Ficompa, 6 mg 28 pcs.

Faicompa has an antiepileptic effect.

Pharmacodynamics

The mechanism of action. Perampanel is a first-in-class selective noncompetitive ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor antagonist on postsynaptic neurons.

Glutamate is the main excitatory neurotransmitter in the CNS and plays an important role in the pathogenesis of several neurological diseases caused by neuronal overexcitation.

The activation of AMPA receptors by glutamate is thought to be responsible for the most rapid excitatory synaptic transmission 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 noncompetitive AMPA receptor antagonists. This indicates that perampanel is a noncompetitive AMPA receptor antagonist.

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

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

Pharmacodynamic effects.

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

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

The effect on cognitive function. When assessed in a series of standard tests of the effects of perampanel on the speed of response to external stimuli and memory in healthy volunteers, no effect was noted with both single and multiple doses of the drug in doses up to 12 mg/day.

Impact on mood and response speed to external stimuli. The speed of reaction to external stimuli (arousal) in healthy volunteers receiving perampanel in doses from 4 to 12 mg/day decreased in a dose-dependent manner. Mood deterioration in the volunteers was observed only on 12 mg/day, the mood changes were insignificant and reflected an overall decrease in the rate of response to external stimuli.

Multiple administration of perampanel at a daily dose of 12 mg increased the worsening effect of alcohol on attention and responsiveness, and increased the severity of irritability, confusion, and depression on a 5-point Mood Profile scale.

The effect on electrophysiological parameters of the heart. Perampanel at daily doses of up to 12 mg did not prolong the QTc interval and had no dose-dependent or clinically significant effect on QRS complex duration.

Clinical efficacy and safety. The efficacy of Ficompa® for partial seizures was established in three 19-week randomized, double-blind, placebo-controlled, multicenter studies in adults and adolescents with partial seizures with or without secondary generalization not adequately controlled by other (one to a combination of three) antiepileptic drugs (PEDs). Patients had to have more than 5 seizures during the 6-week baseline period; the period without seizures was not to exceed 25 days. In all three studies, patients had a mean duration of illness of 21.06 years. Between 85.3 and 89.1% of patients were taking 2 or 3 PEPs with or without concomitant vagus nerve stimulation.

The first two studies compared Ficompa® at daily doses of 8 and 12 mg and the third study at daily doses of 2, 4, and 8 mg with placebo.

In all three studies, after a 6-week baseline period conducted before randomization and necessary to establish baseline epileptic seizure rates, patients were randomized and received doses matched to randomized values. During the dose-fitting period, treatment in all three trials began at a dose of 2 mg/day, which was increased weekly by 2 mg/day until the target dose was reached. Patients with intolerable side effects could remain on the same dose or their dose was reduced to the previously well tolerated dose. In all three studies, the dose adjustment period was followed by a maintenance period of 13 weeks, during which patients had to receive a steady dose of Ficomp.

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

These results indicate that perampanel doses of 4 to 12 mg once daily as adjunctive therapy are significantly more effective in this patient group than placebo.

A clinically significant improvement in seizure control was observed with a single dose of 4 mg/day of Feicomp, and increased when the daily dose was increased to 8 mg. When the daily dose was increased to 12 mg, no additional improvement in efficacy was observed compared with the 8 mg dose in the entire patient population. Increased efficacy of Ficompa at the 12 mg dose was observed only in patients who were resistant to the 8 mg dose.

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

The open extended study

97% (1,186) of patients who completed randomized trials were recruited to participate in an open extended study in which they took perampanel for at least 1 year at a mean daily dose of 10.05 mg.

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

Pharmacokinetics

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

Intake. When administered orally, perampanel is quickly and completely absorbed, the effect of first passage through the liver is negligible. Food intake has no effect on the degree of absorption, but slows down its rate. Compared with fasting when concomitant intake of the drug with food, the Cmax of perampanel in plasma is reduced and its time of attainment is increased by 2 hours.

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

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

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

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

Evacuation. After administration of radioactively labeled perampanel in healthy elderly volunteers, 30% of the radioactive label was detected in the urine and 70% in the feces. The radioactive label excreted was mainly a mixture of oxidized and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase I clinical trials, the mean T1/2 of perampanel was 105 h. When concomitantly used with carbamazepine, a potent inducer of the CYP3A4 isoenzyme, the T1/2 of perampanel was 25 h.

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

Perampanel use in special patient groups

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

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

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

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

Patients in pediatric patients. In a population pharmacokinetic analysis, there were no significant differences from the general population in pediatric patients enrolled in phase III clinical trials.

Drug interaction studies

In vitro drug interaction assessment

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

Induction of enzymes involved in drug metabolism. Compared with positive controls (including phenobarbital and rifampicin), perampanel weakly induced the CYP2B6 (30 μmol/L) and CYP3A4/5 (≥3 μmol/L) isoenzymes among major cytochrome and UDF-glucuronyltransferases in human hepatocyte culture.

Indications

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

Active ingredient

How to take, the dosage

Contraindications

Side effects

Overdose

Pregnancy use

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

The data on the use of perampanel in pregnant women are significantly limited (<300 cases). No direct or indirect toxic effects have been found in studies of reproductive toxicity in animals. As a precautionary measure, it is recommended to avoid the use of Ficompa in pregnancy.

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

Given the benefits of both breastfeeding for the baby and therapy for the woman, you should either stop breastfeeding or refrain from taking/continue taking Ficomp while breastfeeding.

The effect on fertility

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