Lanistor tablets 100 mg blister No. 60

Instructions Lanistor tablets 100 mg blister No. 60

Composition

active ingredient: lamotrigine;

1 tablet contains lamotrigine 25 mg, 50 mg, 100 mg;

excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: white or almost white round, flat, with beveled edges, uncoated tablets embossed with "" on one side and smooth on the other side.

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. The maximum concentration (Cmax) in the blood plasma is reached after approximately 2.5 hours.

Lamotrigine is extensively metabolized, with the major metabolite being the N-glucuronide. The mean elimination half-life in adults is 29 hours. Lamotrigine has a linear pharmacological profile. It is excreted primarily as metabolites and partially unchanged, primarily in the urine. The elimination half-life is shorter in children than in adults.

Special patient groups

Children

The clearance based on body weight 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 did not change 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 volunteers who were given a single dose of 150 mg. The mean clearance value in elderly patients (0.39 ml/min/kg) is between the mean clearance values (from 0.31 to 0.65 ml/min/kg) obtained in 9 studies conducted in non-elderly adult patients after they received a single dose of 30 to 450 mg.

Patients with renal impairment

A single 100 mg dose of lamotrigine was administered to 12 volunteers with chronic renal impairment and 6 patients undergoing haemodialysis. The mean CL/F values were 0.42 mL/min/kg (chronic renal impairment), 0.33 mL/min/kg (inter-haemodialysis) and 1.57 mL/min/kg (during haemodialysis) compared with 0.58 mL/min/kg in healthy volunteers. The mean plasma elimination half-lives were 42.9 hours (chronic renal impairment), 57.4 hours (inter-haemodialysis) and 13.0 hours (during haemodialysis), compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1) of the body-available lamotrigine was removed during a four-hour hemodialysis session. In this patient population, the initial dose of lamotrigine should be based on the antiepileptic drug regimen; a reduction in the maintenance dose may be effective in patients with significant renal impairment.

Patients with liver dysfunction

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

Indication

Epilepsy Adults and children aged 13 years and over

Adjunctive therapy or monotherapy for partial and generalized epileptic seizures, including tonic-clonic seizures.

Seizures associated with Lennox-Gastaut syndrome. Lamotrigine is prescribed as adjunctive therapy, but in Lennox-Gastaut syndrome it may be prescribed as an initial antiepileptic drug (AED).

Children aged 2 to 12 years

Monotherapy of typical absence seizures.

Bipolar disorder

Adults (ages 18 and over)

Prevention of depressive states in patients with bipolar I disorder who predominantly suffer from depressive states.

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

Contraindication

Lanistor 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

Interaction studies have only been conducted in adults.

Uridine 5'-diphospho (UDP)-glucuronyl transferase (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 moderate and has no significant clinical consequences.

Those drugs that have been shown to have a relevant 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, Table 1 lists those drugs that have been shown to have little or no effect on lamotrigine concentrations. Coadministration of such drugs is not generally 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 other drugs on lamotrigine concentrations

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

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits lamotrigine glucuronidation, reduces the metabolism of lamotrigine and increases the mean half-life by approximately 2-fold. For patients receiving concomitant valproate therapy, an appropriate treatment regimen should be used (see section 4.2).

Some AEDs (such as phenytoin, carbamazepine, phenobarbital and primidone) that induce cytochrome P450 enzymes also induce UGT and thereby accelerate the metabolism of lamotrigine. Patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbitone or primidone should use an appropriate treatment regimen (see section "Method of administration and dosage").

Central nervous system (CNS) adverse reactions have been reported, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These reactions 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.

There are reports in the literature of decreased lamotrigine levels when used in combination with oxcarbazepine. However, 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 did not alter the metabolism of oxcarbazepine. Therefore, patients receiving concomitant therapy with oxcarbazepine should use a lamotrigine add-on therapy regimen without valproate and without inducers of lamotrigine glucuronidation (see section "Method of administration and dosage").

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.

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.

Topiramate does not affect the plasma concentration of lamotrigine. The use of lamotrigine increases the concentration of topiramate by 15%.

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.

Lamotrigine plasma concentrations were not affected by concomitant use of lacosamide (200 mg/day, 400 mg/day or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.

In a pooled analysis of data from 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 AEDs, controlled studies have shown that lamotrigine does not affect the plasma concentrations of concomitant AEDs. In vitro studies have shown that lamotrigine does not displace other AEDs from their protein binding.

Interaction with other psychotropic substances

When lamotrigine 100 mg/day and lithium gluconate 2 g administered twice daily for 6 days in 20 patients, the pharmacokinetics of lithium were unchanged.

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

In a study in healthy adult volunteers, 15 mg olanzapine reduced the plasma area under the concentration-time curve (AUC) and Cmax of lamotrigine by an average of 24% and 20%, respectively. 200 mg 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 of 20 volunteers receiving risperidone alone. No cases of somnolence were reported with lamotrigine alone.

In a clinical study of 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 AUC and Cmax.

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 suggest that lamotrigine does not reduce the clearance of drugs that are primarily metabolised by CYP2D6. In vitro experiments also suggest that lamotrigine clearance 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 of 16 female volunteers using the combined tablet "ethinylestradiol 30 mcg/levonorgestrel 150 mcg", an increase in the excretion of lamotrigine was recorded by approximately 2-fold, which in turn caused a decrease in AUC and Cmax of lamotrigine by an average of 52% and 39%, respectively. With a one-week break in contraceptive use (the so-called contraceptive-free week), the concentration of lamotrigine in the blood serum gradually increased, reaching a concentration that was approximately 2-fold higher than with concomitant use of the drugs (see section "Special features of use"). There is no need to adjust the recommended doses of lamotrigine solely due to the use of hormonal contraceptives, but the maintenance dose of lamotrigine can be increased or decreased in most cases when starting or stopping hormonal contraceptives (see section "Method of administration and dosage").

In a study of 16 female volunteers, a fixed dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinylestradiol, a component of a combined oral contraceptive pill. There was a consistent small increase in the clearance of levonorgestrel, resulting in a mean decrease in AUC and Cmax of levonorgestrel of 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol levels throughout the study indicated suppression of ovarian hormonal activity in some women, although measurements of serum progesterone revealed no hormonal symptoms of ovulation in any of the 16 women. The effect of changes in serum follicle-stimulating hormone and luteinizing hormone levels and the small increase in levonorgestrel clearance on ovarian ovulatory activity is unknown (see section 4.4). The effects of lamotrigine at daily doses above 300 mg have not been studied. Studies of other hormonal contraceptives have also not been conducted.

Interaction with other drugs

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 follow the treatment regimen recommended for lamotrigine and appropriate inducers of glucuronidation (see section 4.2).

In studies 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 Dosage and Administration).

According to studies in healthy volunteers, the use of paracetamol at a dosage of 1 g (4 times a day) reduced the AUC and minimum concentration (Cmin) of lamotrigine in blood plasma by an average of 20% and 25%, respectively.

In vitro data indicate that lamotrigine, and not the N(2)-glucuronide metabolite, is an inhibitor of organic transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT 2 with an IC50 of 53.8 µM. Coadministration of lamotrigine with renally excreted drugs that are substrates of OCT 2 (e.g. metformin, gabapentin, and varenicline) may result in increased plasma levels of these drugs.

The clinical significance of this is not clearly defined, but caution should be exercised in patients taking these drugs concomitantly.

Application features

Skin rashes

A skin rash may occur within the first 8 weeks of starting lamotrigine. In most cases, the rash is mild and resolves without treatment, but severe skin reactions requiring hospitalization and discontinuation of lamotrigine have been reported. These have included potentially life-threatening rashes such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), also known as hypersensitivity syndrome (see section 4.8).

In adults who participated in studies using current dosing recommendations for lamotrigine, the incidence of severe skin rashes is approximately 1 in 500 patients with epilepsy. Approximately half of these cases were diagnosed as Stevens-Johnson syndrome (1 in 1000). In patients with bipolar disorder, the incidence of severe skin rashes is approximately 1 in 1000.

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

Studies with lamotrigine have shown that the incidence of rash leading to hospitalization in children ranges 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 be aware of the possibility of 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, as well as to concomitant use of valproate (see section 4.2).

Lamotrigine should be prescribed with caution to patients with a history of allergy or rash to other AEDs, 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.

If a skin rash develops, the patient (both adults and children) should be evaluated immediately and lamotrigine should be discontinued unless there is evidence that the skin rash is unrelated to the drug. It is not recommended to restart lamotrigine if it has been discontinued due to a rash following previous treatment with lamotrigine. In such cases, the decision to restart the drug should be based on the expected benefits of treatment and the potential risks.

Patients who have experienced SSRIs, TEN, and DRESS after using lamotrigine should not be re-administered lamotrigine.

Skin rashes have also been reported as part of DRESS (also known as hypersensitivity syndrome). This condition is accompanied by a variety of systemic symptoms including fever, lymphadenopathy, facial swelling, abnormal blood counts, liver or kidney function and aseptic meningitis (see section 4.8). The syndrome can vary in severity and can occasionally lead to disseminated intravascular coagulation and multi-organ 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 evaluated promptly and, in the absence of other causes, lamotrigine should be discontinued. In most cases, aseptic meningitis resolves 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 had lamotrigine discontinued due to aseptic meningitis during a 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).

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients taking lamotrigine (see section 4.8). HLH is characterised by clinical signs and symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, increased serum ferritin, hypertriglyceridaemia and abnormal liver and coagulation functions. Symptoms usually occur within 4 weeks of initiation of treatment. HLH can be life-threatening.

Patients should be informed about the symptoms associated with GLH and advised to seek immediate medical attention if these symptoms occur during treatment with lamotrigine.

Patients who develop these signs and symptoms should be evaluated promptly and a diagnosis of GLH should be considered. Lamotrigine therapy should be discontinued immediately if another cause for the symptoms cannot be identified.

Clinical deterioration and suicidal risk

Suicidal ideation and behavior have been reported in patients treated with AEDs (for various 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 advice if such signs appear.

Patients with bipolar disorder may experience worsening depressive symptoms and/or suicidality, whether or not they have been treated with medications for bipolar disorder, including lamotrigine. Therefore, patients receiving lamotrigine 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 during dose changes. Some patients, particularly those with a history of suicidal behavior or thoughts, those who are younger, and those 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 and should be monitored closely during treatment.

Hormonal contraceptives

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 Interactions with other medicinal products and other forms of interaction). Decreased lamotrigine levels are associated with loss of seizure control. After titration of lamotrigine, higher maintenance doses (approximately twice as high) will be required in most cases to achieve maximum therapeutic response. When hormonal contraceptives are discontinued, lamotrigine clearance may be halved. Increased lamotrigine concentrations may be associated with dose-related adverse reactions. Patients should be monitored for this.

In women not already taking lamotrigine glucuronidation inducers 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 (see section “Method of administration and dosage”).

Fluctuations in lamotrigine levels in this setting may be associated with adverse reactions. Therefore, the use of contraception that does not have a "contraceptive-free week" should be considered as first-line therapy (e.g., continuous hormonal contraceptives or use of non-hormonal methods).

Interactions between other oral contraceptives or hormone replacement therapy and lamotrigine have not been studied, but they may similarly affect the pharmacokinetics of lamotrigine.

The effect of lamotrigine on the effectiveness 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 informed promptly of any changes in their menstrual cycle, such as breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, so long-term use may affect folate metabolism (see section "Use during pregnancy or lactation"). However, long-term use of lamotrigine did not produce any significant changes in hemoglobin, mean red blood cell volume, serum and red blood cell folate concentrations over 1 year, or red blood cell folate concentrations over 5 years.

Kidney dysfunction

In single-dose studies in patients with end-stage renal disease, lamotrigine plasma concentrations 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

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

Brugada-like changes on ECG

Arrhythmogenic ST-T abnormalities and typical Brugada-like ECG changes have been reported in patients receiving lamotrigine.

In vitro data suggest that lamotrigine has the potential to slow ventricular conduction (widen the QRS complex) and induce proarrhythmia at therapeutically relevant concentrations in patients with cardiac disease. Lamotrigine acts as a weak class IB antiarrhythmic agent with an associated potential risk of serious or fatal cardiac events. Concomitant use of other sodium channel blockers may further increase the risks. At therapeutic doses up to 400 mg/day, lamotrigine did not slow ventricular conduction (widen the QRS complex) or cause QT prolongation in healthy volunteers with careful QT testing. The use of lamotrigine should be carefully considered in patients with clinically significant structural or functional cardiac disease, such as Brugada syndrome or other cardiac channelopathies, heart failure, ischemic heart disease, heart block, or ventricular arrhythmias. If the use of lamotrigine in these patients is clinically warranted, a cardiologist should be consulted before initiating lamotrigine.

Development in children

There are no data on the effects of lamotrigine on growth, puberty, or the development of cognitive, emotional, and behavioral functions.

Precautions for epilepsy

According to the literature, severe epileptic seizures can cause rhabdomyolysis, multiple organ failure, and disseminated intravascular coagulation syndrome, sometimes with fatal outcome. Similar cases are possible during treatment with lamotrigine.

There may be a clinically significant worsening in seizure frequency rather than improvement. In patients with more than one 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.

Precautions for bipolar disorder

Children and adolescents under 18 years of age

Antidepressant treatment is associated with an increased risk of suicidal ideation and behavior in children and adolescents with major depressive disorder and other psychiatric disorders.

Excipients

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.

Use during pregnancy or breastfeeding

Risk associated with the use of AEDs in general

Women of childbearing potential should seek medical advice. When planning pregnancy, the need for AED treatment should be reviewed. Women with epilepsy who are already being treated should avoid abrupt discontinuation of antiepileptic therapy, as this may lead to an exacerbation of seizures and have serious consequences for both the woman and the child.

The risk of birth defects is higher with combination antiepileptic therapy compared to monotherapy, so monotherapy should be used where possible.

Risk associated with the use of lamotrigine

Pregnancy

A large amount of epidemiological data on over 12,700 pregnant women exposed to lamotrigine monotherapy, including over 9,100 exposed during the first trimester, do not indicate that lamotrigine therapy at maintenance doses is associated with an increased risk of major congenital malformations.

Studies of the effect of doses higher than the usual maintenance dose of 100–200 mg/day on the risk of major congenital malformations have shown conflicting results. Some studies have not shown evidence of a dose-related effect, but data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) have shown a statistically significant increase in the incidence of major congenital malformations with lamotrigine doses ≥ 325 mg/day compared with doses < 325 mg/day (OR 1.68, 95% CI 1.01–2.80). Therefore, if lamotrigine therapy is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.

Lamotrigine has a weak inhibitory effect on dihydrofolate reductase. Since folic acid has a protective effect on the risk of neural tube defects, folic acid is recommended during pregnancy planning and in 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 with a potential risk of loss of seizure control. After delivery, lamotrigine levels may increase rapidly with a risk of dose-related adverse reactions. Therefore, lamotrigine serum concentrations should be monitored closely.