Trileptal - instructions for use, dose, side effects, contraindications

Active substanceOxcarbazepineOxcarbazepine

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Trileptal®

pills inwards

Novartis Pharma AG Switzerland

Trileptal®

suspension inwards

Novartis Pharma AG Switzerland

Dosage form: & nbsporal suspension

Composition:

1 ml of suspension for oral administration contains:

active substance: oxcarbazepine 60.00 mg.

Excipients: propyl parahydroxybenzoate 0.30 mg, sodium saccharinate 0.50 mg, sorbic acid 0.50 mg, macrogol-400 stearate 1.00 mg, methylparahydroxybenzoate 1.20 mg, ascorbic acid 10.00 mg, dispersible cellulose (microcrystalline cellulose and carmellose sodium ) 15.00 mg, ** yellow plum-lemon flavor 39K020 (** 39K020 fragrance is a solution containing 36% ethanol and 16% propylene glycol) 2.50 mg, propylene glycol distilled 25.00 mg, sorbitol 70% liquid 250.00 mg, water purified 717.00 mg.

Description:

Suspension for oral administration from almost white to slightly brown or slightly red with a fruity odor.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.F.02 Oxcarbazepine

Pharmacodynamics:The pharmacological activity of Trileptal ® (oxcarbazepine) is due, first of all, to the action of its metabolite - monohydroxy derivative (IHP). The mechanism of action of oxcarbazepine and its IHP is associated, mainly, with the blockade of potential-dependent sodium channels,which leads to the stabilization of overexcited neuronal membranes, inhibition of the occurrence of serial neuronal discharges, and a decrease in synaptic impulses.

The anticonvulsant action of the drug is also promoted by an increase in the conductivity of potassium ions and modulation of calcium channels activated by a high membrane potential. There were no significant interactions with brain neurotransmitters or receptor binding.

In experimental animal studies, it was shown that oxcarbazepine and IHP have a pronounced anticonvulsant effect.

Clinical efficacy

The effectiveness of Trileptal® in epileptic seizures was demonstrated both with monotherapy and with the use of the drug as part of combination therapy in children and adults.

Trileptal® can be used to replace other antiepileptic drugs in cases where a satisfactory therapeutic response to treatment is not achieved with the use of the latter.

Pharmacokinetics:

Suction

After oral administration in tablet form oxcarbazepine completely absorbed and largely metabolized to form a pharmacologically active metabolite - 10-monohydroxy derivative (IHP). After a single dose of Trileptal® in tableted form at a dose of 600 mg by fasting volunteers, the mean maximum concentration of MHP in the blood plasma (C_mOh) is 31.5 μmol / l, the average maximum time of its attainment is about 5 hours.

After a single dose of Trileptal® in the form of a suspension in a dose of 600 mg by fasting volunteers, the mean maximum concentration of MHP in the blood plasma (C_mOh) is 24.9 μmol / l, the average maximum time of its attainment is about 6 hours. Tablets and suspension of oxcarbazepine for oral administration are bioequivalent, since the geometric mean C_mOh in the equilibrium state to the area under the "concentration-time" curve (AUC) Of IHP in a single dose was in the range of 0.85 to 1.06 (90% confidence interval).

In pharmacokinetic studies, it was shown that 2% of unchanged oxcarbazepine and 70% of IHP are detected in the blood plasma; The rest is accounted for by secondary metabolites that are rapidly eliminated from the blood plasma.

Eating does not affect the speed and degree of absorption.

Relationship with plasma proteins and distribution

The apparent volume of distribution of IHL is 49 liters. Approximately 40% of MHP binds to plasma proteins, mainly albumin. In the therapeutic range, the degree of binding does not depend on the concentration of oxcarbazepine in the blood serum. Oxcarbazepine and IHP do not bind to the alpha-1-acid glycoprotein.

Metabolism

Oxcarbazepine is rapidly metabolized by the cytosolic enzymes of the liver to the active metabolite of IHP, which causes the pharmacological effect of the drug. IHL undergoes further conjugation with glucuronic acid. An insignificant amount of MHP (about 4% of the dose) is oxidized with the formation of an inactive metabolite (10,11-dihydroxy derivative, BPH).

Excretion

Oxcarbazepine is excreted from the body mainly in the form of metabolites, mainly kidneys. More than 95% of the dose is excreted by the kidneys in the form of metabolites, less than 1% - in unchanged form. Approximately 80% of the dose is derived in the form of MHP, both in the form of glucuronides (49%), and in the form of unchanged MHP (27%); inactive DHP is about 3%, conjugates of oxcarbazepine - about 13% of the dose.

About 4% of the dose is excreted with feces.

Oxcarbazepine is rapidly excreted from the blood plasma, the apparent half-life is 1.3 to 2.3 hours. In contrast to oxcarbazepine, the apparent half-life of IHP is on average 9.3 ±1,8 hours.

Equilibrium concentrations of MHP in blood plasma are reached on day 2-3 with the administration of Trileptal® 2 times a day.

In the equilibrium state, the pharmacokinetic parameters of MHP are linear and dose-dependent in the range of daily doses of 300 mg-2,400 mg.

Pharmacokinetics in selected patient groups

Patients with hepatic impairment

The pharmacokinetic parameters and metabolism of oxcarbazepine and IHP after a single oral dose of 900 mg were evaluated in healthy volunteers and in patients with impaired hepatic function. Violations of liver function of mild and moderate severity do not affect the pharmacokinetic parameters of oxcarbazepine and IHP. Pharmacokinetics for violations of liver function of a serious degree has not been studied.

Patients with impaired renal function

There is a linear dependence of renal clearance of IHP on creatinine clearance. In patients with impaired renal function (creatinine clearance less than 30 ml / min) after a single dose of 300 mg of oxcarbazepine, the half-life of MHP increases to 19 hours, a AUC increases by 2 times.

Children

The IHP clearance, corrected for body weight, decreases in children with increasing age and body weight, approaching the clearance in adults. The weight-corrected ground clearance in children aged 1 month to 4 years is 93% higher on average than in adults. Thus, it is assumed that AUC IHP in children of this age group is expected to be 2 times less than that of adults when using the same doses (with weight adjustment). The weight-corrected ground clearance in children aged 4 to 12 years is 43% higher on average than in adults. The alleged AUC IHP in children of this age group is 2/3 of that in adults when using the same doses (with weight adjustment). It is assumed that in children aged 13 and older due to the increase in body weight, the MHP clearance, corrected for body weight, corresponds to the IHP clearance in adults.

Pregnant Patients

During pregnancy, a number of physiological changes occur in the body, which can lead to a gradual decrease in the level of IHP in the blood plasma during this period.

Elderly patients

After receiving Trileptal® once (at a dose of 300 mg) and again (at a dose of 600 mg / day) in elderly volunteers aged 60-82 years, C_mOh and values AUC for IHP were 30-60% higher, compared with the same indicators in young volunteers (18-32 years), which is associated with an age-related decrease in creatinine clearance.

Floor

There were no differences in pharmacokinetic parameters, depending on sex in the child, adult or old age.

Indications:

Simple, complex partial epileptic seizures, with or without secondary generalization in adults and children aged 1 month and older.

Generalized tonic-clonic epileptic seizures in adults and children aged 1 month and older.

Contraindications:

Hypersensitivity to oxcarbazepine or any other components of the drug.

Children up to 1 month.

Carefully:

Caution should be used in patients with known hypersensitivity to carbamazepine, as in this group of patients approximately 25-30% of cases may develop sensitivity reactions to oxcarbazepine. In patients who have no history of hypersensitivity to carbamazepine, it is also possible to develop hypersensitivity reactions to the drug, including polyorganism disorders.

The use of Trileptal® in patients with impaired hepatic function has not been severely studied, so it is necessary to carefully dose the drug in this category of patients.

Pregnancy and lactation:

Children of patients with epilepsy are more likely than others to develop developmental disorders, including congenital malformations.

The experience of using Trileptal® during pregnancy is limited. The available reports indicate a possible connection of the drug during pregnancy with the development of birth defects. The most frequent developmental malformations in children whose mothers received Trileptal® during pregnancy were: atrial septal defect, atrioventricular septal defect, cleft palate and upper lip, Down syndrome, hip dysplasia (both single- and multiple- bilateral), tuberous sclerosis and malformations of the ear.

According to the North American Pregnancy Registry, the frequency of gross developmental malformations related to structural anomalies requiring surgical, pharmacological or cosmetic correction diagnosed within 12 weeks after birth,was 2.0% (95% confidence interval from 0.6% to 5.1%) among pregnant women taking the first trimester oxcarbazepine in monotherapy. Compared with pregnant women who did not receive any antiepileptic drugs during pregnancy, the relative risk of developmental malformations in children was 1.6 with a confidence interval of 95% from 0.46 to 5.7.

Patients of childbearing age should use reliable contraceptive methods during therapy with Trileptal® (optimally, intrauterine contraceptives), because when used concomitantly with oral contraceptives containing ethinyl estradiol or levonorgestrel, the effectiveness of these drugs may be reduced.

If the patient is planning a pregnancy or a pregnancy is diagnosed during the use of the drug, and if there is a question about the use of Trileptal® during pregnancy, the expected benefits of therapy and the possible risk of fetal development disorders, especially in the first trimester of pregnancy, should be carefully compared.

In pregnancy, use the minimum effective dose of the drug.

With sufficient clinical efficacy in patients of the childbearing period, Trileptal® should be used in monotherapy.

The patient should be warned about possible violations of fetal development and the need for antenatal diagnosis.

During pregnancy, effective antiepileptic treatment should not be interrupted, as the progression of the disease can have a negative effect on the mother and the fetus.

It is known that a deficiency of folic acid develops during pregnancy. Antiepileptic drugs can increase this deficit, which is one of the possible causes of fetal development disorders, therefore, an additional intake of folic acid preparations is recommended.

When using the drug during pregnancy, it is necessary to take into account that the physiological changes occurring in the body during this period can lead to a gradual decrease in the level of 10-monohydroxy derivative of oxcarbazepine (IHP) in the blood plasma. To achieve maximum control of the symptoms of the disease in pregnant women, it is necessary to regularly assess the clinical effect of the drug and determine the concentration of MHP in the blood plasma.

The determination of the level of IHP in the blood plasma is also recommended in the postpartum period, especially if the dose of the drug has been increased during pregnancy. There are reports that the use of antiepileptic drugs during pregnancy can lead to increased bleeding in newborns. As a precautionary measure, the use of a vitamin K₁ in the last few weeks of pregnancy, as well as in newborns whose mothers received Trileptal®.

Oxcarbazepine and IHP penetrate the placental barrier.

Oxcarbazepine and IHP are excreted in breast milk. The ratio of concentrations in milk and plasma was 0.5 for both substances. Since the impact on newborns of oxcarbazepine and IHP, received with breast milk, is unknown, do not use Trileptal® during breastfeeding.

Use in children under 1 month of age

There is no data on the safety and efficacy of Trileptal® in children under 1 month of age.

Impact on fertility

There is no data on the effect of the drug on fertility in humans.Studies in animals revealed no effects of oxcarbazepine and IHP on fertility in both sexes at daily doses of 150 and 450 mg / kg, respectively. In the application of IHP at maximum doses females, however, noted violation estrous cycle, reduction of lutein body, reducing the number of implantations and the number of live embryos.

Dosing and Administration:

The drug Trileptal ® can be used in both monotherapy and in combination with other antiepileptic drugs. In both cases, treatment with Trileptal® begins with a clinically effective dose, the frequency of administration is 2 times a day. The dose may be increased depending on the response to therapy. If you replace another antiepileptic drug Trileptal ® at the start of Trileptal ®, you should gradually reduce the dose of the drug you are replacing. When Trileptal ® is used as part of combination therapy, a dose reduction of concomitant antiepileptic drugs and / or a slower increase in the dose of Trileptal® may be required.

The drug Trileptal® can be taken regardless of the meal (at the time,after meals or in between meals).

Instructions for use of the suspension for oral administration

A table for the recalculation of the dose of Trileptal® from mg / ml.

The dose in milligrams (mg)	Dose in milliliters (ml)
10 mg	0.2 ml
20 mg	0.3 ml
30 mg	0.5 ml
40 mg	0.7 ml
50 mg	0.8 ml
60 mg	1.0 ml
70 mg	1.2 ml
80 mg	1.3 ml
90 mg	1.5 ml
100 mg	1.7 ml
200 mg	3.3 ml
300 mg	5.0 ml
400 mg	6.7 ml
500 mg	8.3 ml
600 mg	10.0 ml
700 mg	11.7 ml
800 mg	13.3 ml
900 mg	15.0 ml
1000 mg	16.7 ml

Before taking the suspension for oral administration, the vial should be thoroughly shaken and immediately measure the required amount of suspension. The desired dose (ml) is drawn from the vial using the supplied syringe. When using a 10 ml syringe (supplied with a 250 ml vial - for adults and older children), the amount of suspension should be rounded to 0.5 ml. When using a 1 ml syringe (supplied with a 100 ml bottle for infants), the amount of suspension should be rounded to 0.1 ml. After each use, close the vial tightly and wipe the syringe with a clean dry cloth. The suspension can be taken directly from the syringe or diluted with a small amount of water before taking. The open vial should not be stored for more than 7 weeks.

Suspension for oral administration and tablets are bioequivalent and are interchangeable in equivalent doses.

The therapeutic effect of Trileptal® (oxcarbazepine) is due, first of all, to the action of its metabolite, IHP.

Routine determination of the concentration of oxcarbazepine or IHP in blood plasma is not justified. However, monitoring the concentration of IHP in the blood plasma can be used to clarify compliance with the patient's intake of the drug (compliance) or in those situations where a change in the clearance of IHP is possible, for example, changes in kidney function, pregnancy, simultaneous use of "liver" enzymes with inductors. In the above situations, you should adjust the dose of Trileptal® taking into account the concentration of MHP in the blood plasma (measured 2-4 hours after administration), which should be maintained at <35 mg / l.

Adult patients

Monotherapy and combination therapy

The initial dose is 600 mg per day (8-10 mg / kg body weight per day), divided into 2 doses. A good therapeutic response was observed in the dose range of 600-2400 mg per day. If necessary, it is possible to gradually increase the dose by no more than 600 mg / day at intervals of approximately 1 week, until the desired therapeutic response is achieved.Most patients have a good clinical effect at a dose of 900 mg / day.

In patients who had not previously received antiepileptic drugs, the effective dose is 1200 mg / day, in those who received earlier, 2,400 mg / day.

In controlled trials, the use of Trileptal® at a daily dose of 2,400 mg as part of combination therapy without reducing the dose of another antiepileptic drug was associated with poor tolerance mainly due to the development of adverse events from the nervous system. The systematic use of Trileptal® in a daily dose of more than 2,400 mg has not been studied.

Children

When monotherapy with Trileptal® and with the use of the drug in combination therapy, the recommended initial dose of 8-10 mg / kg of body weight per day is divided into 2 divided doses.

In combination therapy, the target dose of Trileptal®, 30-46 mg / kg per day, should be achieved no earlier than 2 weeks after the start of therapy.

If necessary, to achieve the desired therapeutic effect, it is possible to gradually increase the dose - at an interval of about 1 week, the dose is increased - a maximum of 10 mg / kg / day, up to a maximum daily dose of 60 mg / kg body weight.

When Trileptal® is used in monotherapy and as part of a combination therapy, with an adjustment for body weight, the apparent clearance of IHP in children is significantly reduced with age. Children aged 1 month to 4 years may require a dose of the drug, 2 times the dose for adults, when adjusted for body weight; Children between the ages of 4 and 12 may require a dose that is 50% higher than the adult dose when adjusted for body weight.

In children aged 1 month to 4 years, the effect of antiepileptic drugs - inducers of liver enzymes on their apparent clearance is more pronounced than in children of older age groups (with weight adjustment). When Trileptal® is used in children aged 1 month to 4 years, in combination with antiepileptic drugs, liver enzyme inducers may require a dose of oxcarbazepine approximately 60% higher (with body weight adjustment) than with monotherapy with Trileptal® or with its use in combination with antiepileptic drugs that do not induce enzymes. For children of older age groupscombined therapy with Trileptal® with antiepileptic drugs, liver enzyme inducers may require a slight increase in the dose of the drug compared to monotherapy.

In children less than three years old, the drug should be administered in the form of a syrup due to the difficulties of using solid dosage forms in patients of this age group.

Patients aged> 65 years

Special correction of the dosing regimen in this category of patients is necessary only if the kidney function is impaired (creatinine clearance less than 30 ml / min). If there is a risk of hyponatremia, careful monitoring of the sodium content in the blood serum is necessary.

Patients with hepatic impairment

There is no need for correction of the dosing regimen in patients with mild to moderate liver function disorders. Care must be taken when using in patients with impaired hepatic function.

Patients with impaired renal function

For patients with impaired renal function (creatinine clearance less than 30 ml / min), the recommended initial dose is 300 mg / day; increase the dose should be slow,until the desired therapeutic response is achieved. Careful observation of patients during dose selection is necessary.

Side effects:

The most frequently reported adverse reactions were drowsiness, headache, dizziness, diplopia, nausea, vomiting, fatigue (more than 10% of patients).

In clinical studies, it has been shown that unwanted reactions are usually mild or moderate, are transient in nature and are observed mainly at the beginning of therapy.

The data below summarizes information on adverse reactions (HP) recorded during clinical trials, as well as data on the safety profile of the drug obtained during its use in clinical practice. HP are grouped in accordance with the classification of organs and systems of organs MedDRA, while listed in order of decreasing their importance. Criteria for assessing the incidence of adverse reactions: "very often" - ≥1 / 10, "often" - ≥1 / 100 - <1/10, "infrequently" - ≥1 / 1000 - <1/100, "rarely" - ≥ 1/10 000 - <1/1000, "very rarely" - <1/10 000 (including individual messages).

Violations from the blood and lymphatic system: infrequently, leukopenia; very rarely - suppression of bone marrow hematopoiesis, aplastic anemia, agranulocytosis,pancytopenia, thrombocytopenia, neutropenia.

Immune system disorders: very rarely - anaphylactic reactions, reactions, hypersensitivity (including reactions of multi-organ hypersensitivity), which are characterized by such phenomena as rash and fever. Possible damage to the circulatory and lymphatic systems (eosinophilia, thrombocytopenia, leukopenia, lymphadenopathy, splenomegaly), liver (hepatitis, changes in liver function), muscle and joint damage (myalgia, edema in the joints, arthralgia), nervous system (hepatic encephalopathy), kidneys (renal failure, interstitial nephritis, proteinuria), lungs (pulmonary edema, bronchospasm, bronchial asthma, interstitial inflammation, dyspnea), angioedema.

Disorders from the endocrine system: very rarely - hypothyroidism.

Disorders from the metabolism and nutrition: often - hyponatremia (more often observed in patients aged> 65 years); very rarely - clinically significant hyponatremia (sodium concentration <125 mmol / l) - as a rule, during the first 3 months of therapy with the drug; in some patients - more than 1 year after the start of treatment with Trileptal ®.This condition can lead to the development of such manifestations and symptoms as convulsive attacks, encephalopathy, decreased level of consciousness, confusion, visual impairment (including blurred vision), hypothyroidism, vomiting, nausea, folic acid deficiency.

Disorders of the psyche: often - agitation (including nervousness), emotional lability, confusion, depression, apathy.

Disturbances from the nervous system: very often - drowsiness (22.5%), headache (14.6%), dizziness (22.6%); often - ataxia, tremor, nystagmus, attention disturbance, amnesia.

Disturbances on the part of the organ of sight: very often - diplopia (13.9%); often - blurred vision, visual impairment.

Hearing disorders and labyrinthine disorders: often - systemic dizziness.

Heart Disease: very rarely - atrioventricular blockade, arrhythmias.

Vascular disorders: very rarely - hypertension.

Disorders from the gastrointestinal tract: very often - vomiting (11.1%), nausea (14.1%); often - diarrhea, abdominal pain, constipation; very rarely - pancreatitis.

Disturbances from the liver and bile ducts: very rarely - hepatitis.

Disturbances from the skin and subcutaneous tissues: often - rash, alopecia, acne; infrequently - hives; very rarely Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome caused by medication), angioedema, erythema multiforme, systemic lupus erythematosus.

General disorders and disorders at the site of administration: very often - a feeling of fatigue (12%); often - asthenia.

Laboratory and instrumental data: infrequently - increased activity of "liver" enzymes, alkaline phosphatase; very rarely - increased activity of amylase, lipase.

In clinical studies conducted in children aged 1 month to 4 years, the most frequently observed drowsiness (in 11% of patients). With a frequency of ≥1% - <10% (often), ataxia, irritability, vomiting, lethargy, fatigue, nystagmus, tremor, decreased appetite, increased uric acid concentration in the blood.

Undesirable reactions identified in the postmarketing period on the basis of individual reports and cases described in the literature (frequency unknown)

Since the data on unwanted reactions in the postmarketing period were obtained on the basis of voluntary reports from a population of unknown numbers, it is impossible to estimate the frequency of their occurrence (the frequency is unknown).Undesirable reactions are classified according to organ systems, within each organ system, unwanted reactions are arranged in order of decreasing severity of their manifestation.

Disturbances from the skin and subcutaneous tissues

Drug rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis.

Disturbances from musculoskeletal and connective tissue

There have been reports of a decrease in bone mineral density, the detection of osteopenia, osteoporosis and fractures in patients receiving long-term treatment with Trileptal®. The mechanism of influence of oxcarbazepine on the metabolism of bone tissue is not clear.

Disorders from the metabolism and nutrition

Syndrome of inadequate secretion of antidiuretic hormone, manifested by lethargy, nausea, dizziness, decreased osmolality of the blood plasma, vomiting, headache, confusion and other symptoms from the nervous system.

Trauma, intoxication and complications of manipulation

A fall.

Disturbances from the nervous system

Violations of speech (including dysarthria), especially during the selection of a dose.

Overdose:

There are isolated reports of an overdose of the drug. The maximum dose reported in the reports was approximately 48,000 mg.

Symptoms

Violation of the water-electrolyte balance: hyponatremia.

Disorders from the side of the organ of vision: diplopia, miosis, blurred vision.

Disorders from the digestive system: nausea, vomiting, hyperkinesia.

General disorders and disorders at the site of administration: fatigue.

Laboratory and instrumental data: decrease in the frequency of respiratory movements, prolongation of the interval QTc.

Disturbances from the nervous system: drowsiness, dizziness, ataxia, nystagmus, tremor, impaired coordination, convulsions, headache, coma, loss of consciousness, dyskinesia.

Disorders of the psyche: aggression, agitation, confusion.

Vascular disorders: lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs:dyspnea.

Treatment

There is no specific antidote. Conduct symptomatic and supportive treatment. It should be borne in mind that in order to reduce the absorption of oxcarbazepine, gastric lavage can be performed and activated charcoal intake is prescribed.It is recommended to monitor the vital functions of the body, paying particular attention to violations of conduction of the heart, water-electrolyte balance and respiratory system function.

Interaction:

Inhibition of enzymes

Oxcarbazepine and its pharmacologically active metabolite MHP are inhibitors of cytochrome CYP2C19. Thus, simultaneous use of Trileptal® in high doses and preparations that are metabolized with the participation of the CYP2C19 isoenzyme (for example, phenobarbital, phenytoin), can lead to their interaction. For some patients, it may be necessary to reduce the dose of the preparations - the substrates of the isoenzyme CYP2C19. It was shown that oxcarbazepine and IHL have little or no inhibition of the following microsomal isozymes: CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11.

Induction of enzymes

In vitro and in vivo oxcarbazepine and IHL, being weak inducers of cytochromes CYP3A4 and CYP3A5, reduce the plasma concentrations of drugs metabolized by these enzymes: dihydropyridine calcium antagonists, oral contraceptives and antiepileptic drugs (eg, carbamazepine).When used simultaneously with Trileptal®, plasma concentrations of other drugs that are substrates of CYP3A4 and CYP3A5 isoenzymes can also be reduced (for example, preparations from the group of immunosuppressants - ciclosporin).

Because the in vitro oxcarbazepine and IHL are weak inducers of uridine-diphosphate-glucuronyl transferase, it is unlikely that in vivo they are able to have a clinically significant effect on the metabolism of drugs released as conjugates with glucuronic acid (for example, valproic acid and lamotrigine). But, taking into account even the weak inducing ability of oxcarbazepine and IHP, it may be necessary to increase the doses of concomitantly used drugs that are metabolized with the participation of the CYP3A4 isoenzyme or uridine diphosphate-glucouonyl transferase. In the case of the cancellation of Trileptal®, a dose reduction of these drugs may be required on the basis of clinical and laboratory controls.

In vitro studies have confirmed the weak inducing ability of oxcarbazepine and IHP for isozymes of subsystems of CYP2B and CYP3A4 enzymes.The inducing effect of oxcarbazepine and IHP on other CYP isoenzymes is unknown.

Antiepileptic drugs

With the simultaneous use of one or more antiepileptic drugs - powerful inducers of cytochrome P450, such as carbazepine, phenytoin or phenobarbital, with oxcarbazepine in each specific case, it is necessary to perform a careful dose correction and / or monitoring the concentration of drugs in the blood plasma. Possible interactions of Trileptal® and other antiepileptic drugs were evaluated during clinical trials. Data on the effect of these interactions on the AUC and the minimum concentration of C_minare summarized in the table:

Antiepileptic drug (PEP)	Effect of Trileptal® on PEP The minimum concentration in the blood plasma (C_min)	Influence of PET on MGPAUC
Carbamazepine	0-22% decrease (30% increase in carbamazepine-10,11-epoxide)	40% decrease
Clobazam	Not studied	Does not affect
Felbamat	Not studied	Does not affect
Phenobarbital	14-15% increase	30-31% reduction
Phenytoin	0-40% increase	29-35% decrease
Valproic acid	Does not affect	0-18% reduction
Lamotrigine	Does not affect	Does not affect

The concentration of phenytoin in the blood plasma is increased to 40% with the simultaneous use of Trileptal ® at a dose of 1200 mg per day or more. Therefore, when Trileptal® is used in the above doses, it may be necessary to reduce the dose of phenytoin.

An increase in the concentration in the plasma of phenobarbital with simultaneous application with Trileptal® is insignificant (15%).

With the simultaneous use of strong inducers of cytochrome P450 (ie carbamazepine, phenytoin and phenobarbital), the concentration of MHP in blood plasma decreases (by 29-40%). Thus. should monitor the concentration of MHP in the blood plasma and, if necessary, adjust the dose of the drug while using oxcarbazepine with one or more of the above drugs.

The preparation of Trileptal ® did not reveal the phenomena of autoinduction.

Hormonal contraceptives

The interaction of the drug Trileptal® with components of oral contraceptives: ethinyl estradiol and levonorgestrel has been proved. Mean values AUC for them decreased by 48 - 52% and 32 - 52%, respectively. Studies of the interaction of Trileptal® with other oral or implantable contraceptives have not been conducted.Thus, the simultaneous use of Trileptal® and hormonal contraceptives can lead to a decrease in the effectiveness of the latter, and therefore the patients receiving Trileptal® treatment are recommended additional use of reliable non-hormonal methods of contraception.

Calcium channel blockers

The simultaneous use of Trileptal® and felodipine may lead to a decrease in the value AUC felodipine by 28%, although plasma concentrations remain within the therapeutic range.

On the other hand, with the simultaneous use of Trileptal® and verapamil, the concentration of MHP in the serum can be reduced by 20%. Such a decrease in the concentration of MHP in the serum has no clinical significance.

In clinical studies, patients who received tricyclic antidepressants did not have clinically significant interactions. Simultaneous use of drugs of lithium and oxcarbazepine can lead to an increase in neurotoxicity.

Interaction with other drugs

Cimetidine, erythromycin, dextropropoxyphene do not affect the pharmacokinetic parameters of IHP; viloxazine slightly affects the concentration of MHP in the blood plasma (the concentration of MHP is increased by 10% after repeated simultaneous application). There were no interactions with warfarin, either with a single simultaneous administration, or with repeated doses of Trileptal®.

The drug Trileptal ® can enhance the sedative effect of ethanol.

Special instructions:

There are reports of a risk of worsening of epileptic seizures with Trileptal®. An increased risk of worsening of seizures was observed, mainly in children, however, it can also occur in adults. If the Trileptal® drug is observed to worsen the course of epileptic seizures, the drug should be discontinued.

Hypersensitivity reactions

When Trileptal ® was used in clinical practice, in particular cases (postmarketing reports), the development of immediate type hypersensitivity reactions (type I) was noted, including rash, itching, urticaria, angioedema and anaphylactic reactions.Hypersensitivity reactions can cause the development of disorders from the skin, liver, blood and lymphatic system and other organs, either individually or within the framework of a systemic reaction. Angioedema and anaphylactic reactions with lesions of the larynx, vocal folds (glottis region), tongue, lips, eyelids developed both at the first and repeated administration of Trileptal®. If hypersensitivity develops immediately, type Trileptal® and prescribe an alternative therapy.

Hyponatremia

In 2.7% of patients receiving Trileptal ®, hyponatremia (sodium content in the serum less than 125 mmol / l) was observed, which was usually not accompanied by clinical manifestations and did not require correction of therapy. The sodium content is normalized with the abolition (reduction of the dose) of Trileptal® or conservative treatment (restriction of fluid intake). In patients with a history of renal dysfunction and low sodium in the blood serum (for example, in patients with the syndrome of inadequate secretion of antidiuretic hormone), or in patients receiving concurrent treatment with drugs that promote the excretion of sodium from the body (diuretics, drugs affecting secretion of antidiuretic hormone), before the initiation of therapy with Trileptal®, the sodium content in serum should be determined. In the future, the sodium content in the serum should be monitored 2 weeks after the start of therapy and then monthly for 3 months or as needed. With special attention to these risk factors should be treated in elderly patients. If it is necessary to use diuretics and other drugs,which reduce the content of sodium in the blood serum, patients who are receiving Trileptal® should follow the same recommendations. When clinical symptoms of hyponatremia appear, the sodium content in serum should be determined. For other patients, the determination of the sodium content in the serum can be performed during routine blood tests.

It is necessary to carry out weight control in all patients with heart failure to timely diagnose fluid retention. With fluid retention or with the progression of symptoms of heart failure, the sodium content in serum should be determined. In the case of hyponatremia should limit the amount of fluid consumed. Since the application of oxcarbazepine in very rare cases may be a violation of cardiac conduction, careful monitoring of patients with previous conduction disorders (atrioventricular blockade, arrhythmia) receiving Trileptal® is necessary.

Hematologic changes

According to post-marketing reports in the treatment of Trileptal® in patients with very rarecases of development of agranulocytosis, aplastic anemia and pancytopenia. Given the low frequency of occurrence of agranulocytosis, aplastic anemia and pancytopenia, as well as concomitant factors (eg simultaneous administration of other drugs, the presence of concomitant diseases), a causal relationship between the development of these undesirable phenomena and the use of the drug can not be established. With the development of symptoms of severe oppression of bone marrow hematopoiesis, it is necessary to consider the question of withdrawal of the drug.

Suicidal thoughts and behavior

In patients who received anticonvulsants, there were episodes of suicidal behavior and suicidal thoughts. The results of a meta-analysis of randomized placebo-controlled trials showed a slight increase in the risk of suicidal behavior in patients receiving anticonvulsant drugs. The mechanism of increasing the risk of suicide in this category of patients is not established. Therefore, at all stages of treatment, careful monitoring of patients receiving treatment with the drug is necessary.Patients and medical personnel should be warned about the risk of suicidal thoughts and episodes in patients receiving Trileptal®.

Dermatological reactions

With the use of Trileptal ®, very rarely reported on the development of serious dermatological reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exudative erythema multiforme. Patients with the above dermatological reactions may require hospitalization due to the development of life-threatening conditions; very rarely possible deaths. When Trileptal® was used, dermatological reactions were observed in both children and adults, and developed an average of 19 days after the start of the drug. There are separate reports of cases of recurrence of serious skin reactions with the resumption of Trileptal®. With the development of skin reactions against the background of the use of Trileptal®, consideration should be given to the abolition of the drug and the use of another antiepileptic drug.

Correlation with HLA-B * 1502

There is a significant amount of data confirming the role of human leukocyte antigen (HLA) alleles in the development of serious skin reactions in patients with a predisposition to such conditions. Because of the similarity in the chemical structure of oxcarbamazepine and carbamazepine, there is a possibility of the development of Stevens-Johnson syndrome and Lyell's syndrome in patients with the presence of the HLA-B * 1502 allele in the genome, oxcarbazepine.

Patients of Chinese and Thai nationality had a clear connection between the development of Stevens-Johnson syndrome and Lyell's syndrome with carbamazepine and the presence of the human leukocyte antigen HLA-B * 1502 in their genome.

The frequency of occurrence of this allele in patients of Chinese nationality is 2-12%, in Thai - about 8%, among some groups of the population of Malaysia - more than 15%. The frequency of distribution of the HLA-B * 1502 allele in Korea and India is 2% and 6%, respectively. The prevalence of this allele in Caucasians, Negroid races, Latinos, Indians and Japanese is insignificant (<1%).

The frequencies of these alleles represent the percentage of chromosomes in certain population populations that carry the allele.This means that the percentage of patients carrying a copy of the allele in at least one of their two chromosomes is almost twice as high as the frequency of the allele. Thus, the percentage of patients who may be at risk is almost twice as likely to be alleles.

When Trileptal® is used, it is recommended to carry out genotyping using this allele in possible carriers of the HLA-B * 1502 allele. Use the drug in carriers of this allele should be only if the expected benefit from therapy exceeds the possible risk. The presence of this allele in persons of Chinese nationality, taking other antiepileptic drugs, increases the risk of developing severe dermatological reactions. Patients with the HLA-B * 1502 allele should avoid the use of drugs that lead to the development of Stevens-Johnson syndrome or Lyell's syndrome, with the possible replacement with alternative drugs. The genotyping of the HLA-B * 1502 allele before the use of Trileptal® is not necessary in patients belonging to populations with a low frequency of this allele, as well as patients already receiving therapy with this drug, since severe skin reactions in most cases were observed in the first months of treatment (regardless of the presence of HLA-B * 1502).

Correlation with HLA-B * 3101

The presence of the HLA-A * 3101 allele may be a risk factor for developing severe skin lesions (Stevens-Johnson syndrome, Lyell's syndrome, drug rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis and spotty-nasal rash) with carbamazepine.

The frequency of occurrence of the HLA-A * 3101 allele of the human leukocyte antigen (HLA) may differ in different ethnic groups: about 2-5% in the European population, about 10% in the Japanese, in the Western European population about 6.7% depending on the geographic region. The allele frequency is less than 5% in the population of Australia, Asia, Africa and North America, exceptions range from 5% to 12%. The frequency of more than 15% is found in some ethnic groups of South America (Argentina and Brazil), native peoples of North America (Navajo and Siocs, Sanora Seri in Mexico), South India (Tamil Nadu), and 10-15% among other indigenous people these regions.

The frequencies of these alleles represent the percentage of chromosomes in certain population populations that carry the allele. This means that the percentage of patients carrying a copy of the allele in at least one of their two chromosomes is almost twice as high as the frequency of the allele.Thus, the percentage of patients who may be at risk is almost twice as high as the allele frequency.

There is insufficient evidence to recommend genotyping of this allele in patients before initiating oxcarbazepine therapy. Patients already receiving Trileptal® therapy are not recommended to carry out genotyping on this allele, since skin reactions were mostly observed in the first months of application (regardless of the presence of HLA-A * 3101).

However, the results of genotyping should not affect the degree of control of the patient's condition and the doctor's vigilance regarding severe skin reactions. The development of severe skin lesions is possible in patients who are negative for these alleles. Also in many cases, patients with positive HLA-B * 1502 or HLA-A * 3101 alleles did not develop severe skin syndromes when Treleptal® was used.

When carrying out genotyping on the HLA-B * 1502 allele, a high resolution technique should be preferred. A test is considered positive if at least one of the alleles is detected, negative if no alleles are found.The same recommendations should be followed when genotyping the HLA-A * 3101 allele.

The influence of other factors, such as the dose of anticonvulsant drugs, the compliance of patients, simultaneous therapy with other drugs, concomitant diseases or the level of control of dermatological reactions, the frequency of development and the prevalence of severe skin reactions, has not been established.

Impaired liver function

There are reports of very rare cases of hepatitis, which in most cases were safely resolved. If suspected of hepatitis, it is necessary to consider the question of withdrawal of the drug.

Hypothyroidism

Hypothyroidism is an extremely rare AE with the use of oxcarbazepine. Given the influence of thyroid hormones on the development of children, in this category of patients, especially at the age of up to two years, it is recommended to determine the concentration of thyroid hormones before starting therapy with the drug, and to monitor this figure during the use of Trileptal®.

Simultaneous reception of oral contraceptives

Women of childbearing age who take oral contraceptives concomitantly with Trileptal®,should be warned about a possible decrease in the effectiveness of oral contraceptives. This category of patients receiving the drug Trileptal® recommends the additional use of non-hormonal methods of contraception.

The withdrawal syndrome

As with the use of other antiepileptic drugs, the sudden discontinuation of Trileptal® therapy should be avoided because of the risk of an increased incidence of convulsive seizures.

Persons taking alcohol on the background of therapy with Trileptal® should be warned about a possible increase in sedation.

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

In connection with the possibility of development against the background of the use of Trileptal® HP dizziness, drowsiness, ataxia, diplopia, blurred vision, visual impairment, hyponatremia, and depression, especially at the beginning of treatment or during dose selection, patients should be careful when driving vehicles or working with machinery during the period of drug use.

When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Suspension for oral administration, 60 mg / ml.

Packaging:

For 100 or 250 ml in bottles of dark glass with a screw cap provided with a stopper.

The bottle, together with the instruction for use, a 1-ml or 10-ml dosage syringe and a bottle adapter is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

The drug should be stored out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N015745 / 01

Date of registration:18.06.2009

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, S.A.S. France

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp12.08.2015

Illustrated instructions

Instructions

Trileptal® (Trileptal®)