Faycompa film-coated pills 4 mg N28
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Active ingredients
Perampanel
Release form
Pills
Composition
1 tab. Perampanel 4 mg. Excipients: lactose monohydrate - 157 mg, low substituted hyprolosis - 28 mg, povidone - 10 mg, magnesium stearate - 1 mg.
Pharmacological effect
Perampanel is the first in its class of selective non-competitive antagonist of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptors on postsynaptic neurons. Glutamate is the main excitatory neurotransmitter in the CNS, which plays an important role in the pathogenesis of a number of neurological diseases caused by over-stimulation of neurons. It is assumed that the activation of AMPA receptors by glutamate is responsible for the fastest excitatory synaptic transmission in the brain. In in vitro studies, perampanel did not compete with AMPA for binding to the AMPA receptor; however, it was forced out of binding by noncompetitive AMPA antagonists of the receptors. This indicates that perampanel is a noncompetitive antagonist of AMPA receptors. In in vitro studies, perampanel inhibited AMPA-induced (but not N-methyl-D-aspartate (NMDA) induced) increase in intracellular calcium concentration. In vivo, perampanel significantly increased the latent period in the AMPA-induced model of an epileptic seizure. The exact mechanism of development of the anticonvulsant effect of perampanel in humans is for further study. Pharmacodynamic effects: Based on a summary of the three efficacy studies conducted during partial epileptic seizures, the pharmacokinetics and pharmacodynamics of perampanel were analyzed. The analysis of pharmacokinetics and pharmacodynamics of perampanel was also carried out on the basis of data from the efficacy study in primary-generalized tonic-clonic seizures. According to the results of two analyzes, the magnitude of the effect of perampanel correlated with the severity of a decrease in the frequency of attacks. Impact on psychomotor function. In doses of 8 and 12 mg of perampanel, with single and multiple doses, dose-dependently worsened psychomotor functions in healthy volunteers. The effect exerted by 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. Impact on cognitive function. When evaluated in a series of standard tests, the effect of perampanel on attentiveness and memory in healthy volunteers did not show any effect, either with a single dose or with multiple doses of the drug in doses up to 12 mg / day. Influence on mood and speed of reaction to external influence. The rate of reaction to external influence (excitability) in healthy volunteers who received perampanel in doses from 4 mg to 12 mg per day, decreased in a dose-dependent manner. The deterioration of mood in volunteers was noted only while taking 12 mg per day, mood changes were insignificant and reflected an overall decrease in the rate of reaction to external influences. Repeated use of perampanel in a daily dose of 12 mg increased the worsening effect of alcohol on vigilance and speed of reaction to external influence and increased the intensity of irritability, confusion and depression according to the results of a 5-point scale assessing the Profile of the Emotional State. Effect on cardiac electrophysiological parameters: Perampanel in daily doses up to 12 mg did not prolong the QTc interval and did not have any dose-dependent or clinically significant effect on the duration of QRS complexes. Clinical efficacy and safety: Partial epileptic seizures: The efficacy of Ficomp in partial seizures was established during 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 others. (one to a combination of three) antiepileptic drugs (PEP). During the 6-week base period, patients should have had more than 5 attacks, the period without attacks should not exceed 25 days. In these three studies, patients had an average disease duration of 21.06 years. From 85.3 to 89.1% of patients took 2 or 3 PEP with or without concomitant stimulation of the vagus nerve. In the first two studies, Ficompa was administered in daily doses of 8 and 12 mg, and in the third, in daily doses of 2, 4, and 8 mg, compared with placebo.In all three studies, after a 6-week base period conducted prior to randomization and necessary to establish the base rate of epileptic seizures, patients were randomized and received titrated to randomized dose values. During the titration period in all three studies, treatment began with a dose of 2 mg / day, which increased weekly by 2 mg / day until the target dose was reached. Patients with intolerable side effects could remain at the same dose or their dose was reduced to a previously well-tolerated dose. In all three studies, a titration period was followed by a maintenance period that lasted 13 weeks and during which patients should receive a constant dose of Ficomp. According to the combined results of the three studies, the proportion of 50% of the response was respectively 19% for the placebo group, 29% for the 4 mg dosage, 35% for the 8 mg and 35% for 12 mg. A statistically significant reduction in the frequency of seizures in 28 days compared with placebo was shown for dosages of 4 to 12 mg per day in a single dose. These results show that taking perampanel in doses of 4 to 12 mg 1 time per day as an additional therapy in this group of patients is much more effective compared to placebo. A clinically significant improvement in seizure control was observed with a single dose of 4 mg Faycompa per day, and increased with an increase in the daily dose to 8 mg. With an increase in the daily dose of up to 12 mg, there was no additional increase in the effectiveness of the drug compared to the dose of 8 mg for the entire patient population. An increase in the efficacy of Ficomp at a dose of 12 mg was observed only in patients resistant to a dose of 8 mg. A clinically significant reduction in seizure frequency relative to placebo was achieved as early as the second week after reaching a daily dose of 4 mg. 97% (1186) of patients completing randomized trials were included in an open-ended, extended study in which they took perrapanel for at least 1 year at an average daily dose of 10.05 mg. In these three baseline double-blind, placebo-controlled, phase 3 studies, 143 adolescents aged 12 to 18 years participated. The results obtained from adolescents were similar to those of adult patients.Primary generalized tonic-clonic seizures: The effectiveness of Ficomp as an additional therapy for primary generalized tonic-clonic seizures in 164 patients aged 12 years and older with idiopathic generalized epilepsy was established during a multicenter, randomized, double-blind, placebo-controlled study. The study included patients who took stable doses of 1 to 3 AEDs and had at least 3 primary-generalized tonic-clonic seizures during an 8-week base period. Selection of the dose to the target value of 8 mg / day or to the highest tolerated dose took place over 4 weeks. The maintenance period was 13 weeks at the level of the last dose reached at the end of the titration period. The total treatment period was 17 weeks. The study drug was taken 1 time / day. The proportion of 50% response in primary generalized tonic-clonic seizures was 64.2% in the perampanel group and 39.5% in the placebo group. The decrease in the median frequency of primary-generalized tonic-clonic seizures in 28 days was 76.47% in the perampanel group and 38.38% in the placebo group. The calculated difference in treatment efficacy in the perampanel and placebo groups was 30.81%, which indicates a significant improvement in reducing the incidence of primary generalized tonic-clonic seizures in the perampanel group compared to the placebo group. Open extended study. Of the 140 patients who completed the main study, 114 (81.4%) were transferred to perampanel in a daily dose of more than 4–8 mg (73.7% of patients) or more than 8–12 mg (16.7% of patients) for at least 1 year. The study involved 22 adolescents aged 12 to 18 years. The results obtained in adolescents were similar to those obtained in the adult population.
Pharmacokinetics
The pharmacokinetics of perampanel were studied in healthy volunteers from 18 to 79 years old, in adults and adolescents with partial epileptic seizures and primary generalized tonic-clonic seizures, in adults with Parkinson's disease, diabetic nephropathy and multiple sclerosis, as well as in patients with hepatic insufficiency .Absorption: Upon ingestion, perampanel is quickly and completely absorbed, the effect of "first passing" through the liver is negligible. Eating does not affect the degree of absorption, but slows down its speed. Compared with fasting while taking the drug with food, the maximum concentration of perampanel in plasma is reduced, and the time to reach it is increased by 2 hours. Distribution: In vitro studies indicate that perampanel is approximately 95% bound to plasma proteins. In vitro, it was shown that perampanel is neither a substrate nor a significant inhibitor of the transport peptides of organic anions (OATR) 1B1 and 1B3, carriers of organic anions (OAT) 1, 2, 3 and 4, carriers of organic cations (OST) 1, 2 and 3, as well as P-glycoprotein and breast cancer resistance protein (BCRP). Metabolism: Perampanel is largely metabolized by primary oxidation and subsequent glucuronidation. According to the results of in vitro studies with recombinant cytochrome P450 in human liver microsomes, the primary oxidative metabolism is mediated by CYP3A isoenzymes. However, the metabolism of perampanel is not yet fully understood, and its other paths cannot be ruled out. After the application of radiolabeled perampanel in plasma, only trace amounts of its metabolites are determined. Excretion: After taking radioactively labeled perampanel by eight healthy elderly volunteers, 30% of the radioactive label was detected in the urine and 70% in feces. The isolated radioactive label was mainly a mixture of oxidized and conjugated metabolites. In a population pharmacokinetic analysis of summary data from 19 clinical studies of phase 1, the average T1 / 2 of perampanel was 105 hours. With simultaneous use with carbamazepine, which is a potent inducer of the isoenzyme CYP3A, the average T1 / 2 of perampanel was 25 hours. Linearity / nonlinearity: In healthy volunteers, the concentration Perampanel in plasma increases in direct proportion to the dose in the range from 2 to 12 mg. In a population-based pharmacokinetic analysis in patients with partial seizures who received perampanel at doses up to 12 mg per day, and in patients with primary generalized tonic-clonic seizures who received perampanel at doses up to 8 mg / day in placebo-controlled clinical trials, between dose and concentration of perampanel in plasma was established linear dependence. Use in special patient groups: Patients with liver failure.The pharmacokinetics of perampanel after administration of a single dose of 1 mg was evaluated in 12 patients with mild to moderate hepatic insufficiency (Childe-Pugh grades) and 12 healthy volunteers that correspond to them demographically. The average 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 degree. T1 / 2 in patients with liver failure was prolonged: with a mild degree, up to 306 hours versus 125 hours in healthy volunteers, with a moderate degree, up to 295 hours versus 139 hours. Patients with renal insufficiency. The pharmacokinetics of perampanel in patients with renal insufficiency were not studied separately. The elimination of perampanel is carried out almost exclusively by the formation of metabolites with their subsequent rapid excretion. Only trace amounts of perampanel metabolites are detected in plasma. In a population pharmacokinetic analysis in patients with partial seizures and creatinine clearance of 39-160 ml / min, who received perampanel in placebo-controlled studies at doses up to 12 mg per day, the relationship between clearance of perampanel and QC was not observed. In a population pharmacokinetic analysis in patients with primary-generalized tonic-clonic seizures who received perampanel at doses up to 8 mg / day during a placebo-controlled study, the relationship between clearance of perampanel and the initial QC was not observed. The effect of sex. In a population pharmacokinetic analysis in patients with partial seizures who received perampanel in doses up to 12 mg per day in placebo-controlled studies and patients with primary-generalized tonic-clonic seizures who received perampanel in doses up to 8 mg / day, clearance of perampanel in women (0.54 l / h) was 18% lower than in men (0.66 l / h). Elderly patients (65 years). In a population-based pharmacokinetic analysis in patients aged 12 to 74 years with partial seizures who received perampanel in doses up to 12 mg per day in placebo-controlled studies and in patients with primary-generalized tonic-clonic seizures who received perampanel in doses up to 8 mg / day, there was no significant effect of age on clearance of perampanel. Patients of children's age. In a population pharmacokinetic analysis in adolescent patients who participated in phase 3 clinical studies, there were no significant differences from the general population.Studies of drug interactions: Evaluation of drug interactions in vitro: Inhibition of enzymes involved in the metabolism of drugs. In human liver microsomes, perampanel (at a concentration of 30 μmol / l) had a weak inhibitory effect on CYP2C8 and UGT1A9, among other liver enzymes and UDP-glucuronyl transferase (UGT). Induction of enzymes involved in the metabolism of drugs. Compared with control drugs (including phenobarbital and rifampicin), perampanel had a weak inducer effect on CYP2B6 (at a concentration of 30 µmol / l) CYP 3 A 4/5 (at a concentration of at least 3 µmol / l) among the main hepatic enzymes and UHT in cultured human hepatocytes.
Indications
- as part of additional therapy for the treatment of partial seizures in patients with epilepsy aged 12 years and older with or without secondary generalized seizures - as part of additional therapy for the treatment of primary generalized tonic-clonic seizures in patients with epilepsy from the age of 12 years and older.
Contraindications
- hypersensitivity to perampanel or any of the excipients of the drug - pregnancy - lactation period - severe renal failure patients on hemodialysis - severe liver failure - children under 12 years old (data on efficacy and safety are not available) - galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy and lactation
Women with preserved childbearing potential and contraception A woman with preserved childbearing potential who does not use contraceptive methods, taking Fiicomp is recommended only when absolutely necessary. Pregnancy Data on the use of perampanel in pregnant women are significantly limited (less than 300 cases). Animal studies did not reveal a teratogenic effect, but showed embryotoxicity at doses toxic to the maternal organism. As a precautionary measure, it is recommended to avoid using Faycompa during pregnancy. Breastfeeding Period Animal studies have shown that perampanel and / or its metabolites are excreted in breast milk.It is not known whether perampanel is excreted in human breast milk, so the risk to the baby cannot be ruled out. Considering the advantages of both breastfeeding for the child and therapy for the woman, it is necessary either to stop breastfeeding or to refrain from taking / stop taking Faycompa during the breastfeeding period. Impact on fertility In animal studies, it was shown that in high doses (30 mg / kg), perampanel prolongs and disrupts the regularity of the estrous cycle, but these changes did not affect fertility and early fetal development. Effects on male fertility not detected. The effect of perampanel on human fertility has not been studied.
Dosage and administration
Use in adults and adolescents Perampanel taken orally 1 time a day before bedtime, regardless of the meal. The tablet must be swallowed whole with 1 glass of water. A tablet should not be chewed, chopped or broken, because a tablet cannot be neatly divided because there are no risks on it. Partial seizures It has been shown that Ficompa in daily doses of 4 to 12 mg is effective in the treatment of partial epileptic seizures. Administration of Ficomp should be started with a dose of 2 mg / day. The dose can be increased depending on the clinical response and tolerance in 2 mg increments (once a week or once every two weeks) to 4-8 mg / day. Depending on the individual clinical response and tolerability of the drug at a dose of 8 mg per day, it is possible to further increase the dose of Faycompe up to 12 mg / day with a step of 2 mg no more than once a week. In patients simultaneously receiving AEDs that do not reduce the half-life of perampanel, dose titration of perampanel should occur at two-week intervals. In patients receiving concomitant PEPs that reduce the half-life of perampanel, one should titrate (increase) the dose of perampanel once a week (see “Drug Interactions.” Primary-Generalized Tonic-Clonic Seizures effective in the treatment of primary generalized tonic-clonic seizures. Some patients may be shown higher doses (up to 12 mg / day). The drug should be started with a dose of 2 mg / day.The dose may be increased depending on the clinical response and tolerance in 2 mg increments (once a week or once every two weeks, taking into account the half-life of the drug) up to 8 mg / day. Depending on the individual clinical response and tolerability of the drug at a dose of 8 mg / day, it is possible to further increase the dose to 12 mg / day. In patients simultaneously receiving AEDs that do not reduce the half-life of perampanel, dose titration of perampanel should occur at two-week intervals. In patients receiving concomitant PEP, which reduce the half-life of perampanel, one should titrate (increase) the dose of perampanel once a week. Despite the fact that perampanel has a long half-life, it is recommended, as for other AEDs, to cancel it gradually to minimize the likelihood of an increase in the frequency of attacks. Single skipping of the drug: due to the fact that perampanel has a rather long half-life, the patient must wait and take the next scheduled dose in accordance with the agreed regimen of the drug. If more than 1 dose is missed (total duration without drug is less than 5 elimination half-life: 3 weeks for patients not receiving AED, changing perampanel metabolism and 1 week for patients receiving AED, changing perampanel metabolism) taking the drug in the last dose taken. If the patient has interrupted the administration of the drug for a period of more than 5 half-life, it is necessary to follow the recommendations as if initiating treatment. Use in children under 12 years old The safety and efficacy of perampanel in children under 12 years old has not been established (see section "Contraindications"). Use in elderly patients (over 65 years old) An insufficient number of patients with epilepsy over 65 years of age participated in clinical studies to assess differences with younger patients. The analysis of safety information in patients taking perampanel did not reveal differences in safety profile depending on age. These data confirm that corrections I perampanela doses depending on age is not required. In elderly patients perampanel should be used with caution (see."Drug Interactions", "Special instructions"). Use in patients with renal insufficiency In renal insufficiency, mild dose adjustment of perampanel is not required. The use of Ficomp in patients with moderate and severe renal failure or patients on hemodialysis is not recommended (see section "Contraindications"). Use in patients with hepatic insufficiency Increasing the dose in patients with mild and moderate hepatic insufficiency, like in other patients, depending on the clinical response and tolerability. Since mild to moderate liver failure, the half-life of perampanel is prolonged, the minimum The first time interval before each dose increase should be two weeks, and the maximum dose should not exceed 8 mg per day. Use for severe liver failure is not recommended (see the section "Contraindications").
Side effects
Among 1,639 patients with partial seizures who received perampanel in all clinical trials conducted, 1147 took the drug for 6 months and 703 for more than 12 months. In controlled and uncontrolled studies involving patients with primary generalized tonic-clonic seizures, 68 patients took perampanel for 6 months and 36 patients for more than 12 months. Partial seizures Adverse reactions that led to the release of patients with partial seizures from controlled trials of phase 3 were reported in 1.7, 4.2 and 13.7% in patients receiving perampanel, respectively, in doses of 4, 8 and 12 mg per day, and in 1.4% - in patients receiving placebo. The most common causes of exit from research were dizziness and drowsiness. Primary generalized tonic-clonic seizures In a controlled clinical trial of phase 3 involving patients with primary generalized tonic-clonic seizures, adverse reactions leading to the release of patients from the study were observed in 4.9% of patients in the perampanel group and in 1.2% in the placebo group. The undesirable reaction that most often led to exit from the study was dizziness. The following are the undesirable phenomena (AEs) that were observed during the use of perampanel, according to the system-organ classes and their frequency of occurrence. The following classification is used to assess the frequency of occurrence of adverse events: very often (1/10); often (1/100, less than 1/10).Metabolic and nutritional disorders: often - loss of appetite, increased appetite. Mental disorders: often - aggression, anger, anxiety, confusion. Disturbances of the nervous system: very often - dizziness, drowsiness; often - ataxia, dysarthria, imbalance, irritability. Disturbances from the organ of vision: often - diplopia, blurred vision. Disturbances from an organ of hearing and labyrinth disturbances: often - the central dizziness. Disorders from the gastrointestinal tract: often - nausea. Disorders of the musculoskeletal system and connective tissue: often - back pain. General disorders: often - gait disturbance, fatigue. Laboratory and instrumental data: often - weight gain. Injuries, intoxication and complications of manipulation: often - falls. Adolescents Based on data from clinical studies involving 165 adolescents, it can be expected that the frequency, nature and severity of adverse reactions are the same as in adults. Notification of adverse reactions It is extremely important to notify of adverse reactions that occurred during the post-registration use of the drug. This will allow to control the ratio of benefits and risks in its application. Please medical workers to notify about the occurrence of any adverse reactions at the address specified in this manual.
Overdose
The clinical experience of overdose with a person's perampanel is limited. In the report of an intentional overdose, which could lead to a dose of up to 264 mg, the patient experienced a change in consciousness, agitation and aggressive behavior; recovery was without consequences. There is no specific antidote. General supportive therapy is shown, including monitoring of vital signs and the patient’s clinical status. Given the long half-life of perampanel, its effects may have a longer duration. Due to the low renal clearance of perampanel, special procedures, such as forced diuresis, hemodialysis, or hemoperfusion, are ineffective.
Interaction with other drugs
Ficompa is not a potent inducer or inhibitor of cytochrome P450 or UGT.Oral contraceptives At a dose of 12 mg (but not 4 mg or 8 mg) per day, perampanel reduced the maximum concentration (Cmax) and the area under the concentration-time curve (AUC) of levonorgestrel by approximately 40%. Perampanel at a daily dose of 12 mg has no effect on the ethinyl estradiol AUC, but reduces its Cmax by 18%. Patients taking Ficomp should consider the probability of reducing the effectiveness of progestogen-containing contraceptives and use additional methods of contraception (intrauterine devices or condoms). Interaction with other AEDs The potential interaction of Ficompa (with a single daily dose of up to 12 mg) and other AEDs was evaluated based on data from clinical studies and a population-based pharmacokinetic analysis of summary data from four phase 3 studies that included patients with partial and primary-generalized tonic-clonic seizures. The effect of this interaction on the equilibrium concentration of the probe is shown in the table: Jointly applied probe The effect of probe on the concentration of the drug Ficomp The influence of the drug Faikomp on the concentration of the probe Carbamazepine 2.75 times lower Reduction by less than 10% Clobaz Not affected affects Lamotrigine Does not affect Reduction by less than 10% Levetiracetam Does not affect Does not affect Oxcarbazepine Reduction by 1.9 times Increase by 35% * Phenobarbital Does not affect Does not affect Phenytoin Reduction by 1.7 times Does not affect Topiram at. Decrease by 19%. Not affected. Valproic acid. Not affected. Decrease by less than 10%. Zonisamid. Not affected. Not affected. * Without taking into account the active metabolite monohydroxycarbazepine. concentration. In a study involving healthy volunteers, carbamazepine, a well-known powerful enzyme inducer, reduced the concentration of perampanel by 2/3. A similar result was obtained in a population-based pharmacokinetic analysis in patients with partial seizures who received Faycomp in doses up to 12 mg and in patients with primary-generalized tonic-clonic seizures who received Faykomp in doses up to 8 mg per day during placebo-controlled clinical research.The clearance of Ficomp increased while taking carbamazepine (2.75 times), phenytoin (1.7 times) and oxcarbazepine (1.9 times), which are inducers of liver enzyme metabolism. This effect should be taken into account when assigning or canceling AED data. In a population-based pharmacokinetic analysis in patients with partial seizures who received Faycompa at doses up to 12 mg and in patients with primary generalized tonic-clonic seizures who received Faycompe at doses up to 8 mg per day in a placebo-controlled clinical study, taking the drug Ficomp clinically did not significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest dose Perampanel (8 or 12 mg per day). At the same time taking perampanel with oxcarbazepine, the clearance of the latter decreased by 26%. Oxcarbazepine is rapidly metabolized with the participation of cytosolic reductase to the active metabolite of monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is unknown. Perampanel titrated to achieve a clinical effect, regardless of the accompanying AED. Effect of perampanel on CYP3A substrates In healthy volunteers, Ficomp (in a daily dose of 6 mg for 20 days) reduced the AUC of midazolam by 13%. A more significant decrease in the exposure of midazolam (and other sensitive CYP3A substrates) when taking higher doses of Faycomp cannot be ruled out. Effect of cytochrome P450 inducers on the pharmacokinetics of perampanel It is expected that powerful inducers of cytochrome P450 isoenzymes, such as rifampicin and St. John's wort, can also reduce the concentration of perampanel in plasma. Felbamate can also reduce the concentration of perampanel in the plasma. The effect of cytochrome P450 inhibitors on the pharmacokinetics of perampanel In healthy volunteers, ketoconazole (at a daily dose of 400 mg for 10 days), an inhibitor of the CYP3A4 isoenzyme, increased the AUC of perampanel by 20%, prolonged its T1 / 2 by 15% (67.8 h against 58.4 h ). When combining perampanel with another inhibitor of CYP3A4 isoenzyme with a T1 / 2 greater than that of ketoconazole or with a longer intake of the inhibitor, it is not possible to exclude the amplification effect.Potent inhibitors of other cytochrome P450 isoenzymes also have the potential to increase the concentration of perampanel. Interaction with levodopa In healthy volunteers, taking Ficompa (4 mg daily dose for 19 days) did not affect the AUC or Cmax of levodopa. Alcohol Interaction In a study of pharmacodynamic interactions in healthy volunteers, the effect that a penmanel has on alertness and responsiveness, such as driving, was enhanced by alcohol intake. Repeated use of perampanel in a daily dose of 12 mg increased the intensity of irritation, confusion and depression. This effect is also observed when taking the drug Faykompa in combination with other CNS depressants. Use in adolescents Studies of drug interactions were conducted only in adults. In a population pharmacokinetic analysis in adolescents who participated in clinical studies of phase 3, there were no noticeable differences from the general study population.