Oxapin film-coated tablets 300 mg No. 30

Instructions for Oxapin film-coated tablets 300 mg No. 30

Composition

active ingredient: oxcarbazepine;

1 tablet contains oxcarbazepine 300 mg;

excipients: microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry 04F82783 yellow coating: hypromellose, polyethylene glycols, titanium dioxide (E 171), iron oxide yellow (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: capsule-shaped tablets, coated with a yellow film coating, with a score on both sides.

Pharmacotherapeutic group

Antiepileptic drugs. ATX code N03A F02.

Pharmacological properties

Pharmacodynamics.

The pharmacological activity of oxcarbazepine is primarily due to the action of its metabolite, the 10-monohydroxy derivative (MHP). The mechanism of action of oxcarbazepine and MHP is mainly associated with the blockade of voltage-gated sodium channels, which leads to the stabilization of overexcited neuronal membranes, inhibition of repetitive neuronal discharges and a decrease in the propagation of synaptic impulses. In addition, increased potassium ion conductance and modulation of high-potential activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitters or receptor modulator sites have been identified.

Animal studies have shown that oxcarbazepine and its active metabolite (MHP) are potent and effective anticonvulsants.

They protected animals from generalized tonic-clonic and, to a lesser extent, clonic seizures, and stopped or reduced the frequency of chronic recurrent partial seizures in animals with aluminum implants. No tolerance (i.e., loss of anticonvulsant activity) to tonic-clonic seizures was observed when oxcarbazepine or MHP was administered daily to animals for 5 days or 4 weeks.

Clinical efficacy

Oxcarbazepine is used as an antiepileptic drug both in monotherapy and in combination therapy and can replace other antiepileptic drugs that do not provide adequate seizure control.

Pharmacokinetics.

Absorption.

After oral administration, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active metabolite (MHP).

After a single dose of 600 mg oxcarbazepine to healthy male volunteers in the fasted state, the mean Cmax of MHP was 34 μmol/L with a corresponding median tmax of 4.5 hours.

A mass balance study was performed in healthy male subjects and demonstrated that only 2% of the total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70% to MHP, and the remainder to minor, rapidly excreted minor metabolites.

Food does not affect the rate and extent of absorption of oxcarbazepine. Therefore, Oxapine® can be taken regardless of food intake.

Distribution.

The expected volume of distribution of MHP is 49 liters.

Approximately 40% of MHP is bound to serum proteins, mainly albumin. In the therapeutic range, the extent of binding is independent of the serum concentration of oxcarbazepine. Oxcarbazepine and MHP do not bind to alpha-1-acid glycoprotein.

Oxcarbazepine and MHP cross the placenta. In one case, similar concentrations of MHP were reported in the plasma of the newborn and the mother.

Biotransformation.

In the liver, oxcarbazepine is rapidly converted by cytosolic enzymes into a pharmacologically active metabolite (MHP), which is responsible for the pharmacological effect of the drug. MHP is further metabolized by conjugation with glucuronic acid. Small amounts (4% of the dose) are oxidized to a pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHP).

Breeding.

Oxcarbazepine is eliminated from the body primarily as metabolites, primarily by the kidneys. More than 95% of the dose is excreted in the urine, with less than 1% as unchanged oxcarbazepine. Faecal excretion accounts for less than 4% of the dose. Approximately 80% of the dose is excreted in the urine as MHP glucuronides (49%) or unchanged MHP (27%), while inactive BHP accounts for approximately 3% and oxcarbazepine conjugates account for 13% of the dose.

Oxcarbazepine is rapidly eliminated from plasma with apparent half-lives between 1.3 and 2.3 hours. In contrast to oxcarbazepine, the apparent half-life of MHP in plasma averages 9.3±1.8 hours.

Dose proportionality.

Steady-state plasma concentrations of MHP are achieved within 2–3 days of twice-daily administration of oxcarbazepine in patients. At steady state, MHP pharmacokinetics are linear and dose proportional over the dose range of 300–2400 mg/day.

Special patient groups.

Patients with impaired liver function.

Patients with renal impairment.

There is a linear relationship between creatinine clearance and renal clearance of MHP. In patients with renal impairment (creatinine clearance < 30 ml/min) after a single dose of 300 mg oxcarbazepine, the half-life of MHP increased by 60-90% (16-19 hours) and the AUC increased 2-fold compared to adult patients with normal renal function (10 hours).

Children.

The pharmacokinetics of oxcarbazepine have been evaluated in pediatric patients receiving doses ranging from 10 to 60 mg/kg/day. The weight-adjusted clearance of MHP decreases as age and weight increase, approaching that of adults. The mean clearance in children aged 1 month to 4 years is 93% higher than in adults. Thus, MHP exposure in these children is expected to be approximately twice that in adults receiving a similar dose, adjusted for body weight.

The clearance based on average body weight in children aged 4 to 12 years is approximately 40% higher than that in adult patients. Therefore, the exposure to MHP in these children is expected to be approximately 2/3 higher than in adults when treated with a similar weight-adjusted dose. As body weight increases in patients aged 13 years and older, the weight-adjusted clearance of MHP is expected to approach that of adults.

Pregnancy.

Data obtained in a limited number of women indicate a gradual decrease in plasma levels of MHP during pregnancy.

Elderly patients.

After single (300 mg) and repeated (600 mg/day) doses of oxcarbazepine in elderly volunteers (60–82 years), peak plasma concentrations and AUC values for MHP were 30–60% higher than in younger volunteers (18–32 years). Comparisons of creatinine clearance in younger and elderly volunteers suggest that this difference is due to age-related decline in creatinine clearance. No specific dosage recommendations are required as therapeutic doses are individualised by the physician.

Sex.

No pharmacokinetic differences were observed based on gender in children, adults, or the elderly.

Indication

For the treatment of partial seizures with or without secondary generalized tonic-clonic seizures as monotherapy or adjunctive therapy in adults and children aged 6 years and older.

Contraindication

Hypersensitivity to oxcarbazepine, eslicarbazepine or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Enzyme induction.

Oxcarbazepine and its pharmacologically active metabolite (10-monohydroxy derivative, MHP) are weak in vitro and in vivo inducers of the cytochrome P450 enzymes CYP3A4 and CYP3A5, which are responsible for the metabolism of a very large number of drugs, including dihydropyridine calcium antagonists (e.g. felodipine), immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below) and some other antiepileptic drugs (e.g. carbamazepine), leading to decreased plasma concentrations of these drugs (Table 1 shows results for other antiepileptic drugs).

Since oxcarbazepine and MHP are weak inducers of UDP-glucuronyltransferases in vitro (the effect on specific enzymes in this class is unknown), in vivo they may have a slight inducing effect on the metabolism of drugs that are eliminated mainly by conjugation involving UDP-glucuronyltransferase. When starting treatment with oxcarbazepine or when changing its dosage, it may take 2-3 weeks to reach a new level of induction.

In case of discontinuation of oxcarbazepine therapy, a dose reduction of concomitant medications may be necessary, based on clinical and/or laboratory monitoring of plasma drug levels. Induction is likely to gradually decrease over 2–3 weeks after discontinuation of therapy.

Hormonal contraceptives.

Oxcarbazepine has been shown to affect two components of oral contraceptives: ethinyl estradiol and levonorgestrel. The mean AUC values for ethinyl estradiol and levonorgestrel were reduced by 48–52% and 32–52%, respectively. Other hormonal contraceptives have not been studied. Therefore, concomitant administration of oxcarbazepine with hormonal contraceptives may result in ineffectiveness of these agents. Another reliable method of contraception should be used.

Inhibition of enzymes.

Oxcarbazepine and MHP inhibit CYP2C19. Therefore, when high doses of oxcarbazepine are administered concomitantly with drugs that are primarily metabolized by CYP2C19 (e.g. phenytoin), an interaction between the two may occur. Phenytoin plasma levels were increased by 40% when oxcarbazepine was administered at doses exceeding 1200 mg/day (Table 1 shows results for other anticonvulsants). In such cases, a reduction in the dose of the concomitantly administered phenytoin may be necessary.

Antiepileptic drugs.

Potential interactions between oxcarbazepine and other antiepileptic medicinal products have been evaluated in clinical studies. The effect of these interactions on mean AUC and Cmin is presented in Table 1.

Table 1.

Information on the interaction of antiepileptic drugs with oxcarbazepine.

*Does not affect Cmin, AUC or Cmax)

**MHP: monohydroxy derivative (pharmacologically active metabolite of oxcarbazepine)

Potent inducers of cytochrome P450 enzymes (e.g., carbamazepine, rifampicin, phenytoin, and phenobarbital) have been shown to reduce plasma MHP levels (by 29–40%) in adults.

Therefore, plasma level monitoring and/or dose adjustment is necessary if one or more of these drugs are used concomitantly with oxcarbazepine.

In children aged 4–12 years, MHP clearance was increased by approximately 35% when one of the three enzyme-inducing antiepileptic drugs was administered compared to monotherapy. Combination therapy of oxcarbazepine with lamotrigine resulted in an increased risk of adverse events (nausea, drowsiness, dizziness, and headache).

When one or more antiepileptic drugs are co-administered with oxcarbazepine, dose adjustment of the antiepileptic drug and/or dose adjustment of oxcarbazepine may be considered on an individual basis. This is particularly true for pediatric patients receiving concomitant lamotrigine.

No enzyme self-induction was observed when oxcarbazepine was administered.

Interactions with other drugs.

Cimetidine, erythromycin, viloxazine, warfarin, and dextropropoxyphene did not affect the pharmacokinetics of MHP.

An interaction between oxcarbazepine and MAOIs is theoretically possible due to the structural relationship of oxcarbazepine to tricyclic antidepressants.

Tricyclic antidepressants

No clinically significant interactions were observed in clinical studies.

Pharmacodynamic interactions

Concomitant use of lithium preparations with oxcarbazepine may increase neurotoxicity.

Application features

Increased sensitivity.

Hypersensitivity reactions, including Class I and other hypersensitivity reactions, have been reported during treatment with oxcarbazepine. If such symptoms develop, Oxcarbazepine should be discontinued and treatment with another antiepileptic drug should be initiated.

Immediate-type (Class I) hypersensitivity reactions, including rash, edema, pruritus, urticaria, dyspnea, bronchospasm, angioedema, and anaphylaxis, have been reported with oxcarbazepine. Anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have occurred with both the first and subsequent doses of oxcarbazepine. If a patient develops such reactions after taking oxcarbazepine, it should be discontinued and alternative treatment initiated.

Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of such individuals may develop hypersensitivity reactions (e.g. severe skin reactions) when taking oxcarbazepine. For this reason, patients should be asked about previous treatment with carbamazepine before starting treatment with Oxcarbazepine. Patients with a history of hypersensitivity reactions to carbamazepine should generally only use Oxcarbazepine if the expected benefit justifies the potential risk. Hypersensitivity reactions, including multiorgan hypersensitivity reactions, have been observed in both adults and children in close temporal association (mainly within the first 3 weeks, possibly later) with the start of treatment. They can also occur in patients without a history of hypersensitivity to carbamazepine. The symptoms have varied greatly. Such reactions may manifest not only as fever and rash, but also involve the skin, liver, circulatory and lymphatic systems and other organs, either individually or together as a systemic reaction. In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Oxapin® should be discontinued immediately.

There have been reports of asthenia, pruritus, arthralgia, joint swelling, lymphadenopathy, splenomegaly, hematological abnormalities (e.g. eosinophilia, thrombocytopenia, neutropenia), pulmonary edema, interstitial lung changes, abnormal liver function tests, hepatitis, proteinuria, oliguria, interstitial nephritis, renal failure, and hepatorenal syndrome. Symptoms may also occur in other organs. Some cases have led to hospitalization, some of which are considered life-threatening.

Serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported very rarely with oxcarbazepine. Patients with serious skin reactions may require hospitalization as these conditions can be life-threatening and in very rare cases can be fatal. Serious skin reactions associated with oxcarbazepine have occurred in both children and adults. The median time to onset was 19 days. There have been isolated reports of recurrence of serious skin reactions with re-administration of oxcarbazepine. Patients who develop skin adverse reactions during treatment with oxcarbazepine should be evaluated immediately and Oxcarbazepine should be discontinued immediately, unless there is no obvious relationship between the rash and the drug. If oxcarbazepine is discontinued, consideration should be given to replacing it with other antiepileptic drugs to avoid seizures. Oxcarbazepine should not be re-administered in patients in whom it has been discontinued due to hypersensitivity reactions. There is increasing evidence that different HLA alleles play a role in the association of adverse immune and skin reactions in susceptible patients.

Association with the HLA-B*1502 allele

The presence of the human leukocyte antigen (HLA)-B*1502 allele in individuals of Chinese and Thai descent has been shown to be strongly associated with the risk of developing severe skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when treated with carbamazepine. Since the chemical structure of oxcarbazepine is similar to carbamazepine, it is possible that patients with the (HLA)-B*1502 allele are also at risk of developing SJS/TEN when treated with oxcarbazepine. Some evidence suggests that this association exists for oxcarbazepine. The prevalence of (HLA)-B*1502 carrier status is approximately 10% in the Chinese and Thai populations. If possible, these individuals should be tested for this allele before starting treatment with carbamazepine or a chemically related substance. If test results in patients of Chinese and Thai descent indicate the presence of the (HLA)-B*1502 allele, the use of oxcarbazepine is possible only when the benefits outweigh the risks.

Because of the prevalence of this allele in other Asian populations (e.g., >15% in the Philippines and Malaysia), genetic testing of at-risk patients may be appropriate. The prevalence of (HLA)-B*1502 allele is low (<1%), for example, in individuals of European descent, African and Hispanic populations, and in Japanese and Koreans.

The allele frequency indicates the percentage of chromosomes in a population that carry that allele. Since a person carries two copies of each chromosome, even having one copy of the (HLA)-B*1502 allele may be sufficient to increase the risk of developing CVD. Thus, the percentage of patients who may be at risk is almost twice the allele frequency.

Association with the HLA-A*3101 allele

Human leukocyte antigen (HLA)-A*3101 may be a risk factor for the development of adverse skin reactions such as cutaneous lupus erythematosus/TEN, rash with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP) and maculopapular rash. In particular, there is evidence that these reactions have occurred after the use of carbamazepine. Patients with an increased risk of adverse reactions due to their background should be tested before starting oxcarbazepine treatment to determine whether they carry the HLA-A*3101 allele. Screening for HLA-A*3101 is not recommended in populations with a low prevalence. Similarly, screening is not appropriate for patients who have already been using oxcarbazepine for a long time, since cutaneous lupus erythematosus/TEN, DRESS, AGEP and maculopapular rash usually only occur in the first few months of therapy. Carriers of the HLA-A*3101 allele can be treated with oxcarbazepine provided that the benefits outweigh the risks.

Genetic screening results are not a substitute for appropriate monitoring of the patient's condition, especially if the risk of serious skin reactions may be increased by other factors (such as comorbidities).

Risk of exacerbation of attacks.

A risk of exacerbation of seizures has been reported with oxcarbazepine. This risk is specific to children, but may also occur in adults. In case of exacerbation of seizures, oxcarbazepine should be discontinued.

Hyponatremia.

Clinically significant hyponatremia (Na <125 mmol/l) may develop very rarely during oxcarbazepine therapy. This usually occurs within the first three months of treatment, although there have been patients in whom serum sodium first reached a level <125 mmol/l a year after the start of therapy. Cases of seizures, disorientation, depressed level of consciousness, encephalopathy, visual disturbances (e.g. blurred vision), vomiting, nausea and folic acid deficiency have also been reported.

In rare cases, the syndrome of inappropriate ADH secretion (SIADH) may occur during oxcarbazepine therapy.

Existing heart failure

All patients with heart failure should have their weight monitored for fluid retention. In cases of fluid retention or worsening cardiac function, serum sodium levels should be checked. If hyponatremia is present, fluid restriction is an important treatment. Since oxcarbazepine may, in very rare cases, cause cardiac conduction disturbances, patients with a history of conduction disturbances (e.g., atrioventricular block, arrhythmia) should be monitored closely.

Hypothyroidism

Hypothyroidism is a very rare side effect of oxcarbazepine. Given the importance of thyroid hormones for the development of children after birth, it is advisable to perform a thyroid function test before starting oxcarbazepine therapy in the pediatric population, especially in children aged 2 years and older. In children, monitoring of thyroid function is also recommended during oxcarbazepine therapy. In patients with hypothyroidism, monitoring of thyroid function is recommended to determine the dose of hormone replacement therapy.

Liver function.

Very rare cases of hepatitis have been reported, which in most cases regressed with a favorable prognosis. If liver disease is suspected, liver function should be assessed and discontinuation of oxcarbazepine therapy should be considered. Caution should be exercised when treating patients with severe hepatic impairment.

Kidney function.

In patients with renal impairment (creatinine clearance less than 30 ml/min), oxcarbazepine therapy should be administered with caution, especially at the beginning of treatment and during dose titration. Monitoring of plasma MHP levels may be necessary.

Bone metabolism.

There have been reports of decreased bone mineral density leading to overt osteoporosis with fractures with long-term use of oxcarbazepine. The exact mechanism by which oxcarbazepine affects bone metabolism is not currently understood.

Hematological effects.

Very rare cases of agranulocytosis, aplastic anemia and pancytopenia have been reported in patients treated with oxcarbazepine. If any sign of marked bone marrow depression develops, discontinuation of the drug should be considered.

Suicidal behavior.

Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also demonstrated a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with oxcarbazepine. During treatment with oxcarbazepine, patients should be monitored for signs of suicidal ideation and behavior and treated as necessary. Patients (and caregivers of patients) should be advised to seek medical advice if suicidal ideation or behavior emerges.

Hormonal contraceptives.

Female patients of reproductive age should be warned that concomitant use of oxcarbazepine with hormonal contraceptives may result in the ineffectiveness of this type of contraception. Other types of contraception are recommended when using oxcarbazepine.

Vitamin B12 deficiency.

Vitamin B12 deficiency must be ruled out or treated.

Alcohol.

Drinking alcohol while taking oxcarbazepine may cause a cumulative sedative effect.

Cancellation of therapy.

Oxcarbazepine has a weaker enzyme-inducing effect than carbamazepine. The dose of other combined antiepileptic drugs may be reduced.

Fertility

There are no data on the effect on fertility in humans. Animal studies have not shown any impairment of fertility, but have shown a negative effect on female reproductive parameters, i.e. a risk of impairment of female fertility cannot be excluded.

Monitoring of blood plasma levels.

Although the correlation between dosage and plasma oxcarbazepine levels, and between this parameter and clinical efficacy or tolerability of therapy, is rather weak, monitoring of plasma levels may be useful in the following situations (to rule out non-compliance with the dosing regimen or in cases where changes in MHP clearance are expected):

- changes in kidney function (see section "Method of administration and dosage").

- pregnancy (see section "Use during pregnancy or breastfeeding").

- simultaneous use with drugs that induce liver enzymes (see section "Interaction with other medicinal products and other types of interactions").

Use during pregnancy or breastfeeding

Pregnancy.

General risk associated with epilepsy and antiepileptic drugs.

An increased risk of congenital malformations has been observed in women receiving polytherapy with antiepileptic drugs, especially when valproate is included. However, effective antiepileptic therapy should not be interrupted during pregnancy, as exacerbation of the disease is harmful to both the mother and the fetus.

Risk associated with oxcarbazepine.

There is a limited amount of data on the use of oxcarbazepine in pregnant women (300-1000 pregnancy outcomes). However, data on the association between oxcarbazepine use and congenital malformations are limited. There is no increase in the overall incidence of malformations with oxcarbazepine compared to the general population (2-3%). However, a moderate teratogenic risk cannot be completely excluded. The results of studies on the risk of nervous system disorders in children exposed to oxcarbazepine during intrauterine development are contradictory and such a risk cannot be excluded.

In view of the above, it is necessary to keep in mind:

If a woman receiving oxcarbazepine becomes pregnant or plans to become pregnant, the need for this drug should be carefully re-evaluated. The lowest effective dose of oxcarbazepine should be used and, if possible, monotherapy should be preferred for at least the first three months of pregnancy;

Effective antiepileptic treatment with oxcarbazepine should not be interrupted during pregnancy, as exacerbation of the disease is very harmful to both the mother and the fetus.

Monitoring and prevention.

Some antiepileptic drugs can cause folic acid deficiency, which may contribute to fetal abnormalities. Folic acid supplementation is recommended before and during pregnancy. Since the effectiveness of such supplementation has not been proven, specific antenatal screening may be offered even to women who are taking folic acid supplements.

Data from a limited number of women suggest that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHP), may gradually decrease during pregnancy. Close monitoring of the clinical response in women receiving oxcarbazepine therapy during pregnancy is recommended to ensure adequate seizure control. Changes in MHP plasma concentrations should be considered. If the dose of the drug has been increased during pregnancy, monitoring of MHP plasma levels in the postpartum period should also be considered.

Newborns.

Neonatal coagulation disorders associated with hepatic induction by antiepileptic drugs have been reported. As a precaution, vitamin K1 should be administered during the last few weeks of pregnancy and in the newborn.

Rare cases of hypocalcemia have been observed in newborns whose mothers were treated with antiepileptic drugs during pregnancy. These cases were due to disorders of calcium phosphate metabolism and bone mineralization.

Women of reproductive age and contraceptive measures

Oxcarbazepine may impair the therapeutic effect of oral contraceptives containing ethinylestradiol and levonorgestrel (see sections 4.4 and 4.5). Women of childbearing potential should be advised to use highly effective contraception during treatment with oxcarbazepine (preferably non-hormonal contraceptives, such as intrauterine implants).

Oxcarbazepine and its active metabolite (MHP) are excreted in breast milk. According to some reports, the concentration of MHP in the blood plasma of breast-fed infants is 0.2-0.8 μg/ml - up to 5% of the concentration of MHP in the mother's blood plasma. Although the effect is probably small, a risk to the infant cannot be excluded. Therefore, when deciding whether to breast-feed while using Oxcarbazepine®, both the benefit of breastfeeding and the potential risk of adverse reactions in the infant should be taken into account. If the infant is breast-fed, it is necessary to monitor for adverse effects such as drowsiness and poor weight gain.

Ability to influence reaction speed when driving vehicles or other mechanisms

The use of oxcarbazepine has been associated with adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness, especially at the beginning of treatment or in connection with dose adjustment (more often during the dose titration phase). Therefore, patients should exercise appropriate caution when driving or operating machinery.

Method of administration and doses

In monotherapy and adjunctive therapy, oxcarbazepine treatment is initiated at a clinically effective dose divided into two doses. The dose may be increased depending on the patient's clinical response. When switching from other antiepileptic medicinal products to oxcarbazepine, the dose of the concomitant antiepileptic medicinal product(s) should be gradually reduced when oxcarbazepine is initiated. As the patient's overall antiepileptic medicinal product burden increases, the doses of the concomitant antiepileptic medicinal products may need to be reduced and/or the dose of oxcarbazepine may need to be increased more slowly.

The drug can be used regardless of meals.

The following dosage recommendations apply to all patients in the absence of renal impairment. There is no need to monitor plasma levels to optimize oxcarbazepine therapy.

However, monitoring of MHP plasma concentrations should be performed during treatment with oxcarbazepine to rule out non-compliance with the treatment regimen or in situations where changes in MHP clearance are expected, such as:

changes in kidney function (see "Patients with renal impairment" below);

· pregnancy (see "Use during pregnancy or breastfeeding" and "Pharmacological properties");

· concomitant use of drugs that stimulate liver enzymes (see "Interaction with other medicinal products and other types of interactions").

The dose of oxcarbazepine may be adjusted in the situations mentioned above (depending on the plasma concentration measured 2-4 hours after administration) to maintain a maximum plasma concentration of MHP <35 mg/l. The body weight-dependent clearance of MHP (l/h/kg) in children is significantly higher than in adults.

The tablets have a score line and can be divided into two halves to make it easier for the patient to swallow the tablet. However, the tablet cannot be divided into two equal doses.

Adults.

Monotherapy.

Oxcarbazepine should be started at a dose of 600 mg/day (8–10 mg/kg/day) divided into two doses.

If clinically necessary, the dose may be increased at approximately weekly intervals by no more than 600 mg/day from the initial dose to achieve the desired therapeutic effect. Therapeutic effects are observed in the dose range of 600–2400 mg/day.

There is evidence that in patients,