isoenzyme, increased perampanel AUC by 20% and prolonged its elimination half-life by 15% (67.8 hours vs 58.4 hours). Enhanced effect cannot be excluded when perampanel is co-administered with another CYP3A inhibitor having a longer half-life than ketoconazole, or when the inhibitor is administered for a longer treatment period.

Levodopa

In healthy volunteers, administration of perampanel (4 mg once daily for 19 days) did not affect Cmax or AUC of levodopa.

Alcohol

The effect of perampanel on attention and alertness, for example when driving a vehicle, was additive or synergistic to the effect of alcohol itself, as demonstrated in a pharmacodynamic interaction study in healthy volunteers. Repeated administration of perampanel at a dose of 12 mg/day increased levels of irritability, confusion, and depression on a 5-point scale for assessing mood state profile (see section "Pharmacodynamics"). These effects may also occur when perampanel is used in combination with other CNS depressants.

Pediatric population

Drug interaction studies have been conducted in adults only.

According to results of population pharmacokinetic analysis, in adolescents aged ≥12 years and children aged 4 to 11 years, no notable differences were observed compared to the studied adult population.

Special precautions for use

Suicidal thoughts

Suicidal thoughts and behaviour have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown, and available data do not exclude the possibility of an increased risk with the use of perampanel.

Therefore, patients (children, adolescents, and adults) should be monitored for signs of suicidal thoughts and behaviour, and appropriate treatment should be considered when necessary. Patients (and caregivers) should be advised to contact their physician if symptoms of suicidal thoughts or behaviour occur.

Severe skin adverse reactions

Severe cutaneous adverse reactions have been reported with perampanel treatment, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens–Johnson syndrome, which may be life-threatening or fatal (frequency unknown; see section "Adverse reactions"). Patients should be informed about the signs and symptoms of these reactions and closely monitored for skin reactions when initiating therapy.

Symptoms of DRESS syndrome typically include fever, rash, involvement of other organ systems, lymphadenopathy, hepatic dysfunction, and eosinophilia. It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may be present even in the absence of visible rash.

Symptoms of Stevens–Johnson syndrome typically include skin detachment (epidermal necrosis/blistering) < 10%, erythematous skin (confluent), rapid progression, painful atypical lesions resembling targets, purpuric macules with widespread distribution, or extensive erythema (confluent), and bullous/erosive lesions affecting more than two mucous membranes.

If signs or symptoms suggestive of these reactions occur, perampanel should be discontinued immediately and alternative treatment considered (if necessary).

If a patient develops a serious reaction such as Stevens–Johnson syndrome or DRESS syndrome related to perampanel use, perampanel therapy must not be restarted in that patient under any circumstances.

Absence and myoclonic seizures

Absence and myoclonic seizures are two common types of generalized seizures frequently occurring in patients with idiopathic generalized epilepsy. It is known that other AEDs may induce or exacerbate these seizure types. Patients with myoclonic seizures and absence seizures should be closely monitored during perampanel treatment.

Central nervous system effects

Perampanel may cause dizziness and somnolence and thus may impair the ability to drive or operate machinery (see section "Effect on ability to drive or use machines").

Hormonal contraceptives

At a dose of 12 mg/day, perampanel may reduce the efficacy of hormonal contraceptives containing progesterone. In such cases, use of additional non-hormonal contraceptive methods is recommended during perampanel treatment (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").

Falls

There is likely an increased risk of falls, particularly in elderly individuals; the underlying cause is unclear.

Aggression, psychiatric disorders

Aggressive, hostile, and abnormal behaviour have been reported in patients receiving perampanel therapy. In clinical trials, aggression, anger, irritability, and psychotic disorders occurred more frequently with higher doses of perampanel. These events were mostly mild to moderate in severity and resolved spontaneously or after dose adjustment. However, in some patients, thoughts of harming others, physical assault, or threatening behaviour occurred (<1% in perampanel clinical trials). Suicidal ideation towards others, including homicidal thoughts, has also been reported. Patients and caregivers should be advised to immediately report significant mood or behavioural changes to a healthcare provider. The dose of perampanel should be reduced if such symptoms occur, and discontinuation of treatment should be considered if symptoms are severe (see section "Dosage and administration").

Dependence potential

Caution is advised in patients with a history of substance abuse, and patients should be monitored for signs of perampanel misuse.

Concomitant use of enzyme-inducing antiepileptic drugs (CYP3A inducers)

The response rate following the addition of perampanel at fixed doses was lower in patients receiving concomitant antiepileptic drugs that induce CYP3A enzymes (carbamazepine, phenytoin, oxcarbazepine) compared to patients receiving non-inducing antiepileptic drugs. Patients should be monitored for clinical response when switching from concomitant non-inducing to CYP3A-inducing antiepileptic drugs, and vice versa. Depending on individual clinical response and tolerability, the dose may be increased or decreased by 2 mg at a time (see section "Dosage and administration").

Other concomitant (non-antiepileptic) medicinal products that induce or inhibit cytochrome P450

Patients should be closely monitored for tolerability and clinical response when adding or discontinuing cytochrome P450 inducers or inhibitors, as plasma levels of perampanel may be decreased or increased, respectively. Dose adjustments of perampanel may be required accordingly.

Hepatotoxicity

Cases of hepatotoxicity (primarily elevated liver enzymes) have been reported with perampanel use in combination with other antiepileptic drugs. If elevated liver enzymes are observed, liver function monitoring should be considered.

Lactose intolerance

The medicinal product contains lactose and should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Contraception

Perampanel is not recommended for women of childbearing potential who are not using contraception, unless there is a compelling medical need. Perampanel may reduce the efficacy of hormonal contraceptives containing progesterone. Therefore, additional non-hormonal contraception is recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Pregnancy

Data on perampanel use in pregnant women are limited (fewer than 300 cases). Animal studies did not show teratogenic effects in rats and rabbits, but embryotoxicity was observed in rats at maternally toxic doses. Perampanel is not recommended during pregnancy.

Breastfeeding

Lactation studies in rats have shown excretion of perampanel and its metabolites into milk. It is unknown whether perampanel is excreted in human breast milk. Risk to newborns/infants cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue perampanel therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

In a fertility study in female rats, prolonged and irregular oestrous cycles were observed at high doses (30 mg/kg), but these changes did not affect fertility or early embryonic development. No effect on male fertility was observed. The effect of perampanel on human fertility has not been established.

Effect on ability to drive or use machines

Perampanel has a moderate influence on the ability to drive vehicles or operate machinery.

Perampanel may cause dizziness and somnolence and thereby affect the ability to drive a car or operate machinery. Patients should not drive vehicles, operate complex machinery, or engage in other potentially hazardous activities until it is determined whether perampanel affects their ability to perform such activities (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Method of Administration and Dosage

Method of Administration

Perampanel should be taken orally once daily before bedtime, regardless of food intake (see section "Pharmacokinetics"). The tablet should be swallowed whole with a glass of water. The tablet must not be chewed, crushed, or split. The tablet cannot be accurately divided, as it does not have a score line.

Tablets of 6 mg or 8 mg cannot be divided into parts; therefore, if perampanel dosing below 2 mg is required, an alternative medicinal product containing perampanel that allows dosing at 0.5 mg and 1 mg increments should be used.

Dosage

The dosage of the medicinal product should be individualized based on the patient's clinical response to achieve an optimal balance between efficacy and tolerability.

Perampanel is administered orally once daily before bedtime.

The physician should select the most appropriate pharmaceutical form and dosage of the drug according to body weight and the recommended daily dose.

Partial Seizures

Perampanel has been shown to be effective in the treatment of partial seizures at doses ranging from 4 to 12 mg/day.

The recommended dosages for adults, adolescents, and children aged 4 years and older are provided in the table below. See details following the table.

Adults and adolescents aged ≥ 12 years

Treatment should be initiated at a dose of 2 mg once daily. The dose may be increased, depending on clinical response and tolerability, by 2 mg (weekly or every 2 weeks, depending on the half-life; see below) to a maintenance dose of 4–8 mg once daily. Depending on individual clinical response and tolerability to perampanel at 8 mg once daily, further dose increases up to 12 mg once daily in 2 mg increments may be considered. For patients taking concomitant medications that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated with intervals of at least 2 weeks. For patients taking concomitant medications that shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated (increased) with intervals of at least 1 week.

Children (aged 4 to 11 years) with body weight ≥ 30 kg

Treatment should be initiated at a dose of 2 mg once daily. The dose may be increased, depending on clinical response and tolerability, by 2 mg (weekly or every 2 weeks, depending on the half-life; see below) to a maintenance dose of 4–8 mg once daily. Depending on individual clinical response and tolerability to perampanel at 8 mg once daily, further dose increases up to 12 mg once daily in 2 mg increments may be considered. For patients taking concomitant medications that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated with intervals of at least 2 weeks. For patients taking concomitant medications that shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated (increased) with intervals of at least 1 week.

Primary generalized tonic-clonic seizures

Perampanel at doses up to 8 mg once daily has demonstrated efficacy in the treatment of primary generalized tonic-clonic seizures.

The recommended doses for adults, adolescents, and children aged 7 years and older are shown in the table below. See details below the table.

Adults and adolescents aged ≥ 12 years

Treatment should be initiated at a dose of 2 mg once daily. The dose may be increased based on clinical response and tolerability by 2 mg (weekly or every 2 weeks, depending on the half-life, see below) up to a maintenance dose of 8 mg once daily. Depending on individual clinical response and tolerability to perampanel at a dose of 8 mg once daily, the dose may be increased to 12 mg once daily, which may be effective in some patients (see section "Special warnings and precautions for use"). Patients who are concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use") should have their dose titrated with intervals of at least 2 weeks. Patients who are concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special warnings and precautions for use") should have their dose titrated (increased) with intervals of at least 1 week.

Children (aged 7 to 11 years) with body weight ≥ 30 kg

Treatment should be initiated at a dose of 2 mg once daily. The dose may be increased based on clinical response and tolerability by 2 mg (weekly or every 2 weeks, depending on the half-life, see below) up to a maintenance dose of 4 to 8 mg once daily. Depending on individual clinical response and tolerability to perampanel at a dose of 8 mg once daily, further dose increases up to 12 mg once daily in 2 mg/day increments may be considered. Patients who are concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use") should have their dose titrated with intervals of at least 2 weeks. Patients who are concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special warnings and precautions for use") should have their dose titrated (increased) with intervals of at least 1 week.

Discontinuation of treatment

It is recommended to discontinue the medicinal product gradually to minimize the risk of increased seizure frequency. However, due to the long half-life and subsequent slow decline in plasma perampanel concentrations, if absolutely necessary, perampanel may be discontinued abruptly.

Missed doses

One missed dose: because perampanel has a long half-life, the patient should wait and take the next dose at the scheduled time.

If more than one dose has been missed within a time period not exceeding 5 half-lives (3 weeks for patients not taking antiepileptic drugs that induce perampanel metabolism, 1 week for patients taking antiepileptic drugs that induce perampanel metabolism, see section "Interaction with other medicinal products and other forms of interaction"), consideration should be given to resuming treatment at the previous dose level.

If perampanel has not been taken for a period exceeding 5 half-lives, it is recommended to follow the above-mentioned recommendations for initial dosing.

Use in elderly patients (aged 65 years and older)

Clinical trials of perampanel in epilepsy did not include a sufficient number of patients aged 65 years and older to determine whether their response differs from that of younger patients. An analysis of safety data from 905 elderly patients who received perampanel (in double-blind studies conducted for indications unrelated to epilepsy) did not reveal age-related differences in the safety profile. Along with the absence of age-related differences in perampanel exposure, results indicate that dose adjustment in elderly patients is not required. However, perampanel should be used with caution in elderly patients, considering the potential for interactions with other medicinal products in patients taking multiple medications (see section "Special warnings and precautions for use").

Use in patients with renal impairment

Dose adjustment is not required in patients with mild renal impairment. The medicinal product is not recommended for use in patients with moderate or severe renal impairment and in patients undergoing hemodialysis.

Use in patients with hepatic impairment

Dose escalation in patients with mild to moderate hepatic impairment should be based on clinical response and tolerability. Treatment may be initiated at 2 mg once daily in patients with mild or moderate hepatic impairment. The dose should be titrated (increased) by 2 mg increments no more frequently than every 2 weeks, depending on tolerability and efficacy.

The perampanel dose in patients with mild or moderate hepatic impairment should not exceed 8 mg once daily.

The medicinal product is not recommended for use in patients with severe hepatic impairment.

Children

The safety and efficacy of perampanel have not yet been established in children under 4 years of age for partial-onset seizures and in children under 7 years of age for primary generalized tonic-clonic seizures.

This medicinal product is administered to children with body weight ≥ 30 kg in this dosage form.

Overdose

Symptoms: Post-marketing cases of intentional and accidental overdose have been reported in pediatric patients at perampanel doses up to 36 mg and in adult patients at doses up to 300 mg. Observed adverse reactions included: altered mental status, agitation, aggressive behavior, coma, and depressed level of consciousness. Patients recovered without sequelae.

Treatment: There is no specific antidote for the effects of perampanel.

General supportive care is indicated, including monitoring of vital signs and observation of the patient's clinical status. Due to the long half-life of perampanel, effects caused by perampanel may be prolonged. Because of the low renal clearance of perampanel, specialized procedures such as forced diuresis, hemodialysis, or hemoperfusion are likely to be ineffective.

Adverse Reactions

Short description of safety profile

Among 1639 patients with partial seizures who received perampanel in all conducted controlled and uncontrolled clinical studies, 1147 received the drug for 6 months and 703 for longer than 12 months.

In controlled and uncontrolled studies involving patients with primary generalized tonic-clonic seizures, 114 patients received perampanel, of whom 68 received treatment for 6 months and 36 for longer than 12 months.

Adverse reactions leading to study discontinuation

In Phase III controlled clinical studies involving patients with partial seizures, the frequency of treatment discontinuation due to an adverse reaction was 1.7% (3/172), 4.2% (18/431), and 13.7% (35/255) in randomized patients receiving perampanel at recommended doses of 4 mg/day, 8 mg/day, and 12 mg/day, respectively, and 1.4% (6/442) in patients receiving placebo.

The adverse reactions most commonly leading to treatment discontinuation were dizziness and somnolence (occurring at a frequency >1% and more frequently in the overall perampanel group than in the placebo group).

In a controlled Phase III clinical study involving patients with primary generalized tonic-clonic seizures, the frequency of treatment discontinuation due to an adverse reaction was 4.9% (4/81) in patients randomized to receive perampanel 8 mg and 1.2% (1/82) in patients randomized to receive placebo.

The adverse reaction most commonly leading to treatment discontinuation was dizziness (occurring at a frequency >2% and more frequently in the overall perampanel group than in the placebo group).

Post-marketing use

Serious skin adverse reactions have been reported, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with perampanel treatment (see section "Special precautions").

The table below lists adverse reactions identified from the review of the complete clinical studies safety database for perampanel. Adverse reactions are categorized by system organ class and frequency. The following classification is used to assess frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

* See section "Special precautions".

Pediatric population

According to data from 196 adolescents with partial seizures and primarily generalized tonic-clonic seizures who received perampanel in double-blind studies, the overall safety profile in adolescents was similar to that in adults, except for aggression, which was observed more frequently in adolescents than in adults.

According to data from 180 pediatric patients who received perampanel in a multicenter open-label study, the overall safety profile in children was similar to that in adolescents and adults, except for somnolence, irritability, aggression, and hyperactivity, which were observed more frequently in children compared to adults.

Available data in pediatric patients do not indicate any clinically significant effect of perampanel on growth and development parameters, including body weight, height, thyroid function, insulin-like growth factor-1 (IGF-1) levels, cognitive function (assessed by ABNAS), behavior (evaluated by the Child Behavior Checklist — CBCL), and manual dexterity (assessed by the Lafayette Grooved Pegboard Test — LGPT). However, the long-term impact (>1 year) on learning, intelligence, growth, endocrine function, and sexual maturation in children remains unknown.

Reporting of suspected adverse reactions

Reporting of adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

4 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets in a blister, 3 blisters in a carton.

Prescription status

Prescription only.

Manufacturer

JSC "Kyivmedpreparat".

Manufacturer's address and location of its business activities

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.