Exalief - instructions for use, doses, side effects, contraindications

Active substanceEslicarbazepineEslicarbazepine

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Exalieff®

pills inwards

Eysay Europe Limited United Kingdom

Dosage form: & nbsppills

Composition:

1 tablet contains:

active substance: eslcarbazepine acetate (800 mg).

Excipients: povidone To 29/32 62.2 mg, croscarmellose sodium 53.3 mg, magnesium stearate 17.8 mg.

Description:

White oblong tablets with engraving ESL 800 on one side and risk on the other.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.F The carboxamide derivatives

N.03.A.F.04 Eslicarbazepine

Pharmacodynamics:

Mechanism of action

Exact mechanisms of action eslikarbazepine acetate are unknown. However, according to the results electrophysiological research in vitro eslcarbazepine acetate and its metabolites stabilize the inactivated state of potential-dependent sodium channels, preventing their activation and, thus, supporting the periodic excitation of neurons.

Farmakodinameffects

Eslikarbazepine acetate and its active metabolites prevent the development of epileptic seizures in preclinical models, which makes it possible to predict its anticonvulsant effect in humans. In humans, pharmacological activity eslikarbazepine acetate is manifested mainly through its active metabolite - eslikarbazepine.

Clinical efficacy and safety

The efficacy and safety of eslacarbazepine acetate was established in four double-blind, placebo-controlled Phase III studies in 1,703 adult patients with partial epileptic seizures, refractory to treatment by others (from one to a combination of three) antiepileptic drugs (PEP). Accompanying reception Oxcarbazepine and felbamate were excluded in these studies.

The use of eslikarbazepine acetate in single daily doses of 400 mg, 800 mg and 1200 mg was studied. It was found that the use of eslikarbazepine acetate in doses of 800 mg and 1200 mg once a day is significantly more effective in reducing the frequency of seizures compared with placebo during the 12-week maintenance period.

According to the combined results of all research III phase, the proportion of patients with at least 50% response was (among 1581 analyzed) 19.3% for the placebo group, 20.8% for the group, 400 mg eslikarbazepine acetate, 30.5% for the group taking 800 mg eslikarbazepine acetate and 35.3% for 1200 mg eslikarbazepine acetate per day.

Patients of advanced age (over 65 years)

Safety and efficiency eslikarbazepine acetate as an additional therapy for partial epileptic seizures in elderly patients was assessed in an uncontrolled study duration of 26 weeks in 72 patients over the age of 65 years. The results of the study showed that the incidence of adverse events associated with taking the drug in this population (65.3%) was similar to results obtained from patients participating in double-blind phase studies III (66.8%). The most common adverse events associated with taking the drug were dizziness (12.5%), drowsiness (9.7%), fatigue, seizures and hyponatremia (8.3% each), nasopharyngitis (6.9%) and upper respiratory tract infections (5.6%). 50 of the 72 patients who started the study completed a 26-week treatment period, which corresponds to a 69.4% retention rate on the drug.

Pharmacokinetics:

Suction

Eslikarbazepine acetate is largely metabolized in eslikarbazepine. After oral administration, the concentration of eslikarbazepine acetate in blood plasma, as a rule, remains below the level of quantitative determination. The time to reach the maximum concentration (t_max) eslikarbazepine in plasma is 2-3 hours after administration.Bioavailability of the drug can be considered high, since the amount of metabolites found in the urine is more than 90% of the dose eslikarbazepine acetate.

Distribution

The binding of eslikarbazepine to plasma proteins is relatively low (<40%), and does not depend on its concentration. According to the research results in vitro, the presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide ne has a significant effect on the degree of binding of eslikarbazepine to plasma proteins. Eslikarbazepin turn, in turn, practically does not affect the binding to plasma proteins of warfarin, diazepam, digoxin, phenytoin and tolbutamide.

Metabolism

Eslikarbazepine acetate at the first passage through the liver is rapidly and intensely metabolized into its main active metabolite - eslikarbazepine by hydrolysis. The maximum concentration (C_max) of eslikarbazepine in plasma is achieved 2-3 hours after administration, and the equilibrium concentration after 4-5 days of application of the drug once a day, which corresponds to an effective half-life of about 20-24 hours. In studies involving healthy volunteers and adult patients with epilepsy, the apparent period half-life was 10-20 and 13-20 hours, respectively.

A small number of the following metabolites is found in plasma: R-lycarbazepine and oxcarbazepine, which have pharmacological activity, as well as conjugates of eslikarbazepine acetate, eslikarbazepine. R-likarbazepine and oxcarbazepine with glucuronic acid.

Eslikarbazepine acetate does not affect its own metabolism and clearance.

Eslikarbazepine is weak inducer of isoenzyme CYP3A4 and the inhibitory effect on the isoenzyme CYP2C19 (see section "Interaction with other medicinal products ").

In the course of experimental studies on fresh human hepatocytes, eslikarbazepine capacity insignificantly induce isoenzyme activity UGT1A1, participating in the glucuronation reactions.

Excretion

Metabolites of eslikarbazepine acetate are excreted from the systemic blood stream, mainly by the kidneys, in unchanged form and in the form of conjugates with glucuronic acid. Eslicarbazepine and its glucuronide account for more than 90% of all metabolites excreted in urine (about 2/3 are excreted as eslikarbazepine and 1/3 in the form of glucuronide).

Linearity / Nonlinearity

In the dose range of 400-1200 mg, both in healthy volunteers and in patients with epilepsy, eslikarbazepine acetate has a linear and dose-dependent pharmacokinetics.

Use in special patient groups

Patients older than 65 years)

Pharmacokinetic profile eslikarbazepine acetate does not change in elderly patients with creatinine clearance (CK)> 60 ml / min (see section "Method of administration and dose").

Patients with renal insufficiency

Metabolites of eslikarbazepine acetate are excreted from the systemic blood stream, mainly by night. According to the results of the study with the participation of patients with mild to severe renal insufficiency, the clearance of the drug depends on the function of the kidneys. During treatment with the drug Exalieff®, correction of its dose with CC> 60 ml / m and n is recommended (see section "Method of administration and dose").

Metabolites of eslikarbazepine acetate are excreted from the blood plasma during hemodialysis.

Patients with hepatic Mr.insufficiency

The pharmacokinetics and metabolism of eslikarbazepine acetate have been studied in healthy volunteers and patients with moderate hepatic insufficiency after repeated administration of the drug.Moderate hepatic insufficiency did not affect the pharmacokinetics eslikarbazepine acetate. In the case of mild and moderate hepatic insufficiency, dose adjustment is not required (see section "Method of administration and dose").

In patients with severe hepatic insufficiency, pharmacokinetics eslikarbazepine has not been studied.

Effect of sex

Studies involving patients and healthy volunteers did not reveal the dependence of pharmacokinetics eslikarbazepine acetate from the floor.

Indications:

Exalieff® is prescribed to adults as an adjunctive therapy for partial seizures with or without secondary generalization.

Contraindications:

Hypersensitivity to eslikarbazepine acetate, other derivatives carboxamide (e.g., carbamazepine, oxcarbazepine) or any of the excipients of the formulation.

Atrioventricular block of the second or third degree.

Children under 18 years of age (there are no safety and efficacy data for this category of patients).

Patients from severe renal failure (CK <30 mL / min) (data on the use of the drug in this category of patients is not enough).

Patients with severe hepatic impairment (pharmacokinetics eslikarbazepine acetate in this category of patients has not been studied).

Carefully:

Low concentration of thyroxine in the blood.

Cardiac conduction abnormalities or simultaneous administration of drugs that promote the lengthening of the interval PR (see section "Special instructions").

Renal failure of mild to moderate severity (dose adjustment should be performed in accordance with creatinine clearance (see section "Method of administration and dose")).

Hepatic insufficiency of a lethal and moderate severity (in view of the limited number of clinical data).

Hyponatremia (see section "Special instructions").

Pregnancy and lactation:

General risks associated with epilepsy and PEP

There is evidence that the prevalence of developmental malformations in children born to women with epilepsy is 2-3 times higher than in the general population. Most often, the following defects are detected: cleavage of the upper lip, anomalies in the development of the cardiovascular system, and neural tube defects. Combination therapy with anticonvulsant drugs is accompanied by an increased risk of developingcongenital malformations in comparison with monotherapy, in connection with which, it is necessary, if possible, to prescribe monotherapy.

Women with preserved genital potential, especially planning pregnancy, should be observed by a specialist. Necessity antiepileptic therapy is estimated in women planning pregnancy.

It is unacceptable to abruptly cancel anticonvulsant therapy because of the risk of developing an epileptic attack, which can lead to serious consequences for both the mother and the fetus.

Women with preserved childbearing potential and contraception

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

Pregnancy

Data on the use of eslikarbazepine acetate in pregnant women are absent. In the course of animal studies, the drug showed reproductive toxicity. The expediency of prescribing the drug Exalieff® should be assessed repeatedly if pregnancy occurs or is planned during its administration.It is recommended to prescribe the minimum effective dose of the drug and, if possible, give preference monotherapy at least in the first trimester of pregnancy. Patients should be warned about the increased risk of congenital malformations in the fetus and provide an opportunity for prenatal screening.

Monitoring and precautions

Antiepileptic drugs may contribute to the development of a deficiency of folic acid, which is an additional cause of anomalies in the fetus. When planning pregnancy and after its onset, it is recommended to take folic acid supplements in addition.

Specific prenatal diagnosis of congenital malformations should be offered even to those women who take folic acid.

Newborns

In newborns whose mothers received anticonvulsant therapy, there were cases of development of bleeding. As a preventive measure, women should be given vitamin K1 in the last weeks of pregnancy and newborns.

Breast-feeding

There is no data on the penetration of eslikarbazepine acetate into human breast milk.In the course of the studies, the penetration of eslikarbazepine acetate into the breast milk of animals was detected. Breastfeeding should be abolished for the duration of prescribing of eslikarbazepine acetate, as the risk to the child can not be ruled out.

Fertility

The effect of eslikarbazepine acetate on fertility and the first generation of offspring was evaluated in a study in rats and mice. In the study, male and female rats were found to have a violation of female fertility. In a study in mice, there was an effect on the development of embryos, but this effect can also be caused by a decrease in the number of yellow bodies. The mice showed an increased risk of general disorders and major skeletal anomalies. There was no effect on fertility rates of the first generation of offspring in rats and mice.

Dosing and Administration:

Exalieff® is prescribed in addition to ongoing anticonvulsant therapy. Exalieff® is taken orally regardless of food intake. The tablet can be divided into two equal parts.

The recommended initial dose is 400 mg once a day, after 1-2 weeks the dose is increased to 800 mg once a day.Taking into account the individual response to treatment, the dose can be increased to 1200 mg once a day.

The use in elderly patients (over 65 years)

Correction of the vine is not required, provided that the kidney function is not impaired.

Patients with renal insufficiency

In the treatment of patients with renal insufficiency, care should be taken and dosage adjustment should be performed depending on the value of the CC:

- KK> 60 ml / min: correction of a dose is not required.

- CK 30-60 ml / min: initial dose of 400 mg every other day for 2 weeks, then 400 mg once a day. However, taking into account the individual response, the dose can be increased.

- CK <30 ml / min: use of patients with severe renal failure are not recommended because of insufficient data.

Patients with hepatic insufficiency

In the case of mild and moderate hepatic insufficiency, dose adjustment is not required.

The pharmacokinetics of eslikarbazepine acetate in patients with severe hepatic insufficiency was not studied (see the sections "Pharmacokinetics", "Special instructions"), therefore its use in this category of patients is not recommended.

Application the children under 18 years of age

The safety and efficacy of eslacarbazepine acetate in children and adolescents under the age of 18 years have not been established. No data available.

Side effects:

In the course of placebo-controlled studies involving 1842 adult patients with partial epileptic seizures (of which 1282 took eslcarbazepine acetate and 560 - placebo), adverse reactions were noted in 50.7% of patients in the eslcarbazepine acetate group and in 27.7% of patients in the placebo group. Unwanted reactions were generally mild or moderate in severity and occurred mainly in the first weeks of therapy.

The undesirable reactions that occurred during the therapy with the drug Exalieff® are mainly dose-dependent reactions associated with the membership of the carboxamide class. The most frequent adverse reactions that occurred during clinical trials in adult patients with epilepsy, as in the group of eslikarbazepine acetate, and in the control group were dizziness, drowsiness, headache and nausea. Most adverse reactions were observed in less than 3% of patients in both groups.

The table below lists all undesirable reactions, fixed in the database of safety of eslikarbazepine acetate, presented according to the system-organ classification and frequency of their occurrence. In this case, all the undesirable phenomena associated with taking the drug, in double-blind clinical studies in the group of eslikarbazepine acetate. The following criteria were also taken into account: frequency of occurrence,

greater than that in the placebo group, severity, severity and cause-effect relationship in each case, compliance with the pharmacological properties of eslikarbazepine acetate, as well as data from open-label research and post-marketing data.

Unwanted reactions are divided according to their frequency of occurrence: 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, adverse reactions are presented in descending order of severity.

	Highly frequent	Frequent	Infrequent	Rare
Hapmating on the part of the blood and lymphatic system			Anemia	Thrombocytopenia Leukopenia
Immune system disorders			Hypersensitivity
Disorders from the endocrine system			Hypothyroidism
Disorders from the metabolism and nutrition		Hyponatremia Decreased appetite	Balance violations electrolytes Dehydration Hypochloraemia
Violations psyche		Insomnia	Apathy Depression Nervousness Agitation Irritability Attention Deficit / Hyperactivity Syndrome. Confusion consciousnesses Lability moods Tearfulness Deceleration of the speed of psychomotor reactions Psychotic disorders
Disturbances from the nervous system	Dizziness Drowsiness	Head pain Violation attention Tremor Ataxia Violation of balance	Violation coordination of movement Decrease memory Amnesia Increased drowsiness Sedative Effect Aphasia Dysaestia Dystonia Lethargy Parosmia Cerebrospinal Syndromeand Peripheral Neuropathy Nystagmus Violation of speech Dysatria Burning sensation Paresthesia Migraine
Disturbances on the part of the organ of sight		Diplopia Defocused vision	Visual disturbances Oscilloscopy Violations of friendly movements of eyeballs Hyperemia conjunctiva
Violations from the organ of hearing and labyrinthine disorders		Vertigo	Hearing loss Noise in ears
Heart Disease			Heart palpitations Bradycardia
Vascular disorders			Hypertension (including hypertensive crisis) Arterial hypotension Orthostatic hypotension Tides Feeling cold in the hands and feet
Disturbances from the respiratory system, chest organs and mediastinum			Nose bleed Chest pain
Disorders from the gastrointestinal tract		Nausea Rita Diarrhea	Constipation Dyspepsia Gastritis Abdominal pain Dry mouth Discomfort in the abdomen Blowing belly Gingivitis Melena Toothache	Pancreatitis
Violations from the liver and biliary tract			Violation function liver
Violations from the skin and subcutaneous fabrics		Rash	Alopecia Dryness of the skin Increased sweating Erythema Defeat leather Itching
Violations from the musculoskeletal and connective fabrics			Myalgia Disturbance of bone metabolism Muscle weakness Pain in the extremities
Violations from the kidneys and urinary tract			Urinary tract infections
General disorders and violations at the site of administration		Fatigability Gait disturbance Asthenia	Malaise Chills Peripheral edema
Laboratory and instrumental data			Reduction of blood pressure (BP) Weight loss Increase (BP) Reduction of concentration sodium in blood Decrease level of chlorides AT blood Increase content osteocalcin Decrease hematocrit Decrease concentrations Hemoglobin in blood Increase activity "hepatic" transaminases
Trauma, intoxication and complications of manipulation			Toxicity preparation A fall Thermal burn

Description of some unwanted reactions

Impaired vision and nervous system

With the simultaneous administration of eslikarbazepine acetate and carbamazepine during placebo-controlled The following undesirable reactions were noted: diplopia (in 11.4% of patients with simultaneous admission carbamazepine and 2.4% of patients who did not take carbamazepine), impaired coordination of movements (in 6.7% of patients with carbamazepine and 2.7% of patients not taking carbamazepine) and dizziness (in 30.0% of patients with simultaneous administration of carbamazepine and in 11.5% of patients not taking carbamazepine) (see "Interaction with other medicinal products ").

Interval PR

Interval lengthening PR associated with the use of eslikarbazepine. In this case, the occurrence of unwanted reactions, (for example, atrioventricular blockade, syncope, bradycardia). In patients taking eslikarbazepine acetate, atrioventricular blockade of the second and higher degree was not observed.

Undesirable reactions, associated with belonging to the class of carboxamides

During the placebo-controlled studies of eslikarbazepine acetate, there were no rare adverse reactions such as bone marrow suppression, anaphylactic reactions, severe skin reactions (eg, Stevens-Johnson syndrome), systemic lupus erythematosus, or severe arrhythmia. However, these reactions have been identified with the use of oxcarbazepine, in connection with which, their occurrence can not completely be ruled out against the background of the therapy of eslikarbazepine acetate. With long-term use in combination with structurally related NEP carbamazepine and oxcarbazepine, a decrease in bone mineral density, osteopenia, osteoporosis and fractures has been reported.The mechanism of the effect of drugs on the metabolism of bone tissue is not known.

Announcement of unwanted reactions

It is extremely important to inform about undesirable reactions that occurred during post-registration application medicinal product. This will allow you to control the benefit / risk ratio when using it. Please inform medical workers of any undesired reactions to the address given in this manual.

Overdose:

In the case of an accidental overdose of eslikarbazepine with acetate, the following reactions from the central nervous system: vertego, shaky gait and hemiparesis.

The specific antidote is unknown. In case of an overdose, it is shown appropriate symptomatic and supportive treatment. When necessary metabolites eslikarbazepine acetate are effectively removed during hemodialysis (see the section "Pharmacodynamics").

Interaction:

Research of drug interactions were conducted only in adults.

Eslikarbazepine acetate is actively metabolized in eslikarbazepine, which is derived mainly by glucuronation. In vitro eslikarbazepine is a weak isoenzyme inducer CYP3A4 and UDP-glucuronyl transferases. In vivo it increases metabolism medicines that oxidized predominantly isoenzyme CYP3A4 (eg, simvastatin), which may require an increase in the dose of such drugs when combined with eslikarbazepine acetate. Eslicarbazepine in vivo can enhance the metabolism of drugs that enter into a conjugation reaction involving UDP-glucuronyl transferases. When prescribing or canceling the drug Exalifef®. as well as changing the dosage regimen, the activity of the enzymes stabilizes within 2-3 weeks, which should be taken into account when it is necessary to correct the doses of drugs taken together with the drug Exalieff®.

Eslikarbazepine inhibits isoenzyme CYP2CI9, which causes potential opportunity dose-dependent interaction with drugs that are metabolized mainly with the participation of isoenzyme CYP2C19 (e.g., phenytoin).

Interaction with other PEPs

Carbamazepine

In a study involving healthy volunteers, the simultaneous use of eslikarbazepine acetate at a dose of 800 mg once daily and carbamazepine 400 mg twice daily resulted in a decrease the action of the active metabolite of eslikarbazepine (on average by 32%), which is most likely caused by the induction of glucuronidation. At the same time, there was no increase in the action of carbamazepine or its metabolite-carbamazepine epoxide. Thus, taking into account the individual response to treatment, when combined with carbamazepine, an increase in dose may be required eslikarbazepine acetate. Studies involving patients have shown that with simultaneous appointment with carbamazepine increases the risk of the following adverse reactions: diplopia, coordination disorders movement and dizziness. It is impossible to exclude the risk of strengthening others specific undesirable reactions caused by simultaneous reception carbamazepine and eslikarbazepine acetate.

Phenytoin

In a study involving healthy volunteers, concomitant use eslikarbazepine acetate at a dose of 1200 mg once a day and phenytoin led to a decrease in the activity of the active metabolite, eslikarbazepine (an average of 31-33%), which is most likely caused by the induction of glucuronation. At the same time there was an increase in the effect of phenytoin (an average of 31-35%), which is presumably caused by inhibition of the isoenzyme CYP2C19. Thus, taking into account the individual response to treatment for a combined appointment may be required Increase the dose of eslikarbazepine acetate and reduce the dose of phenytoin.

Lamotrigine

Glucuronation is the main pathway of metabolism of eslikarbazepine and lamotrigine, so their interaction is possible. In a study involving healthy volunteers, who took eslcarbazepine acetate in a dose of 1200 mg once a day, there was an insignificant pharmacokinetic interaction with lamotrigine (15% weakening of the action of the latter), and therefore correction of their dosing regimen is usually not required. However, due to the possible individual variability, the interaction Eslikarbazepine acetate and lamotrigine in some patients may be clinically significant.

Topiramate

In a study involving healthy volunteers with simultaneous use of eslcarbazepine acetate at a dose of 1200 mg once daily and topiramate, no significant changes in the effect of eslikarbazepine were noted, but the effect of topiramate decreased by 18%, which is most likely due to a decrease in its bioavailability. Correction of the dose in this case is not required.

Valproate and levetiracetam

Analysis of pharmacokinetic data obtained in phase studies III with the participation of adult patients with epilepsy, found that simultaneous administration of valproate or levetiracetam does not affect the action of eslikarbazepine, but this information is not supported by the results of traditional studies interaction of drugs.

Other medicines

Oral contraceptives

Using eslikarbazepine acetate at a dose of 1200 mg once a day in women using oral contraceptives, weakened systemic action of levonorgestrel and ethinyl estradiol on average by 37% and 42%, respectively, which is most likely due to induction of isoenzyme CYP3A4. Women with preserved reproductive potential should use adequate methods of contraception during treatment with the drug Exalieff® and before the end of the current menstrual cycle after the withdrawal of the drug (see the section on "Application during pregnancy and during breastfeeding").

Simvastatin

In a study involving healthy volunteers with simultaneous use with eslikarbazepine acetate at a dose of 800 mg once dailyweakened systemic action simvastatin on average by 50%, which, most likely due to induction isoenzyme CYP3A4. When combined with eslikarbazepine acetate, an increase in the dose of simvastatin may be required.

Rosuvastatin

In a study involving healthy volunteers with simultaneous use with eslikarbazepine acetate at a dose of 1200 mg once a day, weakened systemic action rosuvastatin on average by 36-39%. The mechanism of this interaction is unknown, possibly because it is caused by a violation of the transport activity of rosuvastatin or a combination of this factor with the inducing of its metabolism. Since the relationship between the action and activity of the drug is unclear, it is recommended to monitor the response to therapy (eg, cholesterol control).

Warfarin

With the simultaneous use of eslikarbazepine acetate at a dose of 1200 mg once a day and warfarin observed a small (23%), but statistically significant weakening of action S- warfarin. Effects of eslacarbazepine acetate on pharmacokinetics R-warfarin or on coagulability of blood was not noted.Due to the possibility of individual variability in the interaction of drugs in the first weeks after the onset or end of the joint use of warfarin and eslikarbazepine acetate, special attention should be paid to monitoring the International normalized relationship (INR).

Digoxin

In a study involving healthy volunteers, there was no effect of eslcarbazepine acetate at a dose of 1200 mg once daily on the pharmacokinetics of digoxin. This suggests that eslcarbazepine acetate does not affect the transport of P-glycoprotein.

Inhibitors of monoamine oxidase (MAO)

Given the structural similarity of eslikarbazepine acetate and tricyclic antidepressants, the interaction between eslikarbazepine acetate and inhibitors MAO is theoretically possible.

Special instructions:

Suicidal behavior

When prescribing anticonvulsant drugs for several indications of suicidal behavior. Meta-analysis of randomized placebo-controlled trials antiepileptic medicines also showed a small increased risk of suicidal behavior.The mechanism of this phenomenon is unknown, the available data do not exclude the possibility of development similar reaction in the foyer of reception of eslikarbazepine acetate. Thus, patients should be monitored for signs suicidal behavior, and consider options for appropriate treatment. If there are any signs of suicidal behavior Patients (and caregivers) should consult a doctor.

Disturbances from the nervous system

The intake of eslikarbazepine acetate may be accompanied by undesirable reactions from the central nervous system, such as dizziness and drowsiness, which increases the risk of accidental injury.

Oral contraception

Eslikarbazepine acetate may decrease the effectiveness of hormonal contraception. When using the drug Exalieff® it is recommended to use additional non-hormonal methods of contraception (see sections "Interaction with other medicines "and "Application during pregnancy and during breast-feeding").

Other Precautions

If it is necessary to discontinue Exxalef®, it should be done gradually to minimize the risk of an increased incidence of epileptic seizures.

It is not recommended to appoint eslikarbazepine acetate concomitantly with oxcarbazepine, since excessive exposure to active metabolites is possible.

Information on the abolition of concomitant antiepileptic drugs during treatment with the drug Exalief® (transition to monotherapy) is absent.

Skin Reactions

In additional placebo-controlled trials involving patients with epilepsy, 1.1% of the entire population of patients receiving Exalieff® showed an unwanted reaction in the form of a skin rash. When there are symptoms of hypersensitivity to the drug, Exalieph® should be discarded.

Allele presence HLA-B*1502

There is evidence that the allele HLA-B*1502, Present in Chinese Han people, natives of Thailand and other Asian countries, is associated with the risk of Stevens-Johnson syndrome in the treatment with carbamazepine. The chemical structure of eslikarbazepine acetate is similar to that of carbamazepine and there is a possibility of an increased risk of Stevens-Johnson syndrome in patients with the presence of the HAA-B * 1502 allele in the treatment of eslikarbazepine acetate. Allele prevalence HLA-B*1502 among Chinese Han people and natives of Thailand is about 10%. Before prescribing carbamazepine or chemically related compounds, if possible, patients of this population should be screened for the presence of this allele. The use of eslikarbazepine acetate in patients with proven presence of an allele HLA-B * 1502 may be justified if the use of the application exceeds the risk.

Because of the prevalence of this allele fromAmong natives of other Asian countries (about 15% in the Philippines and Malaysia), screening for the presence of an allele ULA-B*1502 may also be expedient.

In patients of another ethnicity (Caucasoid race, Africans, Spaniards, Japanese and Koreans) allele HLA-B*1502 is extremely rare (less than 1%).

Allele presence HLA-A *3101

There are data that allow assume that the allele HLA-A*3101, present Caucasoid and Japanese, when treated with carbamazepine, increases the risk of skin allergic reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash accompanied by eosinophilia or in less severe acute generalized exentomatous pustulosis. Allele prevalence HLA- A * 3101 varies widely in the ethnic population and ranges from 2 to 5% in the European population and about 10% in the Japanese. Allele presence HLA-A*3101 may increase the risk of carbamazepine induced skin reactions (in most cases less serious) from 5% in the general population to 26% in representatives of the Caucasoid race, whereas its absence, in turn, can reduce the risk from 5 to 3.8%.

Data for recommending screening of patients for the presence of an allele HLA-A*3101 Before prescribing carbamazepine or chemically related compounds, it is not enough.

The use of carbamazepine or chemically related compounds in patients with a proven allele presence HLA-A*3101 may be justified if the use of the application exceeds the risk.

Hyponatremia

Hyponatremia was noted as an undesirable reaction to the use of the drug Exalieph® in 1.2% of patients. In most cases, hyponatremia is asymptomatic, but it can be accompanied by clinical manifestations such as enhancement epileptic seizures, the emergence of confusion or impaired consciousness.

The frequency of hyponatremia increases with increasing dose of eslikarbazepine acetate. When hyponatremia due to renal insufficiency in the history or as a result of simultaneous administration of drugs that can lead to the emergence of hyponatremia (eg, diuretics, desmopressin, carbamazepine), before and during the treatment of eslikarbazepine acetate, as well as in the development of clinical symptoms of hyponatremia, it is necessary to monitor the concentration of sodium in the blood serum. With the development of clinically significant hyponatraemia eslcarbazepine acetate should be canceled.

Interval PR

In the course of clinical studies of eslikarbazepine acetate, the lengthening of the interval PR. Care must be taken in certain conditions (for example, with a low concentration of thyroxine, cardiac conduction disorders) or simultaneous administration of medicines, which, according to available data, are accompanied by lengthening of the interval PR.

Renal insufficiency

Care of patients with renal insufficiency should be carried out and dose adjustment should be carried out in accordance with creatinine clearance (see section "Method of administration and dose"). With QC <30 ml / min, the use of Exalieff® is not recommended because of insufficient data.

Liver failure

Due to the limited amount of clinical data for patients with mild and moderate hepatic insufficiency, in this category of patients Exalieff® is used with caution. Due to the lack of clinical data, it is not recommended to prescribe Eksalef® to patients with severe hepatic insufficiency.

Effect on the ability to drive transp. cf. and fur:

Special impact studies preparation for the performance of potentially dangerous activities requiring an increased concentration of attention and speed of psychomotor reactionse were conducted. Some patients may develop (especially at the beginning of treatment): dizziness, drowsiness, or visual impairment. Patients should be warned that there is likely a violation of physical and / or mental ability to drive a vehicle or mechanisms and recommend refrain from such activities until the effect on her of taking the drug has been determined.

Form release / dosage:Tablets, 800 mg.

Packaging:

For 10 tablets in a blister (PVC / aluminum) or (aluminum / aluminum).

By 2, 3, 6 or 9 blisters are placed in a cardboard box together with instructions for medical use.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001263

Date of registration:24.11.2011

Date of cancellation:2016-11-24

The owner of the registration certificate:Eysay Europe LimitedEysay Europe Limited United Kingdom

Manufacturer: & nbsp

BIAL-PORTELA & CA., S.A. Portugal

Representation: & nbspEYSIY LLCEYSIY LLCRussia

Information update date: & nbsp03.10.2015

Illustrated instructions

Instructions

Exalieff® (Exalief®)