Syncopa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SYNCOPO (SYNCOPA)

Composition:

Active substance: perampanel;

1 tablet contains 2 mg or 4 mg of perampanel;

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

coating mixture: titanium dioxide (E 171), polyethylene glycol (macrogol), hypromellose (hydroxypropylmethylcellulose), red iron oxide (E 172), yellow iron oxide (E 172) – for the 2 mg dosage; titanium dioxide (E 171), polyethylene glycol (macrogol), hypromellose (hydroxypropylmethylcellulose), red iron oxide (E 172), black iron oxide (E 172) – for the 4 mg dosage.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

• 2 mg tablets: film-coated, light brown, round, biconvex tablets;
• 4 mg tablets: film-coated, red-brown, round, biconvex tablets.

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 post-synaptic neurons. Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS) and plays 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 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 latent period in an AMPA-induced model of epileptic seizures in vivo.

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

Pharmacodynamic effects

A pharmacokinetic and pharmacodynamic analysis of perampanel was conducted based on pooled data from three efficacy studies in partial epileptic seizures. Additionally, a pharmacokinetic and 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, the effect of perampanel 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 (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 significant changes in cognitive abilities were observed after adjunctive therapy with perampanel compared to baseline levels measured using the ABNAS (Attention-Based Neuropsychological Assessment System) (see section "Paediatric population" below).

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

Mood deterioration occurred only at the 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 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 the 6-week baseline period, patients were required to have more than five seizures, with seizure-free intervals 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), doses of perampanel 8 mg and 12 mg/day were compared with placebo, while in the third study (study 306), doses of perampanel 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 appropriate doses. During the titration period in all three studies, treatment was initiated at a dose of 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 the dose to one previously well tolerated. 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 from 4 mg to 12 mg as adjunctive therapy, was significantly more effective than placebo.

Placebo-controlled study data demonstrate 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 the 8 mg dose across the entire patient population. Increased efficacy at the 12 mg dose 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 participation in the randomized study were included 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 population consisted of 164 patients (perampanel N = 82, placebo N = 82). Dose titration to a target of 8 mg/day or to the highest tolerated dose occurred over 4 weeks. The maintenance period lasted 13 weeks at the last achieved dose 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 combined titration and maintenance periods 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 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 resolved 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 extension phase. Patients from the randomized study were transitioned to perampanel over 6 weeks, followed by a long-term maintenance period (≥1 year). In the extension phase, 73.7% (84/114) of patients received a modal daily dose of perampanel greater than 4–8 mg/day, and 16.7% (19/114) received a modal daily dose greater than 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 extension 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 were generally stable from 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 patients with epilepsy 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, and 24 patients (71%) remained on perampanel monotherapy for at least 6 months. Ten (10) patients were followed for at least 18 months, and 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 subgroups of the paediatric population with treatment-resistant epilepsy (epilepsy syndromes related to localization and age) (see section "Posology and method of administration").

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

Study 332 included 22 adolescents aged 12 to 18 years. Data obtained in adolescents were similar to those in the adult population.

A 19-week randomized, double-blind, placebo-controlled study with an open extension phase (study 235) was conducted to evaluate the short-term effect of perampanel as adjunctive therapy (target dose range 8 mg 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 intensity, attention continuity, 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 mean treatment group difference by least squares method (95% CI [confidence interval]) of –2.2 (–5.2, 0.8). There was no statistically significant difference between treatment groups (p = 0.145). Baseline CDR t-Scores in the placebo and perampanel groups were 41.2 (10.7) and 40.8 (13.0), respectively. For patients receiving perampanel in the open extension phase (n = 112), the mean change (SD) from baseline to the end of open 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 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 extension phase received treatment for an additional 29 weeks, with a total exposure duration of 52 weeks.

Among patients with partial seizures (n = 148), the change in median 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%), 50% response rate (40–52 weeks: 62.0%, n = 67/108), and 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%), 50% response rate (40–52 weeks: 80.5%, n = 33/41), and 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 change in median 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%), 50% response rate (40–52 weeks: 61.5%, n = 8/13), and proportion of patients seizure-free (40–52 weeks: 38.5%, n = 5/13) persisted 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%), 50% response rate (weeks 40–52: 54.5%, n = 6/11), and proportion of patients seizure-free (weeks 40–52: 36.4%, n = 4/11) persisted 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 seizures 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 administered fasting when given at equivalent milligram doses. 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 fasting and fed.

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

In vitro, perampanel was 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. Perampanel metabolism is predominantly mediated by CYP3A isoenzymes, based on clinical studies in healthy volunteers receiving 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 healthy elderly volunteers, 30% of the radioactive label was recovered in urine and 70% in feces. The excreted radioactive label 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 administered concomitantly 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 from 0.2 mg to 36 mg as single or multiple doses, one Phase II study, and five Phase III studies in patients with partial seizures receiving perampanel from 2 mg to 16 mg/day, and two Phase III studies in patients with primary generalized tonic-clonic seizures receiving perampanel from 2 mg to 14 mg/day, a linear relationship between dose and perampanel plasma concentration was demonstrated.

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 subjects with matching 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, up to 306 hours versus 125 hours in healthy volunteers; in moderate impairment, up to 295 hours versus 139 hours in healthy volunteers.

Patients with renal impairment. The pharmacokinetics of perampanel in patients with renal impairment were not 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, who received perampanel up to 12 mg/day during placebo-controlled studies, creatinine clearance did not affect perampanel clearance. In patients with primary generalized tonic-clonic seizures receiving perampanel up to 8 mg/day during 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 up to 12 mg/day and patients with primary generalized tonic-clonic seizures receiving perampanel up to 8 mg/day during 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 of patients with partial seizures (aged 12 to 74 years) and primary generalized tonic-clonic seizures (aged 12 to 58 years), who received perampanel up to 8 mg or up to 12 mg/day during 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 agents (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 (weighing ≥ 30 kg), with or without secondarily generalized seizures;
• for primary generalized tonic-clonic seizures in patients aged 7 years and older (weighing ≥ 30 kg) with idiopathic generalized epilepsy.

Contraindications

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

Interaction with other medicinal products and other forms of interaction

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

Hormonal contraceptives

In healthy women receiving 12 mg (but not 4 mg 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 had no effect on ethinylestradiol AUC, while Cmax was reduced by 18%. Therefore, a potential reduction in the efficacy of hormonal contraceptives containing a 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 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.

Concomitantly used AED	Effect of AED on perampanel concentration	Effect of perampanel on AED concentration
Carbamazepine	Three-fold decrease	Less than 10 % decrease
Clobazam	No effect	Less than 10 % decrease
Clonazepam	No effect	No effect
Lamotrigine	No effect	Less than 10 % decrease
Levetiracetam	No effect	No effect
Oxcarbazepine	Two-fold decrease	35 % increase *
Phenobarbital	No effect	No effect
Phenytoin	Two-fold decrease	No effect
Topiramate	20 % decrease	No effect
Valproic acid	No effect	Less than 10 % decrease
Zonisamide	No effect	No effect

• Excluding the active metabolite monohydroxycarbazepine.

According to the 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 enzyme inducers (see section "Pharmacokinetics"). This effect should be taken into account and monitored when adding or discontinuing these antiepileptic drugs in the patient's treatment regimen. Clonazepam, levetiracetam, phenobarbital, topiramate, zonisamide, clobazam, lamotrigine, and valproic acid had no clinically significant effect on perampanel clearance.

Based on population pharmacokinetic analysis, in patients with partial seizures, perampanel had no clinically significant effect on 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) decreased the AUC of midazolam 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 the pharmacokinetics of perampanel

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 ruled out. Felbamate has been shown to reduce the concentration of certain drugs and may also reduce perampanel concentrations.

Effect of cytochrome P450 inhibitors on the pharmacokinetics of perampanel

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

Levodopa

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

Alcohol

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

Pediatric population

Drug interaction studies have been conducted only in adults.

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

Special Warnings and Precautions for Use

Suicidal thoughts

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

Therefore, patients (children, adolescents, and adults) should be monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be considered as necessary. Patients (and caregivers) should be advised to seek medical advice immediately if signs of suicidal thoughts or behavior occur.

Severe skin reactions

Severe cutaneous adverse reactions have been reported during treatment with perampanel, 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 of the signs and symptoms prior to initiating treatment, and skin reactions should be closely monitored.

Symptoms of DRESS syndrome typically include fever, rash, involvement of other organ systems, lymphadenopathy, liver function abnormalities, 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/blisters) <10%, erythematous skin (confluent), rapid progression, painful atypical lesions resembling targets, purpuric macules with widespread distribution, or extensive erythema (confluent), and bullous/erosive involvement of more than two mucous membranes.

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

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

Absence and myoclonic seizures

Absence and myoclonic seizures are two common types of generalized seizures that frequently occur 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 treatment with perampanel.

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 and use machines").

Hormonal contraceptives

At doses of 12 mg/day, perampanel may reduce the efficacy of hormonal contraceptives containing progesterone; under these circumstances, additional non-hormonal contraception is recommended during treatment with perampanel (see sections "Interaction with other medicinal products and other forms of interaction" and "Use in 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 behavior have been reported in patients receiving perampanel therapy. In clinical trials, aggression, anger, irritability, and psychiatric disorders were more frequently observed 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 behavior occurred (<1% in clinical trials with perampanel). Suicidal ideation toward others, including homicidal thoughts, has also been reported. Patients and caregivers should be advised to immediately report significant mood or behavioral 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 fixed-dose perampanel was lower in patients receiving concomitant antiepileptic drugs that induce CYP3A enzymes (e.g., carbamazepine, phenytoin, oxcarbazepine) compared to patients receiving non-inducing antiepileptic drugs. Patients should be monitored for clinical response when switching between concomitant non-inducing and enzyme-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 concomitant use of cytochrome P450 inducers or inhibitors, as plasma levels of perampanel may be decreased or increased, respectively; dose adjustment of perampanel may be required.

Hepatotoxicity

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

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 in 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 "Special Warnings and Precautions for Use" and "Interaction with other medicinal products and other forms of interaction").

Pregnancy

Data on the use of perampanel in pregnant women are limited (fewer than 300 cases). Animal studies did not reveal 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. A risk to newborns/infants cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue perampanel therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

In a fertility study in female rats, prolonged and irregular estrous cycles were observed at high doses (30 mg/kg); however, 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 and use machines

Perampanel has a moderate influence on the ability to drive 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 established whether perampanel affects their ability to perform such activities (see sections "Special Warnings and Precautions for Use" and "Interaction with other medicinal products and other forms of interaction").

Dosage and Administration

Route 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 because it does not have a score line.

The 2 mg and 4 mg tablets cannot be divided; therefore, if a dose of perampanel less than 2 mg is required, another medicinal product containing perampanel that allows dosing at 0.5 mg and 1 mg should be used.

Dosage

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

Perampanel should be taken 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 mg/day to 12 mg/day.

The table below provides the recommended dosages for adults, adolescents, and children aged 4 years and older. See details below the table.

	Adults/adolescents (from 12 years)	Children (4–11 years)
		≥ 30 kg
Recommended initial dose	2 mg/day	2 mg/day
Titration (stepwise increments)	2 mg/day (at intervals of at least 1 week)	2 mg/day (at intervals of at least 1 week)
Recommended maintenance dose	4–8 mg/day	4–8 mg/day
Titration (stepwise increments)	2 mg/day (at intervals of at least 1 week)	2 mg/day (at intervals of at least 1 week)
Recommended maximum dose	12 mg/day	12 mg/day

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) to a maintenance dose of 4 mg/day to 8 mg/day. Depending on individual clinical response and tolerability to perampanel at 8 mg/day, further dose increases up to 12 mg/day in 2 mg/day increments may be considered. For patients concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special precautions for use"), perampanel dose titration should be performed at intervals of at least 2 weeks. For patients concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special precautions for use"), perampanel dose titration (increase) should be performed at intervals of at least 1 week.

Children (aged 4 to 11 years) weighing ≥ 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) to a maintenance dose of 4 mg/day to 8 mg/day. Depending on individual clinical response and tolerability to perampanel at 8 mg/day, further dose increases up to 12 mg/day in 2 mg/day increments may be considered. For patients concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special precautions for use"), perampanel dose titration should be performed at intervals of at least 2 weeks. For patients concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special precautions for use"), perampanel dose titration (increase) should be performed at intervals of at least 1 week.

Primary generalized tonic-clonic seizures

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

The table below provides recommended dosing for adults, adolescents, and children aged 7 years and older. See below the table for further details.

	Adults/adolescents (from 12 years)	Children (7–11 years)
		≥ 30 kg
Recommended initial dose	2 mg/day	2 mg/day
Titration (incremental steps)	2 mg/day (at intervals of at least 1 week)	2 mg/day (at intervals of at least 1 week)
Recommended maintenance dose	Up to 8 mg/day	4–8 mg/day
Titration (incremental steps)	2 mg/day (at intervals of at least 1 week)	2 mg/day (at intervals of at least 1 week)
Recommended maximum dose	12 mg/day	12 mg/day

Adults and adolescents aged ≥ 12 years

Treatment should be initiated at a dose of 2 mg/day. 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/day. Depending on individual clinical response and tolerability to perampanel at a dose of 8 mg/day, the dose may be increased to 12 mg/day, which may be effective in some patients (see section "Special warnings and precautions for use"). For patients concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use"), dose titration should be performed at intervals of at least 2 weeks. For patients concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated (increased) at intervals of at least 1 week.

Children (aged 7 to 11 years) weighing ≥ 30 kg

Treatment should be initiated at a dose of 2 mg/day. 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 mg/day to 8 mg/day. Depending on individual clinical response and tolerability to perampanel at a dose of 8 mg/day, further dose increases up to 12 mg/day in 2 mg/day increments may be considered. For patients concurrently taking medicinal products that do not shorten the half-life of perampanel (see section "Special warnings and precautions for use"), dose titration should be performed at intervals of at least 2 weeks. For patients concurrently taking medicinal products that shorten the half-life of perampanel (see section "Special warnings and precautions for use"), the dose of perampanel should be titrated (increased) at intervals of at least 1 week.

Discontinuation of treatment

Gradual discontinuation of the medicinal product is recommended to minimize the risk of increased seizure frequency. However, due to the long half-life and subsequent slow decline in plasma perampanel concentrations, abrupt discontinuation of perampanel may be considered in cases of urgent need.

Missed doses

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

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

Use in elderly patients (aged 65 years and older)

A sufficient number of patients aged 65 years and older have not been enrolled in clinical studies of perampanel in epilepsy to determine whether their response differs from that in younger patients. 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 the elderly 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. Use in patients with moderate or severe renal impairment and in patients undergoing hemodialysis is not recommended.

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/day in patients with mild or moderate hepatic impairment. Patients should be titrated (increased) in 2 mg increments no more frequently than every 2 weeks, depending on tolerability and efficacy.

The perampanel dose in patients with mild to moderate hepatic impairment should not exceed 8 mg/day.

Use in patients with severe hepatic impairment is not recommended.

Children

The safety and efficacy of perampanel have not 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 indicated for use in children with a body weight of ≥ 30 kg.

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 the safety profile

Among 1639 patients with partial-onset 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, including 68 patients who received treatment for 6 months and 36 patients for longer than 12 months.

Adverse reactions leading to discontinuation from studies

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

The adverse reactions most commonly leading to 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 Phase III controlled clinical study involving patients with primary generalized tonic-clonic seizures, the incidence of 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 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 warnings and precautions for use").

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 frequency classification was used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Body systems	Very common	Common	Uncommon	Unknown
Metabolism and nutrition		Decreased appetite Increased appetite
Psychiatric		Aggression Anger Anxiety Confusion	Suicidal thoughts Suicide attempt Hallucinations Psychotic disorder
Nervous system	Dizziness Somnolence	Ataxia Dysarthria Loss of balance Irritability
Eye disorders		Diplopia Blurred vision
Ear and labyrinth disorders		Dizziness
Gastrointestinal disorders		Nausea
Skin and subcutaneous tissue				Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)* Stevens-Johnson syndrome*
Musculoskeletal and connective tissue		Back pain
General disorders		Gait disturbance Fatigue
Investigations		Weight increased
Injury, poisoning and procedural complications		Fall

* See section "Special precautions".

Paediatric population

Based on data from 196 adolescents with partial seizures and primary generalized tonic-clonic seizures receiving 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.

Based on data from 180 paediatric patients receiving perampanel in a multicentre 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 children 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), behaviour (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 suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

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

Keep out of reach and sight of children.

Packaging

10 tablets per blister, 3 blisters per carton.

Prescription status

Prescription only.

Manufacturer

JSC "Kyivmedpreparat"

Manufacturer's address and place of business

139 Saksaganskogo Street, Kyiv, 01032, Ukraine