Epileptal tablets 50 mg blister No. 30

Instructions Epileptal tablets 50 mg blister No. 30

Composition

active ingredient: lamotrigine;

1 tablet contains lamotrigine 25 mg, 50 mg or 100 mg in terms of 100% substance;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, yellow iron oxide (E 172), magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: 25 mg and 100 mg tablets are round with a biconvex surface, pale yellow in color; 50 mg tablets are round, flat-cylindrical with a score and a bevel, pale yellow in color. Minor marbling and inclusions are allowed on the surface.

Pharmacotherapeutic group

Antiepileptic drugs. Lamotrigine.

ATX code N03A X09.

Pharmacological properties

Pharmacodynamics.

Lamotrigine is an anticonvulsant drug whose mechanism of action is associated with blocking voltage-gated sodium channels of presynaptic neuronal membranes in the slow inactivation phase and inhibiting excessive release of glutamate (an amino acid that plays a significant role in the development of an epileptic seizure).

Pharmacokinetics.

After oral administration, the drug is rapidly and completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached after approximately 2.5 hours.

Lamotrigine is extensively metabolized, with the main metabolite being the N-glucuronide. The mean elimination half-life in adult patients is 29 hours. Epileptal® has a linear pharmacological profile. It is excreted mainly as metabolites and partly unchanged, mainly in the urine. In children, the elimination half-life is shorter than in adults.

Special patient groups.

Children.

Weight-based clearance is higher in children than in adults, with the highest values in children under 5 years of age. The elimination half-life of lamotrigine in children is generally shorter than in adults, with a mean value of approximately 7 hours when co-administered with enzyme inducers such as carbamazepine and phenytoin, and an increase in the mean value to 45 to 50 hours when co-administered exclusively with valproate.

Elderly patients.

A pharmacokinetic analysis of a population of patients, which included both elderly and young patients with epilepsy, in a single study showed that the clearance of lamotrigine was not changed to a clinically significant extent. After single doses, apparent clearance decreased by 12% from 35 mL/min/kg at age 20 to 31 mL/min/kg at age 70. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly patients who were given a single dose of 150 mg. The mean clearance in elderly patients (0.39 mL/min/kg) is within the range of the mean clearance (0.31 to 0.65 mL/min/kg) obtained in 9 studies conducted in non-elderly adult patients after receiving a single dose of 30 to 450 mg.

Patients with impaired renal function.

A single 100 mg dose of lamotrigine was administered to 12 volunteers with chronic renal failure and 6 patients undergoing hemodialysis. The mean CL/F values were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (inter-hemodialysis), and 1.57 mL/min/kg (during hemodialysis) compared with 0.58 mL/min/kg in healthy volunteers. The mean plasma elimination half-lives were 42.9 hours (chronic renal failure), 57.4 hours (inter-hemodialysis), and 13 hours (during hemodialysis), compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1) of the body's lamotrigine levels were reduced during a four-hour hemodialysis session. For this group of patients, the initial dose of lamotrigine should be based on the patient's antiepileptic drug regimen; a reduction in the maintenance dose may be effective in patients with significant renal impairment.

Patients with impaired liver function.

A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy controls. The mean apparent clearance of lamotrigine was 0.31, 0.24 and 0.10 mL/min/kg in patients with Child-Pugh A, B and C hepatic impairment, respectively, compared with 0.34 mL/min/kg in healthy controls. Typically, the initial, titrated and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh B) and by 75% in patients with severe hepatic impairment (Child-Pugh C). The titrated and maintenance doses should be adjusted based on response to treatment.

Indication

Epilepsy.

Adults and children aged 13 years and over: monotherapy and adjunctive therapy in epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures.

Children aged 2 to 12 years: adjunctive therapy in epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome.

Monotherapy of typical absence seizures.

Bipolar disorder (adults aged 18 years and over).

To prevent phases of emotional disturbances in patients with bipolar I disorder, primarily by preventing depressive episodes.

Epileptal® is not indicated for the emergency treatment of manic or depressive episodes.

Contraindication

Epileptal® is contraindicated in patients with known hypersensitivity to lamotrigine or any other component of the drug.

Interaction with other medicinal products and other types of interactions

Uridine-5'-diphosphate-glucuronyltransferase (UGT) has been identified as the enzyme responsible for the metabolism of lamotrigine. Therefore, drugs that induce or inhibit glucuronidation may affect the clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are known to induce UGT, may also increase the metabolism of lamotrigine. There is no evidence that lamotrigine can cause clinically significant stimulation or inhibition of cytochrome P450 enzymes. Lamotrigine can induce its own metabolism, but this effect is modest and has no significant clinical consequences.

Those drugs that have some clinical effect on lamotrigine concentrations are listed in Table 1. Specific dosing recommendations for these drugs are provided in the Dosage and Administration section. In addition, this table lists those drugs that have little or no effect on lamotrigine concentrations. In general, the concomitant use of such drugs is not expected to have any clinical effect. However, caution should be exercised in patients with epilepsy whose disease state is particularly sensitive to fluctuations in lamotrigine concentrations.

Table 1.

Effect of drugs on lamotrigine concentrations

For dosage details, see the section “General dosage recommendations for special patient groups” in the section “Method of administration and dosage”. For dosage instructions for women taking hormonal contraceptives, see the section “Hormonal contraceptives” in the section “Special warnings and precautions for use”.

Interaction with antiepileptic drugs (see section "Method of administration and dosage").

Valproate, which inhibits lamotrigine glucuronidation, reduces lamotrigine metabolism and increases the mean half-life by approximately 2-fold.

Some antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital and primidone) that induce hepatic cytochrome P450 enzymes also induce UGT and, as a result, accelerate the metabolism of lamotrigine.

There have been reports of central nervous system adverse events including dizziness, ataxia, diplopia, blurred vision, and nausea in patients receiving carbamazepine concomitantly with lamotrigine. These events usually resolve when the carbamazepine dose is reduced. A similar effect has been observed in studies of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction has not been studied.

In a study in healthy adult volunteers using a dose of lamotrigine 200 mg and a dose of oxcarbazepine 1200 mg, it was found that oxcarbazepine did not alter the metabolism of lamotrigine, and lamotrigine in turn did not alter the metabolism of oxcarbazepine.

In a study in healthy volunteers, it was found that the concomitant use of felbamate at a dose of 1200 mg twice daily and lamotrigine at a dose of 100 mg twice daily for 10 days had no clinically significant effect on the pharmacokinetics of the latter.

A retrospective analysis of plasma levels in patients receiving lamotrigine with or without gabapentin showed that gabapentin did not alter the baseline clearance of lamotrigine.

The potential drug interaction between levetiracetam and lamotrigine was studied by evaluating the serum concentrations of both drugs in placebo-controlled clinical trials. According to these data, the substances do not alter the pharmacokinetics of each other.

Steady-state plasma concentrations of lamotrigine are not altered by co-administration with pregabalin (200 mg 3 times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin.

According to the study, the use of zonisamide (200–400 mg/day) together with lamotrigine (150–500 mg/day) for 35 days for the treatment of epilepsy had no significant effect on the pharmacokinetics of lamotrigine.

Concomitant administration of lacosamide (200, 400 or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures had no effect on lamotrigine plasma concentrations. In three placebo-controlled clinical trials investigating the adjunctive use of perampanel in patients with partial-onset and primary generalized tonic-clonic seizures, the highest dose of perampanel tested (12 mg/day) increased lamotrigine clearance by less than 10%.

Although there have been reports of changes in plasma concentrations of other antiepileptic drugs, controlled studies have shown that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic drugs. In vitro studies have shown that lamotrigine does not displace other antiepileptic drugs from their protein binding.

Interaction with other psychotropic substances (see section "Method of administration and dosage").

Coadministration of 100 mg/day of lamotrigine and 2 g of lithium gluconate administered twice daily for 6 days to 20 healthy volunteers did not alter the pharmacokinetics of lithium.

Multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of lamotrigine in a study of 12 patients, only resulting in a slight increase in lamotrigine glucuronide levels.

In a study in healthy adult volunteers, 15 mg of olanzapine reduced the area under the concentration-time curve and Cmax of lamotrigine by an average of 24% and 20%, respectively. 200 mg of lamotrigine had no effect on the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg/day had no clinically significant effect on the pharmacokinetics of risperidone given as a single 2 mg dose in a study of 14 healthy adult volunteers. When risperidone 2 mg was coadministered with lamotrigine, 12 of 14 volunteers reported somnolence compared to 1 in 20 volunteers receiving risperidone alone. No cases of somnolence were reported with lamotrigine alone.

In a clinical study involving 18 adult patients with bipolar disorder receiving lamotrigine (≥100 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and administered for an additional 7 days. Overall, there was an approximately 10% decrease in lamotrigine Cmax and AUC.

In vitro experiments have shown that the formation of the primary metabolite of lamotrigine, the N-glucuronide, is only minimally affected by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam. Studies of the metabolism of bufuralol in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs that are primarily metabolised by CYP2D6. In vitro experiments also suggest that the clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone.

Interaction with hormonal contraceptives.

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine.

In a study involving 16 female volunteers using the combination tablet "ethinylestradiol 30 mcg / levonorgestrel 150 mcg", an increase in the excretion of lamotrigine by approximately 2-fold was noted, which in turn caused a decrease in the area under the "concentration-time" curve and Cmax of lamotrigine by an average of 52% and 39%, respectively. The concentration of lamotrigine in the blood serum gradually increased during the week-long break in taking the contraceptive (the so-called contraceptive-free week), reaching a concentration on average approximately 2-fold higher than with concomitant use of the drugs (see sections "Method of administration and dosage" and "Special instructions for use").

The effect of lamotrigine on the pharmacokinetics of hormonal contraceptives.

In a study of 16 female volunteers, a fixed dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive pill. There was a consistent small increase in the clearance of levonorgestrel, which resulted in a mean decrease in the area under the concentration-time curve and Cmax of levonorgestrel of 19% and 12%, respectively. Measurements of serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppression of ovarian hormonal activity in some women, although measurements of serum progesterone revealed no hormonal signs of ovulation in any of the 16 women. The effect of changes in serum follicle-stimulating hormone and luteinizing hormone levels and the slight increase in levonorgestrel excretion on ovarian ovulatory activity is unknown (see the section “General dosage recommendations for special patient groups” in the “Method of administration and dosage” section for dosage in women taking hormonal contraceptives and the section “Hormonal contraceptives” in the “Special warnings and precautions for use” section). The effect of lamotrigine at daily doses above 300 mg has not been studied. Studies of other hormonal contraceptives have also not been conducted.

In a study of 10 male volunteers, rifampicin increased the clearance and decreased the half-life of lamotrigine due to induction of hepatic enzymes responsible for glucuronidation. Patients receiving concomitant rifampicin therapy should be treated with the same regimen recommended for lamotrigine and appropriate inducers of glucuronidation (see section 4.2).

In healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine by inducing glucuronidation. For the treatment of patients already taking lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and glucuronidation inducers should be followed (see section 4.2).

In studies in healthy volunteers, atazanavir/ritonavir (300 mg/100 mg) decreased the plasma AUC and Cmax of lamotrigine (100 mg) by an average of 32% and 6%, respectively (see section 4.2, General dosing recommendations for special patient populations).

According to studies, in healthy volunteers, the use of paracetamol at a dose of 1 g (four times a day) reduced the AUC and Cmin of lamotrigine in blood plasma by an average of 20% and 25%, respectively.

In vitro studies of the effects of lamotrigine on organic cation transporter 2 (OCT2) have shown that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2 with an IC50 of 53.8 µM (see section 4.4).

Interaction with the involvement of laboratory tests.

Lamotrigine has been reported to interact with tests used to rapidly detect certain drugs in urine, resulting in false-positive results, particularly for phencyclidine. An alternative, more specific chemical method should be used to confirm positive results.

Application features

Special precautions.

Skin rashes.

Skin rash may occur as a side effect within the first 8 weeks of treatment with lamotrigine. In most cases, the rash is mild and resolves without treatment, but severe skin reactions requiring hospitalization and discontinuation of Epileptal® have been reported. These include potentially life-threatening rashes such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section 4.8).

Patients who have experienced Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) after using lamotrigine should not be re-administered with lamotrigine.

In adults taking lamotrigine in studies using current dosing recommendations, the incidence of severe skin rashes is approximately 1 in 500 patients with epilepsy. Approximately half of these cases were Stevens-Johnson syndrome (1 in 1,000).

The incidence of severe skin rashes in patients with bipolar disorder is 1 in 1,000.

Children are at higher risk of developing serious skin rashes than adults.

According to studies of lamotrigine use, the incidence of rash cases leading to hospitalization in children varies from 1 in 300 to 1 in 100 patients.

In children, the first signs of skin rashes may be mistaken for infection, so doctors should pay attention to the possibility of developing an adverse reaction to the drug in children who develop rashes and fever during the first 8 weeks of therapy.

The overall risk of skin rash appears to be closely related to high initial doses of lamotrigine and exceeding the recommended dose escalation schedule for lamotrigine therapy (see section 4.2), as well as to concomitant use of valproate (see section 4.2).

Lamotrigine should be used with caution in patients with a history of allergy or rash to other antiepileptic drugs, as the incidence of moderate rash after treatment with lamotrigine in this group of patients was 3 times higher than in the group without such a history.

Skin rashes have also been reported to be part of the DRESS syndrome, also known as hypersensitivity syndrome, which is accompanied by various systemic manifestations including fever, lymphadenopathy, facial edema, blood changes, liver and kidney dysfunction and aseptic meningitis (see section "Adverse reactions"). The syndrome can have varying degrees of severity and can occasionally lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early signs of hypersensitivity (e.g. fever and lymphadenopathy) may occur even in the absence of skin rashes. If such symptoms occur, the patient should be examined immediately and, in the absence of other causes, Epileptal® should be discontinued.

In most cases, aseptic meningitis is reversible after discontinuation of the drug, but in some cases it may recur when lamotrigine is re-administered. Re-administration of lamotrigine causes a rapid return of symptoms, often of a more severe nature. Lamotrigine should not be re-administered to patients who have been discontinued due to aseptic meningitis during previous administration.

Photosensitivity reactions have also been reported with lamotrigine (see section 4.8). In a few cases, the reaction occurred with high doses (400 mg or more), after dose increases, or during rapid titration. If a patient with signs of photosensitivity (e.g. severe sunburn) is suspected of having photosensitivity related to lamotrigine, discontinuation of treatment should be considered. If continued treatment with lamotrigine is considered clinically warranted, the patient should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g. use of protective clothing and sunscreen).

The HLA-B*1502 allele in individuals of Asian (predominantly Chinese and Thai) descent is associated with an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis with lamotrigine. If a patient tests positive for the HLA-B*1502 allele, the decision to use lamotrigine should be carefully considered.

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients taking lamotrigine (see section 4.8). HLH is characterized by clinical symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, elevated serum ferritin, hypertriglyceridemia, liver function abnormalities, and coagulation abnormalities. Symptoms usually occur within 4 weeks of starting treatment. HLH can be life-threatening.

Patients should be warned about possible symptoms associated with GLH and advised to seek immediate medical attention if they occur during treatment with lamotrigine.

Patients presenting with these symptoms should be evaluated promptly and a diagnosis of GLH should be considered. If an alternative etiology for the above symptoms cannot be established, lamotrigine therapy should be discontinued.

Suicidal risk.

Patients with epilepsy may experience symptoms of depression and/or bipolar disorder, and there is evidence that patients with epilepsy and bipolar disorder have an increased risk of suicide.

Between 25% and 50% of patients with bipolar disorder have at least one suicide attempt and may experience worsening depressive symptoms and/or the emergence of suicidal thoughts and behavior (suicidality) regardless of whether they have used medications for the treatment of bipolar disorder, including Epileptal®.

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for a variety of indications, including epilepsy. A meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, has shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility of an increased risk with lamotrigine. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior. Patients and caregivers should seek medical attention if such signs appear.

Clinical deterioration in bipolar disorder.

Patients treated with Epileptal® for bipolar disorder should be observed closely for clinical worsening (including the appearance of new symptoms) and for suicidality, particularly at the beginning of treatment or at the time of dose changes. Some patients, those with a history of suicidal behavior or thoughts, the young, and patients who have demonstrated a significant degree of suicidal ideation prior to initiation of treatment, may be at greater risk of suicidal thoughts or suicide attempts, which will require careful monitoring during treatment.

In this case, the situation should be assessed and appropriate changes made to the therapeutic regimen, including possible discontinuation of treatment in patients with clinical worsening (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behavior, especially if these symptoms are severe, occur suddenly and are not part of a pre-existing symptomatology.

Hormonal contraceptives.

The effect of hormonal contraceptives on the efficacy of lamotrigine.

The combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg has been shown to increase the clearance of lamotrigine by approximately 2-fold, which in turn reduces lamotrigine levels (see section 4.5). In most cases, the maintenance dose of lamotrigine will need to be increased (by titration) to achieve maximum therapeutic effect. In women not already taking inducers of lamotrigine glucuronidation and already taking hormonal contraceptives (with a one-week break between courses, the so-called contraceptive-free week), a gradual temporary increase in lamotrigine levels may be observed during the one-week break. This increase will be greater if the lamotrigine dose is increased a few days before or during the one-week break. For more information on dosing, see section 4.2, General dosing recommendations for special patient groups. Therefore, women who start taking oral contraceptives or finish a course of oral contraceptives should be under constant medical supervision and in most cases will require a dose adjustment of lamotrigine.

Other oral contraceptives and hormone replacement drugs have not been studied, but they may similarly affect the pharmacokinetics of lamotrigine.

The effect of lamotrigine on the efficacy of hormonal contraceptives.

A clinical interaction study in 16 healthy volunteers showed a slight increase in levonorgestrel excretion and changes in serum levels of follicle-stimulating hormone and luteinizing hormone when lamotrigine was administered with a hormonal contraceptive (combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg) (see section 4.5). The effect of these changes on ovarian ovulation is unknown. However, it cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives, these changes may lead to a decrease in the effectiveness of the latter. Therefore, patients should be promptly informed of any changes in their menstrual cycle, such as breakthrough bleeding.

Effect of lamotrigine on organic cation transporter 2 (OCT 2) substrates.

Lamotrigine is an inhibitor of renal tubular secretion via organic cation transporter proteins (see section "Interaction with other medicinal products and other forms of interaction"). This may lead to increased plasma levels of some drugs that are excreted primarily by the above-mentioned route. Therefore, the use of Epileptal® with OCT 2 substrates with a narrow therapeutic index, such as dofetilide, is not recommended.

Dihydrofolate reductase.

Epileptal® is a weak inhibitor of dihydrofolate reductase, therefore, with prolonged use, its effect on folate metabolism is possible. However, with prolonged use of Epileptal®, there were no significant changes in hemoglobin, mean erythrocyte volume, serum and erythrocyte folate concentrations over 1 year, and erythrocyte folate concentrations over 5 years.

Kidney dysfunction.

In single-dose studies in patients with end-stage renal disease, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is possible. Therefore, caution should be exercised when treating patients with renal impairment.

Patients taking other medications containing lamotrigine.

Epileptal® should not be used in patients who are already being treated with any other drug containing lamotrigine without consulting a doctor.

Brugada syndrome.

Arrhythmogenic ST-T abnormalities and typical Brugada syndrome ECGs have been observed in patients taking lamotrigine. The use of lamotrigine in patients with Brugada syndrome should be carefully considered.

Development in children.

There are no data on the effects of lamotrigine on growth, puberty, cognitive, emotional and behavioral changes in children.

Epilepsy.

Abrupt discontinuation of Epileptal®, as with other antiepileptic drugs, may result in an increase in seizure frequency. Except in cases where the patient's condition requires abrupt discontinuation of the drug (such as the appearance of rashes), the dose of Epileptal® should be reduced gradually, over at least 2 weeks.

There may be a clinically significant worsening in seizure frequency rather than improvement. In patients with more than 1 seizure type, improvement in control of one seizure type should be carefully weighed against worsening control of another seizure type.

Treatment with lamotrigine may exacerbate myoclonic seizures.

There is evidence that the response to lamotrigine in combination with enzyme inducers is weaker than to lamotrigine in combination with non-enzyme-inducing antiepileptic drugs. The reason for this is unknown.

When treating children with typical minor epileptic seizures, the effect is not achieved in all patients.

Bipolar disorders.

Children (under 18 years of age)

Antidepressant treatment is associated with an increased risk of suicidal ideation and behavior in children (under 18 years of age) with major depressive disorder and other psychiatric disorders.

Fertility.

The use of lamotrigine in animal reproduction studies did not impair fertility. There are no data on the effect of Epileptal® on fertility in humans.

Teratogenicity.

Epileptal® is a weak inhibitor of dihydrofolate reductase. There is a theoretical risk of congenital malformations in humans if a woman is treated with folate inhibitors during pregnancy. Reproductive toxicology studies with lamotrigine in animals administered doses less than the human dose of 400 mg/day [calculated on a body surface area (mg/m2)] showed developmental toxicity (increased mortality, decreased body weight, increased structural changes, neurobehavioral abnormalities), but did not reveal a teratogenic effect.

Epileptal® contains lactose, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use the drug.

Use during pregnancy or breastfeeding

Risk associated with the use of antiepileptic drugs in general.

Women of childbearing potential should seek medical advice. When planning pregnancy, the need for antiepileptic treatment should be reconsidered. In women with epilepsy who are already being treated, abrupt discontinuation of antiepileptic treatment should be avoided, as this may lead to an exacerbation of seizures and have serious consequences for both the woman and the child. In any case, monotherapy should be preferred, since the use of combination therapy with AEDs may increase the risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with the use of lamotrigine.

Pregnancy.

Postmarketing data from a study involving over 8,700 women exposed to lamotrigine monotherapy during the first trimester of pregnancy have been obtained. Overall, these data did not indicate a significant increase in the risk of major congenital malformations, including oral clefts.

Animal studies have shown embryofetal toxicity.

If therapy with Epileptal® is necessary during pregnancy, the lowest possible therapeutic doses should be used.

Lamotrigine has a weak inhibitory effect on dihydrofolate reductase and theoretically may increase the risk of embryo-fetal malformations due to decreased folic acid levels (see section 4.4). Therefore, folic acid supplementation should be considered during pregnancy and early pregnancy.

Physiological changes during pregnancy may affect lamotrigine concentrations and/or its therapeutic effect. There have been reports of decreased lamotrigine plasma concentrations during pregnancy, which have been associated with an increased risk of loss of seizure control. After delivery, lamotrigine levels may increase rapidly with the potential for dose-related adverse reactions. Therefore, serum lamotrigine levels should be monitored.