Trileptal pills 600mg, 50pcs

Composition

of 1 tab. oxcarbazepine 600 mg

Auxiliary substances:

colloidal silicon dioxide,

microcrystalline cellulose,

hypromellose, crospovidone,

magnesium stearate,

macrogol 8000,

talc,

titanium dioxide (E171),

purified water,

yellow iron oxide (E172).

Pharmacological activity

The pharmacological activity of the drug Trileptal® (oxcarbazepine) is primarily due to the action of its metabolite – a monohydroxy derivative (MHP). The mechanism of action of oxcarbazepine and its MHP is mainly associated with the blockade of potential-dependent sodium channels, which results in stabilization of overexcited neuronal membranes, inhibition of the occurrence of serial neuronal discharges, and a decrease in synaptic conduction of impulses.

The realization of the anticonvulsant effect of the drug is facilitated by an increase in the conductivity of potassium ions and modulation of calcium channels activated by a high membrane potential. No significant interactions with brain neurotransmitters or binding to receptors were observed in the study of the drug.

Experimental studies have shown that oxcarbazepine and MHP have a pronounced anticonvulsant effect.

Clinical efficacy

The efficacy of Trileptal® in epileptic seizures has been demonstrated both in monotherapy and in combination therapy with Trileptal in children and adults.

The drug Trileptal can be used to replace other antiepileptic drugs in cases where the use of the latter does not achieve a satisfactory therapeutic response to treatment.

Pharmacokinetics

Suction

After oral use, oxcarbazepine in tablet form is rapidly and almost completely (>95%) absorbed into the gastrointestinal tract and is largely metabolized to form a pharmacologically active metabolite – the 10-monohydroxy derivative (MHP). After a single dose of Trileptal® in the form of coated tablets at a dose of 600 mg in healthy volunteers on an empty stomach, the average Cmax in the blood plasma of MHD is 31.5 mmol/l, the average time to reach it (Tmax) is about 5 hours.

After a single dose of Trileptal® in suspension at a dose of 600 mg in healthy volunteers on an empty stomach, the average Cmax of MHD in blood plasma is 24.9 mmol/l, the average maximum time to reach it is about 6 hours. Film – coated tablets and oral suspension are bioequivalent, since the geometric mean ratio of Cmax and AUC of MHD when using a single dose of oxcabazepine in tablet form and in suspension 0.85 to 1.06 (90% confidence interval).

Pharmacokinetic studies have shown that 2% of unchanged oxcarbazepine and 70% of MHD are detected in the blood plasma; the rest is accounted for by secondary metabolites that are rapidly eliminated from the blood plasma.

Food intake does not affect the rate and degree of absorption of oxcarbazepine.

Plasma protein binding and distribution

The apparent Vd of the 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 the drug in the blood serum. Oxcarbazepine and MHP do not bind to the α1-acid glycoprotein.

Metabolism

Oxcarbazepine is rapidly metabolized by cytosolic liver enzymes to a pharmacologically active metabolite of MHP, which determines the pharmacological effect of the drug. PGM undergoes further conjugation with glucuronic acid. Small amounts of MHP (about 4% of the dose) are oxidized to form an inactive metabolite (10,11-dihydroxy derivative (DHP)).

Deduction

Oxcarbazepine is mainly excreted as metabolites, mainly by the kidneys. More than 95% of the dose is excreted by the kidneys in the form of metabolites, less than 1% – in unchanged form. About 4% of the dose is excreted in the faeces. Approximately 80% of the dose is excreted as MHD, both as glucuronides (49%) and as unchanged MHD (27%); inactive BPH is about 3%, oxcarbazepine conjugates are about 13% of the dose. About 4% of the dose is excreted in the faeces.

Oxcarbazepine is rapidly eliminated from the blood plasma, with an apparent T1 / 2 of 1.3-2.3 h. In contrast to oxcarbazepine, an apparent T1 / 2 MHD averages 9.3±1.8 h

. Css MHD in the blood plasma is achieved on 2-3 days when taking Trileptal® 2 times / day. At steady state, the pharmacokinetic parameters of MHD are linear and dose-dependent in the daily dose range of 300 mg-2400 mg

. Pharmacokinetics in special clinical cases

Children

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

Elderly patients

After taking the drug Trileptal® only once (at a dose of 300 mg) and repeated (at a dose of 600 mg/day) in elderly volunteers aged 60-82 years Cmax and AUC values for IHL were 30-60% higher compared to the same parameters in younger volunteers (18-32 years) that is associated with age-related decrease in QC.

Gender

There were no differences in pharmacokinetic parameters depending on gender in childhood, adult or old age.

Patients with impaired liver function

Pharmacokinetic parameters and metabolism of oxcarbazepine and MHP after a single oral dose of 900 mg were evaluated in healthy volunteers and in patients with impaired liver function. Mild to moderate hepatic impairment does not affect the pharmacokinetic parameters of oxcarbazepine and MHD. The pharmacokinetics of severe hepatic impairment have not been studied.

Patients with impaired renal function

There is a linear relationship between the renal clearance of MHD and creatinine clearance. In patients with impaired renal function (creatinine clearance less than 30 ml/min) after a single dose of 300 mg of oxcarbazepine, T 1/2 MHD increases by 60-90% (up to 16-19 hours), and AUC increases 2-fold.

Indications

• Simple and 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 2 years and older.

Use during pregnancy and lactation

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

Experience with the use of Trileptal® during pregnancy is limited. Available reports indicate a possible association of taking the drug during pregnancy with the development of congenital malformations (CVD). The most common malformations in children whose mothers received Trileptal®therapy were:  During pregnancy, there were: atrial septal defect, atrioventricular septal defect, cleft hard palate and upper lip, Down syndrome, hip dysplasia (both single and bilateral), tuberous sclerosis and ear malformations.

According to the North American Pregnancy Registry, the incidence of gross malformations related to structural abnormalities requiring surgical, medical, 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 oxcarbazepine alone in the first trimester. Compared with pregnant women who did not receive any antiepileptic drugs during pregnancy, the relative risk of developing malformations in children is 1.6 with a 95% confidence interval of 0.46 to 5.7.

Patients of childbearing age should use reliable methods of contraception during therapy with Trileptal® (ideally, intrauterine contraceptives), since when used simultaneously with oral contraceptives containing ethinyl estradiol or levonorgestrel, the effectiveness of these drugs may decrease.

If the patient is planning pregnancy or pregnancy is diagnosed during the use of the drug, as well as if there is a question about the use of Trileptal® during pregnancy, it is necessary to carefully compare the expected benefits of therapy and the possible risk to the fetus, especially in the first trimester of pregnancy.

During pregnancy, the minimum effective dose of the drug should be used. If there is sufficient clinical efficacy in women of childbearing age, Trileptal® should be used in monotherapy.

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

Effective antiepileptic treatment should not be interrupted during pregnancy, as the progression of the disease can have a negative impact on the mother and fetus. Folic acid deficiency is known to develop during pregnancy. Antiepileptic drugs can increase this deficiency, which is one of the possible causes of fetal development disorders, so additional folic acid preparations are recommended.

When using the drug during pregnancy, it should be taken into account that physiological changes occurring in the body during pregnancy can lead to a gradual decrease in the level of 10-monohydroxy derivative (MHP) in blood plasma. To achieve maximum control over the symptoms of the disease in pregnant patients, it is necessary to regularly evaluate the clinical effect of the drug and determine the concentration of MHP in blood plasma.

Determination of the level of MHP in blood plasma is also recommended in the postpartum period, especially if the dose of the drug was 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 vitamin K1 is recommended in the last few weeks of pregnancy, as well as in newborns whose mothers received Trileptal®.

Oxcarbazepine and MHP cross the placental barrier. Oxcarbazepine and MHP are excreted in breast milk. The ratio of concentrations in milk and plasma was 0.5 for both substances. Since the effects of oxcarbazepine and MHP in breast-fed children are unknown, Trileptal should not be used during breast-feeding.

Use in children under 1 month of age

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

Impact on fertility

There are no data on the effect of the drug on human fertility. Animal studies did not reveal the effect of oxcarbazepine and MHP on fertility in individuals of both sexes at daily doses of 150 and 450 mg/kg, respectively. When using the maximum doses of MHP in females, however, there was a violation of the astral cycle, a decrease in the number of luteal bodies, a decrease in the number of implantations and the number of live embryos.

Contraindications

• children under 1 month of age;
• hypersensitivity to oxcarbazepine or any other components of the drug.

Caution should be exercised when prescribing the drug to patients with known hypersensitivity to carbamazepine, as this group of patients may develop hypersensitivity reactions to oxcarbazepine in approximately 25-30% of cases. Patients who do not have a history of hypersensitivity to carbamazepine may also develop hypersensitivity reactions to the drug, including multiple organ disorders.

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

Use in patients with liver function disorders

No dosage adjustment is required in patients with mild to moderate hepatic impairment. Caution should be exercised when used in patients with severe hepatic impairment.

Use in patients with impaired renal function

For patients with impaired renal function (creatinine clearance less than 30 ml / min), the recommended starting dose is 300 mg/day; the dose should be increased slowly, at intervals of at least 1 week, until the desired therapeutic response is achieved. Patients should be carefully monitored during dose selection.

Use in children

Application is possible according to the dosage regimen.

Contraindicated in children under 1 month of age.

Use in elderly patients

Special correction of the dosage regimen in this category of patients is necessary if renal function is impaired (creatinine clearance is less than 30 ml / min). If there is a risk of hyponaraemia, careful monitoring of the sodium content in the blood plasma is necessary.

Side effects

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

In clinical studies, it has been shown that undesirable effects 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) reported in clinical trials, as well as data on the safety profile of the drug obtained during its use in clinical practice. HPAs are grouped according to the MedDRA classification of organs and organ systems, and are listed in descending order of importance.

Criteria for evaluating the frequency of adverse events: very common (≥1/10), common (≥1/100,

Blood and lymphatic system disorders: infrequently-leukopenia; very rarely-suppression of bone marrow hematopoiesis, agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia.

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

From the endocrine system: very rarely – hypothyroidism.

From the side of metabolism and nutrition:often-hyponatremia (more often observed in patients aged >65 years); very rarely-clinically significant hyponatremia (sodium concentration). This condition can lead to the development of such manifestations and symptoms as seizures, encephalopathy, decreased consciousness, confusion, visual disturbances (including blurred vision), hypothyroidism, vomiting, nausea, folic acid deficiency.

From the side of the psyche: often – agitation (including nervousness), emotional lability, confusion, depression, apathy.

Nervous system disorders: very often – drowsiness (22.5%), headache (14.6%), dizziness (22.6%); often – ataxia, tremor, nystagmus, attention disorder, amnesia.

From the side of the visual organ: very often – diplopia (13.9%); often – blurred vision, visual disturbances.

Hearing disorders and labyrinth disorders: often-systemic dizziness.

From the side of the heart: very rarely – AV block, arrhythmias.

From the side of blood vessels: very rarely – arterial hypertension.

From the digestive system: very often – vomiting (11.1%), nausea (14.1%); often – diarrhea, abdominal pain, constipation; very rarely – pancreatitis.

Liver and biliary tract disorders: very rarely – hepatitis.

Skin and subcutaneous tissue disorders: often – rash, alopecia, acne; infrequently-urticaria; 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 injection site: very often – feeling tired (12%); often – asthenia.

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

In clinical studies conducted in children aged 1 month to 4 years, drowsiness was most often observed (in 11% of patients). With frequency >1%->

Adverse reactions identified in the post-marketing period based on individual reports and cases described in the literature.

Since data on adverse reactions in the post-marketing 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). Adverse reactions are classified by organ system, and within each organ system, adverse reactions are arranged in order of decreasing severity of their manifestation.

From the side of the track and subcutaneous tissues

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

Musculoskeletal and connective tissue disorders

Reduced bone mineral density, osteopenia, osteoporosis, and fractures have been reported in patients receiving long-term treatment with Trileptal®. The mechanism of oxcarbazepine’s effect on bone metabolism has not been elucidated.

From the side of metabolism and nutrition

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

Injuries, intoxications, and manipulation complications

Fall.

Nervous system disorders

Speech disorders (including dysarthria), especially during dose selection.

Interaction

Inhibition of enzymes

Oxcarbazepine and its pharmacologically active metabolite MHP are inhibitors of cytochrome CYP2C19. Thus, the concomitant use of Trileptal® in high doses and preparations that are metabolized with the participation of the CYP2C19 isoenzyme (for example, phenobarbital, phenytoin) may lead to their interaction. Some patients may need to reduce the dose of CYP2C19 substrates. Oxcarbazepine and MHP have been shown to interact weakly or not at all with the following microsomal isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D9, CYP2E1, CYP4A4, and CYP4C11.

Induction of enzymes

Being weak inducers of cytochromes CYP3A4 and CYP3A5, they reduce plasma concentrations of drugs metabolized by these enzymes: dihydropyridine calcium antagonists, oral contraceptives and antiepileptic drugs (for example, carbamazepine). When used concomitantly with Trileptal®, it is also possible to reduce the plasma concentration of other drugs that are substrates of the CYP3A4 and CYP3A5 isoenzymes (for example, drugs from the group of immunosuppressants-cyclosporine).

Since oxcarbazepine and MHP are weak inducers of uridine diphosphate-glucuronyl transferase in vitro, it is unlikely that in vivo they can have a clinically significant effect on the metabolism of drugs derived as conjugates with glucuronic acid (for example, valproic acid and lamotrigine). However, taking into account even the weak inducing ability of oxcarbazepine and MHP, 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-glucuronyl transferase. In case of discontinuation of Trileptal®, it may be necessary to reduce the dose of these drugs based on clinical and laboratory monitoring. In vitro studies have confirmed the weak inducing ability of oxcarbazepine and MHP against isoenzymes of the CYP2B and CYP3A4 subsystems. The inducing effect of oxcarbazepine and MHP on other CYP isoenzymes is unknown.

Antiepileptic drugs (AEDs)

Possible interactions between Trileptal and other antiepileptic drugs have been evaluated in clinical trials. Data on the effect of these interactions on AUC and the minimum concentration of Cmin are summarized in the table:

PEP effect of the drug Trileptal® on PEP CMIN Effect of PEP on MPG auccarbamazepine 0-22% decrease (30% increase in carbamazepine-10,11-epoxide)40% decrease in carbazam has not been studied does not affect Felbamate has not been studied does not affect phenobarbital 14-15% increase 30-31% decrease in Phenytoin 0-40% increase 29-35% decrease in Valproic acid affects 0-18% decrease

The concentration of phenytoin in blood plasma increases up to 40% with simultaneous use of the drug Trileptal® at a dose of 1200 mg / day and above. Therefore, when using the drug Trileptal® in the above doses, it may be necessary to reduce the dose of phenytoin.

The increase in the concentration of phenobarbital in blood plasma with simultaneous use with Trileptal® is insignificant (15%).

Concomitant use of strong cytochrome P 450 inducers (i. e. carbamazepine, phenytoin, and phenobarbital) decreases the concentration of MHP in blood plasma (by 29-40%). Thus, the concentration of MHP in blood plasma should be monitored and, if necessary, the dose of the drug should be adjusted when oxcarbazepine is co-administered with one or more of the above drugs.

For the drug Trileptal® no autoinduction phenomena were detected.

Hormonal contraceptives

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

Calcium Channel Blockers

Concomitant use of Trileptal and felodipine may result in a 28% decrease in felodipine AUC, although plasma concentrations remain within the therapeutic range.

On the other hand, when used concomitantly with verapamil, it is possible to reduce the concentration of MHP in blood plasma by 20%. This decrease in MPG concentration is not clinically relevant.

Interaction with other drugs

Cimetidine, erythromycin, dextropropoxifene do not affect the pharmacokinetic parameters of MHD; viloxazine slightly affects the concentration of MHD in plasma (the concentration of MHD increases by 10% after repeated co-use). There was no interaction with warfarin when taking both single and multiple doses of Trileptal®.

There were no interactions with warfarin, either with a single simultaneous use or with repeated doses of Trileptal®.

The drug Trileptal® may increase the sedative effect of ethanol.

How to take, course of use and dosage

They are taken orally.

The initial dose is 8-10 mg / kg of body weight/day. Further, the dose is adjusted depending on the treatment regimen, the patient’s age, the effectiveness of treatment, and kidney function.

For patients with impaired renal function (creatinine clearance less than 30 ml/min), adjustment of the initial dose and dosage regimen is required.

The drug Trileptal® can be used both as monotherapy and in combination with other antiepileptic drugs. In both cases, the course of treatment begins with a clinically effective dose, the frequency of use is 2 times / day. The dose may be increased depending on the response to therapy. If you replace another antiepileptic drug with Trileptal® at the beginning of taking Trileptal®, you should gradually reduce the dose of the drug being replaced. When using Trileptal® as part of a combination therapy, it may be necessary to reduce the dose of concomitant antiepileptic drugs and/or increase the dose of Trileptal® more slowly due to an increase in the total dose of antiepileptic drugs.

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

Table of conversion of the dose of Trileptal® from mg to ml.

Dose in milligrams (mg)The dose in milliliters (ml)10 mg 0.2 ml of 20 mg 0.3 ml 30 mg in 0.5 ml of 40 mg 0.7 ml 50 mg in 0.8 ml of 60 mg 1.0 ml of 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 of 1000 mg 16.7 ml

Before taking the suspension for oral use, the bottle should be thoroughly shaken and the required amount of suspension should be measured immediately. The required dose (ml) is collected from the vial using the supplied syringe. When using a 10 ml syringe (supplied with a 250 ml bottle 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 young children), the amount of suspension should be rounded to 0.1 ml. After each use, close the bottle 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 use. Keep an open bottle for no more than 7 weeks.

The oral suspension and tablets are bioequivalent and interchangeable in equivalent doses.

The therapeutic effect of the drug Trileptal® (oxcarbazepine) is primarily due to the action of its metabolite, MHP.

Routine determination of the concentration of oxcarbazepine or MHP in blood plasma is not justified. However, monitoring the concentration of MHP in blood plasma can be used to clarify the patient’s compliance with the drug regimen (compliance) or in situations where it is possible to change the clearance of MHP, for example, changes in renal function, pregnancy, simultaneous use with drugs that increase the activity of “liver” enzymes. In the above situations, the dose of Trileptal®should be adjusted taking into account the concentration of MHP in blood plasma (measured 2-4 hours after use), which should be maintained at the level of

Adult patients

Monotherapy:and combination therapy

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

In patients who have not previously received antiepileptic drugs, the effective dose is 1200 mg / day, in patients who have previously received, but did not respond well to therapy with other antiepileptic drugs-2400 mg / day.

The use of Trileptal® in a daily dose of 2400 mg as part of a combination therapy without reducing the dose of another antiepileptic agent was accompanied by poor tolerance in most patients, mainly due to the development of adverse events from the nervous system. The use of Trileptal® in a daily dose above 2400 mg has not been studied.

Children

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

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

If necessary, to achieve the desired therapeutic effect, a gradual increase in the dose is possible – with an interval of approximately 1 week, the dose is increased-by a maximum of 10 mg/kg / day, up to a maximum daily dose of 60 mg/kg of body weight.

When using the drug Trileptal® in monotherapy and as part of combination therapy, when adjusted for body weight, the apparent clearance of MHD in children decreases significantly with increasing age. Children aged 1 month to 4 years may require a dose of the drug that is 2 times higher than the adult dose when adjusted for body weight; children aged 4 to 12 years may need 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 (when adjusted for body weight). When using the drug Trileptal® in children aged 1 month to 4 years in combination with antiepileptic drugs – inducers of liver enzymes, the dose of oxcarbazepine may be 60% higher (when adjusted for body weight) than with monotherapy with Trileptal® or when used in combination with antiepileptic drugs that do not induce enzymes. For children of older age groups, when combined therapy with Trileptal® with inducers of liver enzymes, a slight increase in the dose of the drug may be required compared to monotherapy.

In children under 3 years of age, the drug should be used in the form of syrup due to the difficulties of using solid dosage forms in this age group.

Patients aged ≥65 years

Special correction of the dosage regimen in this category of patients is necessary if renal function is impaired (creatinine clearance is less than 30 ml / min). If there is a risk of hyponaraemia, careful monitoring of the sodium content in the blood plasma is necessary.

Patients with impaired liver function

No dosage adjustment is required in patients with mild to moderate hepatic impairment. Caution should be exercised when used in patients with severe hepatic impairment.

Patients with impaired renal function

For patients with impaired renal function (creatinine clearance less than 30 ml / min), the recommended starting dose is 300 mg/day; the dose should be increased slowly, at intervals of at least 1 week, until the desired therapeutic response is achieved. Patients should be carefully monitored during dose selection.

Overdose

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

Symptoms:

Violations of the water-electrolyte balance: hyponatremia.

From the side of the visual organ: diplopia, miosis, blurred vision.

From the digestive system: nausea, vomiting, hyperkinesia.

General disorders and disorders at the injection site: fatigue.

Laboratory and instrumental data: reduced respiratory rate, prolongation of the QTc interval.

Nervous system disorders: drowsiness, dizziness, ataxia, nystagmus, tremor, coordination disorders, seizures, headache, coma, loss of consciousness, dyskinesia.

Mental disorders: aggression, agitation, confusion.

From the side of blood vessels: reduction of blood pressure.

Respiratory, thoracic and mediastinal disorders:shortness of breath.

Treatment. There is no specific antidote. Conduct symptomatic and supportive treatment. It should be borne in mind that to reduce the absorption of oxcarbazepine, gastric lavage can be performed and activated charcoal can be prescribed. Vital functions of the body should be monitored, paying special attention to violations of the water-electrolyte balance, cardiac conduction and respiratory system disorders.

Special instructions

There are reports of a risk of worsening the course of epileptic seizures when using the drug Trileptal®. An increased risk of worsening the course of seizures was observed mainly in children, but it can also occur in adults. If on the background of the use of the drug Trileptal® there is a worsening of the course of epileptic seizures, the use of the drug should be discontinued.

Hypersensitivity reactions

Hypersensitivity reactions of immediate type (type I), including rash, pruritus, urticaria, angioedema and anaphylactic reactions, have been reported in some cases (post-marketing reports) when using Trileptal® in clinical practice. Hypersensitivity reactions can cause the development of disorders of the skin, liver, blood and lymphatic system and other organs, both individually and as part of a systemic reaction. Angioedema and anaphylactic reactions with lesions of the larynx, vocal folds (glottis), tongue, lips, and eyelids developed both during the first and repeated use of Trileptal®. If immediate hypersensitivity develops, Trileptal® should be discontinued immediately and alternative therapy should be prescribed.

The drug should be used with caution in patients with known hypersensitivity to carbamazepine, since in this group of patients, hypersensitivity reactions to oxcarbazepine may develop in approximately 25-30% of cases. Patients who do not have a history of hypersensitivity to carbamazepine may also develop hypersensitivity reactions to the drug, including multiple organ disorders. If signs and symptoms of hypersensitivity reactions occur, Trileptal should be discontinued immediately.

Hyponatremia

2.7% of patients receiving Trileptal® experienced hyponatremia (serum sodium content less than 125 mmol / L), which was usually not accompanied by clinical manifestations and did not require correction of therapy. The sodium content is normalized with discontinuation (dose reduction) of the drug Trileptal® or conservative treatment (restriction of fluid intake). In patients with a history of impaired renal function and low serum sodium levels (for example, in patients with inadequate antidiuretic hormone secretion syndrome), or in patients receiving concomitant treatment with drugs that promote the elimination of sodium from the body (diuretics, drugs that affect the secretion of antidiuretic hormone), the serum sodium content should be determined before starting therapy with Trileptal®. In the future, you should monitor the sodium content in the blood serum 2 weeks after the start of therapy and then monthly for 3 months or as needed. Special attention should be paid to these risk factors in elderly patients. If diuretics and other drugs that reduce serum sodium levels are necessary, the same recommendations should be followed in patients receiving Trileptal® therapy. If clinical symptoms of hyponatremia occur, the serum sodium content should be determined. For other patients, the determination of serum sodium can be performed during routine blood tests.

It is necessary to monitor body weight in all patients with heart failure for timely diagnosis of fluid retention. If there is fluid retention or if the symptoms of heart failure are progressing, the serum sodium content should be determined. If hyponatremia occurs, limit the amount of fluid consumed. Since oxcarbazepine may cause cardiac conduction disorders in very rare cases, patients with previous conduction disorders (atrioventricular block, arrhythmia) receiving Trileptal®should be carefully monitored.

Hematological changes

According to post-marketing reports, agranulocytosis, aplastic anemia, and pancytopenia have been reported in very rare cases during treatment with Trileptal®. Given the low incidence of agranulocytosis, aplastic anemia and pancytopenia, as well as concomitant factors (for example, concomitant use of other medications, the presence of concomitant diseases), a causal relationship between the development of these adverse events and the use of the drug cannot be established. If symptoms of severe suppression of bone marrow hematopoiesis develop, discontinuation of the drug should be considered.

Suicidal thoughts and behavior

Patients treated with anticonvulsant medications experienced episodes of suicidal behavior and suicidal thoughts. Results of a meta-analysis of randomized placebo-controlled trials showed a slight increase in the risk of suicidal behavior in patients treated with anticonvulsants. The mechanism of increasing the risk of suicide in this category of patients has not been 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®therapy.

Dermatological reactions

When using the drug Trileptal® Very rarely, serious dermatological reactions have been reported, 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, fatal outcomes are possible. When using the drug Trileptal®, dermatological reactions were observed in both children and adults, and developed on average 19 days after the start of taking the drug. There are isolated reports of cases of relapse of serious skin reactions when taking Trileptal®again. If skin reactions develop during the use of Trileptal®, discontinuation of the drug and the use of another antiepileptic agent should be considered.

Correlation with HLA-B*1502

There is a significant body of evidence supporting the role of human leukocyte antigen (HLA) alleles in the development of serious skin reactions in patients predisposed to these conditions. Due to the similarity in the chemical structure of oxcarbamazepine and carbamazepine, there is a possibility of developing Stevens-Johnson syndrome and Lyell’s syndrome in patients with the presence of the HLA-B*1502 allele in the genome, taking oxcarbazepine.

In Chinese and Thai patients, there was a clear association between the development of Stevens-Johnson syndrome and Lyell’s syndrome when using carbamazepine and the presence of the human leukocyte antigen HLA-B*1502 allele 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 Malaysian population-more than 15%. The prevalence of the HLA-B * 1502 allele in Korea and India is 2% and 6%, respectively. The prevalence of this allele in people of Caucasian, Black, Hispanic, Native American, and Japanese races is insignificant (

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

When using Trileptal® in possible carriers of the HLA-B*1502 allele, genotyping for this allele is recommended. The drug should only be used in carriers of this allele if the expected benefit of therapy exceeds the possible risk. The presence of this allele in people of Chinese nationality who take other antiepileptic drugs increases the risk of developing severe dermatological reactions. In patients with the HLA-B*1502 allele, it is necessary to avoid the use of drugs that lead to the development of Stevens-Johnson syndrome or Lyell’s syndrome, with possible replacement with alternative drugs. Genotyping for the HLA-B * 1502 allele before using Trileptal® is not necessary in patients belonging to populations with a low frequency of this allele, as well as in 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 the development of severe skin lesions (Stevens-Johnson syndrome, Lyell’s syndrome, drug rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis and spot-nodular rash) when using carbamazepine. The frequency of occurrence of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene may differ among different ethnic groups: about 2-5% in the European population, about 10% in the Japanese population, and about 6.7% in the Western European population, depending on the geographical region. The allele frequency is less than 5% in the population of Australia, Asia, Africa, and North America, with exceptions ranging from 5% to 12%. The frequency of more than 15% is found in some ethnic groups of South America (Argentina and Brazil), indigenous people of North America (Navajo and Siox tribes, in Mexico – Sanora Seri), Southern India (Tamil Nadu), and 10-15% among other indigenous people of these regions.

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

There are no sufficient grounds to recommend genotyping for this allele in patients before starting oxcarbazepine therapy. Patients already receiving therapy with Trileptal® are not recommended to perform genotyping for this allele, since skin reactions in most cases were observed in the first months of using the drug (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 alertness to severe skin reactions. The development of severe skin lesions is possible in patients who are negative for these alleles. Also, in many cases, in patients who are positive for the HLA-B*1502 or HLA-A*3101 alleles, when using the drug Trilertal® there was no development of severe skin syndromes.

When performing genotyping for the HLA-B * 1502 allele, preference should be given to the method with high resolution. The test is considered positive if at least one of the alleles is detected, and negative if no allele is detected. The same recommendations should be followed when performing genotyping for the HLA-A*3101 allele. The effect of other factors, such as the dose of anticonvulsant medications, patient compliance, concomitant therapy with other drugs, concomitant diseases or the level of control of dermatological reactions, on the frequency and 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 successfully resolved. If hepatitis is suspected, discontinuation of the drug should be considered.

Hypothyroidism

Hypothyroidism is an extremely rare adverse event when using oxcabazepine. Taking into account the influence of thyroid hormones on the development of children, in this category of patients, especially under the age of two, it is recommended to determine the concentration of thyroid hormones before starting therapy with the drug, as well as to monitor this indicator during the use of Trileptal®.

Concomitant use of oral contraceptives

Women of childbearing age who take oral contraceptives at the same time as Trileptal® should be warned about the possible decrease in the effectiveness of oral contraceptives. In this category of patients receiving Trileptal®, additional use of non-hormonal methods of contraception is recommended.

Withdrawal syndrome

As with other antiepileptic drugs, abrupt discontinuation of Trilertal therapy should be avoided due to the risk of an increased frequency of seizures.

People who take alcohol during therapy with Trileptal® should be warned about the possible increase in sedation.

The drug Trileptal® in the form of an oral suspension contains ethanol in an amount of less than 100 mg per dose. The suspension also contains parabens, which can cause allergic reactions (possibly delayed).

The oral suspension contains sorbitol, so the drug Trileptal® in suspension form should not be used in patients with hereditary problems of fructose tolerance.

Impact on the performance of potentially dangerous activities that require special attention and quick reactions

Due to the possibility of developing adverse events such as dizziness, drowsiness, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia, and depression of consciousness or other disorders of the central nervous system, especially at the beginning of treatment or during dose selection, patients should exercise caution when driving vehicles or working with mechanisms during the use of the drug.

If the described adverse events occur, you should refrain from performing these types of activities.

Form of production

Tablets coated with a yellow color, oval, slightly biconvex, with a risk on both sides, on one side marked “TF/TF”, on the other – “CG/CG”.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Oxcarbazepine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as prescribed by a doctor, Children over 1 month old, Children as prescribed by a doctor

Indications

Epilepsy