Lanistor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LANISTOR (LANISTOR®)

Composition:

Active substance: lamotrigine;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, flat, bevelled-edged, film-coat-free tablets with embossing « » on one side and smooth on the other.

Pharmacotherapeutic group. Antiepileptic drugs. Lamotrigine.

ATC code N03A X09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Pharmacological studies have shown that lamotrigine is a use-dependent and voltage-dependent blocker of voltage-gated sodium channels. It suppresses sustained repetitive neuronal firing and inhibits the release of glutamate (a neurotransmitter that plays a key role in the initiation of epileptic seizures). This effect is likely responsible for the anticonvulsant properties of lamotrigine.

However, the mechanisms underlying the therapeutic effect of lamotrigine in bipolar disorder remain unclear, although interaction with voltage-gated sodium channels is considered to play an important role.

Pharmacokinetics.

Absorption

In the absence of significant first-pass metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract.

Following oral administration of lamotrigine, peak plasma concentration is reached in approximately 2.5 hours. The time to reach peak concentration is slightly prolonged when the drug is taken after food, but this does not affect the extent of absorption. There are considerable inter-individual variations in steady-state peak concentrations, although intra-individual values in a single patient are generally consistent.

Distribution

Approximately 55% of the drug dose is bound to plasma proteins. The risk of a toxic effect due to displacement from plasma proteins is low.

The volume of distribution ranges from 0.92 to 1.22 L/kg.

Biotransformation

UDP-glucuronosyltransferase has been identified as the main enzyme responsible for lamotrigine metabolism.

Lamotrigine induces its own metabolism to only a minor extent, depending on the dose. However, there is no established effect of lamotrigine on the pharmacokinetics of other anticonvulsants, and available data suggest that interactions between lamotrigine and other drugs metabolized via the cytochrome P450 system are unlikely.

Elimination

Theoretical plasma clearance in healthy volunteers is approximately 30 mL/min. Clearance of lamotrigine occurs primarily through metabolism followed by excretion of glucuronide-conjugated metabolites in urine. Less than 10% of the dose is excreted unchanged in urine. Only 2% of metabolized lamotrigine is excreted via the intestine. Clearance and elimination half-life are dose-independent. The theoretical elimination half-life in plasma of healthy volunteers is approximately 33 hours (range 14 to 103 hours). In a study involving patients with Gilbert's syndrome, the mean theoretical clearance in these subjects was 32% lower than in the control group, but still within the range observed in the general patient population.

The elimination half-life of lamotrigine is significantly influenced by concomitantly administered drugs. The mean half-life may be reduced by approximately 14 hours when co-administered with glucuronidation inducers such as carbamazepine and phenytoin, or increased by approximately 70 hours when co-administered solely with valproate (see section «Interaction with other medicinal products and other forms of interaction»).

Linearity

Up to the highest studied dose of 450 mg, the pharmacokinetics of lamotrigine demonstrated linear kinetics.

Special patient groups

Children

Clearance, normalized per body weight, is higher in children than in adults, and highest 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 increasing to a mean of 45 to 50 hours when co-administered exclusively with valproate (see section «Interaction with other medicinal products and other forms of interaction»).

Children aged 2 to 26 months

In 143 patients aged 2 to 26 months with body weights ranging from 3 to 16 kg, oral administration of equivalent doses normalized per kg of body weight resulted in lower clearance compared to children over 2 years of age with similar body weight. The mean elimination half-life in children under 26 months was 23 hours when enzyme-inducing therapy was used, 136 hours when co-administered with valproate, and 38 hours without concomitant use of enzyme-inducing or enzyme-inhibiting drugs. Inter-individual variability in clearance following oral dosing in patients aged 2 to 26 months was high (47%). Predicted serum concentrations in this age group were within the range observed in older patients, although patients with body weight below 10 kg showed higher peak concentrations in some cases.

Elderly patients

Pharmacokinetic analysis across patient groups, including both elderly and younger patients with epilepsy participating in one study, showed no clinically significant change in lamotrigine clearance. After single doses, apparent clearance decreased by 12%, from 35 mL/min/kg at age 20 to 31 mL/min/kg at age 70. After 48 weeks of treatment, the reduction was 10%, from 41 to 37 mL/min between younger and elderly groups. Additionally, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly volunteers who received a single 150 mg dose. The mean clearance in elderly patients (0.39 mL/min/kg) falls within the range of mean clearance values (0.31 to 0.65 mL/min/kg) observed in 9 studies conducted in non-elderly adult patients after single doses 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 hemodialysis. Mean CL/F values were 0.42 mL/min/kg (chronic renal impairment), 0.33 mL/min/kg (interdialytic period), and 1.57 mL/min/kg (during hemodialysis), compared to 0.58 mL/min/kg in healthy volunteers. Mean elimination half-life in plasma was 42.9 hours (chronic renal impairment), 57.4 hours (interdialytic period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1%) of the body load of lamotrigine was removed during a four-hour hemodialysis session. For this patient group, initial dosing of lamotrigine should be based on the regimen of concomitant antiepileptic drugs; reduction of the maintenance dose may be effective in patients with significant renal functional impairment (see sections «Dosage and administration» and «Special warnings and precautions for use»).

Patients with hepatic impairment

A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy volunteers in the control group. 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 class A, B, and C hepatic impairment, respectively, compared to 0.34 mL/min/kg in healthy control volunteers. Initial, escalation, and maintenance doses should be reduced in patients with moderate to severe hepatic impairment (see section «Dosage and administration»).

Clinical characteristics.

Indications.

Epilepsy Adults and children aged 13 years and older

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

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

Children aged 2 to 12 years

Adjunctive therapy of partial and generalized epileptic seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

Monotherapy of typical absence seizures.

Bipolar disorder

Adults (aged 18 years and older)

Prevention of depressive episodes in patients with bipolar I disorder who predominantly experience depressive episodes.

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

Contraindications.

The medicinal product Lanistor is contraindicated in patients with known hypersensitivity to lamotrigine or to any other component of the product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

It has been established that uridine 5’-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for lamotrigine metabolism. Therefore, medicinal products that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Enzyme inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate activity, which are known to induce UGT, may also enhance lamotrigine metabolism.

There is no evidence that lamotrigine causes clinically significant induction or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and has no significant clinical consequences.

Medicinal products that have been shown to have a relevant clinical effect on lamotrigine concentration are listed in Table 1. Specific dosage recommendations for these medicinal products are provided in the section "Method of administration and dosage". In addition, Table 1 lists medicinal products that have been shown to have little or no effect on lamotrigine concentration. Concomitant use of such medicinal products is generally not expected to have any clinical effect. However, patients with epilepsy whose condition is particularly sensitive to fluctuations in lamotrigine concentration should be cautioned.

Table 1

Effect of other medicinal products on lamotrigine concentration

Medicinal products that increase lamotrigine concentration	Medicinal products that decrease lamotrigine concentration	Medicinal products that have little or no effect on lamotrigine concentration
Valproate	Atazanavir/ritonavir*, carbamazepine, combination ethinylestradiol/levonorgestrel*, lopinavir/ritonavir, phenobarbital, phenytoin, primidone, rifampicin	Aripiprazole, bupropion, felbamate, gabapentin, lacosamide, levetiracetam, lithium, olanzapine, oxcarbazepine, paracetamol, perampanel, pregabalin, topiramate, zonisamide

*For detailed dosing information, see the section "General dosing recommendations for special patient populations" in "Dosage and administration". For dosing recommendations in women taking hormonal contraceptives, see the section "Hormonal contraceptives" in "Special populations".

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases the average elimination half-life approximately two-fold. For patients receiving concomitant valproate therapy, an appropriate dosing regimen should be used (see section "Dosage and administration").

Some AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 enzymes, also induce UGT enzymes and thereby accelerate lamotrigine metabolism. Patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbital, or primidone should use an appropriate dosing regimen (see section "Dosage and administration").

There have been reports of central nervous system (CNS) adverse reactions, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These reactions usually resolve with a reduction in carbamazepine dose. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.

Literature reports indicate reduced lamotrigine levels when used in combination with oxcarbazepine. However, in a study in healthy adult volunteers receiving 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism. Therefore, patients receiving concomitant oxcarbazepine therapy should follow the lamotrigine adjunctive dosing regimen without valproate and without inducers of lamotrigine glucuronidation (see section "Dosage and administration").

In a study in healthy volunteers, co-administration 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 lamotrigine.

According to data from a retrospective analysis of plasma levels in patients taking lamotrigine with or without gabapentin, gabapentin does not alter the existing clearance rate of lamotrigine.

The potential drug interaction between levetiracetam and lamotrigine was studied by assessing serum concentrations of both drugs during placebo-controlled clinical trials. According to these data, the two substances do not affect each other's pharmacokinetics.

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

Topiramate does not affect plasma concentrations of lamotrigine. Lamotrigine increases topiramate concentrations by 15%.

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

Co-administration of lacosamide (200 mg/day, 400 mg/day, or 600 mg/day) did not affect lamotrigine plasma concentrations in placebo-controlled clinical trials in patients with partial seizures.

In a pooled analysis of data from three placebo-controlled clinical trials investigating add-on perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied dose of perampanel (12 mg/day) increased lamotrigine clearance by less than 10%.

Although cases of altered plasma concentrations of other AEDs have been described, controlled studies have shown that lamotrigine does not affect plasma concentrations of concomitant AEDs. In vitro studies demonstrated that lamotrigine does not displace other AEDs from their plasma protein binding sites.

Interaction with other psychotropic agents

When 100 mg/day lamotrigine was administered concomitantly with 2 g of anhydrous lithium gluconate given twice daily for 6 days to 20 patients, the pharmacokinetics of lithium were unchanged.

Multiple oral doses of bupropion had no statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients and resulted only in a minor increase in the area under the concentration-time curve (AUC) of lamotrigine glucuronide.

In a study in healthy adult volunteers, 15 mg of olanzapine reduced the AUC and Cmax of lamotrigine in plasma by an average of 24% and 20%, respectively. 200 mg of lamotrigine did not affect the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg/day did not cause a clinically significant effect on the pharmacokinetics of risperidone following a single 2 mg dose in studies involving 14 healthy adult volunteers. When 2 mg risperidone was co-administered with lamotrigine, 12 out of 14 volunteers reported somnolence, compared to 1 out of 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 (100–400 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and maintained for another 7 days. Overall, an approximately 10% decrease in AUC and Cmax of lamotrigine was observed.

In vitro experiments showed that the formation of the primary metabolite of lamotrigine, 2-N-glucuronide, is minimally affected by amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. These studies also demonstrated that lamotrigine metabolism is not inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone. Data from bufuralol metabolism studies in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs primarily metabolized by CYP2D6.

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine pharmacokinetics

In a study involving 16 female volunteers taking a combined tablet containing ethinylestradiol 30 µg/levonorgestrel 150 µg, lamotrigine clearance increased approximately two-fold, resulting in a mean reduction in AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the weekly contraceptive-free interval (the so-called "pill-free week"), lamotrigine serum concentrations gradually increased, reaching levels approximately twice as high as during concomitant use (see section "Special populations"). There is no need to adjust the recommended lamotrigine doses solely due to the use of hormonal contraceptives; however, the maintenance dose of lamotrigine may need to be increased or decreased in most cases when starting or stopping hormonal contraceptives (see section "Dosage and administration").

Effect of lamotrigine on hormonal contraceptive pharmacokinetics

Study data in 16 female volunteers showed that a fixed dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptives. A consistent small increase in levonorgestrel clearance was observed, resulting in a mean reduction in AUC and Cmax of levonorgestrel by 19% and 12%, respectively. Serum measurements of follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppression of ovarian hormonal activity in some women, although serum progesterone measurements indicated no signs of ovulation in any of the 16 women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the minor increase in levonorgestrel clearance on ovulatory ovarian activity is unknown (see section "Special populations"). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Studies with other hormonal contraceptives have also not been conducted.

Interaction with other medicinal products

In a study involving 10 male volunteers receiving rifampicin, lamotrigine clearance increased and elimination half-life decreased due to induction of hepatic enzymes responsible for glucuronidation. Patients receiving concomitant rifampicin therapy should follow the dosing regimen recommended for lamotrigine with inducers of glucuronidation (see section "Dosage and administration").

Study data in healthy volunteers show that lopinavir/ritonavir reduces lamotrigine plasma concentrations by approximately half via induction of glucuronidation. For patients already taking lopinavir/ritonavir, the dosing regimen recommended for lamotrigine with inducers of glucuronidation should be followed (see section "Dosage and administration").

Study data in healthy adult volunteers showed that administration of atazanavir/ritonavir (300 mg/100 mg) for 9 days reduced the AUC and Cmax of lamotrigine in plasma (after a single 100 mg dose) by an average of 32% and 6%, respectively. Patients already taking lopinavir/ritonavir should follow the appropriate lamotrigine dosing regimen (see section "Dosage and administration").

Study data in healthy volunteers showed that administration of paracetamol at a dose of 1 g (four times daily) reduced the AUC and minimum concentration (Cmin) of lamotrigine in plasma by an average of 20% and 25%, respectively.

In vitro data indicate that lamotrigine, but not its metabolite N(2)-glucuronide, is an inhibitor of organic cation transporter 2 (OCT2) at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2 with an IC50 value of 53.8 µM. Concomitant administration of lamotrigine with medicinal products that are eliminated renally and are substrates of OCT2 (e.g., metformin, gabapentin, and varenicline) may lead to increased plasma levels of these drugs.

The clinical significance of this is not clearly defined; however, caution is advised in patients receiving these medicinal products concomitantly.

Special precautions for use.

Skin rashes

Skin rash may occur within the first 8 weeks of initiating lamotrigine therapy. In most cases, rashes are mild and resolve without treatment; however, severe skin reactions requiring hospitalization and discontinuation of lamotrigine have been reported. These include 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 "Adverse reactions").

In adults participating in clinical trials using current dosing recommendations for lamotrigine, the incidence of severe skin rashes is approximately 1 in 500 patients with epilepsy. About 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 have a higher risk of developing serious skin rashes compared to adults.

Clinical trial data with lamotrigine indicate that the incidence of rashes leading to hospitalization in children ranges from 1 in 300 to 1 in 100 patients.

In children, early signs of skin rash may be mistaken for infection; therefore, physicians should consider the possibility of an adverse drug reaction in children presenting with rash and fever during the first 8 weeks of therapy.

The overall risk of developing skin rashes appears to be closely related to high initial doses of lamotrigine, exceeding the recommended dose escalation regimen, and concomitant use of valproate (see section "Dosage and administration").

Lamotrigine should be prescribed with caution in patients with a history of allergy or rash to other antiepileptic drugs (AEDs), as the frequency of mild rashes after lamotrigine treatment in this patient group was three times higher than in those without such history.

The HLA-B*1502 allele in individuals of Asian (particularly Chinese and Thai) descent is associated with an increased risk of developing SJS/TEN with lamotrigine use. If a patient tests positive for the HLA-B*1502 allele, the decision to use lamotrigine should be carefully considered.

Skin rash should prompt immediate evaluation of the patient (both adult and child) and discontinuation of lamotrigine unless there is clear evidence that the rash is unrelated to the drug. Reinitiation of lamotrigine therapy is not recommended after prior discontinuation due to rash. In such cases, the decision to re-prescribe lamotrigine should carefully weigh the expected benefits against potential risks.

Lamotrigine must not be re-administered to patients who previously experienced SJS, TEN, or DRESS following lamotrigine use.

Skin rashes have also been reported as part of DRESS (also known as hypersensitivity syndrome). This condition is associated with various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, liver or kidney dysfunction, and aseptic meningitis (see section "Adverse reactions"). The syndrome may vary in severity and rarely may lead to disseminated intravascular coagulation and multiorgan failure. Importantly, early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rash. Patients presenting with such symptoms should be evaluated immediately, and lamotrigine should be discontinued if no other cause is identified. In most cases, aseptic meningitis resolves after drug withdrawal, but in some cases it may recur upon re-challenge with lamotrigine. Re-administration of lamotrigine leads to rapid recurrence of symptoms, often with greater severity. Lamotrigine must not be re-administered to patients who previously experienced aseptic meningitis during prior lamotrigine treatment.

Photosensitivity reactions associated with lamotrigine use have also been reported (see section "Adverse reactions"). In several cases, the reaction occurred with high-dose therapy (400 mg or more), dose escalation, or rapid titration. If a patient presents with signs of photosensitivity (e.g., severe sunburn) suggestive of lamotrigine-related photosensitivity, discontinuation of therapy should be considered. If continuation of lamotrigine therapy is clinically justified, patients should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g., wearing protective clothing and using sunscreen).

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients taking lamotrigine (see section "Adverse reactions"). HLH is characterized by clinical signs and symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, elevated serum ferritin, hypertriglyceridemia, and liver dysfunction and coagulopathy. Symptoms typically develop within 4 weeks of starting therapy. HLH may be life-threatening.

Patients should be informed about symptoms associated with HLH and advised to seek immediate medical attention if such symptoms occur during lamotrigine therapy.

Patients who develop these signs and symptoms should be evaluated immediately, and HLH should be considered in the differential diagnosis. Lamotrigine therapy should be discontinued immediately if no other cause for the symptoms can be established.

Clinical worsening and suicide risk

Suicidal ideation and behavior have been reported in patients treated with AEDs (for various indications, including epilepsy).

Meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, has shown a small but increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility that this risk may be increased by lamotrigine use.

Therefore, patients should be closely monitored for signs of suicidal ideation and behavior. If such signs occur, patients and caregivers should seek immediate medical help.

In patients with bipolar disorders, symptoms of depression and/or suicidal behavior may worsen, regardless of whether they are receiving treatment for bipolar disorder, including lamotrigine. Therefore, patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including emergence of new symptoms) and suicidal behavior, particularly at the beginning of treatment or during dose adjustments. Some patients, particularly those with a history of suicidal behavior or ideation, younger individuals, and those who exhibited marked suicidal ideation before treatment initiation, may be at higher risk of suicidal thoughts or attempts and require careful monitoring during treatment.

The clinical situation should be evaluated and appropriate changes to the therapeutic regimen made, including possible discontinuation of treatment in patients who experience clinical worsening (including new symptoms) and/or emergence of suicidal ideation/behavior, especially if these symptoms are severe, sudden in onset, and not part of pre-existing symptoms.

Hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine efficacy

The combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg increases lamotrigine clearance approximately two-fold, thereby reducing lamotrigine levels (see section "Interaction with other medicinal products and other forms of interaction"). Reduced lamotrigine levels are associated with loss of seizure control. After dose titration, higher maintenance doses (almost twice as high) are usually required to achieve optimal therapeutic response. Upon discontinuation of hormonal contraceptives, lamotrigine clearance may decrease by half. Increased lamotrigine concentrations may be associated with dose-dependent adverse reactions. Patients should be monitored accordingly.

In women not taking other lamotrigine glucuronidation inducers who are using hormonal contraceptives with a weekly break between cycles (so-called "hormone-free week"), a gradual, transient increase in lamotrigine levels may occur during the hormone-free week (see section "Dosage and administration").

Fluctuations in lamotrigine levels in this situation may be associated with adverse reactions. Therefore, consideration should be given to using contraception without a "hormone-free week" as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods).

The interaction between other oral contraceptives or hormone replacement therapies and lamotrigine has not been studied, but they may similarly affect lamotrigine pharmacokinetics.

Effect of lamotrigine on hormonal contraceptive efficacy

A clinical interaction study involving 16 healthy volunteers showed a slight increase in levonorgestrel clearance and changes in serum levels of follicle-stimulating and luteinizing hormones when lamotrigine was co-administered with hormonal contraceptives (ethinylestradiol 30 mcg/levonorgestrel 150 mcg) (see section "Interaction with other medicinal products and other forms of interaction"). The impact of these changes on ovulation is unknown. However, it cannot be ruled out that in some patients, these changes may lead to reduced contraceptive efficacy when lamotrigine is used concomitantly with hormonal contraceptives. Therefore, patients should promptly report any changes in their menstrual cycle, such as sudden breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, and therefore prolonged use may affect folate metabolism (see section "Use during pregnancy or breastfeeding"). However, long-term lamotrigine use has not resulted in any significant changes in hemoglobin levels, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentrations over 5 years.

Renal impairment

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 is required when treating patients with renal impairment.

Patients using other lamotrigine-containing medicines

Lamistore must not be used in patients already receiving any other lamotrigine-containing medication without physician consultation.

Brugada-like ECG changes and other cardiac rhythm disturbances and conduction abnormalities

Cases of arrhythmogenic ST-T changes and typical Brugada-like ECG changes have been reported in patients receiving lamotrigine.

In vitro data suggest that lamotrigine may potentially slow ventricular conduction (QRS widening) and induce proarrhythmia at therapeutically relevant concentrations in patients with heart 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 these risks. At therapeutic doses up to 400 mg/day, lamotrigine did not slow ventricular conduction (QRS widening) or prolong the QT interval in healthy volunteers in a thorough QT study. Lamotrigine use should be carefully considered in patients with clinically significant structural or functional heart disease, such as Brugada syndrome or other cardiac channelopathies, heart failure, ischemic heart disease, heart block, or ventricular arrhythmias. If lamotrigine use is clinically justified in such patients, consultation with a cardiologist should be obtained before initiating therapy.

Development in children

There are no data on the effects of lamotrigine on growth, sexual maturation, or the development of cognitive, emotional, and behavioral functions in children.

Precautions in epilepsy

Abrupt discontinuation of lamotrigine, as with other AEDs, may provoke increased seizure frequency. Except in cases where the patient's condition requires immediate discontinuation (e.g., in case of rash), the dose of lamotrigine should be tapered gradually over at least 2 weeks.

According to literature, severe epileptic seizures, including status epilepticus, may lead to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes with fatal outcomes. Similar cases are possible during lamotrigine therapy.

Significant clinical worsening in seizure frequency instead of improvement may occur. 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.

Lamotrigine therapy may exacerbate myoclonic seizures.

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

In children with typical absence seizures, treatment response is not achieved in all patients.

Precautions in bipolar disorders

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 disorders and other psychiatric disorders.

Excipients

The product contains lactose. Patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

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

Use during pregnancy or breastfeeding

Risk associated with use of AEDs in general

Women of reproductive potential should seek medical advice. The need for AED treatment should be reviewed when planning pregnancy. Women with epilepsy who are already being treated should avoid abrupt discontinuation of antiepileptic therapy, as this may provoke seizure exacerbation and have serious consequences for both mother and child.

Monotherapy should be preferred, as combined antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with lamotrigine use

Pregnancy

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

Studies on the impact of doses higher than the usual maintenance dose of 100–200 mg/day on the risk of major congenital malformations have yielded conflicting results. Some studies found no evidence of a dose-dependent effect, but data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) showed a statistically significant increase in the frequency of major congenital malformations with lamotrigine doses ≥ 325 mg/day compared to doses < 325 mg/day (OR 1.68, 95% CI 1.01–2.80). Therefore, if lamotrigine therapy is considered necessary during pregnancy, the lowest effective therapeutic dose is recommended.

Lamotrigine has a weak inhibitory effect on dihydrofolate reductase. Since folic acid has a protective effect against the risk of neural tube defects, folic acid supplementation is recommended during pregnancy planning and early pregnancy.

Physiological changes during pregnancy may affect lamotrigine concentrations and/or its therapeutic effect. Reports indicate decreased plasma lamotrigine concentrations during pregnancy, with a potential risk of loss of seizure control. After delivery, lamotrigine levels may rise rapidly, increasing the risk of dose-dependent adverse reactions. Therefore, serum lamotrigine concentrations should be monitored before, during, and after pregnancy, and shortly after delivery.

If necessary, the lamotrigine dose should be adjusted to maintain serum concentrations at pre-pregnancy levels or adapted according to clinical status. Dose-dependent adverse reactions should be closely monitored after childbirth.

Animal studies have shown embryofetal toxicity.

Breastfeeding period

Lamotrigine has been reported to pass into breast milk at variable concentrations, resulting in infant lamotrigine levels reaching up to 50% of maternal levels. Therefore, in some breastfed infants, serum lamotrigine levels may reach concentrations at which a pharmacological effect is possible.

The potential benefits of breastfeeding should be weighed against the possible risk of adverse reactions in the infant. If a woman receiving lamotrigine therapy decides to breastfeed, the infant should be closely monitored for adverse reactions such as sedation, rash, and poor weight gain.

Fertility

Animal studies did not reveal any effect of lamotrigine on fertility.

Ability to affect reaction speed when driving or operating machinery

Because individual response to any AED therapy varies, patients taking lamotrigine for epilepsy treatment should consult their physician regarding driving restrictions in such cases.

No studies have been conducted on the effect on the ability to drive or operate machinery. Two studies in volunteers demonstrated that lamotrigine had no greater effect on fine visual motor skills, eye movements, body sway, or subjective sedative effects than placebo. During clinical trials of lamotrigine, neurological adverse reactions such as dizziness and diplopia were reported. Therefore, patients should assess how lamotrigine therapy affects them before driving or operating machinery.

Method of administration and dosage.

Lamictal tablets should be swallowed whole, without chewing or breaking.

If the calculated dose of lamotrigine (e.g., for treating children with epilepsy or patients with impaired liver function) is not a multiple of the available tablet strengths, the administered dose should correspond to the nearest lower number of whole tablets.

If the calculated dose of lamotrigine is less than 25 mg, lamotrigine formulations allowing such dosing should be used.

Reinitiation of treatment

Physicians should assess the need to increase the dose to maintenance levels when resuming lamotrigine in patients who have discontinued treatment for any reason, as the risk of developing serious rash is associated with high initial doses and exceeding the recommended dose escalation regimen (see section "Special precautions"). The longer the time since the last dose was taken, the greater the caution required when increasing the dose to maintenance levels. If the interval since discontinuation of lamotrigine exceeds 5 half-lives (see section "Pharmacokinetics"), the dose should be increased to the maintenance dose according to the established regimen.

Reinitiation of lamotrigine is not recommended in patients who previously discontinued treatment due to rash associated with prior lamotrigine therapy, except when the potential benefit clearly outweighs the risk.

Epilepsy

Recommended dose escalation regimens and maintenance doses for adults and children aged 13 years and older (see Table 2), as well as for children aged 2 to 12 years (see Table 3), are provided below. Due to the risk of rash, the initial dose and the rate of subsequent dose escalation should not be exceeded (see section "Special precautions").

When discontinuing concomitant antiepileptic drugs (AEDs) or adding other AEDs/medicinal products to lamotrigine-containing regimens, the potential impact on lamotrigine pharmacokinetics should be considered (see section "Interaction with other medicinal products and other forms of interaction").

Table 2

Recommended treatment regimens for epilepsy in adults and children aged 13 years and older

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Usual maintenance dose
Monotherapy	25 mg/day (1 dose)	50 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, it should be increased by no more than 50–100 mg every 1 or 2 weeks until optimal response is achieved. Some patients required a dose of 500 mg/day to achieve the desired response.
Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen involves the use of valproate regardless of the use of other concomitant medicinal products.	12.5 mg/day (take 25 mg every other day)	25 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, it should be increased by no more than 25–50 mg every 1 or 2 weeks until optimal response is achieved.
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen does not involve the use of valproate, but includes the use of phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	50 mg/day (1 dose)	100 mg/day (2 doses)	200–400 mg/day (2 doses). To reach the maintenance dose, it should be increased by no more than 100 mg every 1 or 2 weeks until optimal response is achieved. Some patients required a dose of 700 mg/day to achieve the desired response.
Adjunctive therapy without valproate and inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen involves the use of other medicinal products that do not exhibit significant inhibitory or inductive effects on lamotrigine glucuronidation.	25 mg/day (1 dose)	50 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, it should be increased by no more than 50–100 mg every 1 or 2 weeks until optimal response is achieved.
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the treatment regimen recommended for concomitant use of lamotrigine and valproate should be used.

Table 3

Children aged 2 to 12 years: recommended epilepsy treatment regimen (total daily dose in mg/kg body weight/day)*

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Usual maintenance dose
Monotherapy for typical absence seizures	0.3 mg/kg/day (1 or 2 divided doses per day)	0.6 mg/kg/day (1 or 2 divided doses per day)	1–15 mg/kg/day (1 or 2 divided doses per day). To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen assumes concomitant use of valproate, regardless of other concomitant medications.	0.15 mg/kg/day (once daily)	0.3 mg/kg/day (once daily)	1–5 mg/kg/day (1 or 2 divided doses per day). To reach the maintenance dose, it should be increased by no more than 0.3 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen does not include valproate, but includes use of phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	0.6 mg/kg/day (twice daily)	1.2 mg/kg/day (twice daily)	5–15 mg/kg/day (1 or 2 divided doses). To reach the maintenance dose, it should be increased by no more than 1.2 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 400 mg/day.
Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen includes other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation.	0.3 mg/kg/day (1 or 2 divided doses)	0.6 mg/kg/day (1 or 2 divided doses)	1–10 mg/kg/day (1 or 2 divided doses). To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the dosing regimen recommended for concomitant use of lamotrigine and valproate should be used.
If the calculated dose for patients taking valproate is less than 1 mg, lamotrigine should not be administered.

*If the calculated dose of lamotrigine is less than 25 mg, lamotrigine formulations allowing such dosing should be used.

To maintain the therapeutic dose, body weight of the child should be monitored and the dose adjusted accordingly in case of changes in body weight. Patients aged 2 to 6 years will likely require a maintenance dose approaching the upper end of the recommended range.

If seizure control is achieved with adjunctive therapy, concomitant AEDs may be discontinued, allowing continuation of lamotrigine monotherapy.

Children under 2 years of age

Data on the efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years (see section "Dosage and administration") are limited. Data on the use of lamotrigine in children under 1 month of age are lacking. Therefore, lamotrigine is not recommended for use in children under 2 years of age. If a decision to initiate lamotrigine therapy is made based on clinical need, see sections "Pharmacological properties" and "Dosage and administration".

Bipolar disorder

Recommended dose escalation and maintenance doses for adults aged 18 years and older are provided in the tables below. The conversion scheme includes increasing the lamotrigine dose to a maintenance stabilizing dose over 6 weeks (see Table 4), after which other psychotropic and/or AEDs may be discontinued if clinically appropriate (see Table 5). Dose adjustment schemes following the addition of other psychotropic medicinal products and/or AEDs are provided in Table 6. Due to the risk of rash, the initial dose and rate of subsequent dose escalation should not be exceeded (see section "Dosage and administration").

Table 4

Adults (aged 18 years and older): recommended dose escalation regimen to achieve maintenance stabilizing daily dose in the treatment of bipolar disorder

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Week 5	Target maintenance dose (week 6)*
Lamotrigine monotherapy or adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen assumes the use of other medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation.	25 mg/day (once daily)	50 mg/day (once or twice daily)	100 mg/day (once or twice daily)	200 mg/day – usual target dose to achieve optimal response (once or twice daily). Doses ranging from 100–400 mg/day have been used in clinical studies.
Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation – see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen assumes the use of valproate, regardless of other concomitant medicinal products.	12.5 mg/day (25 mg every other day)	25 mg/day (once daily)	50 mg/day (once or twice daily)	100 mg/day – usual target dose to achieve optimal response (once or twice daily). The maximum dose of 200 mg/day may be used depending on clinical response.
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen does not include valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	50 mg/day (once daily)	100 mg/day (twice daily)	200 mg/day (twice daily)	300 mg/day in week 6; if necessary, the usual target dose is increased to 400 mg/day in week 7 to achieve optimal response (twice daily)
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interactions"), the dose escalation regimen recommended for concomitant use of lamotrigine with valproate should be applied.

* The target maintenance dose varies depending on the clinical response.

Table 5

Adults (aged 18 years and older): maintenance stabilizing daily dose after discontinuation of concomitant medications for the treatment of bipolar disorders

After reaching the required maintenance stabilizing dose, other psychotropic drugs may be discontinued according to the schemes outlined below.

Treatment regimen	Current maintenance dose of lamotrigine (prior to discontinuation)		Week 1 (starting upon discontinuation)	Week 2	Week 3 and onwards*
Discontinuation of valproate (inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") depending on the initial lamotrigine dose.
When discontinuing valproate, the maintenance dose should be doubled, not exceeding an increase of more than 100 mg/week.	100 mg/day		200 mg/day	Maintain dose at 200 mg/day (2 doses)
	200 mg/day		300 mg/day	400 mg/day	Maintain dose at 400 mg/day
Discontinuation of inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") depending on the initial lamotrigine dose.
This treatment regimen applies when discontinuing phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	400 mg/day		400 mg/day	300 mg/day	200 mg/day
	300 mg/day		300 mg/day	225 mg/day	150 mg/day
	200 mg/day		200 mg/day	150 mg/day	100 mg/day
Discontinuation of medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen involves using other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation.		Maintain the target dose achieved during titration (200 mg/day in two doses) (dose range 100–400 mg/day)
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the recommended lamotrigine treatment regimen involves initially maintaining the current dose, followed by dose adjustments based on clinical response.

* If necessary, the dose can be increased to 400 mg/day.

Table 6

Adults (aged 18 years and older): adjustment of daily dose when co-administering other drugs in patients with bipolar disorders

There is no clinical experience regarding dose adjustment of lamotrigine when other drugs are co-administered. However, based on data on drug interactions, the following regimens may be recommended.

Treatment regimen	Current maintenance dose (prior to add-on therapy)		Week 1 (initiation of add-on therapy)	Week 2	Week 3 and onwards
Add-on therapy with valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interaction") depending on the initial lamotrigine dose.
This treatment regimen should be used when adding valproate regardless of concomitant medications.	200 mg/day		100 mg/day	Maintain dose at 100 mg/day
	300 mg/day		150 mg/day	Maintain dose at 150 mg/day
	400 mg/day		200 mg/day	Maintain dose at 200 mg/day
Add-on therapy with inducers of lamotrigine glucuronidation in patients not taking valproate (see section "Interaction with other medicinal products and other forms of interaction"), depending on the initial lamotrigine dose.
This treatment regimen should be used when adding the following medications without valproate: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	200 mg/day		200 mg/day	300 mg/day	400 mg/day
	150 mg/day		150 mg/day	225 mg/day	300 mg/day
	100 mg/day		100 mg/day	150 mg/day	200 mg/day
Add-on therapy with medicinal products that have no significant inhibitory or inductive effect on lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen should be used when adding other medicinal products that have no significant inhibitory or inductive effect on lamotrigine glucuronidation.		Maintain the target dose achieved during titration (200 mg/day; dose range 100–400 mg/day).
Patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction") should follow the treatment regimen recommended for concomitant use of lamotrigine and valproate.

Discontinuation of lamotrigine in patients with bipolar disorders

According to clinical trial data, there was no increase in the frequency, severity, or type of adverse reactions after rapid discontinuation of lamotrigine compared to placebo. Therefore, patients may discontinue lamotrigine without tapering the dose.

Children (under 18 years of age)

Lamotrigine is not recommended for use in children with bipolar disorders (under 18 years of age), as randomized discontinuation trials did not demonstrate significant efficacy and showed an increased rate of suicidality (see sections "Pharmacodynamics" and "Special precautions for use").

General dosing recommendations for special patient groups

Women taking hormonal contraceptives

The use of a combination of ethinylestradiol/levonorgestrel (30 mcg/150 mcg) approximately doubles the clearance of lamotrigine, leading to reduced lamotrigine levels. After titration, higher maintenance doses of lamotrigine (almost twice as high) may be required to achieve optimal therapeutic response. A doubling of lamotrigine levels has been observed during the week when the contraceptive is not taken. Dose-dependent adverse reactions cannot be excluded. Therefore, consideration should be given to using contraception that does not include a week without active treatment as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Initiation of hormonal contraceptives in patients receiving maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will usually need to be doubled (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). It is recommended that the dose of lamotrigine be increased by 50–100 mg/day each week following the initiation of hormonal contraceptives, according to individual clinical response. Dose increases should not exceed this rate unless required based on clinical response to treatment.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine concentrations are maintained. In women using hormonal contraceptives with a 1-week inactive treatment interval (tablet-free week), monitoring of lamotrigine serum levels should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Consideration should be given to using contraceptive products that do not include a tablet-free week as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and NOT taking drugs that induce lamotrigine glucuronidation

The maintenance dose of lamotrigine will usually need to be reduced by 50% (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). It is recommended to gradually reduce the daily dose of lamotrigine by 50–100 mg per week (not more than 25% of the total daily dose per week) over 3 weeks, unless otherwise indicated based on individual clinical response.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine concentrations are maintained. In women who wish to discontinue hormonal contraceptives with a 1-week inactive treatment interval (tablet-free week), monitoring of lamotrigine serum levels should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Blood samples for assessing lamotrigine levels after permanent discontinuation of the contraceptive should not be collected during the first week after stopping the contraceptive.

Initiation of lamotrigine therapy in women already taking hormonal contraceptives

Dose escalation should follow the standard dosing recommendations provided in the tables.

Initiation and discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and also taking inducers of lamotrigine glucuronidation

Adjustment of the recommended maintenance dose of lamotrigine is not required.

Concomitant use with atazanavir/ritonavir

Adjustment of the recommended lamotrigine dose when adding it to existing atazanavir/ritonavir therapy is not required.

Patients already receiving a maintenance dose of lamotrigine and not taking inducers of glucuronidation may require an increase in lamotrigine dose when atazanavir/ritonavir is added, and a decrease when atazanavir/ritonavir is discontinued.

Monitoring of lamotrigine levels in plasma should be performed before and within 2 weeks after starting or stopping atazanavir/ritonavir to determine the need for dose adjustment of lamotrigine (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with lopinavir/ritonavir

Adjustment of the recommended lamotrigine dose when adding it to existing lopinavir/ritonavir therapy is not required.

Patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation may require an increase in lamotrigine dose when lopinavir/ritonavir is added, and a decrease when lopinavir/ritonavir is discontinued. Monitoring of lamotrigine in plasma should be performed before and within 2 weeks after starting or stopping lopinavir/ritonavir to determine the need for dose adjustment of lamotrigine (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients (aged 65 years and older)

Dose adjustment according to the recommended regimen is not required. The pharmacokinetics of lamotrigine in this age group does not differ significantly from that in adult patients under 65 years of age (see section "Pharmacokinetics").

Renal impairment

Caution should be exercised when administering lamotrigine to patients with renal impairment. For patients with end-stage renal disease, the initial dose of lamotrigine should be based on concomitant medications; dose reduction may be effective in patients with significant renal function impairment (see sections "Pharmacokinetics" and "Special precautions for use").

Hepatic impairment

Initial, titration, and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh class B) and by 75% in patients with severe (Child-Pugh class C) hepatic impairment. Titration and maintenance doses should be adjusted according to clinical response (see section "Pharmacokinetics").

Children.

The use of lamotrigine as monotherapy for treating children under 2 years of age or as adjunctive therapy for treating children under 1 month of age has not been studied. The efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years have not been established. Therefore, the drug is not recommended for use in children in this age group.

Lamotrigine is not indicated for use in children (under 18 years of age) with bipolar disorder due to lack of demonstrated efficacy and an increased risk of suicidal ideation (see section "Special precautions for use").

Overdose.

Symptoms and signs

There have been reports of acute overdose (with doses 10–20 times higher than the maximum therapeutic doses), including fatal cases. Symptoms of overdose included ataxia, nystagmus, impaired consciousness, generalized seizures, and coma. Prolongation of the QRS interval on electrocardiogram (intraventricular conduction delay) and QT interval prolongation have also been observed in patients with overdose. QRS widening to more than 100 msec may be associated with more severe toxicity.

Treatment

In case of overdose, the patient should be hospitalized for appropriate supportive therapy. Therapy aimed at reducing absorption (activated charcoal) should be administered if necessary. Further treatment should be based on clinical indications, taking into account the potential effects on cardiac conduction (see section "Special precautions for use"). Intravenous lipid therapy may be considered for treating cardiotoxicity that is insufficiently responsive to sodium bicarbonate. There is no experience with the use of hemodialysis for treating overdose. In six volunteers with renal impairment, 20% of lamotrigine was eliminated during a 4-hour hemodialysis session (see section "Pharmacological properties").

Adverse reactions.

Adverse reactions for indications in the treatment of epilepsy and bipolar disorder, based on available data from controlled clinical trials and other clinical experience, are listed below. Frequency categories were derived from controlled clinical trials (epilepsy monotherapy (denoted as †) and bipolar disorder (denoted as §)). If frequency categories differ between epilepsy and bipolar disorder clinical data, the lowest frequency is applied. In the absence of controlled clinical trial data, frequency categories were derived from other clinical experience.

The following classification was used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Skin and subcutaneous tissue disorders: very common – skin rashes^5†§; uncommon – alopecia, photosensitivity reactions; rare – erythema multiforme, Stevens–Johnson syndrome^§; very rare – toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms².

Blood and lymphatic system disorders: very rare – haematological abnormalities¹ (including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, and agranulocytosis), haemophagocytic lymphohistiocytosis (see section "Special warnings and precautions for use"); frequency not known – lymphadenopathy¹, pseudolymphoma.

Immune system disorders: very rare – hypersensitivity syndrome²; frequency not known – hypogammaglobulinaemia.

Psychiatric disorders: common – aggression, irritability; very rare – tics (motor and/or vocal tics), hallucinations and confusion; frequency not known – nightmares.

Nervous system disorders: very common – headache^§; common – somnolence^†§, insomnia^†, dizziness^†§, tremor^†, anxiety^§; uncommon – ataxia^†; rare – nystagmus^†, aseptic meningitis (see section "Special warnings and precautions for use"); very rare – unsteadiness, movement disorders, exacerbation of Parkinson’s disease³, extrapyramidal effects, choreoathetosis^†, increased seizure frequency.

Eye disorders: uncommon – diplopia^†, blurred vision^†; rare – conjunctivitis.

Gastrointestinal disorders: common – nausea^†, vomiting^†, diarrhoea^†, dry mouth^§.

Hepatobiliary disorders: very rare – increased liver function test parameters, liver function impairment⁴, liver failure.

Renal and urinary disorders: frequency not known – tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis syndrome.

Musculoskeletal and connective tissue disorders: common – arthralgia^§; very rare – lupus-like reactions.

General disorders: common – fatigue^†, pain^§, back pain^§.

Description of selected adverse reactions

1 Haematological abnormalities and lymphadenopathy may be associated or not associated with drug reaction with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome (see section "Special warnings and precautions for use" and "Immune system disorders").

2 Skin rash has also been reported as part of this syndrome, also known as DRESS. This condition is accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, blood parameter abnormalities, and liver and kidney function impairment. The syndrome may vary in severity and, in rare cases, may 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 appear even in the absence of skin rash. If such symptoms occur, the patient should be examined immediately and lamotrigine should be discontinued unless another cause is identified (see section "Special warnings and precautions for use").

3 These reactions were observed in clinical practice in other clinical conditions.

Worsening of Parkinsonism symptoms in patients with Parkinson’s disease has been reported with lamotrigine, and there have been isolated reports of extrapyramidal effects and choreoathetosis in patients without this condition.

4 Liver function impairment is usually associated with hypersensitivity reactions, but isolated cases without prominent hypersensitivity symptoms have been described.

5 In clinical trials among adults, skin rash was observed in 8–12% of patients receiving lamotrigine and in 5–6% of patients receiving placebo. Rash led to drug discontinuation in 2% of patients. The rash was maculopapular in nature, most commonly occurring within eight weeks of starting treatment and resolving after lamotrigine discontinuation (see section "Special warnings and precautions for use"). Serious, potentially life-threatening skin reactions have been reported, including Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although most patients recover after lamotrigine discontinuation, some patients may have permanent scarring; in rare cases, these syndromes have been fatal (see section "Special warnings and precautions for use").

The overall risk of skin rash appears to be closely related to:

• high initial doses of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy (see section "Dosage and administration");
• concomitant use of valproate (see section "Dosage and administration").

There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients on long-term lamotrigine therapy. The mechanism by which lamotrigine affects bone metabolism has not been established.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister. 3 or 6 blisters in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and location of business activity.

54 Davydovskoho Hryhoriia Street, Sumy, Sumy region, 40020, Ukraine.

INSTRUCTIONS

for medical use of the medicinal product

LANISTOR

(LANISTOR®)

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.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round, flat tablets with bevelled edges, uncoated, with an embossed mark « » on one side and smooth on the other.

Pharmacotherapeutic group. Antiepileptic drugs. Lamotrigine.

ATC code N03A X09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Pharmacological studies have shown that lamotrigine is a use-dependent and voltage-dependent blocker of voltage-gated sodium channels. It suppresses sustained repetitive neuronal firing and inhibits the release of glutamate (a neurotransmitter that plays a key role in the occurrence of epileptic seizures). This effect is likely responsible for the anticonvulsant properties of lamotrigine.

In contrast, the mechanisms underlying the therapeutic effect of lamotrigine in bipolar disorder remain to be fully elucidated, although interaction with voltage-gated sodium channels is considered to play an important role.

Pharmacokinetics.

Absorption

In the absence of significant first-pass metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract.

Following oral administration of lamotrigine, maximum plasma concentration is reached in approximately 2.5 hours. Time to maximum concentration is slightly prolonged when the drug is taken after food, but this does not affect the extent of absorption. There are considerable inter-individual variations in steady-state maximum concentrations, although intra-individual values in a single patient are generally consistent.

Distribution

Approximately 55% of the drug dose is bound to plasma proteins. The risk of a toxic effect due to displacement from plasma proteins is unlikely.

The volume of distribution ranges from 0.92 to 1.22 L/kg.

Biotransformation

The primary enzyme responsible for lamotrigine metabolism has been identified as UDP-glucuronosyltransferase.

Lamotrigine only slightly, in a dose-dependent manner, induces its own metabolism. However, the effect of lamotrigine on the pharmacokinetics of other anticonvulsant drugs has not been established, and available data suggest that interactions between lamotrigine and other drugs metabolized via the cytochrome P450 system are unlikely.

Elimination

Theoretical plasma clearance in healthy volunteers is approximately 30 mL/min. Clearance of lamotrigine occurs primarily via formation of a metabolite, followed by excretion of glucuronide-conjugated material in urine. Less than 10% of the dose is excreted unchanged in urine. Only 2% of metabolized lamotrigine is excreted via the intestine. Clearance and elimination half-life are independent of dose. The theoretical elimination half-life in plasma of healthy volunteers is approximately 33 hours (range 14 to 103 hours). In a study involving patients with Gilbert's syndrome, the mean theoretical clearance in these subjects was 32% lower than in the control group, but remained within the range observed in the general patient population.

The elimination half-life of lamotrigine is significantly influenced by concomitantly administered drugs. The average half-life may decrease by approximately 14 hours when co-administered with inducers of glucuronidation such as carbamazepine and phenytoin, or increase by approximately 70 hours when administered concurrently with valproate alone (see section "Interaction with other medicinal products and other forms of interaction").

Linearity

Up to the highest studied dose of 450 mg, the pharmacokinetics of lamotrigine showed linear behavior.

Special patient populations

Children

Clearance, normalized per body weight, is higher in children than in adults, and highest 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 increasing to a mean of 45 to 50 hours when administered concurrently with valproate alone (see section "Interaction with other medicinal products and other forms of interaction").

Children aged 2 to 26 months

In 143 patients aged 2 to 26 months with body weights ranging from 3 to 16 kg, oral administration of equivalent doses per kilogram of body weight resulted in lower clearance compared to children over 2 years of age with similar body weight. The mean elimination half-life in children up to 26 months of age was 23 hours when enzyme-inducing therapy was used, 136 hours when co-administered with valproate, and 38 hours in the absence of enzyme-inducing or enzyme-inhibiting drugs. Inter-individual variability in clearance following oral dosing in patients aged 2 to 26 months was high (47%). Predicted serum concentrations in this age group were within the range observed in older patients, although patients with body weight below 10 kg showed higher maximum concentration values in some cases.

Elderly patients

Pharmacokinetic analysis in patient groups, including both elderly and younger patients with epilepsy participating in one study, revealed that lamotrigine clearance 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 reduction after 48 weeks of treatment was 10%, from 41 to 37 mL/min between younger and elderly groups. Additionally, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly volunteers who received a single 150 mg dose. The mean clearance value in elderly patients (0.39 mL/min/kg) falls within the range of mean clearance values (0.31 to 0.65 mL/min/kg) obtained in 9 studies conducted in younger adult patients after single doses 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 hemodialysis. Mean CL/F values were 0.42 mL/min/kg (chronic renal impairment), 0.33 mL/min/kg (interdialytic period), and 1.57 mL/min/kg (during hemodialysis), compared to 0.58 mL/min/kg in healthy volunteers. Mean elimination half-life in plasma was 42.9 hours (chronic renal impairment), 57.4 hours (interdialytic period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1) of the body load of lamotrigine was removed during a four-hour hemodialysis session. For this patient group, initial dosing of lamotrigine should be based on concomitant antiepileptic drug regimen; reduction of maintenance dose may be effective in patients with significant renal functional impairment (see sections "Dosage and administration" and "Special warnings and precautions for use").

Patients with hepatic impairment

A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy volunteers in the control group. 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 class A, B, and C hepatic impairment, respectively, compared to 0.34 mL/min/kg in healthy control volunteers. Initial, escalation, and maintenance doses should be reduced in patients with moderate to severe hepatic impairment (see section "Dosage and administration").

Clinical characteristics.

Indications.

Epilepsy Adults and children aged 13 years and older

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

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

Children aged 2 to 12 years

Adjunctive therapy for partial and generalized seizures of epilepsy, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

Monotherapy for typical absence seizures.

Bipolar disorder

Adults (aged 18 years and older)

Prevention of depressive episodes in patients with bipolar I disorder who predominantly experience depressive episodes.

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

Contraindications.

The medicinal product Lanistor is contraindicated in patients with known hypersensitivity to lamotrigine or to any other component of the product.

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adults.

It has been established that uridine 5’-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for lamotrigine metabolism. Therefore, medicinal products that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Enzyme inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate intensity, which are known to induce UGT, may also enhance lamotrigine metabolism.

There is no evidence that lamotrigine may cause clinically significant induction or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and has no significant clinical consequences.

Medicinal products that have been shown to have a relevant clinical effect on lamotrigine concentration are listed in Table 1. Specific dosage recommendations for these medicinal products are provided in the section "Method of administration and dosage". In addition, Table 1 lists medicinal products that have been shown to have little or no effect on lamotrigine concentration. Generally, no clinically relevant interaction is expected with concomitant use of such medicinal products. However, patients with epilepsy, whose condition is particularly sensitive to fluctuations in lamotrigine concentration, should be cautioned.

Table 1

Effect of other medicinal products on lamotrigine concentration

Medicinal products that increase lamotrigine concentration	Medicinal products that decrease lamotrigine concentration	Medicinal products that have little or no effect on lamotrigine concentration
Valproate	Atazanavir/ritonavir*, carbamazepine, combination ethinylestradiol/levonorgestrel*, lopinavir/ritonavir, phenobarbital, phenytoin, primidone, rifampicin	Aripiprazole, bupropion, felbamate, gabapentin, lacosamide, levetiracetam, lithium, olanzapine, oxcarbazepine, paracetamol, perampanel, pregabalin, topiramate, zonisamide

*For detailed dosing information, see the section "General dosing recommendations for special patient populations" in "Directions for use and dosage". For dosing instructions for women taking hormonal contraceptives, see the section "Hormonal contraceptives" in "Special precautions for use".

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases the average elimination half-life by approximately two-fold. For patients receiving concomitant valproate therapy, an appropriate dosing regimen should be used (see section "Directions for use and dosage").

Some AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 enzymes, also induce UGT and thereby accelerate lamotrigine metabolism. Patients receiving concomitant therapy with phenytoin, carbamazepine, phenobarbital, or primidone should use an appropriate dosing regimen (see section "Directions for use and dosage").

There have been reports of central nervous system (CNS) adverse reactions, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These reactions usually resolve upon reduction of the carbamazepine dose. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.

Literature reports indicate reduced lamotrigine levels when used in combination with oxcarbazepine. However, in a study in healthy adult volunteers receiving a 200 mg dose of lamotrigine and a 1200 mg dose of oxcarbazepine, oxcarbazepine did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism. Therefore, patients receiving concomitant oxcarbazepine therapy should use the lamotrigine adjunctive therapy regimen without valproate and without inducers of lamotrigine glucuronidation (see section "Directions for use and dosage").

In a study in healthy volunteers, concomitant administration 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 lamotrigine.

According to data from a retrospective analysis of plasma levels in patients taking lamotrigine with or without gabapentin, gabapentin does not alter the existing clearance rate of lamotrigine.

Potential drug interaction between levetiracetam and lamotrigine was studied by assessing serum concentrations of both drugs during placebo-controlled clinical trials. According to these data, the two substances do not affect each other's pharmacokinetics.

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

Topiramate does not affect plasma concentrations of lamotrigine. Lamotrigine administration increases topiramate concentrations by 15%.

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

Concomitant administration of lacosamide (200 mg/day, 400 mg/day, or 600 mg/day) did not affect lamotrigine plasma concentrations in placebo-controlled clinical trials in patients with partial seizures.

In a pooled analysis of data from three placebo-controlled clinical trials investigating add-on concurrent perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied perampanel dose (12 mg/day) increased lamotrigine clearance by less than 10%.

Although cases of altered plasma concentrations of other AEDs have been described, controlled studies have shown that lamotrigine does not affect plasma concentrations of concomitant AEDs. In vitro study results demonstrated that lamotrigine does not displace other AEDs from their protein binding sites in blood.

Interaction with other psychotropic agents

When 100 mg/day lamotrigine and 2 g anhydrous lithium gluconate (administered twice daily for 6 days) were given concomitantly to 20 patients, the pharmacokinetics of lithium were unchanged.

Multiple oral doses of bupropion had no statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients and resulted only in a slight increase in the area under the concentration-time curve (AUC) of lamotrigine glucuronide.

In a study in healthy adult volunteers, 15 mg olanzapine reduced the AUC and Cmax of lamotrigine in plasma by an average of 24% and 20%, respectively. 200 mg lamotrigine did not affect the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg/day did not cause a clinically significant effect on the pharmacokinetics of risperidone when a single 2 mg dose was administered in studies involving 14 healthy adult volunteers. When 2 mg risperidone was co-administered with lamotrigine, 12 out of 14 volunteers reported somnolence compared to 1 out of 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 (100–400 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and maintained for another 7 days. Overall, an approximately 10% decrease in AUC and Cmax of lamotrigine was observed.

In vitro experiments showed that the formation of the primary metabolite of lamotrigine, 2-N-glucuronide, is minimally affected by amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. These studies also indicated that lamotrigine metabolism is not inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone. Data from bufuralol metabolism studies in human liver microsomes suggest that lamotrigine does not reduce the clearance of drugs primarily metabolized by CYP2D6.

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine pharmacokinetics

In a study involving 16 female volunteers taking a combined tablet containing ethinylestradiol 30 µg/levonorgestrel 150 µg, lamotrigine clearance increased approximately two-fold, resulting in a mean reduction of lamotrigine AUC and Cmax by 52% and 39%, respectively. During the weekly break from contraceptive use (the so-called "pill-free week"), lamotrigine serum concentrations gradually increased, reaching levels approximately two-fold higher than during concomitant use (see section "Special precautions for use"). There is no need to adjust recommended lamotrigine doses solely due to the use of hormonal contraceptives; however, the maintenance dose of lamotrigine may need to be increased or decreased in most cases when starting or stopping hormonal contraceptives (see section "Directions for use and dosage").

Effect of lamotrigine on hormonal contraceptive pharmacokinetics

Study data in 16 female volunteers showed that a fixed 300 mg dose of lamotrigine did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptives. A consistent slight increase in levonorgestrel clearance was observed, resulting in mean reductions in AUC and Cmax of levonorgestrel by 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppression of ovarian hormonal activity in some women, although serum progesterone measurements indicated no hormonal signs of ovulation in any of the 16 women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the slight increase in levonorgestrel clearance on ovarian ovulatory activity is unknown (see section "Special precautions for use"). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Studies of other hormonal contraceptives have also not been conducted.

Interaction with other medicinal products

In a study involving 10 male volunteers receiving rifampicin, lamotrigine clearance increased and elimination half-life decreased due to induction of hepatic enzymes responsible for glucuronidation. Patients receiving concomitant rifampicin therapy should follow the dosing regimen recommended for lamotrigine with inducers of glucuronidation (see section "Directions for use and dosage").

Study data in healthy volunteers indicate that lopinavir/ritonavir reduces lamotrigine plasma concentrations by approximately two-fold through induction of glucuronidation. For treatment of patients already taking lopinavir/ritonavir, the therapeutic regimen recommended for lamotrigine with inducers of glucuronidation should be followed (see section "Directions for use and dosage").

Study data in healthy adult volunteers showed that administration of atazanavir/ritonavir (300 mg/100 mg) for 9 days reduced AUC and Cmax of lamotrigine in plasma (after a single 100 mg dose) by an average of 32% and 6%, respectively. Patients already taking lopinavir/ritonavir should follow the appropriate lamotrigine dosing regimen (see section "Directions for use and dosage").

Study data in healthy volunteers showed that administration of paracetamol at a dose of 1 g (four times daily) reduced lamotrigine AUC and minimum plasma concentration (Cmin) by an average of 20% and 25%, respectively.

In vitro data indicate that lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT2) at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2 with an IC50 value of 53.8 µM. Concomitant administration of lamotrigine with renally excreted drugs that are OCT2 substrates (e.g., metformin, gabapentin, and varenicline) may lead to increased plasma levels of these drugs.

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

Special precautions for use.

Skin rashes

Skin rashes may occur within the first 8 weeks of initiating lamotrigine treatment. In most cases, rashes are mild and resolve without treatment. However, severe skin reactions requiring hospitalization and discontinuation of lamotrigine have been reported. These include 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 "Adverse reactions").

In adults participating in clinical trials using current lamotrigine dosing recommendations, 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 have a higher risk of developing serious skin rashes compared to adults.

Clinical trial data indicate that the incidence of rashes leading to hospitalization in children ranges from 1 in 300 to 1 in 100 patients.

In children, early signs of skin rashes may be mistaken for infection. Therefore, physicians should consider the possibility of an adverse drug reaction in any child presenting with rash and fever during the first 8 weeks of therapy.

The overall risk of developing skin rashes appears closely related to high initial doses of lamotrigine, exceeding the recommended dose escalation regimen, and concomitant use of valproate (see section "Dosage and administration").

Lamotrigine should be prescribed with caution in patients with a history of allergy or skin rash to other antiepileptic drugs (AEDs), as the incidence of mild rashes after lamotrigine treatment in this patient group was three times higher than in those without such history.

The HLA-B*1502 allele in individuals of Asian (particularly Chinese and Thai) ancestry is associated with an increased risk of SJS/TEN with lamotrigine use. If a patient tests positive for the HLA-B*1502 allele, the decision to use lamotrigine should be carefully considered.

If a rash develops, the patient (adult or child) should be examined immediately, and lamotrigine should be discontinued unless there is clear evidence that the rash is unrelated to the drug. Reinitiating lamotrigine therapy after prior discontinuation due to rash is not recommended. In such cases, the potential benefits of treatment should be weighed against the possible risks when considering re-prescription.

Lamotrigine must not be re-administered to patients who previously experienced SJS, TEN, or DRESS following lamotrigine use.

Skin rashes have also been reported as part of DRESS (also known as hypersensitivity syndrome). This condition is associated with various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, liver or kidney dysfunction, and aseptic meningitis (see section "Adverse reactions"). The syndrome may vary in severity and rarely may lead to disseminated intravascular coagulation and multiorgan failure. Importantly, early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rashes. Patients presenting with such symptoms should be examined immediately, and lamotrigine should be discontinued if no other cause is identified. In most cases, aseptic meningitis resolves after drug withdrawal, but in some cases, it may recur upon re-exposure to lamotrigine. Reintroduction of lamotrigine often results in rapid recurrence of symptoms, which may be more severe. Lamotrigine must not be re-administered to patients who previously developed aseptic meningitis during lamotrigine treatment.

Photosensitivity reactions associated with lamotrigine use have also been reported (see section "Adive reactions"). In several cases, the reaction occurred with high doses (400 mg or more), after dose increases, or during rapid titration. If a patient presents with signs suggestive of photosensitivity (e.g., severe sunburn), lamotrigine-related photosensitivity should be suspected, and discontinuation of therapy should be considered. If continuing lamotrigine treatment is clinically justified, patients should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g., wearing protective clothing and using sunscreen).

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients taking lamotrigine (see section "Adverse reactions"). HLH is characterized by clinical signs and symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, elevated serum ferritin levels, hypertriglyceridemia, and liver dysfunction and coagulopathy. Symptoms typically develop within 4 weeks of starting treatment. HLH may be life-threatening.

Patients should be informed about symptoms associated with HLH and advised to seek immediate medical attention if such symptoms occur during lamotrigine therapy.

Patients who develop these signs and symptoms should be examined immediately, and HLH should be considered in the differential diagnosis. Lamotrigine therapy should be discontinued immediately if no other cause for the symptoms can be established.

Clinical worsening and suicide 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 with antiepileptic drugs, including lamotrigine, demonstrated a small but increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility that lamotrigine may contribute to this risk.

Therefore, patients should be closely monitored for signs of suicidal ideation and behavior. If such signs occur, patients and caregivers should seek immediate medical help.

In patients with bipolar disorders, symptoms of depression and/or suicidal behavior may worsen, regardless of whether they are receiving treatment for bipolar disorder, including lamotrigine. Therefore, patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including new symptoms) and for suicidal behavior, particularly at the beginning of treatment or during dose adjustments. Patients at higher risk of suicidal thoughts or attempts—such as those with a history of suicidal behavior or ideation, younger individuals, or those with marked suicidal ideation before treatment initiation—require careful monitoring during therapy.

The clinical situation should be evaluated, and appropriate changes to the therapeutic regimen should be made, including possible discontinuation of treatment in patients showing clinical worsening (including new symptoms) and/or emergence of suicidal ideation/behavior, especially if these symptoms are severe, sudden in onset, or not part of pre-existing symptoms.

Hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine efficacy

The combination of ethinylestradiol 30 µg/levonorgestrel 150 µg increases lamotrigine clearance approximately twofold, thereby reducing lamotrigine levels (see section "Interaction with other medicinal products and other forms of interaction"). Reduced lamotrigine levels are associated with loss of seizure control. After dose titration, most patients will require higher maintenance doses (almost double) to achieve optimal therapeutic response. Upon discontinuation of hormonal contraceptives, lamotrigine clearance may decrease by half. Increased lamotrigine concentration may be associated with dose-dependent adverse reactions. Patients should be monitored accordingly.

In women not taking other lamotrigine glucuronidation inducers but using hormonal contraceptives with a weekly break between cycles (the so-called "pill-free week"), a gradual, temporary increase in lamotrigine levels may occur during the pill-free week (see section "Dosage and administration").

Fluctuations in lamotrigine levels in this situation may be associated with adverse reactions. Therefore, the use of contraception without a "pill-free week" should be considered as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods).

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

Effect of lamotrigine on hormonal contraceptive efficacy

A clinical interaction study involving 16 healthy volunteers showed a slight increase in levonorgestrel clearance and changes in serum follicle-stimulating and luteinizing hormone levels when lamotrigine was co-administered with hormonal contraceptives (ethinylestradiol 30 µg/levonorgestrel 150 µg) (see section "Interaction with other medicinal products and other forms of interaction"). The impact of these changes on ovulation is unknown. However, it cannot be ruled out that in some patients taking lamotrigine and hormonal contraceptives simultaneously, these changes may lead to reduced contraceptive efficacy. Therefore, patients should promptly report any changes in their menstrual cycle, such as sudden breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, and thus may affect folate metabolism during long-term use (see section "Use during pregnancy or lactation"). However, long-term lamotrigine treatment has not been associated with significant changes in hemoglobin levels, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentrations over 5 years.

Renal impairment

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 is required when treating patients with renal impairment.

Patients using other lamotrigine-containing medicines

Lamotrigine-containing medicine Lanistor must not be used in patients already receiving any other lamotrigine-containing medicine without physician consultation.

Brugada-like ECG changes and other cardiac rhythm disturbances and conduction abnormalities

Cases of arrhythmogenic ST-T changes and typical Brugada-like ECG changes have been reported in patients receiving lamotrigine.

In vitro data indicate that lamotrigine may potentially slow ventricular conduction (widen QRS) and induce proarrhythmia at therapeutically relevant concentrations in patients with heart disease. Lamotrigine acts as a weak class IB antiarrhythmic agent, with a potential risk of serious or fatal cardiac events. Concomitant use of other sodium channel blockers may further increase these risks. At therapeutic doses up to 400 mg/day, lamotrigine did not slow ventricular conduction (widen QRS) or prolong the QT interval in healthy volunteers in a thorough QT study. Lamotrigine use should be carefully considered in patients with clinically significant structural or functional heart disease, such as Brugada syndrome or other cardiac channelopathies, heart failure, ischemic heart disease, heart block, or ventricular arrhythmias. If lamotrigine use is clinically justified in such patients, consultation with a cardiologist is recommended before initiation.

Child development

There are no data on the effects of lamotrigine on growth, sexual maturation, or the development of cognitive, emotional, and behavioral functions in children.

Precautions in epilepsy

Abrupt discontinuation of lamotrigine, as with other AEDs, may provoke increased seizure frequency. Except in cases where the patient's condition requires abrupt discontinuation (e.g., in case of rash), the dose of lamotrigine should be tapered gradually over at least 2 weeks.

According to the literature, severe epileptic seizures, including status epilepticus, may lead to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes with fatal outcomes. Similar cases are possible during lamotrigine therapy.

Significant clinical worsening, including increased seizure frequency, may occur instead of improvement. In patients with more than one seizure type, improvement in control of one seizure type should be carefully weighed against worsening of control of another seizure type.

Lamotrigine treatment may exacerbate myoclonic seizures.

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

Not all children with typical absence seizures respond to lamotrigine treatment.

Precautions in bipolar disorders

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 disorders and other psychiatric disorders.

Excipients

The medicine contains lactose. If the patient has known intolerance to certain sugars, medical advice should be sought before taking this medicine.

This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Risk associated with use of AEDs in general

Women of childbearing potential should seek medical advice. The need for AED treatment should be reviewed during pregnancy planning. Women with epilepsy already on treatment should avoid abrupt discontinuation of antiepileptic therapy, as this may provoke seizure exacerbation and have serious consequences for both mother and child.

Monotherapy is preferred, as combined antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with lamotrigine use

Pregnancy

Extensive epidemiological data from studies involving over 12,700 pregnant women receiving lamotrigine monotherapy, including over 9,100 women treated during the first trimester, do not indicate that lamotrigine therapy at maintenance doses is associated with an increased risk of major congenital malformations.

Studies on the effect of doses higher than the usual maintenance dose of 100–200 mg/day on the risk of major congenital malformations have yielded conflicting results. Some studies found no evidence of a dose-dependent effect, but data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) showed a statistically significant increase in the frequency of major congenital malformations with lamotrigine doses ≥ 325 mg/day compared to doses < 325 mg/day (OR 1.68, 95% CI 1.01–2.80). Therefore, if lamotrigine therapy is considered necessary during pregnancy, the lowest effective therapeutic dose is recommended.

Lamotrigine has a weak inhibitory effect on dihydrofolate reductase. Since folic acid has a protective effect against the risk of neural tube defects, folic acid supplementation is recommended during pregnancy planning and early pregnancy.

Physiological changes during pregnancy may affect lamotrigine concentrations and/or its therapeutic effect. Reports indicate decreased plasma lamotrigine concentrations during pregnancy, with a potential risk of loss of seizure control. After delivery, lamotrigine levels may rise rapidly, increasing the risk of dose-dependent adverse reactions. Therefore, serum lamotrigine concentrations should be monitored before, during, and after pregnancy, and shortly after delivery.

If necessary, the lamotrigine dose should be adjusted to maintain serum concentrations at pre-pregnancy levels or adapted according to clinical status. Dose-dependent adverse reactions should also be monitored closely after childbirth.

Animal studies have shown embryofetal toxicity.

Lactation period

Lamotrigine has been reported to pass into breast milk at variable concentrations, resulting in infant lamotrigine levels reaching up to 50% of maternal levels. Therefore, in some breastfed infants, serum lamotrigine levels may reach concentrations at which a pharmacological effect is possible.

The potential benefits of breastfeeding should be weighed against the possible risk of adverse reactions in the infant. If a woman receiving lamotrigine decides to breastfeed, the infant should be closely monitored for adverse reactions such as sedation, rash, or poor weight gain.

Fertility

Animal studies did not reveal any effect of lamotrigine on fertility.

Ability to affect reaction speed when driving or operating machinery.

Since individual response to any AED therapy varies, patients taking lamotrigine for epilepsy should consult their physician regarding driving.

No studies have been conducted on the effect of lamotrigine on the ability to drive or operate machinery. Two studies in volunteers demonstrated that lamotrigine's effects on fine visual motor skills, eye movements, body sway, and subjective sedative effects were no different from placebo. During clinical trials, neurological adverse reactions such as dizziness and diplopia were reported. Therefore, patients should assess how lamotrigine therapy affects them before driving or operating machinery.

Dosage and Administration

Lamictal tablets should be swallowed whole, without chewing or breaking.

If the calculated dose of lamotrigine (e.g., for treatment of children with epilepsy or patients with impaired liver function) is not a multiple of whole tablets, the administered dose should correspond to the nearest lower number of whole tablets.

If the calculated dose of lamotrigine is less than 25 mg, lamotrigine formulations allowing such dosing should be used.

Reinitiation of Treatment

Physicians should assess the need for dose escalation to maintenance levels when resuming lamotrigine in patients who have discontinued treatment for any reason, as the risk of developing serious rash is associated with high initial doses and exceeding the recommended dose escalation regimen (see section "Special Warnings and Precautions for Use"). The longer the interval since the last dose, the more caution should be exercised when escalating the dose to maintenance levels. If the interval since discontinuation of lamotrigine exceeds 5 half-lives (see section "Pharmacokinetics"), the dose should be re-escalated to maintenance levels according to the established regimen.

Reinitiation of lamotrigine is not recommended in patients who discontinued treatment due to rash associated with prior lamotrigine therapy, unless the potential benefit clearly outweighs the risk.

Epilepsy

Recommended dose escalation regimens and maintenance doses for adults and children aged 13 years and older (see Table 2), as well as for children aged 2 to 12 years (see Table 3), are provided below. To minimize the risk of rash, the initial dose and rate of subsequent dose escalation should not be exceeded (see section "Special Warnings and Precautions for Use").

When concomitant antiepileptic drugs (AEDs) are discontinued or other AEDs/medicinal products are added to lamotrigine-containing regimens, the potential impact on lamotrigine pharmacokinetics should be considered (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Table 2

Recommended treatment regimens for epilepsy in adults and children aged 13 years and older

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Usual maintenance dose
Monotherapy	25 mg/day (1 dose)	50 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, increase by no more than 50–100 mg every 1 or 2 weeks until optimal response is achieved. Some patients required a dose of 500 mg/day to achieve the desired response.
Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen applies when valproate is used, regardless of other concomitant medicinal products.	12.5 mg/day (take 25 mg every other day)	25 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, increase by no more than 25–50 mg every 1 or 2 weeks until optimal response is achieved.
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen does not include valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ ritonavir.	50 mg/day (1 dose)	100 mg/day (2 doses)	200–400 mg/day (2 doses). To reach the maintenance dose, increase by no more than 100 mg every 1 or 2 weeks until optimal response is achieved. Some patients required a dose of 700 mg/day to achieve the desired response.
Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen includes other medicinal products that do not exhibit significant inhibitory or inductive effects on lamotrigine glucuronidation.	25 mg/day (1 dose)	50 mg/day (1 dose)	100–200 mg/day (1–2 doses). To reach the maintenance dose, increase by no more than 50–100 mg every 1 or 2 weeks until optimal response is achieved.
Patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interactions") should follow the dosing regimen recommended for concomitant use of lamotrigine and valproate.

Table 3

Children aged 2 to 12 years: recommended epilepsy treatment regimen (total daily dose in mg/kg body weight/day)*

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Usual maintenance dose
Monotherapy for typical absence seizures	0.3 mg/kg/day (1 or 2 divided doses per day)	0.6 mg/kg/day (1 or 2 divided doses per day)	1–15 mg/kg/day (1 or 2 divided doses per day). To reach the maintenance dose, increase by no more than 0.6 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen involves the use of valproate, regardless of the use of other concomitant medications.	0.15 mg/kg/day (1 dose per day)	0.3 mg/kg/day (1 dose per day)	1–5 mg/kg/day (1 or 2 divided doses per day). To reach the maintenance dose, increase by no more than 0.3 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen does not involve the use of valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	0.6 mg/kg/day (2 divided doses)	1.2 mg/kg/day (2 divided doses)	5–15 mg/kg/day (1 or 2 divided doses). To reach the maintenance dose, increase by no more than 1.2 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 400 mg/day.
Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen involves the use of other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation.	0.3 mg/kg/day (1 or 2 divided doses)	0.6 mg/kg/day (1 or 2 divided doses)	1–10 mg/kg/day (1 or 2 divided doses). To reach the maintenance dose, increase by no more than 0.6 mg/kg/day* every 1 or 2 weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day.
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the dosing regimen recommended for concomitant use of lamotrigine and valproate should be used.
If the calculated dose for patients taking valproate is less than 1 mg, lamotrigine administration is not recommended.

*If the calculated dose of lamotrigine is less than 25 mg, lamotrigine formulations allowing such dosing should be used.

To maintain therapeutic dosing, the child's body weight should be monitored and the dose adjusted accordingly if body weight changes. Patients aged 2 to 6 years will likely require a maintenance dose approaching the upper end of the recommended range.

If seizure control is achieved with adjunctive therapy, concomitant antiepileptic drugs (AEDs) may be discontinued, continuing lamotrigine monotherapy.

Children under 2 years of age

Data on the efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years (see section "Use in specific populations") are limited. There are no data on the use of lamotrigine in children under 1 month of age. Therefore, lamotrigine is not recommended for use in children under 2 years of age. If, based on clinical need, a decision to initiate lamotrigine therapy is made, see sections "Pharmacological properties" and "Use in specific populations".

Bipolar disorder

Recommended dose escalation and maintenance doses for adults aged 18 years and older are provided in the tables below. The titration regimen includes increasing the dose of lamotrigine to the maintenance stabilizing dose over 6 weeks (see Table 4), after which other psychotropic and/or antiepileptic drugs (AEDs) may be discontinued if clinically appropriate (see Table 5). Dose adjustment regimens when adding other concomitant psychotropic medications and/or AEDs are provided in Table 6. Due to the risk of rash, the initial dose and rate of subsequent dose escalation should not be exceeded (see section "Use in specific populations").

Table 4

Adults (aged 18 years and older): recommended dose escalation regimen to achieve maintenance stabilizing daily dose in the treatment of bipolar disorder

Treatment regimen	Weeks 1 and 2	Weeks 3 and 4	Week 5	Target maintenance dose (week 6)*
Lamotrigine monotherapy or adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen involves the use of other medicinal products that do not exhibit significant inhibitory or inductive effects on lamotrigine glucuronidation.	25 mg/day (once daily)	50 mg/day (once or twice daily)	100 mg/day (once or twice daily)	200 mg/day – usual target dose to achieve optimal response (once or twice daily). Doses ranging from 100–400 mg/day have been used in clinical studies.
Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation – see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen includes valproate, regardless of the use of other concomitant medicinal products.	12.5 mg/day (25 mg every other day)	25 mg/day (once daily)	50 mg/day (once or twice daily)	100 mg/day – usual target dose to achieve optimal response (once or twice daily). A maximum dose of 200 mg/day may be used depending on clinical response.
Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions").
This treatment regimen does not include valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	50 mg/day (once daily)	100 mg/day (twice daily)	200 mg/day (twice daily)	300 mg/day in week 6; if necessary, the usual target dose of 400 mg/day is increased in week 7 to achieve optimal response (twice daily)
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interactions"), the dose escalation regimen recommended for concomitant use of lamotrigine with valproate should be used.

* Target maintenance dose varies depending on clinical response.

Table 5

Adults (aged 18 years and older): maintenance stabilizing daily dose after discontinuation of concomitant medicinal products for the treatment of bipolar disorders

After achieving the required maintenance stabilizing dose, other psychotropic medications may be discontinued according to the schemes outlined below.

Treatment regimen	Current maintenance dose of lamotrigine (prior to discontinuation)		Week 1 (starting upon discontinuation)	Week 2	Week 3 and beyond*
Discontinuation of valproate (inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interaction") depending on the initial lamotrigine dose.
When discontinuing valproate, the maintenance dose should be doubled, not exceeding an increase of more than 100 mg/week.	100 mg/day		200 mg/day	Maintain dose at 200 mg/day (2 doses)
	200 mg/day		300 mg/day	400 mg/day	Maintain dose at 400 mg/day
Discontinuation of inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") depending on the initial lamotrigine dose.
This treatment regimen applies when discontinuing phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	400 mg/day		400 mg/day	300 mg/day	200 mg/day
	300 mg/day		300 mg/day	225 mg/day	150 mg/day
	200 mg/day		200 mg/day	150 mg/day	100 mg/day
Discontinuation of medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen applies to other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation.		Maintain the target dose achieved through titration (200 mg/day in two doses) (dose range 100–400 mg/day)
For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the recommended lamotrigine regimen involves initially maintaining the current dose, followed by dose adjustments based on clinical response.

• If necessary, the dose may be increased to 400 mg/day.

Table 6

Adults (aged 18 years and older): adjustment of daily dose when co-administering other drugs in patients with bipolar disorder

There is no clinical experience regarding dosage adjustment of lamotrigine when other drugs are co-administered. However, based on data concerning drug interactions, the following regimens may be recommended.

Treatment regimen	Current maintenance dose (prior to add-on therapy)		Week 1 (initiation of add-on therapy)	Week 2	Week 3 and onwards
Add-on therapy with valproate (inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") depending on the initial dose of lamotrigine.
This treatment regimen should be used when adding valproate regardless of concomitant medications.	200 mg/day		100 mg/day	Maintain dose at 100 mg/day
	300 mg/day		150 mg/day	Maintain dose at 150 mg/day
	400 mg/day		200 mg/day	Maintain this dose at 200 mg/day
Add-on therapy with inducers of lamotrigine glucuronidation in patients not taking valproate (see section "Interaction with other medicinal products and other forms of interaction"), depending on the initial dose of lamotrigine.
This treatment regimen should be used when adding the following medications without concomitant valproate: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir.	200 mg/day		200 mg/day	300 mg/day	400 mg/day
	150 mg/day		150 mg/day	225 mg/day	300 mg/day
	100 mg/day		100 mg/day	150 mg/day	200 mg/day
Add-on therapy with medicinal products that have no significant inhibitory or inductive effect on lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").
This treatment regimen should be used when adding other medicinal products that have no significant inhibitory or inductive effect on lamotrigine glucuronidation.		Maintain the target dose achieved through titration (200 mg/day; dose range 100–400 mg/day).
Patients taking medicinal products with unknown effect on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction") should follow the treatment regimen recommended for concomitant use of lamotrigine and valproate.

Discontinuation of lamotrigine in patients with bipolar disorders

Clinical trial data have not shown an increase in the frequency, severity, or type of adverse reactions after rapid discontinuation of lamotrigine compared to placebo. Therefore, patients may discontinue lamotrigine without tapering the dose.

Children (under 18 years of age)

Lamotrigine is not recommended for use in children with bipolar disorders (under 18 years of age), as randomized discontinuation studies did not demonstrate its significant efficacy and showed an increased rate of suicidality (see sections "Pharmacodynamics" and "Special precautions").

General dosing recommendations for special patient groups

Women taking hormonal contraceptives

The use of a combination of ethinylestradiol/levonorgestrel (30 mcg/150 mcg) approximately doubles the clearance of lamotrigine, leading to reduced lamotrigine levels. After titration, it may be necessary to use higher maintenance doses of lamotrigine (almost twice as high) to achieve optimal therapeutic response. A doubling of lamotrigine levels has been observed during the week when the contraceptive is not taken. Dose-dependent adverse reactions cannot be excluded. Therefore, consideration should be given to using contraception that does not include a week without active treatment as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Initiation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will usually need to be doubled (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions"). It is recommended that, starting with the initiation of hormonal contraceptives, the lamotrigine dose be increased by 50–100 mg/day each week, according to individual clinical response. Dose increases should not exceed this rate unless clinically justified.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women taking hormonal contraceptives with a one-week inactive treatment period (tablet-free week), monitoring of lamotrigine serum levels should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Consideration should be given to using contraceptive products that do not include a tablet-free week as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").

Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and NOT taking drugs that induce lamotrigine glucuronidation

The maintenance dose of lamotrigine will usually need to be reduced by 50% (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions"). It is recommended to gradually reduce the daily dose of lamotrigine by 50–100 mg per week (not more than 25% of the total daily dose per week) over 3 weeks, unless otherwise indicated based on individual clinical response.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women who wish to discontinue hormonal contraceptives with a one-week inactive treatment period (tablet-free week), monitoring of lamotrigine serum levels should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Blood samples for assessing lamotrigine levels after permanent discontinuation of the contraceptive should not be collected during the first week after stopping it.

Initiation of lamotrigine therapy in women already taking hormonal contraceptives

Dose escalation should follow the standard dosing recommendations provided in the tables.

Initiation and discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and also taking inducers of lamotrigine glucuronidation

Adjustment of the recommended maintenance dose of lamotrigine is not required.

Concomitant use with atazanavir/ritonavir

Adjustment of the recommended lamotrigine dose when adding lamotrigine to existing atazanavir/ritonavir therapy is not required.

Patients already receiving a maintenance dose of lamotrigine and not taking inducers of glucuronidation may require an increase in lamotrigine dose when atazanavir/ritonavir is added, and a dose reduction when atazanavir/ritonavir is discontinued.

Monitoring of lamotrigine levels in plasma should be performed before and within 2 weeks after starting or stopping atazanavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with lopinavir/ritonavir

Adjustment of the recommended lamotrigine dose when adding lamotrigine to existing lopinavir/ritonavir therapy is not required.

Patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation may require an increase in lamotrigine dose when lopinavir/ritonavir is added, and a dose reduction when lopinavir/ritonavir is discontinued. Monitoring of lamotrigine in plasma should be performed before and within 2 weeks after starting or stopping lopinavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients (aged 65 years and older)

Dose adjustment according to the recommended regimen is not required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from those in adult patients under 65 years of age (see section "Pharmacokinetics").

Renal impairment

Caution should be exercised when administering lamotrigine to patients with renal impairment. For patients with end-stage renal disease, the initial dose of lamotrigine should be based on concomitant medications; dose reduction of the maintenance dose may be effective in patients with significant renal dysfunction (see sections "Pharmacokinetics" and "Special precautions").

Hepatic impairment

Initial, titration, and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh class B) and by 75% in patients with severe (Child-Pugh class C) hepatic impairment. Titration and maintenance doses should be adjusted according to clinical response (see section "Pharmacokinetics").

Children

The use of lamotrigine as monotherapy for the treatment of children under 2 years of age or as adjunctive therapy for children under 1 month of age has not been studied. The efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years have not been established. Therefore, the drug is not recommended for use in children of this age group.

Lamotrigine is not indicated for use in children (under 18 years of age) with bipolar disorder due to lack of demonstrated efficacy and an increased risk of suicidal ideation (see section "Special precautions").

Overdose.

Symptoms and signs

There have been reports of acute overdose (with doses 10–20 times higher than the maximum therapeutic doses), including fatal cases. Symptoms of overdose included ataxia, nystagmus, impaired consciousness, generalized seizures, and coma. Prolongation of the QRS interval on electrocardiogram (intraventricular conduction delay) and QT interval prolongation have also been observed in patients with overdose. QRS widening to more than 100 msec may be associated with more severe toxicity.

Treatment

In case of overdose, the patient should be hospitalized for appropriate supportive therapy. Therapy aimed at reducing absorption (activated charcoal) should be administered if necessary. Further treatment should be managed according to clinical indications, taking into account the potential effects on cardiac conduction (see section "Special precautions"). Intravenous lipid therapy may be considered for treating cardiotoxicity that is insufficiently responsive to sodium bicarbonate. There is no experience with hemodialysis for treating overdose. In six volunteers with renal impairment, 20% of lamotrigine was removed during a 4-hour hemodialysis session (see section "Pharmacological properties").

Adverse reactions.

Adverse reactions for indications in the treatment of epilepsy and bipolar disorder, based on available data from controlled clinical trials and other clinical experience, are listed below. Frequency categories were derived from controlled clinical trials (epilepsy monotherapy, denoted as †, and bipolar disorder, denoted as §). If frequency categories differ between epilepsy and bipolar disorder clinical data, the lowest frequency is applied. In the absence of controlled clinical trial data, frequency categories were derived from other clinical experience.

The following classification was used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Skin and subcutaneous tissue disorders: very common – skin rash^5†§; uncommon – alopecia, photosensitivity reactions; rare – erythema multiforme, Stevens–Johnson syndrome^§; very rare – toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)².

Blood and lymphatic system disorders: very rare – haematological abnormalities¹ (including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, and agranulocytosis), haemophagocytic lymphohistiocytosis (see section "Special warnings and precautions for use"); frequency not known – lymphadenopathy¹, pseudolymphoma.

Immune system disorders: very rare – hypersensitivity syndrome²; frequency not known – hypogammaglobulinaemia.

Psychiatric disorders: common – aggression, irritability; very rare – tics (motor and/or vocal tics), hallucinations and confusion; frequency not known – nightmares.

Nervous system disorders: very common – headache^§; common – somnolence^†§, insomnia^†, dizziness^†§, tremor^†, anxiety^§; uncommon – ataxia^†; rare – nystagmus^†, aseptic meningitis (see section "Special warnings and precautions for use"); very rare – unsteadiness, movement disorders, exacerbation of Parkinson's disease³, extrapyramidal effects, choreoathetosis^†, increased seizure frequency.

Eye disorders: uncommon – diplopia^†, blurred vision^†; rare – conjunctivitis.

Gastrointestinal disorders: common – nausea^†, vomiting^†, diarrhoea^†, dry mouth^§.

Hepatobiliary disorders: very rare – elevated liver function tests, liver function impairment⁴, liver failure.

Renal and urinary disorders: frequency not known – tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis syndrome.

Musculoskeletal and connective tissue disorders: common – arthralgia^§; very rare – lupus-like reactions.

General disorders: common – fatigue^†, pain^§, back pain^§.

Description of selected adverse reactions

1 Haematological abnormalities and lymphadenopathy may be associated or not associated with drug reaction with eosinophilia and systemic symptoms (DRESS) or hypersensitivity syndrome (see section "Special warnings and precautions for use" and "Immune system disorders").

2 Skin rash has also been reported as part of this syndrome, also known as DRESS. This condition is accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, haematological abnormalities, and liver and kidney function impairment. The syndrome may vary in severity and, in rare cases, may 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 appear even in the absence of skin rash. If such symptoms occur, the patient should be examined immediately and, in the absence of other causes, lamotrigine should be discontinued (see section "Special warnings and precautions for use").

3 These reactions were observed in clinical practice in other clinical conditions.

It has been noted that lamotrigine may worsen symptoms of parkinsonism in patients with Parkinson's disease, and there have been isolated reports of extrapyramidal effects and choreoathetosis in patients without this condition.

4 Liver function impairment is usually associated with hypersensitivity reactions, but isolated cases without prominent hypersensitivity symptoms have been described.

5 In clinical trials among adults, skin rash was observed in 8–12% of patients receiving lamotrigine and in 5–6% of patients receiving placebo. Rash led to drug discontinuation in 2% of patients. The rash was maculopapular in nature, most commonly occurring within eight weeks of starting treatment and resolving after discontinuation of lamotrigine (see section "Special warnings and precautions for use"). Serious, potentially life-threatening skin reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported. Although most patients recover after discontinuation of lamotrigine, some patients may have irreversible scarring; in rare cases, these syndromes have been fatal (see section "Special warnings and precautions for use").

The overall risk of developing skin rash appears to be closely related to:

• high initial doses of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy (see section "Dosage and administration");
• concomitant use of valproate (see section "Dos游戏副本 and administration").

There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients on long-term lamotrigine therapy. The mechanism by which lamotrigine affects bone metabolism has not been established.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister. 3 or 6 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.