Inovelon

General characteristics. Structure:

Active ingredient: 100 mg or 200 mg of a rufinamid.

Excipients: sodium lauryl sulfate, starch corn, gipromelloza, lactoses monohydrate, cellulose microcrystallic, sodium of a kroskarmelloz, silicon dioxide colloid anhydrous, magnesium stearate.

Structure of a film cover: Opadry 00F44042 (gipromelloza, macrogoal 8000/polyethyleneglycol 8000, titanium dioxide (E171), talc, ferrous oxide red (E172)).

Pharmacological properties:

Pharmacodynamics. Action mechanism. Rufinamid modulates activity of natrium channels, prolonging their inactivated state. Rufinamid is active in a number of epilepsy models on animals.

Clinical experience. Inovelon applied in double-blind, placebo - a controlled research at doses to 45 mg/kg/days within 84 days at 139 patients with insufficiently controlled spasms caused by Lennox-Gasto's syndrome (including atypical absentias epileptica and akinetic attacks). The research included male and female patients (age from 4 to 30 years) who at the same time received from 1 to 3 antiepileptic drugs with the fixed doses. Each patient in a month before inclusion in testing had not less than 90 attacks. Considerable improvement on all three main indicators is noted: percent of changes of the general frequency of attacks in 28 days in the supporting phase, in comparison with initial (-35.8% in Inovelon's group in comparison with –1.6% in group of placebo, р =0.0006); number of tonic-atonic spasms (-42.9% in Inovelon's group in comparison with 2.2% in group of placebo, р =0.0002), severity of attacks according to the principles of the Global assessment which is carried out by parents/trustees of patients by the end of a double-blind phase (considerable or very considerable improvement at 32.2% in Inovelon's group in comparison with 14.5% in group of placebo, р =0.0041).

Pharmacokinetic / фармакодинамическое modeling in population showed that such parameters as decrease in all and tonic-atonic spasms, improvement of global assessment of severity of attacks and increase in probability of decrease in frequency of attacks, depended on concentration of a rufinamid.

Pharmacokinetics. Absorption. The maximum levels in plasma are reached approximately in 6 h after introduction. At healthy volunteers (on an empty stomach and after food) and at patients of Cmax and AUC of a rufinamid increase in plasma with a dose less, than in proportion that is probably caused by the absorption limited on a dose. After single doses meal increases bioavailability (AUC) of a rufinamid approximately for 34%, and peak concentration in plasma - for 56%.

Distribution. In the researches in vitro only a small part of a rufinamid (34%) contacted proteins of plasma at the person, and linkng with albumine made about 80% of this indicator. It indicates the minimum risk of medicinal interactions by shift from a binding site at simultaneous use of other drugs. Rufinamid is evenly distributed between erythrocytes and plasma.

Biotransformation. Rufinamid is almost completely brought at metabolism. The main way of metabolism is hydrolysis of karboksilamidny group to pharmacological inactive acid derivative CGP 47292. Metabolism through P450 cytochrome very insignificant. It is impossible to exclude formation of small amounts of conjugates of glutathione.

It is shown what руфинамид has small or insignificant ability of invitrodeystvovat as the competitor or inhibitor on the mechanism of the following P450 of enzymes of the person: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 CYP4A9/11-2.

Removal. Plasma elimination half-life makes about 6-10 h at healthy subjects and at patients with epilepsy. At introduction twice a day with 12-hour intervals руфинамид collects in the degree predetermined by terminal T1/2 and it demonstrates that the pharmacokinetics of a rufinamid does not depend on time (i.e. there is no metabolism autoinduktion).

At a research with a radioactive label at three healthy volunteers initial substance (руфинамид) was the main radioactive component in plasma, making about 80% of the general radioactivity, the metabolite of CGP 47292 made about 15%. The main way of removal of the substance connected with operating was renal excretion which corresponded to 84.7% of a dose.

Linearity/nonlinearity. Bioavailability of a rufinamid depends on a dose. At increase of a dose bioavailability decreases.

Pharmacokinetics at special groups of patients. Floor. For impact assessment of a sex of the patient on pharmacokinetics of a rufinamid carried out modeling of pharmacokinetics to populations. Results of assessment showed that the sex of the patient has no clinically significant influence on pharmacokinetics of a rufinamid.

Renal failure. The pharmacokinetics of a single dose of 400 mg of a rufinamid did not change at subjects with a chronic and heavy renal failure in comparison with that at healthy volunteers. However when using a hemodialysis after introduction of a rufinamid levels in plasma decreased approximately by 30% that demonstrates advantage of a hemodialysis in case of overdose.

Abnormal liver function. At patients with abnormal liver functions researches were not conducted. Therefore Inovelon it is not necessary to apply at patients with heavy abnormal liver functions.

Children (2-12 years)

Usually the clearance of a rufinamid at children is lower, than at adults that is connected with differences in body sizes. Researches at newborns and children are younger than 2 years were not conducted.

Elderly people

The pharmacokinetics research at elderly healthy volunteers did not reveal considerable difference of pharmacokinetic parameters in comparison with more young people.

Indications to use:

It is shown as auxiliary therapy at treatment of the attacks connected with Lennox-Gasto's syndrome at patients at the age of 4 years and is more senior.

Route of administration and doses:

Rufinamidy the doctor specializing in the field of pediatrics or neurology with experience of treatment of epilepsy has to appoint treatment.

Dosing mode. Children aged from 4 years are also more senior with body weight less than 30 kg. Patients with body weight less than 30 kg which are not receiving therapy by Valproatum: the initial daily dose has to make 200 mg. Depending on clinical reaction and portability the dose can be increased by 200 mg/days not more often than each 2 days, before achievement of the maximum recommended dose of 1000 mg/days.

Patients with body weight less than 30 kg receiving therapy by Valproatum: As Valproatum considerably reduces clearance of a rufinamid, less than 30 kg are recommended to patients with body weight the lowered maximum dose of Inovelon against the background of therapy by Valproatum. The initial daily dose has to make 200 mg. Depending on clinical reaction and portability the dose can be increased by 200 mg/day through time interval making not less than 2 days before achievement of the maximum recommended dose of 600 mg/days.

Adults, teenagers and children aged from 4 years are also more senior with the body weight of 30 kg and more. The initial daily dose has to make 400 mg. Depending on clinical reaction and portability the dose can be increased by 400 mg/days, not more often than each 2 days, before achievement of the maximum recommended dose provided below in the table.

Treatment termination. In need of therapy cancellation rufinamidy administration of drug should be stopped gradually. Cancellation of a rufinamid was carried out by a dose decline approximately for 25% by each two days.

In case of the admission of one or more doses it is necessary to make the decision in each separate case.

By results of uncontrollable open researches steady long efficiency is expected; controlled researches more than three months were not conducted.

Children. Safety and efficiency of a rufinamid at children are younger than 4 years is not established.

Elderly people. Information on use of a rufinamid for patients of advanced age is limited. As the pharmacokinetics of a rufinamid at elderly people does not change, dose adjustment for patients is more senior than 65 years it is not required.

Patients with a renal failure. Dose adjustment is not required to patients with heavy renal failures.

Patients with an abnormal liver function. Use for patients with an abnormal liver function was not studied. At treatment of patients from easy to moderate degree it is recommended to be careful with abnormal liver functions and to carefully titrate a dose. It is not recommended to use drug at patients with heavy abnormal liver functions.

Route of administration. Rufinamid is intended for intake. Drug should be accepted twice a day, in the morning and in the evening, two equal doses, washing down with water. As food influences bioavailability of a rufinamid, Inovelon it is necessary to accept together with food. If it is difficult for patient to swallow, a tablet it is possible to crush, stir the received powder in half of glass of water and to drink.

Features of use:

Pregnancy. The general risk connected with epilepsy and antiepileptic medicines

It is established that at the children born by women with epilepsy, malformations meet by two-three times more often, than at population in general, prevalence of such malformations at which makes about 3%. In the group receiving treatment increase of frequency of malformations at polytherapy use is noted, however it is unknown in what degree it depends on treatment and/or a disease. It is not necessary to interrupt effective antiepileptic therapy as the exacerbation of a disease can have serious effects for mother and a fruit.

The risk connected srufinamidy. Researches on animals did not find teratogenic effect, however toxicity for a fruit with maternal toxicity is noted. The potential risk for the person is unknown.

Clinical these uses of a rufinamid during pregnancy are absent.

Rufinamid it is not necessary to apply during pregnancy without emergency. Drug is not recommended to be used to women of reproductive age who do not use contraceptive means.

At treatment of the woman of reproductive age by Inovelon have to apply contraceptive means.

If the woman accepting руфинамид plans pregnancy, use of this drug has to be carefully reconsidered. During pregnancy it is not necessary to interrupt effective antiepileptic therapy rufinamidy as the exacerbation of a disease can have serious effects for mother and a fruit.

Feeding by a breast. It is unknown whether it is allocated руфинамид in breast milk. As it is impossible to exclude potential dangerous impact on the child when breastfeeding, it is necessary to avoid feeding by a breast during treatment of mother rufinamidy.

Fertility. The therapies given about influence rufinamidy on fertility are absent.

Special instructions. Cancellation of a rufinamid. For decrease in probability of the spasms caused by drug withdrawal руфинамид it is necessary to cancel gradually. In clinical tests cancellation of a rufinamid was carried out by a dose decline approximately for 25% every two days. There are not enough data on cancellation of the accompanying antiepileptic means on reaching control over spasms by means of introduction of a rufinamid to the scheme of treatment.

Reactions from TsNS. Treatment rufinamidy was associated with dizziness, drowsiness, an ataxy and disturbances of gait that can increase probability of accidental falling at this category of patients. The patients and persons who are carrying out care of such patients have to be careful if they are not informed on potential effects of this drug.

Shortening of an interval of QT. According to data of the research QT руфинамид causes shortening of an interval of QT sproportsionalno concentration. Though the mechanism of this phenomenon and its influence on safety are not known, making decision on purpose of a rufinamid to patients for whom further shortening of an interval of QT spredstavlyaet the risk (for example, patients with an inborn syndrome of a short interval of QT or patients with the family anamnesis of such syndrome), demands clinical assessment.

Women of reproductive age. At treatment of the woman of reproductive age by Inovelon have to apply contraceptive means. The doctor needs to be convinced of use by the patient of appropriate contraception and to estimate adequacy of the used peroral contraceptive means and its doses, proceeding from an individual clinical picture of the patient.

Lactose. Inovelon contains lactose. Patients with rare hereditary problems of intolerance of a galactose, deficit of lactase of Lapp or with disturbance of absorption of glucose galactose should not use this drug.

Preventions. Epileptic status. In clinical tests of a rufinamid cases of the epileptic status which were absent in groups of placebo are noted. In 20% of cases it led to cancellation of a rufinamid. At development in the patient of new type of spasms and/or at increase of frequency of cases of the epileptic status in comparison with исходньм a state it is necessary to carry out repeated assessment of a ratio "advantage risk" of therapy.

Hypersensitivity reactions. Therapy rufinamidy was associated with a heavy syndrome of hypersensitivity to antiepileptic means, including DRESS syndrome (the reaction to drug which is followed by an eosinophilia and system manifestations) and Stephens-Johnson's syndrome. Signs and symptoms of such frustration had various character; as a rule, but it is not exclusive, at patients the fever and rash connected with involvement of other systems and bodies were noted. A lymphadenopathy, disturbances of indicators of function of a liver at a laboratory research belong to other manifestations connected with a hypersensitivity syndrome and a hamaturia. As these disturbances are various on the expressiveness, also other not specified signs and symptoms from other systems of bodies can be noted. The hypersensitivity syndrome to antiepileptic means developed in close connection with time of the beginning of therapy rufinamidy, and also at children. At suspicion on such reaction it is necessary to stop reception of a rufinamid and to begin alternative treatment. In total patients who had a rash against the background of reception of a rufinamid have to be under careful observation of the doctor.

Suicide thinking. At patients who were treated antiepileptic means in connection with various indications, noted suicide thinking and behavior. Meta-analysis of randomized placebos - controlled clinical trials of antiepileptic means also showed small increase in risk of suicide thinking and behavior. The mechanism of it is not known, the available data do not exclude a possibility of increase in such risk connected using Inovelon.

In this regard patients have to be under observation concerning signs of suicide thinking and behavior, if necessary it is necessary to consider expediency of the corresponding treatment. At emergence of signs of suicide thinking or behavior patients (and to the persons which are carrying out care of such patients) are recommended to see a doctor.

Features of influence of drug on ability to manage motor transport and to work with mechanisms. Inovelon can cause dizziness, drowsiness and an ambiguity of sight. Depending on individual sensitivity руфинамид can exert impact, from minimum to strong, on ability to manage motor transport and to work with mechanisms. Patients should recommend to be careful at implementation of the types of activity demanding high degree of attention, for example, at control of motor transport or during the work with mechanisms.

Side effects:

Within the program of clinical development at patients with various types of epilepsy which received руфинамид, such reactions as a headache, dizziness, fatigue and drowsiness were most often noted. Drowsiness and vomiting were the most widespread side reactions which were more often observed at the patients with Lennox-Gasto's syndrome receiving руфинамид than at those who received placebo. Side reactions were, as a rule, from weak to moderate degree. Drug withdrawal frequency at Lennox-Gasto's syndrome because of side reactions made 8.2% at the patients receiving руфинамид and 0% - in group of placebo. Rash and vomiting were the most widespread side reactions leading to cancellation of therapy in group of a rufinamid.

At assessment of frequency of side reactions the following gradation is used: "it is very frequent" - ≥1/10, is "frequent" - from ≥1/100 to <1/10, "it is not frequent" - from ≥1/1000 to <1/100, is "rare" - from ≥1/10000 to <1/1000.

Side reactions which arose at patients with Lennox-Gasto's syndrome in the general population receiving руфинамид more often than in group of placebo are listed below.

Infections and invasions: often - pneumonia, flu, a nasopharyngitis, an ear infection, sinusitis, rhinitis.

Disturbances from immune system: not often - hypersensitivity reactions.

Disbolism and frustration of food: often - anorexia, disturbance of food, a loss of appetite.

Mental disorders: often - uneasiness, sleeplessness.

Disturbances of a nervous system: very often - drowsiness, a headache, dizziness, it is frequent - the epileptic status, spasms, lacks of coordination, a nystagmus, a psychomotor hyperactivity, a tremor.

Disturbances from organs of sight: often - a diplopia, a sight ambiguity.

Disturbances from acoustic organs: often - вертиго.

Disturbances from respiratory organs, a thorax and a mediastinum: often - nasal bleeding.

Disturbances from digestive organs: very often - nausea, vomiting, it is frequent - pain in epigastric area, a lock, dyspepsia, diarrhea.

Disturbances from gepatobiliarny system: not often - increase in level of enzymes of a liver.

Disturbances from skin and hypodermic cellulose: often - rash, an acne.

Disturbances from a musculoskeletal system and connecting fabric: often - a dorsodynia.

Disturbances from reproductive system and mammary glands: often - disturbance of a menstrual cycle.

The general disturbances and states on the site of introduction: very often - fatigue, it is frequent - gait disturbance.

The disturbances revealed at laboratory researches: often - weight reduction.

Injuries, poisonings and effects of influence of the external reasons: often - head injuries, a contusion.

Interaction with other medicines:

Potential influence of other medicines on руфинамид. Other antiepileptic medicines. Concentration of a rufinamid are not exposed to clinically significant changes at combined use with known enzyme - the inducing antiepileptic means.

The patients receiving Inovelon who began to accept Valproatum can have a substantial increase of concentration of a rufinamid in plasma. The most expressed increase in such concentration was observed at patients with the low body weight (less than 30 kg). Therefore for patients with body weight less than 30 kg at the beginning of therapy by Valproatum it is necessary to provide Inovelon dose decline.

Introduction to the scheme of treatment or cancellation of these medicines, or correction of their dose in the course of therapy rufinamidy can demand the corresponding dose adjustment of a rufinamid.

Considerable changes of concentration of a rufinamid at combined use with lamotridzhiny, topiramaty or benzodiazepines were not observed.

Potential impact of a rufinamid on other medicines. Other antiepileptic medicines. Pharmacokinetic interaction between rufinamidy and other antiepileptic means was estimated at patients with epilepsy, using pharmacokinetic modeling at population. It is shown what руфинамид does not make clinically significant impact on equilibrium concentration of carbamazepine, a lamotridzhin, phenobarbital, a topiramat, Phenytoinum or Valproatum.

Oral contraceptives. Combined use of 800 mg of a rufinamid twice a day and the combined oral contraceptive (ethinylestradiol of 35 mkg and norethindrone of 1 mg) within 14 days leads to decrease in AUC0-24 of ethinylestradiol, on average, for 22%, and norethindrone - for 14%. Researches of other oral or implanted contraceptives were not conducted. The women of reproductive age using hormonal contraceptives are recommended to apply an additional safe and effective method of contraception.

P450 cytochrome enzymes. Rufinamid is metabolized by hydrolysis and is practically not metabolized by P450 cytochrome enzymes. Rufinamid does not inhibit activity of enzymes of P450 cytochrome. Therefore clinically significant interactions connected with inhibition rufinamidy systems of P450 cytochrome are improbable. Rufinamid induces CYP3A4 enzyme of P450 cytochrome and therefore can reduce concentration in plasma of substances which are metabolized by this enzyme. Degree of manifestation of this effect - from weak to moderate. In 11 days of use of 400 mg of a rufinamid twice a day the average activity of CYP3A4 estimated on clearance of a triazolam increased for 55%. Exposure of a triazolam decreased by 36%. Higher doses of a rufinamid can lead to more expressed induction. It is impossible to exclude ability of a rufinamid to reduce exposure of substances which are metabolized by other enzymes or are transferred by transport proteins, such as the R-glycoprotein.

It is recommended to carry out careful monitoring of the patients accepting substances which are metabolized by CYP3A4 enzyme, within two weeks after the beginning or the end of treatment rufinamidy, and also after essential change of a dose. Dose adjustment of the accompanying medicines can be required. These recommendations should be considered also at simultaneous use of a rufinamid with the substances having a narrow therapeutic window such as warfarin and digoxin.

In a special research of interaction at healthy subjects influence of a rufinamid in a dose of 400 mg twice a day on pharmacokinetics of olanzapine, CYP3A4 substrate is not revealed.

Data on interaction of a rufinamid with alcohol are absent.

Contraindications:

— hypersensitivity to active ingredient, derivatives of triazole or to any of excipients;

— children are younger than 4 years.

Overdose:

After acute overdose it is recommended to wash out a stomach or to cause vomiting. The specific antidote of a rufinamid does not exist. The maintenance therapy, including a hemodialysis is recommended.

At introduction of repeated doses on 7200 mg/days significant signs or symptoms of overdose were not observed.

Storage conditions:

To store drug in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 4 years.

Issue conditions:

According to the recipe

Packaging:

10 pieces - blisters from aluminum foil (1) - boxes cardboard. 10 pieces - blisters from aluminum foil (5) - boxes cardboard. 10 pieces - blisters from aluminum foil (6) - boxes cardboard.