Trileptal, 60 mg/ml 100 ml

The pharmacological activity of Trileptal® (oxcarbazepine) is primarily due to the action of its metabolite – monohydroxy derivative (MND). The mechanism of action of oxcarbazepine and its MND is mainly related to the blockade of potential-dependent sodium channels, resulting in the stabilization of overexcited neuronal membranes, inhibition of serial neuronal discharges and reduction of synaptic impulse conduction.

The realization of the anticonvulsant action of the drug is promoted by increasing the conductance of potassium ions and modulation of calcium channels activated by the high membrane potential. In the study of the drug no significant interactions with brain neuromediators or binding to receptors were observed.

In experimental studies, oxcarbazepine and MNP have been shown to have significant anticonvulsant effects.

The clinical efficacy of Trileptal^® for epileptic seizures has been demonstrated both with monotherapy and when using Trileptal as part of combination therapy in children and adults.

Trileptal may be used as a substitute for other antiepileptic drugs when satisfactory therapeutic response to treatment is not achieved with the latter.

Pharmacokinetics

Intake

After oral administration oxcarbazepine in tablet form is rapidly and almost completely (>95%) is absorbed in the gastrointestinal tract and is largely metabolized to form the pharmacologically active metabolite, 10-monohydroxy derivative (MGD). After a single administration of Trileptal^® in the form of coated tablets at a dose of 600 mg in healthy volunteers on an empty stomach, the average C_max in plasma MND is 31.5 μmol/L, the average time to reach it (T_max ) is about 5 hours.

After a single administration of the drug Trileptal^® in suspension form at a dose of 600 mg in healthy volunteers on an empty stomach, the average C_max of IHL in plasma is 24.9 μmol/l, the average maximum time of its achievement – about 6 hours. Film-coated tablets and oral suspension are bioequivalent, as the geometric mean ratio of C_max and AUC of MND when using a single dose of oxcabazepine in tablet form and in suspension form and in equilibrium was in the range of 0.85 to 1.06 (90% confidence interval).

Pharmacokinetic studies have shown that 2% of unchanged oxcarbazepine and 70% of MGP are detected in plasma; the remainder is due to secondary metabolites that are rapidly eliminated from plasma.

Eating does not affect the rate and degree of absorption of oxcarbazepine.

Binding to plasma proteins and distribution

The apparent V_d of MND is 49 l. Approximately 40% of MND is bound to plasma proteins, mainly to albumin. In the therapeutic range the degree of binding is independent of the drug concentration in serum. Oxcarbazepine and MNP do not bind to α₁-acid glycoprotein.

Metabolism

Occarbazepine is rapidly metabolized by hepatic cytosolic enzymes to the pharmacologically active metabolite MND, which accounts for the pharmacological effect of the drug. MND undergoes further conjugation with glucuronic acid. Minor amounts of MND (about 4% of the dose) are oxidized to form an inactive metabolite (10,11-dihydroxy derivative (DHD)).

Elevation

Occarbazepine is excreted mainly as metabolites, mainly by the kidneys. More than 95% of the dose is excreted by the kidneys as metabolites, less than 1% – unchanged. About 4% of the dose is excreted with feces. Approximately 80% of the dose is excreted as MND, both as glucuronides (49%) and as unchanged MND (27%); inactive DGP is about 3%, oxcarbazepine conjugates are about 13% of the dose. About 4% of the dose is excreted with the feces.

Occarbazepine is rapidly excreted from plasma, the apparent T_1/2 is 1.3 to 2.3 h. In contrast to oxcarbazepine, the apparent T_1/2 of MHP averages 9.3±1.8 h.

The C_ss of MGP in plasma is reached by 2-3 days when Trileptal^® is taken 2 times/day. In equilibrium, the pharmacokinetic parameters of MND are linear and dose-dependent in the range of daily doses of 300 mg-2400 mg.

Pharmacokinetics in Special Clinical Cases

Children

The weight-adjusted clearance of MND decreases in children with increasing age and body weight, approaching that of adults. Weight-adjusted clearance in children aged 1 month to 4 years is on average 93% higher than in adults. Thus, it is expected that the AUC of IHL in children of this age group is half that of adults when using the same doses (when adjusted by body weight). Weight-adjusted clearance in children aged 4 to 12 years is on average 43% higher than in adults. Estimated AUC of IHL in children of this age group is 2/3 of that in adults when using the same doses (when adjusted by body weight). It is assumed that in children aged 13 years and older due to weight gain, MND clearance adjusted by body weight corresponds to MND clearance in adults.

Pregnant patients

A number of physiological changes occur in the body during pregnancy that can lead to a gradual decrease in plasma IHL levels during this period.

Elderly patients

After administration of Trileptal^® once (at a dose of 300 mg) and again (at a dose of 600 mg/day) in older volunteers aged 60-82 years C_max and AUC values for IHL were 30-60% higher compared to the same values in younger volunteers (18-32 years old), which is associated with age-related CK decrease.

Paired

No differences in pharmacokinetic parameters were observed by sex in childhood, adulthood, or old age.

Patients with hepatic impairment

Pharmacokinetic parameters and metabolism of oxcarbazepine and MGP after a single oral dose of 900 mg were evaluated in healthy volunteers and in patients with hepatic impairment. Mild to moderate hepatic dysfunction does not affect pharmacokinetic parameters of oxcarbazepine and MND. Pharmacokinetics in severe hepatic impairment have not been studied.

Patients with impaired renal function

There is a linear dependence of renal clearance of MND on CK. In patients with impaired renal function (CKR less than 30 ml/min) after a single administration of 300 mg oxcarbazepine the T_1/2 MGP is increased by 60-90% (up to 16-19 h) and AUC is increased 2-fold.

Indications

Epilepsy, Seizures

• 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.

Active ingredient

Oxcarbazepine

Composition

Associates:

propylparahydroxybenzoate – 0.3 mg,

sodium saccharinate – 0.5 mg,

sorbic acid – 0.5 mg,

macrogoal 400 stearate – 1 mg,

methyl parahydroxybenzoate – 1.2 mg,

ascorbic acid – 10 mg,

dispersible cellulose (microcrystalline cellulose and sodium carmellose) – 15 mg,

Plum-lemon yellow fragrance 39K020 (which is a solution containing 36% ethanol and 16% propylene glycol) – 2.5 mg,

propylene glycol distilled – 25 mg,

sorbitol 70% liquid – 250 mg,

purified water – 717 mg.

How to take, the dosage

It is taken orally.

The initial dose is 8-10 mg/kg body weight/day. Then the dose is adjusted depending on the treatment regimen, patient’s age, treatment efficacy, and renal function.

In patients with impaired renal function (CKG less than 30 ml/min), the initial dose and dosage regimen need to be adjusted.

Trileptal® can be used both as monotherapy and in combination with other antiepileptic drugs. In both cases, the course of treatment begins with clinically effective dose, the frequency of administration is 2 times per day. The dose may be increased depending on the response to therapy. If another antiepileptic drug is substituted with Trileptal®® , the dose of the substituted drug should be gradually reduced at the beginning of taking Trileptal® . When using Trileptal^® as part of combination therapy, it may be necessary to decrease 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.

Trileptal^® can be taken regardless of meals (during, after or between meals).

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

Before taking the oral suspension, the bottle should be shaken thoroughly and the desired amount of suspension should be measured immediately. The desired dose (ml) is drawn from the bottle using the syringe provided. If the 10 ml syringe (supplied with the 250 ml bottle for adults and older children) is used, the amount of suspension should be rounded up to 0.5 ml. When using a 1 ml syringe (supplied with a 100 ml bottle for younger children) the amount of suspension should be rounded up to 0.1 ml. After each use the vial should be closed tightly and the syringe should be wiped with a clean dry cloth. The suspension can be taken directly from the syringe or diluted with a little water before intake. Keep the bottle open 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, MGP.

The routine determination of plasma concentrations of oxcarbazepine or MND is not warranted. However, control of plasma concentrations of MND can be used to clarify adherence to the drug by the patient (compliance), or in situations where there may be changes in MND clearance, such as changes in renal function, pregnancy, simultaneous use with drugs that increase activity of “liver” enzymes. In the above situations, the dose of Trileptal® should be adjusted with regard to plasma concentrations of MND (measured 2-4 h after administration), which should be maintained at

Adult patients

Monotherapy:and combination therapy

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

In patients who have not previously received therapy with antiepileptic agents the effective dose is 1200 mg/day, in patients who previously received but poorly responded to therapy with other antiepileptic agents – 2400 mg/day.

The use of the drug Trileptal® at a daily dose of 2400 mg in combination therapy without reducing the dose of another antiepileptic agent was accompanied by poor tolerability in most patients mainly due to the development of adverse events in the nervous system. The use of Trileptal® in a daily dose higher than 2400 mg has not been studied.

In children

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

In combination therapy, the target dose of Trileptal® of 30-46 mg/kg/day should not be reached before 2 weeks from the start of therapy.

If necessary to achieve the desired therapeutic effect, the dose may be gradually increased – at an interval of about 1 week the dose is increased – by maximum 10 mg/kg/day, up to maximum daily dose of 60 mg/kg of body weight.

When using Trileptal^® in monotherapy and as part of combination therapy, the apparent clearance of MND in children decreases significantly with increasing age. Children aged 1 month to 4 years may require a dose of the drug that is twice the adult dose when adjusted by body weight; children aged 4 to 12 years may require a dose that is 50% higher than the adult dose when adjusted by body weight.

In children aged 1 month to 4 years, the effect of antiepileptic drugs – hepatic enzyme inducers on their apparent clearance is more pronounced than in children of older age groups (when adjusted by body weight). When using Trileptal^® in children aged 1 month to 4 years in combination with antiepileptic drugs – inducers of liver enzymes may require a 60% higher dose of oxcarbazepine (when adjusted for body weight) than when monotherapy with Trileptal^® or when used in combination with anti-epileptic agents that do not induce enzymes. For older children, combination therapy with Trileptal^® with liver enzyme inducers may require a slight increase in the drug dose compared to monotherapy.

In children younger than 3 years of age the drug should be used in the syrup form due to the difficulty of using solid dosage forms in this age group.

Patients aged ≥65 years

Special dosing adjustment in this category of patients is necessary if renal function is impaired (CKR less than 30 ml/min). If there is a risk of hyponaremia, careful monitoring of plasma sodium is necessary.

Patients with hepatic impairment

There is no need for dosing adjustment in patients with mild to moderate hepatic impairment. Caution should be used in patients with severe hepatic impairment.

Patients with renal impairment

For patients with renal impairment (CKR 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 closely monitored during dose adjustment.

Interaction

Enzyme inhibition

Occarbazepine and its pharmacologically active metabolite MND are inhibitors of cytochrome CYP2C19. Thus, concomitant use of Trileptal^® at high doses and preparations that are metabolized with participation of CYP2C19 isoenzyme (e.g., phenobarbital, phenytoin) may lead to their interaction. For some patients it may be necessary to reduce the dose of drugs – substrates of CYP2C19. Oxcarbazepine and MND 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

As they are weak inducers of cytochrome CYP3A4 and CYP3A5, they decrease plasma concentrations of drugs metabolized by these enzymes: dihydropyridine calcium antagonists, oral contraceptives and antiepileptic drugs (e.g. carbamazepine). When concomitant use with the preparation Trileptal® ^®, plasma concentrations of other drugs, which are substrates of CYP3A4 and CYP3A5 isoenzymes (e.g., drugs from immunosuppressant group – cyclosporine) may also decrease.

As in vitro oxcarbazepine and MNP are weak inducers of uridine diphosphate-glucuronyl transferase, it is unlikely that in vivo they can have a clinically significant effect on the metabolism of drugs excreted as glucuronic acid conjugates (for example, valproic acid and lamotrigine). But, taking into account even weak inducing ability of oxcarbazepine and MND, it may be necessary to increase doses of concomitantly used drugs that are metabolized with participation of CYP3A4 isoenzyme or uridine diphosphate-glucourene transferase. In case of withdrawal of Trileptal^®, a dose reduction of these drugs may be required based on clinical and laboratory monitoring. In vitro studies have confirmed the weak inducing ability of oxcarbazepine and MND against isoenzymes of CYP2B and CYP3A4 enzyme subsystems. The inducing effect of oxcarbazepine and MND on other CYP isoenzymes is unknown.

Antiepileptic drugs (PEDs)

Possible interactions of Trileptal® and other antiepileptic drugs have been evaluated in clinical studies. The data on the effect of these interactions on AUC and minimum C_min concentration are summarized in the table:

Plasma phenytoin concentrations are increased by up to 40% when Trileptal^® is concomitantly prescribed at a dose of 1200 mg/day or higher. Therefore, when using Trileptal^® in the above doses, it may be necessary to reduce the dose of phenytoin.

The increase in plasma concentrations of phenobarbital when concomitantly used with Trileptal® is negligible (15%).

Concomitant use of strong cytochrome P450 inducers (i.e. carbamazepine, phenytoin and phenobarbital) decreases plasma concentrations of MND (by 29-40%). Thus it is necessary to monitor plasma concentrations of MND and if necessary to adjust the dose of the drug in case of concomitant use of oxcarbazepine with one or more of the above mentioned drugs.

Trileptal^® has not shown any autoinduction phenomena.

Hormonal contraceptives

Trileptal^® has been shown to interact with the components of oral contraceptives: ethinylestradiol and levonorgestrel. Average AUC values for them were decreased by 48-52% and 32-52%, respectively. No studies on the interaction of Trileptal® with other oral or implantable contraceptives have been conducted. Thus, the simultaneous use of Trileptal® and hormonal contraceptives may decrease the effectiveness of the latter, and in this regard, patients receiving treatment with Trileptal®® should use additional reliable non-hormonal contraceptive methods.

Calcium channel blockers

Combined use of Trileptal® and felodipine may decrease AUC of felodipine by 28%, although plasma concentrations remain within the therapeutic range.

On the other hand, concomitant use with verapamil may decrease plasma concentrations of MPG by 20%. This decrease in plasma concentrations is not clinically relevant.

Interaction with other medicinal products

Cimetidine, erythromycin, dextropropoxyphene do not influence pharmacokinetic parameters of MND; viloxazine slightly influences plasma concentration of MND (concentration of MND is increased by 10% after reuse together). No interaction with warfarin has been observed with both single and multiple doses of Trileptal®.

No interactions with warfarin have been noted with both single concomitant and repeated doses of Trileptal®.

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

Special Instructions

There are reports about the risk of worsening of the course of epileptic seizures when using Trileptal®. An increased risk of seizure worsening has been observed mainly in children, however, it may also occur in adults. If a worsening of the course of epileptic seizures is observed during the use of Trileptal®® , the drug should be discontinued.

Hypersensitivity reactions

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

The drug should be used with caution in patients with known hypersensitivity to carbamazepine because in this group of patients in about 25-30% of cases hypersensitivity reactions to oxcarbazepine may develop. Patients with no 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, the drug Trileptal^® should be discontinued immediately.

Hyponatremia

In 2.7% of patients receiving the drug Trileptal^®, hyponatremia (serum sodium less than 125 mmol/L) was observed, which usually was not accompanied by clinical manifestations and did not require correction of therapy. Sodium content is normalized with discontinuation (dose reduction) of Trileptal® or conservative treatment (restriction of fluid intake). In patients with renal dysfunction in anamnesis and low serum sodium content (for example, in patients with inadequate secretion of antidiuretic hormone syndrome) or in patients concomitantly treated with agents that promote sodium excretion from the body (diuretics, drugs affecting antidiuretic hormone secretion), before start of therapy with Trileptal® .sup>® should be determined in serum sodium content. Later on it is necessary to monitor sodium content in serum in 2 weeks after the therapy start and further every month during 3 months or as it is necessary. Elderly patients should be treated with particular attention to these risk factors. If it is necessary to use diuretics and other drugs that reduce sodium content in blood serum in patients receiving the therapy with the drug Trileptal®, the same recommendations should be followed. If clinical symptoms of hyponatremia occur, serum sodium content should be determined. For other patients determination of sodium content in serum can be performed during routine blood tests.

Body weight control should be performed in all patients with heart failure for timely diagnosis of fluid retention. In case of fluid retention or in case of progression of heart failure symptoms serum sodium content should be determined. In case of hyponatremia the amount of fluid intake should be limited. As far as in very rare cases of oxcarbazepine use cardiac conduction disorders may occur, the patients with previous conduction disorders (atrioventricular blockade, arrhythmia) treated with Trileptal® should be closely monitored.

Hematologic changes

According to post-marketing reports, the development of agranulocytosis, aplastic anemia and pancytopenia have been reported in very rare cases in patients treated with Trileptal^®. Taking into account the low incidence of agranulocytosis, aplastic anemia and pancytopenia, as well as concomitant factors (e.g., concomitant use of other drugs, 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 marked suppression of medullary hematopoiesis develop, it is necessary to consider discontinuation of the drug.

Suicidal thoughts and behavior

Patients receiving anticonvulsants have had episodes of suicidal behavior and suicidal thoughts. Results of a meta-analysis of randomized placebo-controlled trials showed a small increase in the risk of suicidal behavior in patients receiving anticonvulsants. The mechanism for the increased risk of suicide in this patient population has not been established. Therefore, close monitoring of patients treated with the drug is necessary at all stages of treatment. Patients and medical personnel should be alerted to the risk of suicidal thoughts and episodes in patients treated with Trileptal^®.

Dermatological reactions

The development of serious dermatological reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and erythema exudative multiforme have very rarely been reported with the use of Trileptal^®. Patients with the above dermatological reactions may require hospitalization due to the development of life-threatening conditions; very rarely lethal outcomes are possible. When using Trileptal®® dermatological reactions have been observed in both children and adults, and have developed on average 19 days after initiation of the drug. There have been isolated reports of cases of recurrence of serious skin reactions upon resumption of Trileptal®. If skin reactions develop during the use of Trileptal®® , discontinuation of the drug and use of another antiepileptic agent should be considered.

Correlation with HLA-B*1502

There is considerable evidence to support a role for human leukocyte antigen (HLA) alleles in the development of serious skin reactions in patients with predisposition to these conditions. Because of the similarity in chemical structure between oxcarbamazepine and carbamazepine, there is a possibility of developing Stevens-Johnson syndrome and Lyell’s syndrome in patients with the HLA-B*1502 allele in the genome who take oxcarbamazepine.

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 HLA-B*1502 human leukocyte antigen allele in their genome.

The incidence of this allele in Chinese patients is 2-12%, in Thai patients it is about 8%, and in some Malaysian populations it is more than 15%. The frequency of the HLA-B*1502 allele in Korea and India is 2% and 6%, respectively. The prevalence of this allele in individuals of Caucasoid, Negroid, 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 in at least one of their two chromosomes is almost twice the frequency of the allele. Thus, the percentage of patients at risk is almost twice the frequency of the allele.

When using Trileptal^® in possible carriers of the HLA-B*1502 allele, genotyping for this allele is recommended. The drug should be used in carriers of this allele only if the expected benefits of therapy exceed the possible risks. The presence of this allele in Chinese people taking other antiepileptic drugs increases the risk of severe dermatological reactions. Patients with the HLA-B*1502 allele should avoid the use of drugs leading to Stevens-Johnson syndrome or Lyell syndrome, with possible substitution with alternative drugs. Genotyping for HLA-B*1502 allele before the use of Trileptal® is not necessary in patients belonging to populations with low frequency of this allele and also in patients already treated with this drug, because 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 HLA-A*3101 allele may be a risk factor for severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, drug rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis and spot-nodule rash) when using carbamazepine. The frequency of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene may vary in different ethnic groups: about 2-5% in the European population, about 10% in the Japanese population, about 6.7% in the population of Western Europe, depending on the geographic region. The frequency of the allele is less than 5% in the populations of Australia, Asia, Africa and North America, with exceptions ranging from 5% to 12%. Frequencies higher than 15% are found in some ethnic groups in South America (Argentina and Brazil), indigenous people in North America (Navajo and Siocs tribes, in Mexico – Sanora Ceri), South India (Tamil Nadu), and 10-15% among other indigenous people in 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 in at least one of their two chromosomes is almost twice the frequency of the allele. Thus, the percentage of patients who might be at risk is almost twice the frequency of the allele.

There is insufficient evidence to recommend genotyping for this allele in patients before starting oxcarbazepine therapy. Patients already receiving therapy with Trileptal^® should not be genotyped for this allele because skin reactions were observed in most cases 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 and the physician’s alertness to severe skin reactions. The development of severe skin lesions is possible in patients negative for these alleles. Also in many cases patients positive for HLA-B*1502 or HLA-A*3101 alleles have not developed severe skin syndromes when using Trilertal^®.

A high resolution technique should be preferred when genotyping for the HLA-B*1502 allele. The test is positive if at least one of the alleles is detected; it is negative if no alleles are detected. The same guidelines should be followed when genotyping for the HLA-A*3101 allele. The influence of other factors, such as anticonvulsant medication dosage, patient compliance, concomitant therapy with other drugs, comorbidities, or level of dermatologic reaction control, on the incidence and prevalence of severe skin reactions has not been established.

Liver dysfunction

There have been reports of very rare cases of hepatitis, which in most cases have resolved safely. If hepatitis is suspected, discontinuation of the drug should be considered.

Hypothyroidism

Hypothyroidism is an extremely rare adverse event with oxcabazepine. Taking into consideration the effect of thyroid hormones on child development, it is recommended to determine thyroid hormone concentration before initiating therapy with this medicine and to monitor this indicator during the use of Trileptal® in this group of patients, especially at the age of less than two years.

Concomitant use of oral contraceptives

Women of childbearing age taking oral contraceptives concomitantly with Trileptal® should be warned about possible decrease in effectiveness of oral contraceptives. Additional use of non-hormonal contraceptive methods is recommended for this category of patients receiving the drug Trileptal®.

The withdrawal syndrome

As with other antiepileptic drugs, abrupt discontinuation of therapy with Trileptal^® should be avoided because of the risk of increased frequency of seizures.

Persons taking alcohol during therapy with the drug Trileptal^® should be warned about possible increase in sedative effect.

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

The oral suspension contains sorbitol, therefore Trileptal^® in suspension form should not be used in patients with hereditary fructose tolerance disorder.

Impact on potentially hazardous activities requiring particular attention and quick reactions

In connection with the possibility of developing during the use of the drug Trileptal^® such adverse events as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia, and depressed consciousness or other central nervous system disorders, especially at the start of treatment or during dose adjustment, patients should use caution when driving or operating machinery while using the drug.

In case of the occurrence of the described adverse events, patients should refrain from performing the specified activities.

Contraindications

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

Patients with known hypersensitivity to carbamazepine should be prescribed with caution because this group of patients may develop hypersensitivity reactions to oxcarbazepine in approximately 25-30% of cases. In patients with no history of hypersensitivity to carbamazepine it is also possible to develop hypersensitivity reactions to the drug, including multiple organ disorders.

The use of the drug Trileptal® in patients with liver dysfunction has not been studied; therefore, the drug should be used with caution in this category of patients.

Hepatic disorders

The dosing regimen does not need to be adjusted in patients with mild to moderate hepatic impairment. Caution is necessary when used in patients with severe hepatic impairment.

Performance with renal impairment

For patients with renal impairment (CKR less than 30 ml/min), the recommended initial 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 closely monitored during dose adjustment.

Performance in children

Performance is possible according to the dosing regimen.

It is contraindicated in children under 1 month of age.

The use in elderly patients

Particular dosage regimen adjustment is necessary in this category of patients with impaired renal function (CKG less than 30 ml/min). If there is a risk of hyponaremia, careful monitoring of plasma sodium is necessary.

Side effects

The following adverse reactions have been reported most frequently: somnolence, headache, dizziness, diplopia, nausea, vomiting, feeling of fatigue (in more than 10% of patients).

In clinical trials it has been shown that the undesirable effects are usually mild to moderate, transient, and occur mostly at the beginning of therapy.

The following data summarizes the 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. HPs are grouped according to the MedDRA organ and system classification, and are listed in decreasing order of importance.

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

Blood and lymphatic system disorders: infrequent – leukopenia; very rare – suppression of medullary hematopoiesis, agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia.

In immune system disorders: very rarely – anaphylactic reactions, hypersensitivity reactions (including multi-organ disorders), characterized by such phenomena as rash and increased body temperature. Blood and lymphatic systems may be affected (eosinophilia, thrombocytopenia, leukopenia, lymphadenopathy, splenomegaly), liver (hepatitis, changes in liver function parameters), muscles and joints (myalgia, edema in joints, arthralgia), nervous system (hepatic encephalopathy), kidneys (renal failure, interstitial nephritis, proteinuria), lungs (pulmonary edema, bronchospasm, bronchial asthma, interstitial inflammation, dyspnea), angioedema.

Endocrine system disorders: very rarely – hypothyroidism.

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

Psychiatric disorders: often – agitation (including nervousness), emotional lability, confusion, depression, apathy.

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

VIight: very common – diplopia (13.9%); common – blurred vision, visual disturbances.

Hearing organ and labyrinth disorders: often – systemic dizziness.

Heart: very rare – AV-blockade, arrhythmia.

Vascular disorders: very rarely – arterial hypertension.

Gastrointestinal system: very common – vomiting (11.1%), nausea (14.1%); common – diarrhea, abdominal pain, constipation; very rare – pancreatitis.

Liver and biliary tract: very rare – hepatitis.

Skin and subcutaneous tissue disorders: common – rash, alopecia, acne; infrequent – urticaria; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome caused by taking medicinal products), angioedema, erythema multiforme, systemic lupus erythematosus.

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

Laboratory and instrumental data: infrequent – increased activity of liver enzymes, ALP; very rare – increased activity of amylase, lipase.

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

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

Because data on post-marketing adverse reactions were derived from voluntary reports from a population of unknown size, the incidence cannot be estimated (frequency is unknown). The adverse reactions are classified by organ system, and within each organ system, the adverse reactions are arranged in decreasing order of severity.

Germ and subcutaneous tissue disorders

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

Skeletal, musculoskeletal and connective tissue disorders

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients receiving long-term treatment with Trileptal^®. The mechanism of oxcarbazepine effect on bone metabolism is not known.

Metabolic and nutritional disorders

The syndrome of inadequate secretion of antidiuretic hormone manifested by lethargy, nausea, dizziness, decreased plasma osmolality, vomiting, headache, confusion and other nervous system symptoms.

Injuries, intoxications, and complications of manipulation

Fall.

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

Overdose

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

Symptoms:

Disorders of water-electrolyte balance: hyponatremia.

Visually: diplopia, miosis, blurred vision.

Digestive system disorders: nausea, vomiting, hyperkinesia.

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

Laboratory and instrumental findings: decreased respiratory rate, prolonged QTc interval .

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

Mental disorders: aggression, agitation, confusion.

Vascular disorders: decreased BP.

Respiratory system, chest and mediastinal organs: dyspnea.

Treatment. There is no specific antidote. Symptomatic and supportive treatment is carried out. It should be borne in mind that to reduce absorption of oxcarbazepine gastric lavage may be conducted and intake of activated charcoal may be prescribed. Vital body functions should be monitored, with special attention paid to disorders of water-electrolyte balance, cardiac conduction and disorders of the respiratory system.

Pregnancy use

Children of patients with epilepsy are more often predisposed to developmental disorders, including congenital defects.

The experience with the use of Trileptal® in pregnancy is limited. Available reports indicate a possible association of the drug administration during pregnancy with the development of congenital malformations (CHD). The most common malformations in children whose mothers were treated with Trileptal® during pregnancy were: atrial septal defect, atrial-ventricular septal defect, cleft palate and upper lip, Down syndrome, hip dysplasia (both unilateral 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 0.6 to 5.1%) among pregnant women who received oxcarbazepine monotherapy in the first trimester. Compared with pregnant women who did not receive therapy with any antiepileptic drugs during pregnancy, the relative risk of malformations in children was 1.6 with a 95% confidence interval of 0.46 to 5.7.

Patients of childbearing age should use reliable contraception during therapy with Trileptal^® (optimally, intrauterine contraceptives) because the effectiveness of these medications may decrease when used concomitantly with oral contraceptives containing ethinylestradiol or levonorgestrel.

If a patient is planning a pregnancy or a pregnancy is diagnosed during the use of the drug, and if the use of Trileptal^® during pregnancy is considered, the expected benefits of therapy and the possible risk to the fetus, especially in the first trimester of pregnancy, must be carefully compared.

In pregnancy, the lowest effective dose of the drug should be used. Trileptal^® should be used in monotherapy if there is sufficient clinical efficacy in women of childbearing age.

The patient should be warned about possible fetal abnormalities and the need for antenatal diagnostics.

The effective antiepileptic treatment should not be interrupted during pregnancy, because the progression of the disease may have a negative impact on the mother and fetus. Folic acid deficiency is known to develop during pregnancy. Antiepileptic drugs can exacerbate this deficiency, which is one of the possible causes of fetal abnormalities, so additional folic acid medication is recommended.

When using the drug during pregnancy, it should be taken into account that physiological changes that occur in the body during pregnancy may lead to a gradual decrease in plasma levels of 10-monohydroxy derivative (MGD). To maximize symptom control in pregnant patients, regular assessment of the clinical effect of the drug and determination of plasma concentrations of MND should be performed.

The determination of plasma levels of MND is also recommended in the postpartum period, especially if the drug dose was increased during pregnancy.

There are reports that the use of antiepileptic drugs during pregnancy may lead to increased bleeding in the newborn. The use of vitamin K₁ in the last few weeks of pregnancy is recommended as a precautionary measure, as well as in newborns whose mothers have received Trileptal^®.

Occarbazepine and MND penetrate the placental barrier. Oxcarbazepine and MND are excreted with breast milk. The ratio of concentrations in milk to plasma was 0.5 for both substances. Since the effect of oxcarbazepine and MND excreted with breast milk on neonates is unknown, Trileptal® should not be used during breastfeeding.

Performance in children less than 1 month

There are no data on the safety and effectiveness of Trileptal^® in children less than 1 month of age.

Impact on fertility

There are no data on the effect of the drug on fertility in humans. Animal studies have found no effect of oxcarbazepine and MNP on fertility in individuals of either sex at daily doses of 150 and 450 mg/kg, respectively. When maximum doses of MND were used in females, however, there was a disruption 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.