Эксалиеф®

General characteristics. Structure:

Active ingredients: 800 mg of an eslikarbazepin acetate.

Excipients: povidone K, croscarmellose sodium, magnesium stearate.

Pharmacological properties:

Pharmacodynamics. Exact mechanisms of action of an eslikarbazepin of acetate are unknown. However, according to results of the electrophysiologic researches in vitro, an eslikarbazepina acetate and its metabolites stabilize the inactivated condition of voltage-dependent natrium channels, preventing their activation and, thus, supporting periodic excitement of neurons.

Eslikarbazepina acetate and its active metabolites prevent development of epileptic seizures in preclinical models on the basis of which it is possible to predict its anticonvulsant action on the person. At people pharmacological activity of an eslikarbazepin of acetate is shown, mainly, through its active metabolite - эсликарбазепин.

Pharmacokinetics. Absorption. Eslikarbazepina acetate is actively metabolized in эсликарбазепин. After oral administration concentration of an eslikarbazepin of acetate in a blood plasma, as a rule, remains lower than the level of quantitative definition. The maximum concentration of an eslikarbazepin in a blood plasma (tmax) is reached in 2-3 h after reception. As the quantity of the metabolites found in urine corresponds more than 90% of a dose of an eslikarbazepin of acetate, bioavailability of drug can be considered high.

Distribution. Rather low linkng of an eslikarbazepin with proteins of a blood plasma (<40%), not depending on its concentration is observed. According to results of the researches in vitro presence of warfarin, diazepam, digoxin, Phenytoinum and Tolbutamidum did not exert considerable impact on linkng of an eslikarbazepin with proteins of a blood plasma. Presence of an eslikarbazepin did not exert considerable impact on linkng with proteins of a blood plasma of warfarin, diazepam, digoxin, Phenytoinum and Tolbutamidum.

Biotransformation. Eslikarbazepina acetate is quickly and intensively metabolized in the main active metabolite - эсликарбазепин by hydrolysis at "the first passing" through a liver. The maximum concentration of an eslikarbazepin in a blood plasma (Cmax) is reached in 2-3 h after reception, equilibrium concentration in a blood plasma - in 4-5 days of use of drug according to an effective elimination half-life about 20-24 h once a day. During the researches with participation of healthy volunteers and adult patients with epilepsy, the seeming elimination half-life made 10-20 h and 13-20 h respectively.

In a blood plasma carry R-likarbazepin to minor metabolites and окскарбазепин which according to the obtained data, conjugates of an eslikarbazepin of acetate, an eslikarbazepin, R-likarbazepina and an okskarbazepin with glucuronic acid are active, and also.

Eslikarbazepina acetate does not influence own metabolism and clearance. During the researches of an eslikarbazepin in fresh hepatocytes of the person insignificant induction of an isoenzyme of UGT1A1 by means of a glyukuronirovaniye was observed.

Removal. Metabolites of an eslikarbazepin of acetate are brought out of a system blood-groove, mainly, by kidneys in not changed species and a species of a conjugate with glucuronic acid. In general, эсликарбазепин and its glucuronide make more than 90% of all metabolites removed with urine (about two thirds are removed in an invariable look and one third - in the form of a glucuronide).

Linearity/nonlinearity. In the range of doses of 400-1200 mg both at healthy volunteers, and at patients with epilepsy эсликарбазепин possesses linear and dozozavisimy pharmacokinetics.

Patients of advanced age (65 years are more senior). The pharmacokinetic profile of an eslikarbazepin of acetate does not change at patients of advanced age with clearance of creatinine> 60 ml/min.

Renal failure. Metabolites of an eslikarbazepin of acetate are brought out of a system blood-groove mainly by kidneys. According to results of a research with participation of patients with a renal failure from easy to heavy severity, the clearance of drug depends on function of kidneys. During treatment of Eksaliyef® correction of its dose at clearance of creatinine is recommended <60 ml/min. Metabolites of an eslikarbazepin of acetate are brought out of a blood plasma at a hemodialysis.

Liver failure. Assessment of pharmacokinetics and metabolism of an eslikarbazepin of acetate at healthy volunteers and patients with a moderate liver failure after multiple dose of drug was carried out. The moderate liver failure did not influence pharmacokinetics of an eslikarbazepin of acetate. In case of a slight and moderate liver failure dose adjustment is not required.

At patients with a heavy liver failure the pharmacokinetics of an eslikarbazepin was not estimated.

Floor. According to results of researches with participation of patients and healthy volunteers, the pharmacokinetics of an eslikarbazepin of acetate does not depend on a floor.

Indications to use:

Эксалиеф® appoint the adult as additional therapy at partial epileptic seizures with secondary generalization or without it.

Route of administration and doses:

Эксалиеф® appoint as an additional tool to the carried-out anticonvulsant therapy. The tablet can be divided into equal parts.

The recommended initial dose - 400 mg once a day, in 1-2 weeks raise a dose to 800 mg once a day. Taking into account individual reaction to treatment the dose can be raised to 1200 mg once a day.

Эксалиеф® it is possible to accept as with food, and on an empty stomach.

Patients of advanced age (65 years are more senior): to patients of advanced age this drug is appointed with care as information on safety of Eksaliyef® at this category of patients is limited.
Patients with a renal failure: at treatment of patients with a renal failure it is necessary to be careful and carry out dose adjustment according to the clearance of creatinine (CC):

• KK> 60 ml/min.: dose adjustment is not required.
• KK of 30-60 ml/min.: an initial dose of 400 mg every other day within 2 weeks, then 400 mg once a day. However taking into account individual reaction the dose can be increased.
Patients with a liver failure: in case of a slight and moderate liver failure dose adjustment is not required.

Features of use:

Use during pregnancy and during feeding by a breast. Data on use of an eslikarbazepin of acetate for pregnant women are absent. During the researches on animals at drug reproductive toxicity is revealed. If during reception of an eslikarbazepin of acetate pregnancy comes or is planned, then expediency of use of Eksaliyef® should be estimated repeatedly. It is recommended to appoint minimal effective doses of drug and, whenever possible, to give preference to monotherapy at least in the first trimester of pregnancy. Patients need to be warned about the increased risk of malformations and to give an opportunity for carrying out prenatal screening.

Undesirable interaction of an eslikarbazepin of acetate with oral contraceptives is noted. Therefore, during treatment and until the end of the current menstrual cycle after completion of treatment it is necessary to use an alternative, effective and safe method of contraception.

It is unknown whether the eslikarbazepina acetate gets into breast milk at the person. During the researches penetration of an eslikarbazepin of acetate into breast milk of animals is noted. As it is impossible to exclude risk for the child, breastfeeding should be cancelled for the period of purpose of Eksaliyef®.

There are data that prevalence of malformations at the children who were born at women with epilepsy is 2-3 times higher, than on the population in general (about 3%). Such frustration are most often noted: crevice of an upper lip, anomaly of cardiovascular system and defects of a neurotubule. Complex therapy by anticonvulsant drugs can be followed by increase in risk of inborn malformations in comparison with monotherapy. Thus, it is necessary to appoint, at an opportunity, monotherapy. To the women capable to a child-bearing, it is necessary to consult previously with the specialist. If the woman plans pregnancy, it is necessary to analyze need of anticonvulsant therapy. It is not necessary to carry out sharp cancellation of anticonvulsant therapy as it can lead to development of an epileptic seizure that can have serious effects both for mother, and for the child.

Antiepileptic drugs can promote development of insufficiency of folic acid that can serve as an additional origin of anomalies at a fruit. When planning pregnancy and after its approach it is recommended to accept drugs of folic acid in addition. As efficiency of these drugs is not proved, specific prenatal diagnosis can be offered even to those women who accept folic acid.

At newborns the cases of bleedings caused by effect of anticonvulsant drugs were noted. As prophylactic to women last weeks to pregnancy and newborn children appoint K1 vitamin.

In certain cases reception of Eksaliyef® was followed by undesirable reactions from the central nervous system, such as dizziness and drowsiness which increased risk of accidental injuries.

Эксалиеф® can reduce efficiency of hormonal contraceptives. At use of Eksaliyef® it is recommended to use additional non-hormonal contraceptives.

As well as in a case with other antiepileptic medicines, Eksaliyef® it is necessary to cancel gradually to minimize risk of increase in frequency of epileptic seizures.

It is not recommended to apply Eksaliyef® along with okskarbazepiny as perhaps excessive influence of active metabolites.

Data on cancellation of the accompanying antiepileptic drugs during treatment of Eksaliyef® (transition to monotherapy) are absent.

During additional placebos - controlled researches with participation of patients with epilepsy at 1,1% of all population of patients receiving Eksaliyef® undesirable reaction in the form of rash is noted. At emergence of symptoms of hypersensitivity to the drug Eksaliyef® it is necessary to cancel.

About cases of heavy skin reactions in connection with use of an eslikarbazepin of acetate it was not reported.

There are data that HLA-B*1502 allele which is present at nationality Han (natives of China and Thailand) is connected with risk of development of a syndrome of Stephens-Johnson at treatment by carbamazepine. Thus, before purpose of carbamazepine or chemically related connections, at an opportunity, it is necessary to carry out screening of patients of nationality Han (natives of China and Thailand), on existence of the specified allele. The allele of HLA-B*1502 occurs at patients of other ethnic origin very seldom. At persons of Caucasian race existence of an allele of HLA-B*1502 is not followed by risk of emergence of a syndrome of Stephens-Johnson.

The hyponatremia was noted as undesirable reaction to use of Eksaliyef® less than at 1% of patients.

In most cases the hyponatremia is asymptomatic, however it can be followed by such clinical manifestations as strengthening of epileptic seizures, confusion or disturbance of consciousness. Frequency of development of a hyponatremia increases with increase in a dose of an eslikarbazepin of acetate. At a hyponatremia owing to a renal failure in the anamnesis or as a result of a concomitant use of drugs which can lead to emergence of a hyponatremia (for example, diuretics, desmopressin), to and during treatment of an eslikarbazepin acetate it is necessary to investigate concentration of sodium in blood serum. Also concentration of sodium needs to be measured in blood serum at emergence of clinical symptoms of a hyponatremia. Besides, concentration of sodium in blood serum is defined during the routine laboratory researches. At development of clinically significant hyponatremia of Eksaliyef® it is necessary to cancel.

Influence of Eksaliyef® on initially generalized epileptic seizures was not investigated. Thus, this drug is not recommended for use in this group of patients.

During clinical trials of an eslikarbazepin of acetate lengthening of an interval of PR was observed. It is necessary to be careful at certain states (for example, at low concentration of thyroxine, disturbances of cordial conductivity) or a concomitant use of medicines which, according to the available data, are followed by lengthening of an interval of PR.

At treatment of patients with a renal failure it is necessary to be careful and carry out dose adjustment according to clearance of creatinine. At KK <30 ml/min. use of Eksaliyef® is not recommended owing to the insufficient number of data.

In view of the limited number of clinical data for patients with a slight and moderate liver failure, at this category of patients of Eksaliyef® apply with care. Owing to lack of clinical data it is not recommended to appoint Eksaliyef® to patients with a heavy liver failure.

At treatment of patients anticonvulsants according to several indications noted cases of suicide thinking and behavior. Meta-analysis of randomized placebos - controlled tests of antiepileptic medicines also showed small increase in risk of suicide thinking and behavior. The mechanism of this risk is unknown, available data do not exclude a possibility of increase in risk owing to reception of an eslikarbazepin of acetate. Thus, it is necessary to watch patients regarding emergence of signs of suicide thinking and behavior, and also to consider options of the corresponding treatment. At emergence of any signs of suicide thinking and behavior patients (and to the persons which are carrying out care of patients) should see a doctor.

Antiepileptic drugs can promote development of insufficiency of folic acid that can serve as an additional origin of anomalies of development in a fruit. When planning pregnancy and after its approach it is recommended to accept drugs of folic acid in addition. As efficiency of these drugs is not proved, specific prenatal diagnosis can be offered even to those women who accept folic acid.

Researches of influence of drug on ability to drive the car and moving mechanisms were not conducted. Some patients can have a dizziness, drowsiness or a vision disorder, especially in an initiation of treatment. Respectively, it is necessary to warn patients that disturbance of their physical and/or mental capacity is probable to drive the car or mechanisms and to recommend to refrain from similar activity before establishment of influence of administration of drug on it.

Side effects:

During placebo - controlled researches with participation of 1192 adult patients with partial epileptic seizures (856 patients accepted an eslikarbazepin acetate, 336 - placebo) undesirable reactions were noted at 45,3% of patients from group of an eslikarbazepin of acetate and at 24,4% of patients from group of placebo.

Undesirable reactions were, as a rule, easy or moderate severity and arose mainly in the first weeks of treatment of an eslikarbazepin acetate.

In the table all undesirable reactions which arose more often in group of an eslikarbazepin of acetate, than in group of placebo are listed below, and were noted more than at 1 patient. Undesirable reactions are presented on a class of system of bodies and frequency: very frequent? 1/10, frequent from ≥1/100 to <1/10, infrequent from ≥1/1000 to <1/100, rare from ≥1/10 000 to <1/1000. In each category undesirable reactions are presented in decreasing order of weight.

	Very frequent	Frequent	Infrequent	Rare
From blood and lymphatic system			Anemia	Thrombocytopenia, leukopenia
From immune system			Hypersensitivity
From endocrine system			Hypothyroidism
Metabolism and disturbance of food			The increased appetite, hyporexia, hyponatremia, disturbance of electrolytic balance, cachexia, dehydration, obesity
Mental disturbances			Sleeplessness, apathy, depression, nervousness, agitation, deficit attention / hyperactivity, confusion of consciousness, differences of mood, crying, delay of psychomotor activity, nervous tension, psychotic frustration
From a nervous system	Dizziness *, drowsiness	Headache, lacks of coordination of movements *, disturbances of attention, tremor	Memory disturbances, balance disturbance, amnesia, hypersomnia, sedation, aphasia, dizesteziya, dystonia, slackness, parosmiya, imbalance of the autonomic nervous system, cerebellar ataxy, cerebellar syndrome, big epileptic seizure, peripheral neuropathy, disturbance of phases of a dream, nystagmus, disturbance of the speech, dysarthtia, hypesthesia, ageusia, burning sensation
From an organ of sight		Diplopia *, out-of-focus sight	Vision disorder, ostsillopsiya, disturbance of consensual movements of eyeglobes, conjunctiva hyperemia, sakkadichesky movement of eyes, eye pain
From an acoustic organ and balance		Dizziness	Ear pain, decrease in hearing, sonitus
From heart			Heart consciousness, bradycardia, sinus bradycardia
From vessels			Increase or lowering of arterial pressure, orthostatic hypotension
From respiratory system, bodies of a thorax and a mediastinum			Dysphonia, nasal bleeding
From a GIT		Nausea, vomiting, diarrhea	Dyspepsia, gastritis, an abdominal cavity pain, dryness in a mouth, discomfort from a GIT, abdominal distention, a duodenum inflammation, unpleasant feeling in epigastric area, a hypertrophic ulitis, an ulitis, an irritable colon, a tar-like chair, a dysphagy, unpleasant feelings in a stomach, stomatitis, a dentagra	Pancreatitis
From a liver and gall bladder			Liver failure
From skin and hypodermic fabric		Rash	Alopecia, xeroderma, the increased sweating, erythema, damage of nails, damage of skin
From a musculoskeletal system and connecting fabric			Mialgiya, dorsodynia, neck pain
From kidneys and urinary tract			Nocturia
From a reproductive system and a mammary gland			Irregular periods
Complications of the general character and reaction in an injection site		Fatigue, gait disturbance	Adynamy, indisposition, fever, hypostasis of hands and legs, undesirable reaction to drug, cold sense in hands and legs
Researches			Lowering of arterial pressure (ABP), decrease in body weight, decrease in the diastolic ABP, decrease in the systolic ABP, decrease in concentration of sodium in blood, decrease in a hematocrit, decrease in a hemoglobin content in blood, increase in heart rate, increase in activity of transaminases in blood, increase in content of triglycerides in blood, decrease in content of free triiodothyronine (ST-3) in blood, decrease in content of free thyroxine (ST-4)
Injuries and poisonings			Toxicity of drug, falling, injury of joints, poisoning, injury of skin

* At co-administration of carbamazepine and an eslikarbazepin of acetate during placebo - controlled researches the diplopia, a lack of coordination of movements and dizziness were more often noted.

Use of an eslikarbazepin of acetate is followed by lengthening of an interval of PR. Emergence of the undesirable reactions connected with lengthening of an interval of PR is possible (for example, antrioventrikulyarny blockade, a syncope, bradycardia). At the patients accepting an eslikarbazepin acetate, antrioventrikulyarny blockade of the second and above degree were not observed.

During placebo - the controlled researches relating to the antiepileptic program of a research of an eslikarbazepin of acetate were not observed such rare undesirable reactions as suppression of function of marrow, anaphylactic reactions, heavy skin reactions (for example, Stephens-Johnson's syndrome), a system lupus erythematosus or the expressed heart arrhythmia. However these reactions noted at use of an okskarbazepin. Thus, it is impossible to exclude their emergence after treatment of Eksaliyef®.

Interaction with other medicines:

Researches of interaction of drug were conducted only at adults. Eslikarbazepina acetate is actively metabolized in эсликарбазепин which is removed mainly by a glyukuronirovaniye. in vitro эсликарбазепин is the weak inductor of an isoenzyme CYP3A4 and UDF-glyukuroniltransferaza. Thus, эсликарбазепин in vivo can have the inducing effect on metabolism of medicines which are metabolized preferential by an isoenzyme of CYP3A4 or at conjugation by means of UDF-glyukuroniltransferaza. At the beginning or cancellation of treatment of Eksaliyef®, and also at change of a dose of drug new activity of enzymes is reached within 2-3 weeks. This delay should be considered at use of Eksaliyef® to or during reception of other drugs which dose needs to be adjusted at combined use with Eksaliyef®.

Eslikarbazepin inhibits CYP2C19 isoenzyme. Thus, at use of an eslikarbazepin of acetate in high doses with drugs which are metabolized mainly with the participation of CYP2C19 isoenzyme interaction of these medicines is possible.

Interaction with other antiepileptic drugs. Phenytoinum. During the research with participation of healthy volunteers simultaneous use of Phenytoinum and eslikarbazepin of acetate in a dose of 1200 mg led to reduction of influence of an active metabolite, eslikarbazepin, on average for 31-33% once a day that, most likely, is caused by induction of a glyukuronirovaniye. At the same time strengthening of influence of Phenytoinum on average for 31-35% was observed that, is presumably caused by CYP2C19 isoenzyme inhibition. Thus, taking into account individual reaction to treatment increase in a dose of Eksaliyef® and reduction of a dose of Phenytoinum can be required.

Lamotridzhin. Glyukuronirovaniye is the main way of metabolism of an eslikarbazepin and a lamotridzhin therefore their interaction is possible. During the research with participation of the healthy volunteers accepting an eslikarbazepin of acetate in a dose of 1200 mg once a day insignificant pharmacokinetic interaction of an eslikarbazepin of acetate and a lamotridzhin (weakening of action of a lamotridzhin for 15%) is on average noted therefore dose adjustment is not required. However owing to individual variability some patients can have clinically significant effect of this interaction.

Topiramat. During the research with participation of healthy volunteers at simultaneous use of a topiramat and eslikarbazepin of acetate in a dose of 1200 mg significant changes of action of an eslikarbazepin are noted once a day, however action of a topiramat decreased by 18% that, most likely, is caused by reduction of its bioavailability. Dose adjustment in this case is not required.

Carbamazepine, valproic acid and to levetiratseta. At co-administration by carbamazepine the risk of the following undesirable reactions increases: a diplopia (at 11,4% of patients at a concomitant use of carbamazepine and at 2,4% of the patients who were not accepting carbamazepine); an incoordination (at 6,7% of patients at a concomitant use of carbamazepine and at 2,7% of the patients who were not accepting carbamazepine); dizziness (at 30,0% of patients at a concomitant use of carbamazepine and at 11,5% of the patients who were not accepting carbamazepine). It is impossible to exclude risk of strengthening of other specific undesirable reactions caused by simultaneous use of carbamazepine and an eslikarbazepin of acetate. Results of the analysis of the data of pharmacokinetics received in phase III researches with participation of adult patients with epilepsy showed that carbamazepine promotes increase in clearance of an eslikarbazepin. According to the available data, the concomitant use of valproic acid or a levetiratsetam does not influence action of an eslikarbazepin, however these data are not supported with results of traditional researches of interaction of drugs.

Eslikarbazepina acetate increases clearance of carbamazepine a little. However owing to the insufficient number of data these results need to be considered with care.

Other medicines. Oral contraceptives. At use of an eslikarbazepin of acetate in a dose of 1200 mg once a day at the women applying oral contraceptives weakening of systemic action of levonorgestrel and ethinylestradiol on average for 37% and 42% respectively was observed that, most likely, is caused by induction of an isoenzyme of CYP3A4. Thus, women of childbearing age have to use adequate methods of contraception during treatment of Eksaliyef® and before the termination of the current menstrual cycle after cancellation of this drug.

Warfarin. At simultaneous use of warfarin and an eslikarbazepin of acetate in a dose of 1200 mg small (23%), but statistically significant weakening of effect of S-warfarin was observed once a day. Influence of an eslikarbazepin of acetate on pharmacokinetics of R-warfarin or on coagulability of blood is noted. However, owing to individual variability of interaction of drugs in the first weeks after the beginning or the end of simultaneous use of warfarin and an eslikarbazepin of acetate it is necessary to pay special attention to observation of the patient.

Digoxin. During the research with participation of healthy volunteers influence of an eslikarbazepin of acetate in a dose of 1200 mg at reception is noted on digoxin pharmacokinetics once a day. It allows to assume that the eslikarbazepina acetate does not make impact on a P-glycoprotein.

Monoaminooxidase inhibitors. Considering structural interrelation of an eslikarbazepin of acetate and tricyclic antidepressants, interaction between an eslikarbazepin acetate and inhibitors of a monoaminooxidase theoretically perhaps.

Contraindications:

Hypersensitivity to active ingredient, other derivatives of a karboksamid (for example, to carbamazepine, an okskarbazepin) or to any of excipients.

Atrioventricular block of the second or third degree.

Patients of children's age: Эксалиеф® it is not recommended to apply at children up to 18 years as data on safety and efficiency of drug for this category of patients are absent.

Patients with a heavy renal failure: data on use of drug for this category of patients are not enough.

Patients with a heavy liver failure: Эксалиеф® it is not recommended to apply at patients with a heavy liver failure as the pharmacokinetics of an eslikarbazepin for this category of patients was not investigated.

Overdose:

At accidental overdose of Eksaliyef® such reactions from the central nervous system were observed as dizziness, shaky gait and a hemiparesis. The specific antidote of this drug is unknown.

In case of overdose the corresponding symptomatic and supporting treatment is shown. If necessary metabolites of an eslikarbazepin of acetate effectively are removed at a hemodialysis.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Tablets of 800 mg. On 10 tablets in the blister (PVC/aluminium) or (aluminum/aluminium). On 2, 3, 6 or 9 blisters place in a cardboard pack together with the instruction on a medical use.