Trileptal^® (Tablets, Suspension) Instructions for Use

ATC Code

N03AF02 (Oxcarbazepine)

Active Substance

Oxcarbazepine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Antiepileptic drug. The pharmacological activity is primarily due to the action of the metabolite – the monohydroxy derivative (MHD) of oxcarbazepine. The mechanism of action of oxcarbazepine and its metabolite is associated mainly with the blockade of voltage-gated sodium channels, which leads to stabilization of overexcited neuronal membranes, inhibition of serial neuronal discharges and reduction of synaptic impulse conduction.

The implementation of the anticonvulsant action is facilitated by an increase in potassium ion conductance and modulation of calcium channels activated by a high membrane potential. No significant interaction with brain neurotransmitters or receptor binding was noted. Experimental studies have shown that Oxcarbazepine and its metabolite have a pronounced anticonvulsant effect.

The efficacy of oxcarbazepine in epileptic seizures has been demonstrated both in monotherapy and in the use of oxcarbazepine as part of combination therapy in children and adults.

Pharmacokinetics

After oral administration, Oxcarbazepine is completely absorbed and largely metabolized to form a pharmacologically active metabolite – the 10-monohydroxy derivative. After a single dose of oxcarbazepine, depending on the dosage form used, the C_max of the metabolite in plasma is 24.9-34 µmol/L, and the average time to reach it is about 4.5-6 hours. Pharmacokinetic studies have shown that 2% of oxcarbazepine and 70% of MHD are determined in plasma; the remainder consists of secondary metabolites that are rapidly eliminated from the plasma.

The binding of the metabolite to plasma proteins, mainly albumin, is about 40%. In the therapeutic range, the degree of binding does not depend on the concentration of the drug in the blood serum. Oxcarbazepine and MHD do not bind to α₁-acid glycoprotein. The apparent V_d is 49 L. The C_ss of MHD in plasma is reached on days 2-3 when taking oxcarbazepine 2 times/day. At steady state, the pharmacokinetic parameters of MHD are linear and dose-dependent in the range of daily doses of 300 mg – 2400 mg.

Oxcarbazepine is rapidly metabolized by cytosolic liver enzymes to the pharmacologically active metabolite MHD, which is further glucuronidated. Minor amounts of MHD (about 4% of the dose) are oxidized to form an inactive metabolite – the 10, 11-dihydroxy derivative (DHD).

Oxcarbazepine is excreted in the form of metabolites mainly by the kidneys (95%), less than 1% is excreted unchanged. Approximately 80% of the excreted metabolites are MHD, of which 49% are glucuronides and 27% are unchanged MHD. DHD is excreted unchanged (about 3%), oxcarbazepine conjugates account for 13%. About 4% of the dose is excreted in the feces.

Oxcarbazepine is rapidly eliminated from plasma, the apparent T_1/2 is 1.3 – 2.3 hours. The apparent T_1/2 of MHD is on average 9.3±1.8 hours.

There is a linear dependence of the renal clearance of MHD on creatinine clearance. With a CrCl of less than 30 ml/min after a single dose of 300 mg of oxcarbazepine, the T_1/2 of MHD increases to 19 hours, and the AUC doubles.

Body weight-adjusted clearance of MHD in children decreases with increasing age and body weight, approaching the clearance in adults. Body weight-adjusted clearance in children aged 1 month to 4 years is 93% higher than in adults. Consequently, it is assumed that the AUC of MHD in children of this age group will be 2 times lower than in adults when using the same doses (adjusted for body weight). Body weight-adjusted clearance in children aged 4 to 12 years is 43% higher than in adults. The estimated AUC of MHD in children of this age group is 2/3 of that in adults when using the same doses (adjusted for body weight). It is assumed that in children aged 13 years and older, due to increased body weight, the body weight-adjusted clearance of MHD corresponds to the clearance of MHD in adults.

After a single dose of 300 mg or multiple doses of 600 mg/day of oxcarbazepine in healthy volunteers aged 60-82 years, the C_max in plasma and AUC values for MHD were 30-60% higher compared to the same indicators in young volunteers (18-32 years), which is associated with an age-related decrease in CrCl.

A number of physiological changes occur in the body of pregnant women, which may lead to a gradual decrease in the level of MHD in plasma during pregnancy.

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.

ICD codes

Dosage Regimen

Administer orally with or without food.

Initiate therapy at 8-10 mg/kg/day in two divided doses.

Titrate the dose gradually based on clinical response and tolerability.

For monotherapy in adults, start with 600 mg/day. Increase by a maximum of 600 mg/day at weekly intervals. The recommended maintenance dose is 1200 mg/day. Doses up to 2400 mg/day have been used.

For adjunctive therapy in adults, start with 600 mg/day. The effective dose range is typically 600-2400 mg/day.

For children aged 2-4 years, start with a maximum of 16-20 mg/kg/day, not to exceed 60 mg/kg/day.

For children aged 4-16 years, initiate at 8-10 mg/kg/day. The maintenance dose is dependent on weight: for 20-29 kg, 900 mg/day; for 29.1-39 kg, 1200 mg/day; for >39 kg, 1800 mg/day.

For children aged 1 month to less than 4 years, initiate at 16-20 mg/kg/day in two divided doses. Titrate to a target maintenance dose over 2-4 days. The recommended maintenance dose is 60 mg/kg/day.

For patients with renal impairment (CrCl <30 mL/min), initiate therapy at half the usual starting dose. Titrate slowly according to clinical response.

Monitor serum sodium levels during treatment, especially during the first three months.

Do not abruptly discontinue treatment; withdraw therapy gradually to minimize the potential for increased seizure frequency.

Adverse Reactions

Most frequently (≥ 10%): drowsiness, headache, dizziness, diplopia, nausea, vomiting, feeling tired.

From the hematopoietic system: sometimes – leukopenia; very rarely – bone marrow suppression, agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia.

From the immune system: very rarely – hypersensitivity reactions accompanied by fever and rash (including multiorgan disorders). In the event of hypersensitivity reactions, damage to the blood and lymphatic systems (eosinophilia, thrombocytopenia, lymphadenopathy, splenomegaly), muscles and joints (myalgia, joint swelling, arthralgia), nervous system (encephalopathy), kidneys (proteinuria, interstitial nephritis, renal failure), lungs (dyspnea, pulmonary edema, bronchospasm, interstitial inflammation), deviation from normal liver function parameters, angioedema, anaphylactic reactions may occur.

From metabolism: often – hyponatremia; very rarely – clinically significant hyponatremia (sodium concentration <125 mmol/L — usually within the first 3 months of drug therapy; in some patients — more than 1 year after starting treatment), leading to the development of such manifestations and symptoms as seizures, confusion, decreased level of consciousness, encephalopathy, visual disturbances (including blurred vision), nausea, vomiting, folic acid deficiency; very rarely – hypothyroidism.

From the CNS: very often – drowsiness, headache, dizziness; often – ataxia, tremor, nystagmus, attention disturbance, amnesia; confusion, depression, apathy, agitation, emotional lability.

From the senses: very often – diplopia; often – visual disturbances, blurred vision, vertigo.

From the cardiovascular system: very rarely – arrhythmias, AV block, arterial hypertension.

From the digestive system: very often – nausea, vomiting; often – diarrhea, constipation, abdominal pain; sometimes – increased activity of liver enzymes, increased concentration of ALP in the blood; very rarely – pancreatitis and/or increased levels of lipase and/or amylase, hepatitis.

Dermatological reactions: often – rash, alopecia, acne.

Allergic reactions: sometimes – urticaria; very rarely – angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme.

Other: very often – feeling tired; often – asthenia; very rarely – systemic lupus erythematosus.

In children under 4 years of age very often (11%) – drowsiness; often (≥1%-<10%) – ataxia, irritability, vomiting, lethargy, feeling tired, nystagmus, tremor, decreased appetite, increased concentration of uric acid in the blood.

Contraindications

Children under 3 years of age; hypersensitivity to oxcarbazepine.

Use in Pregnancy and Lactation

Experience with use during pregnancy is limited. Available reports indicate a possible association between the use of oxcarbazepine during pregnancy and the development of congenital defects (e.g., cleft palate).

In experimental studies, when oxcarbazepine was used in toxic doses, an increase in embryonic mortality, slowing and impairment of fetal development and growth were noted. If a patient plans to become pregnant or becomes pregnant while using oxcarbazepine, as well as when the question of using oxcarbazepine during pregnancy arises, it is necessary to carefully weigh the expected benefits of therapy and the possible risk to the fetus, especially in the first trimester of pregnancy.

During pregnancy, Oxcarbazepine should be used in the minimum effective dose.

With sufficient clinical efficacy in women of childbearing age, Oxcarbazepine should be used as monotherapy.

Effective antiepileptic treatment should not be interrupted during pregnancy, as the progression of the disease can have a negative impact on the mother and the fetus.

It is known that folic acid deficiency develops during pregnancy. Antiepileptic drugs may exacerbate this deficiency, which is one of the possible causes of fetal developmental disorders, so additional intake of folic acid preparations is recommended.

When used during pregnancy, it must be taken into account that physiological changes occurring in the body of a pregnant woman may lead to a gradual decrease in the concentration of the active metabolite in plasma. To achieve maximum control of disease symptoms, the clinical effect of oxcarbazepine should be regularly assessed and the concentration of the metabolite in plasma should be determined. Determination of MHD concentration in plasma is also recommended in the postpartum period, especially if the dose of oxcarbazepine was increased during pregnancy.

There are reports that the use of antiepileptic drugs during pregnancy may lead to increased bleeding in newborns. As a precaution, administration of vitamin K₁ is recommended in the last few weeks of pregnancy, as well as to newborns whose mothers received Oxcarbazepine.

Oxcarbazepine and MHD cross the placental barrier and are excreted in breast milk. The milk-to-plasma concentration ratio was 0.5 for both substances. Since the effect on newborns of oxcarbazepine and MHD ingested with mother’s milk is unknown, Oxcarbazepine should not be used during breastfeeding.

Special Precautions

Use with caution in patients with known hypersensitivity to carbamazepine, as in this group of patients hypersensitivity reactions to Oxcarbazepine may develop in approximately 25-30% of cases. In patients with no history of hypersensitivity to carbamazepine, hypersensitivity reactions to Oxcarbazepine, including multiorgan disorders, may also develop. In case of development of immediate-type hypersensitivity reactions, Oxcarbazepine should be immediately discontinued and alternative therapy prescribed.

Use with caution in patients with severe liver dysfunction.

In patients with impaired renal function and low serum sodium concentration, or in patients receiving concomitant treatment with drugs that promote sodium excretion (diuretics, drugs affecting ADH secretion), serum sodium concentration should be determined before starting therapy with oxcarbazepine. Subsequently, serum sodium concentration should be monitored 2 weeks after the start of therapy and then monthly for 3 months or as needed. Particular attention should be paid to these risk factors in elderly patients. If it is necessary to prescribe diuretics and other drugs that reduce serum sodium concentration to patients receiving Oxcarbazepine, the same recommendations should be followed. If clinical symptoms suggestive of hyponatremia appear, serum sodium concentration should be measured. For other patients, serum sodium concentration measurement may be performed during routine blood tests.

If symptoms of pronounced bone marrow suppression develop, discontinuation of oxcarbazepine should be considered.

Episodes of suicidal behavior and thinking have rarely been reported in patients taking antiepileptic drugs. The mechanism of increased suicide risk in this category of patients has not been established. Therefore, careful monitoring of patients receiving Oxcarbazepine is necessary at all stages of treatment.

Body weight should be monitored in all patients with heart failure to timely detect fluid retention. In case of fluid retention or progression of heart failure symptoms, serum sodium concentration should be determined. If hyponatremia occurs, fluid intake should be restricted. When using oxcarbazepine, cardiac conduction disturbances may occur in very rare cases, so careful monitoring of patients with pre-existing conduction disorders (AV block, arrhythmia) is necessary during treatment.

Dermatological reactions when using oxcarbazepine were observed in both children and adults and developed on average 19 days after the start of treatment. There are isolated reports of cases of recurrence of skin reactions when oxcarbazepine was resumed. If skin reactions develop during the use of oxcarbazepine, its discontinuation and the appointment of another antiepileptic drug should be considered.

If hepatitis is suspected, discontinuation of oxcarbazepine should be considered.

Like any other antiepileptic drugs, Oxcarbazepine should be discontinued gradually due to the risk of increased frequency of seizures.

Effect on ability to drive vehicles and operate machinery

Patients who experience dizziness, drowsiness or other CNS disorders while using oxcarbazepine should not drive vehicles or operate machinery during treatment.

Drug Interactions

Oxcarbazepine and its pharmacologically active metabolite MHD are inhibitors of cytochrome CYP2C19. Therefore, when using oxcarbazepine in high doses, drug interaction with drugs metabolized by CYP2C19 (phenobarbital, phenytoin) is possible. For some patients, a dose reduction of CYP2C19 substrate drugs may be required. It has been shown that Oxcarbazepine and MHD interact weakly or not at all with the following microsomal isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D9, CYP2E1, CYP4A4 and CYP4C11.

Being inducers of CYP3A4 and CYP3A5, Oxcarbazepine and MHD reduce the plasma concentrations of drugs metabolized by these isoenzymes: dihydropyridine calcium antagonists, oral contraceptives and antiepileptic drugs (e.g., carbamazepine). When used concomitantly with oxcarbazepine, a decrease in plasma concentration of other drugs that are substrates of CYP3A4 and CYP3A5 enzymes (e.g., immunosuppressant drugs – cyclosporine) is also possible.

Since in vitro MHD is a weak inducer of UDP-glucuronyl transferase and, therefore, it is unlikely that in vivo it is able to influence the metabolism of drugs excreted as conjugates with glucuronic acid (e.g., valproic acid and lamotrigine). However, given even the weak inducing ability of oxcarbazepine and MHD, it may be necessary to increase the doses of concurrently used drugs metabolized by CYP3A4 or UDP-glucuronyltransferase. In case of discontinuation of oxcarbazepine, a dose reduction of these drugs may be required.

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

The plasma concentration of phenytoin increases by up to 40% when used concomitantly with oxcarbazepine at a dose of 1200 mg/day and higher. Therefore, when using oxcarbazepine in such doses, a dose reduction of phenytoin may be required.

The increase in serum concentration of phenobarbital when used concomitantly with oxcarbazepine is insignificant (15%).

Concomitant administration of strong inducers of cytochrome P450 isoenzymes (i.e., carbamazepine, phenytoin and phenobarbital) reduces MHD concentrations in plasma (by 29-40%).

Interaction of oxcarbazepine with ethinyl estradiol and levonorgestrel has been proven. Their mean AUC values decreased by 48-52% and 35-52%, respectively. Studies of the interaction of oxcarbazepine with other oral or implantable contraceptives have not been conducted. Thus, concomitant use of oxcarbazepine and hormonal contraceptives may lead to a decrease in the effectiveness of the latter.

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

On the other hand, when used concomitantly with verapamil, a decrease in the serum concentration of MHD by 20% is possible. Such a decrease has no clinical significance.

Cimetidine, erythromycin, dextropropoxyphene do not affect the pharmacokinetic parameters of MHD; viloxazine slightly affects the concentration of MHD in plasma (MHD concentration increases by 10% after repeated concomitant use). No interaction with warfarin was noted when taking both single and multiple doses of oxcarbazepine.

Oxcarbazepine may enhance the sedative effect of ethanol.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.