Lamotrigine 50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMOTRIN 25 (LAMOTRIN 25) LAMOTRIN 50 (LAMOTRIN 50) LAMOTRIN 100 (LAMOTRIN 100)

Composition:

Active substance: lamotrigine;

One tablet contains lamotrigine 25 mg or 50 mg or 100 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets, white or almost white, with a biconvex surface, round-shaped (Lamotrin 25), with a score line on one side (Lamotrin 50 and Lamotrin 100).

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 believed to play an important role.

Pharmacodynamic effects

Studies assessing the effects of drugs on the central nervous system revealed no difference between healthy volunteers receiving 240 mg of lamotrigine and those receiving placebo, whereas both 1000 mg of phenytoin and 10 mg of diazepam significantly impaired fine visuomotor coordination, eye movements, and body balance, as well as caused a subjective sedative effect.

In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visuomotor coordination, eye movements, and body balance, and increased heart rate. In contrast, the effects of lamotrigine at single doses of 150 mg and 300 mg did not differ from placebo.

Effect of lamotrigine on cardiac conduction

In a study involving healthy adult volunteers, the effect of repeated doses of lamotrigine (up to 400 mg/day) on cardiac conduction was assessed using 12-lead ECG. Compared to placebo, lamotrigine did not show any clinically significant effect on the QT interval.

Clinical efficacy and safety

Prevention of mood episodes in patients with bipolar disorder

The efficacy of lamotrigine in the prevention of mood episodes in patients with bipolar disorder type I was evaluated in two studies.

Study SCAB2003 was a multicenter, double-blind, double-dummy, placebo- and lithium-controlled, randomized, fixed-dose study assessing long-term prevention of recurrent and relapsing depressive and/or manic episodes in patients with bipolar disorder type I who had a current or recent major depressive episode. After stabilization with lamotrigine monotherapy or adjunctive therapy, patients were randomly assigned to one of five treatment groups for up to 76 weeks (18 months): lamotrigine (50, 200, or 400 mg/day), lithium (serum level 0.8–1.1 mmol/L), or placebo. The primary endpoint was "time to intervention for a mood episode (TIME)," where interventions were defined as the addition of pharmacotherapy or electroconvulsive therapy (ECT). Study SCAB2006 was conducted using a design similar to SCAB2003 but with a more flexible dosing regimen of lamotrigine (100–400 mg/day) and included patients with bipolar disorder type I who had a current or recent manic episode. Results are presented in Table 1.

Table 1

Summary of results from efficacy studies of lamotrigine in the prevention of mood episodes in patients with bipolar disorder type I

Proportion of patients event-free at week 76
	Study SCAB2003 Type I Bipolar Disorder			Study SCAB2006 Type I Bipolar Disorder
Inclusion criterion	Major Depressive Episode			Major Manic Episode
	Lamotrigine	Lithium	Placebo	Lamotrigine	Lithium	Placebo
Intervention-free	0.22	0.21	0.12	0.17	0.24	0.04
log rank test p-value	0.004	0.006	-	0.023	0.006	-
Depression-free	0.51	0.46	0.41	0.82	0.71	0.40
log rank test p-value	0.047	0.209	-	0.015	0.167	-
Mania-free	0.70	0.86	0.67	0.53	0.64	0.37
log rank test p-value	0.339	0.026	-	0.280	0.006	-

Additional analysis of time to first depressive episode and time to first manic/hypomanic or mixed episode showed that the first depressive episode occurred statistically later in patients receiving lamotrigine than in patients in the placebo group. No statistically significant difference was observed in time to first manic/hypomanic or mixed episode.

The efficacy of lamotrigine in combination with mood stabilizers has not been adequately studied.

Children

Children aged 1 to 24 months

Efficacy and safety of adjunctive therapy for partial seizures in children aged 1 to 24 months were evaluated in a small double-blind, placebo-controlled withdrawal study. Treatment was initiated in 177 patients using a dosing regimen recommended for children aged 2 to 12 years. The lowest available dose of lamotrigine is contained in 2 mg tablets. Therefore, in some cases, the standard dosing regimen during the titration phase was appropriately adjusted (e.g., by administering a 2 mg tablet every other day when the calculated dose was less than 2 mg). Serum concentrations were measured at the end of the 2nd week of the titration phase and during the subsequent dose phase, with dose reduction or no increase implemented upon reaching concentrations exceeding 0.41 μg/mL—the predicted concentrations in adult patients at this time point of therapy. By the end of the 2nd week, some patients required a dose reduction of up to 90%. Thirty-eight patients who responded to treatment (≥ 40% reduction in seizure frequency) were randomized into two groups: placebo or continued lamotrigine. Treatment failure was observed in 84% of patients in the placebo group (16 out of 19) and in 54% of patients in the lamotrigine group (11 out of 19). The difference was not statistically significant: 26.3%, 95% CI –2.6% < > 50.2%, p = 0.07.

Overall, 256 patients aged 1 to 24 months received lamotrigine at doses ranging from 1 to 15 mg/kg/day for up to 72 weeks. The safety profile of lamotrigine in this age group was similar to that in older children, except for seizure progression (≥ 50%), which occurred statistically more frequently in children under 2 years of age (26%) compared to older children (14%).

Lennox–Gastaut syndrome

Data on monotherapy for seizures associated with Lennox–Gastaut syndrome are lacking.

Prevention of mood episodes in children (10–12 years) and adolescents (13–17 years)

In a multicenter, parallel-group, placebo-controlled, double-blind, randomized withdrawal study, the safety and efficacy of immediate-release (IR) lamotrigine tablets as adjunctive maintenance therapy in delaying mood episodes were evaluated in children and adolescents (10–17 years of age) of both sexes diagnosed with bipolar I disorder who had achieved remission or improvement with lamotrigine in combination with antipsychotic medications or other antidepressants. The primary efficacy analysis (time to a bipolar event) did not show a statistically significant result (p = 0.0717), indicating lack of efficacy. Additionally, safety analysis revealed a higher incidence of suicidal behavior in the lamotrigine group: 5% (4 patients) compared to 0 in the placebo group.

Pharmacokinetics

Absorption

In the absence of significant first-pass metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, peak plasma concentration is reached approximately within 2.5 hours. Time to 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. Toxic effects due to displacement from plasma proteins are unlikely.

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

Biotransformation

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

Lamotrigine induces its own metabolism to a minor, dose-dependent extent. However, the effect of lamotrigine on the pharmacokinetics of other anticonvulsants has not been established, and available data suggest that interactions between lamotrigine and other drugs metabolized by cytochrome P450 are unlikely.

Elimination

Theoretical plasma clearance in healthy volunteers is approximately 30 mL/min. Lamotrigine clearance occurs predominantly via metabolite formation, followed by urinary excretion of glucuronide-conjugated material. 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-dependent. The theoretical plasma half-life in healthy volunteers is approximately 33 hours (range 14 to 103 hours). In a study involving patients with Gilbert's syndrome, mean theoretical clearance in these subjects was 32% lower than in the control group, but within the range defined for the general patient population.

The elimination half-life of lamotrigine is significantly influenced by concomitant medications. The average half-life may decrease by approximately 14 hours when co-administered with glucuronidation inducers such as carbamazepine and phenytoin, or increase 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 showed linear dependence.

Special patient groups.

Children.

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

Children aged 2 to 26 months

In 143 patients aged 2 to 26 months with body weight 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 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 inhibitors or inducers. Inter-individual variability in clearance after 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 had some higher peak concentration values.

Elderly patients.

Pharmacokinetic analysis results from a study group including both elderly and younger epilepsy patients showed that lamotrigine clearance did not change to a clinically significant extent. After single doses, apparent clearance decreased by 12%, from 35 mL/min/kg in 20-year-old patients to 31 mL/min/kg in 70-year-old patients. The decrease after 48 weeks of treatment was 10%, from 41 mL/min in younger patients to 37 mL/min in elderly patients. 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 non-elderly adult patients receiving 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 on hemodialysis. Mean CL/F values were 0.42 mL/min/kg (chronic renal impairment), 0.33 mL/min/kg (inter-dialysis period), and 1.57 mL/min/kg (during hemodialysis), compared to 0.58 mL/min/kg in healthy subjects. Mean plasma elimination half-life was 42.9 hours (chronic renal impairment), 57.4 hours (inter-dialysis period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy subjects. During a four-hour hemodialysis session, lamotrigine levels decreased by approximately 20% (range 5.6 to 35.1%). For this patient group, initial lamotrigine dosing should be based on the patient's antiepileptic medication regimen; reduction of maintenance dose may be effective in patients with significant functional renal impairment.

Patients with hepatic impairment.

A single-dose pharmacokinetic study was conducted in patients with varying degrees of hepatic impairment and healthy volunteers. 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 subjects. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh class B) and by 75% in patients with severe hepatic impairment (Child-Pugh class C). Escalation and maintenance doses should be adjusted according to treatment response.

Preclinical safety data

In vitro studies showed that lamotrigine, at concentrations corresponding to therapeutic doses, exhibits class IB antiarrhythmic activity. It inhibits human cardiac sodium channels, demonstrating rapid onset and offset kinetics and strong voltage dependence, consistent with the action of other class IB antiarrhythmics. At therapeutic doses, lamotrigine did not slow ventricular conduction (QRS widening) in healthy volunteers in a thorough QT study. However, in patients with clinically significant structural or functional heart disease, lamotrigine may potentially slow ventricular conduction (QRS widening) and cause proarrhythmia (see section "Special precautions for use").

Clinical characteristics.

Indications.

Epilepsy.

Adults and children aged 13 years and older: monotherapy and adjunctive therapy of partial and generalized seizures, including tonic-clonic seizures, as well as seizures associated with Lennox–Gastaut syndrome. Lamotrigine may be used as adjunctive therapy, but in Lennox–Gastaut syndrome it may be initiated as the first antiepileptic drug (AED).

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

Monotherapy for typical absence seizures.

Bipolar disorders in adults.

Adults (aged 18 years and older).

For prevention of depressive episodes in patients with bipolar I disorder who are predominantly affected by depressive episodes.

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

Contraindications.

Hypersensitivity to lamotrigine or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients. It has been established that uridine 5’-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for lamotrigine metabolism. Therefore, drugs that induce or inhibit glucuronidation may affect the theoretical 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 oxidative 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 2. Specific dosage recommendations for these medicinal products are provided in the section "Method of administration and dosage." Table 1 lists medicinal products that have been shown to have little or no effect on lamotrigine concentration. Generally, no clinically relevant effect is expected when these medicinal products are used concomitantly. However, patients with epilepsy, whose condition is particularly sensitive to fluctuations in lamotrigine concentration, should be cautioned.

Table 2

Effect of other drugs on lamotrigine concentration

Drugs that increase lamotrigine concentration	Drugs that decrease lamotrigine concentration	Drugs 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 groups" in the "Dosage and administration" section. For dosing recommendations for women taking hormonal contraceptives, see the section "Hormonal contraceptives" in the "Special precautions for use" section.

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits glucuronidation of lamotrigine, slows the metabolism of lamotrigine and approximately doubles its mean elimination half-life. Patients receiving valproate concomitantly should follow an appropriate dosing regimen (see section "Dosage and administration").

Some AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 microsomal enzymes, induce UGT and accelerate the metabolism of lamotrigine. Patients receiving phenytoin, carbamazepine, phenobarbital, or primidone concomitantly should follow an appropriate dosing regimen (see section "Dosage and administration").

There have been reports of central nervous system adverse reactions, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These effects usually resolve upon reduction of the carbamazepine dose. Similar effects were observed in a study of lamotrigine and oxcarbazepine in adult volunteers, although dose reduction was not studied. It is known that 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 the metabolism of lamotrigine, and lamotrigine did not alter the metabolism of oxcarbazepine. Patients receiving oxcarbazepine concomitantly should follow the dosing regimen for lamotrigine adjunctive therapy without valproate and without inducers of glucuronidation (see section "Dosage and administration").

It has been reported that in a study involving 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 theoretical clearance of lamotrigine.

It is known that 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.

The steady-state plasma concentration of lamotrigine is not altered when administered concomitantly with pregabalin (200 mg three times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin.

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

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

Concomitant administration of lamotrigine with lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial seizures did not affect lamotrigine plasma concentration. Data from three placebo-controlled clinical studies showed that additional concomitant administration of perampanel with lamotrigine in patients with partial and primary generalized tonic-clonic seizures resulted in the highest studied dose of perampanel (12 mg/day) increasing lamotrigine clearance by less than 10%.

Although cases of altered plasma concentrations of other antiepileptic drugs have been described, available study data indicate that lamotrigine does not affect the plasma concentration of concomitant antiepileptic agents. In vitro study results showed that lamotrigine does not affect the protein binding of other antiepileptic drugs to serum proteins.

Interaction with other psychotropic agents

It is known that in a study of 20 healthy volunteers receiving 100 mg/day lamotrigine and 2 g anhydrous lithium gluconate administered twice daily for 6 days, the pharmacokinetics of lithium were unchanged. In a study involving 12 patients, multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and resulted only in a slight increase in the area under the concentration-time curve (AUC) of lamotrigine glucuronide. It is known that in a study involving adult volunteers, 15 mg of olanzapine reduced the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of lamotrigine by an average of 24% and 20%, respectively. Lamotrigine at a dose of 200 mg does not affect the pharmacokinetics of olanzapine.

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

It is known that in a clinical study involving 18 adult patients with bipolar disorder receiving lamotrigine (100–400 mg/day) and gradually increasing doses of aripiprazole from 10 mg/kg to 30 mg/kg over 7 days, followed by another 7 days, an approximately 10% decrease in Cmax and AUC of lamotrigine was observed.

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

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine

There is evidence that the combination "ethinylestradiol 30 µg/levonorgestrel 150 µg" increases the elimination of lamotrigine by approximately two-fold, resulting in a reduction of the AUC and Cmax of lamotrigine by an average of 52% and 39%, respectively. During the weekly break from contraceptive use (the so-called "pill-free week"), serum lamotrigine concentrations gradually increase, reaching levels approximately twice as high as those observed during concomitant use (see section "Special precautions for use"). During the titration phase, dose adjustments of lamotrigine are not required when hormonal contraceptives are used concomitantly. However, maintenance doses of lamotrigine should be increased or decreased each time a woman starts or stops taking hormonal contraceptives (see section "Dosage and administration").

Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives

According to study data in 16 female volunteers, lamotrigine at steady-state concentrations achieved with a 300 mg dose did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptive tablets. A consistent slight increase in the elimination of levonorgestrel was observed, resulting in a reduction of the AUC and Cmax of levonorgestrel by an average of 19% and 12%, respectively. Measurements of serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppression of ovarian hormonal activity in some women, although serum progesterone measurements revealed no hormonal signs of ovulation in any of the women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the slight increase in levonorgestrel elimination on ovarian ovulatory activity is unknown (see the subsection "General dosing recommendations for special patient groups" in the "Dosage and administration" section for dosing recommendations for women taking hormonal contraceptives and the subsection "Hormonal contraceptives" in the "Special precautions for use" section). It is known that the effect of lamotrigine at daily doses exceeding 300 mg has not been studied. It has been reported that studies of other hormonal contraceptives have also not been conducted.

Interaction with other medicinal products

It is known that in a study involving 10 male volunteers, rifampicin accelerated the clearance and shortened the elimination half-life of lamotrigine due to induction of hepatic enzymes responsible for glucuronidation.

For patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for lamotrigine with concomitant inducers of glucuronidation should be followed (see section "Dosage and administration").

According to study data in healthy volunteers, lopinavir/ritonavir reduced the plasma concentration of lamotrigine by approximately half by inducing glucuronidation.

For patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for concomitant use of lamotrigine with inducers of glucuronidation should be followed (see section "Dosage and administration").

Administration of atazanavir/ritonavir (300 mg/100 mg) reduces the AUC and Cmax of lamotrigine (100 mg dose) in plasma by an average of 32% and 6%, respectively. Patients already receiving lopinavir/ritonavir should follow the appropriate lamotrigine dosing regimen (see section "Dosage and administration").

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

In vitro data on the effect of lamotrigine on organic cation transporter 2 (OCT2) demonstrated that lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data indicate that lamotrigine is an inhibitor of OCT2 with an IC50 of 53.8 µM. Concomitant administration of lamotrigine with medicinal products that are substrates of OCT2 and eliminated by the kidneys (e.g., metformin, gabapentin, varenicline) may lead to increased plasma concentrations of these drugs. The clinical significance of this effect remains unclear, but lamotrigine should be used with caution in patients taking such medicinal products concomitantly.

Special precautions

Skin rashes

Skin rash 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 the drug have been reported. These include potentially life-threatening rashes such as Stevens−Johnson syndrome and toxic epidermal necrolysis, as well as drug reaction with eosinophilia and systemic symptoms (DRESS), also known as hypersensitivity syndrome (HSS) (see section "Adverse reactions").

In adults participating in clinical trials and treated according to current dosing recommendations, the incidence of severe skin rashes was approximately 1 in 500 patients with epilepsy. In about half of these cases, Stevens−Johnson syndrome was diagnosed (1 in 1000). In patients with bipolar disorder, the incidence of severe skin rashes was 1 in 1000.

The risk of serious skin rashes is higher in children than in 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, initial signs of skin rash may be mistaken for infection. Therefore, physicians should consider the possibility of an adverse drug reaction in any child who develops rash and fever during the first 8 weeks of therapy.

The overall risk of skin rash appears to be closely related to high initial doses of lamotrigine, exceeding the recommended dose escalation regimen (see section "Dosage and administration"), 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, as the incidence of mild rashes following lamotrigine treatment in this group was three times higher than in patients without such history.

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

All patients (adults and children) who develop a rash should be immediately evaluated by a physician and lamotrigine treatment should be discontinued immediately, unless the rash is clearly unrelated to lamotrigine. Reinitiating lamotrigine after prior discontinuation due to skin reactions is not recommended. If reinitiation is considered, the potential benefits must be weighed against the possible risks.

Lamotrigine must not be re-administered to patients who previously experienced Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS) following lamotrigine use.

Skin rashes have been reported as manifestations of DRESS syndrome, also known as hypersensitivity syndrome. This condition is associated with various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, liver and 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. Early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rash. In such cases, the patient should be immediately evaluated and lamotrigine discontinued unless another cause is identified.

In most cases, aseptic meningitis resolves after discontinuation of lamotrigine, but in some cases it may recur upon re-exposure. Reinitiating lamotrigine may lead to rapid recurrence of symptoms, often with greater severity. Lamotrigine must not be re-administered to patients in whom aseptic meningitis occurred during prior treatment.

Photosensitivity reactions associated with lamotrigine use have also been reported (see section "Adverse reactions"). In several cases, the reaction occurred with high doses (400 mg or more), dose increases, or rapid titration. If a patient presents with signs of photosensitivity (e.g., severe sunburn), and lamotrigine-related photosensitivity is suspected, discontinuation of treatment should be considered. If continued 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 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 treatment.

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 is identified.

Clinical worsening and suicide risk

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications, including epilepsy. Meta-analyses of antiepileptic drugs, including lamotrigine, have shown a small increased risk of suicidal thoughts 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 suicidal thoughts and behavior. Patients and caregivers should seek medical help immediately if such signs occur.

In patients with bipolar disorders, worsening of depressive symptoms and/or suicidal behavior may occur regardless of whether they are receiving treatment for bipolar disorder, including lamotrigine. Patients receiving lamotrigine for bipolar disorders should be closely monitored for clinical worsening (including emergence of new symptoms) and suicidality, particularly at the beginning of treatment or during dose adjustments.

Patients with a history of suicidal behavior or ideation, or those who exhibited marked suicidal ideation prior to treatment initiation, are at higher risk of developing suicidal thoughts or attempts and require careful monitoring during treatment.

If clinical worsening (including new symptoms) and/or emergence of suicidal thoughts/behavior occurs, particularly if symptoms are severe, sudden in onset, or not part of the patient's pre-existing condition, consideration should be given to modifying the therapeutic regimen, including discontinuation of the drug.

Hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine efficacy

The combination of ethinylestradiol 30 µg/levonorgestrel 150 µg 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 may result in loss of seizure control. To achieve optimal therapeutic effect, in most cases the maintenance dose of lamotrigine needs to be increased (by titration), typically by two-fold. After discontinuation of hormonal contraceptives, lamotrigine clearance may double again. Increased lamotrigine concentrations may provoke dose-dependent adverse reactions; therefore, patients should be closely monitored by a physician. In women who are not yet using lamotrigine-inducing agents and who are using hormonal contraceptives with a weekly break between cycles (so-called "pill-free week"), a gradual, temporary increase in lamotrigine levels may occur during the pill-free week. This increase may provoke dose-dependent adverse reactions; therefore, consideration should be given to using contraception without a weekly break (e.g., continuous hormonal contraception or non-hormonal methods).

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

Effect of lamotrigine on hormonal contraceptive efficacy

A drug interaction study in 16 healthy volunteers receiving lamotrigine and the hormonal contraceptive combination ethinylestradiol 30 µg/levonorgestrel 150 µg showed a slight increase in levonorgestrel clearance and changes in serum levels of follicle-stimulating hormone and luteinizing hormone (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 excluded that in some patients receiving 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; therefore, long-term use of lamotrigine may affect folate metabolism. However, during long-term lamotrigine treatment, no significant changes have been observed 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 may occur. The drug should be used with caution in patients with renal impairment.

Patients taking other lamotrigine-containing products

Lamotrigine should not be taken by patients who are already being treated with any other lamotrigine-containing product without consulting a physician.

Brugada-type ECG

Arrhythmogenic ST-T abnormalities and Brugada-type ECG patterns have been observed in patients receiving lamotrigine. In vitro studies have shown that lamotrigine at concentrations corresponding to therapeutic doses may slow ventricular conduction (with QRS widening) and induce proarrhythmia in patients with heart disease. Lamotrigine acts as a weak class IB antiarrhythmic agent, which may pose potential risks of severe or fatal cardiac events. Concomitant use of other sodium channel blockers may increase these risks. A thorough QT-interval assessment in healthy volunteers showed that lamotrigine at therapeutic doses up to 400 mg/day did not slow ventricular conduction (QRS widening) or prolong the QT interval. The use of lamotrigine 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, should be carefully considered. If lamotrigine use is clinically justified in such patients, consultation with a cardiologist is recommended before initiating treatment.

Development in children

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

Epilepsy

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

Published data indicate that severe epileptic seizures, including status epilepticus, may lead to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes with fatal outcome. Similar events may occur during lamotrigine treatment. A significant clinical worsening in seizure frequency, rather than improvement, may occur. 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 response to combination therapy with enzyme-inducing antiepileptic drugs is weaker than to combination therapy 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.

Bipolar disorders

Children and adolescents (under 18 years of age)

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

The medicinal product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Risk associated with use of antiepileptic drugs in general

Women of childbearing potential require specialist counseling. When pregnancy is planned, antiepileptic therapy should be appropriately reviewed. If a patient is already receiving antiepileptic drugs, abrupt discontinuation should be avoided, as this may lead to seizure recurrence, which may have serious consequences for both the woman and the fetus. Monotherapy should be preferred whenever possible, as combination antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the antiepileptic drugs used.

Risk associated with use of lamotrigine

Pregnancy

A large amount of data from pregnant women receiving lamotrigine monotherapy during the first trimester of pregnancy (over 8700 cases) does not indicate a significant increase in the risk of major congenital malformations, including cleft lip and palate. Animal studies have shown embryofetal toxicity.

If lamotrigine therapy is considered necessary during pregnancy, it is recommended to use the lowest possible therapeutic dose.

Lamotrigine has a weak inhibitory effect on dihydrofolate reductase and, therefore, theoretically may increase the risk of embryonic developmental abnormalities by reducing folic acid levels (see section "Special precautions"). Therefore, the need for folic acid supplementation should be considered during preconception planning and early pregnancy.

Physiological changes during pregnancy may affect lamotrigine levels and/or its therapeutic effect. Cases of decreased lamotrigine levels during pregnancy have been reported, potentially increasing the risk of loss of seizure control. After delivery, lamotrigine levels may rapidly increase, with a potential risk of dose-dependent adverse reactions. Therefore, serum lamotrigine levels should be monitored before, during, and after pregnancy. If necessary, the lamotrigine dose should be adjusted to maintain serum concentrations at pre-pregnancy levels or adapted according to clinical status. Additionally, monitoring for dose-dependent adverse effects is required after delivery.

Breastfeeding period

Lamotrigine is excreted in breast milk in variable concentrations. The infant's lamotrigine level may reach up to 50% of the maternal level. Therefore, in some breastfed infants, serum lamotrigine levels may reach concentrations associated with pharmacological effects. Consequently, the benefit of breastfeeding should be weighed against the potential risk of adverse reactions in the infant. If a woman receiving lamotrigine treatment decides to breastfeed, the infant should be closely monitored for adverse effects 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

Available data indicate that lamotrigine's effects on visual coordination, eye movements, body control, and subjective sedation are not different from placebo. However, neurological adverse reactions such as dizziness and diplopia have been reported in clinical trials with lamotrigine. Therefore, patients should first assess their individual response to lamotrigine before driving or operating machinery. Since individual responses to antiepileptic drugs vary, patients should consult their physician regarding specific recommendations for driving in their case.

Method of Administration and Dosage.

Lamotrin 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.

When Lamotrin cannot be appropriately dosed for children, lamotrigine in another pharmaceutical form and appropriate dosage strength should be used.

Reinitiation of Treatment.

Physicians should evaluate the need to increase the dose to maintenance levels when resuming lamotrigine treatment in patients who have discontinued lamotrigine for any reason, as the risk of developing serious rashes 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 carefully the dose escalation regimen to maintenance dose should be considered. When the interval since discontinuation of lamotrigine exceeds five times the elimination half-life (see section "Pharmacokinetics"), lamotrigine should be reinitiated and the dose increased to the maintenance dose according to the established regimen.

Reinitiating lamotrigine treatment is not recommended if treatment was previously discontinued due to a rash caused by prior lamotrigine therapy. In such cases, the decision to re-prescribe the drug should carefully weigh the expected benefits against the potential risks of treatment.

Epilepsy.

Recommended dose escalation regimens and maintenance doses for adults and children aged 13 years and older (Table 3), as well as for children aged 2 to 12 years (Table 4), are provided below. To minimize the risk of rash, the initial dose and the rate of subsequent dose escalation should not be exceeded (see section "Special Warnings and Precautions for Use").

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

Table 3

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

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy:	25 mg/day (single dose)	50 mg/day (single dose)	100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 50 – 100 mg every one or two weeks until optimal response is achieved. Some patients required a dose of 500 mg/day to achieve the desired response.
Adjunctive therapy with valproate (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 other concomitant medicinal products	12.5 mg/day (take 25 mg every other day)	25 mg/day (single dose)	100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 25 – 50 mg every one or two 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: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir	50 mg/day (single dose)	100 mg/day (two doses)	200 – 400 mg/day (two doses). To reach the maintenance dose, increase by no more than 100 mg every one or two 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 have a significant inhibitory or inductive effect on lamotrigine glucuronidation	25 mg/day (single dose)	50 mg/day (single dose)	100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 50 – 100 mg every one or two weeks until optimal response is achieved.
Patients taking medicinal products with unknown effect on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction") should be treated according to the regimen recommended for concomitant use of lamotrigine and valproate.

Table 4

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

Treatment regimen	Weeks 1 + 2		Weeks 3 + 4		Usual maintenance dose
Monotherapy of typical absence seizures	0.3 mg/kg/day (once or twice daily)		0.6 mg/kg/day (once or twice daily)		1 – 15 mg/kg/day (once or twice daily). To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose – 200 mg/day.
Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interactions")
This treatment regimen involves the use of valproate, regardless of the use of other concomitant medicinal products		0.15 mg/kg/day* (once daily)		0.3 mg/kg/day (once daily)		1 – 5 mg/kg/day (once or twice daily). To reach the maintenance dose, it should be increased by no more than 0.3 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose – 200 mg/day.
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 involve the use of valproate, but includes the 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 (once or twice daily). To reach the maintenance dose, it should be increased by no more than 1.2 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose – 400 mg/day.
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 significantly inhibit or induce lamotrigine glucuronidation		0.3 mg/kg/day (once or twice daily)		0.6 mg/kg/day (once or twice daily)		1 – 10 mg/kg/day (once or twice daily) To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose – 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 interactions"), 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 cannot be achieved with whole tablets, the dose should be rounded to the nearest whole tablet.

To maintain the therapeutic dose, the child's body weight should be monitored and the dose adjusted as body weight changes. Patients aged two to six 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, and lamotrigine monotherapy continued.

Children under 2 years of age.

There is insufficient information on the efficacy and safety of using lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years; therefore, the medicinal product is not recommended for use in this age group. Data on the use of lamotrigine in children under 1 month of age are lacking. Lamotrigine is not recommended for use in children under 2 years of age. If a clinical decision to initiate lamotrigine therapy is made, see section "Dosage and Administration" and "Pharmacological Properties".

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 lamotrigine dose to the maintenance stabilizing dose over six weeks (Table 5), after which other psychotropic and/or antiepileptic drugs may be discontinued if clinically appropriate (Table 6). Dose adjustment regimens when additional psychotropic drugs and/or AEDs are co-administered are provided in Table 7. Due to the risk of rash, the initial dose and rate of subsequent dose escalation must not be exceeded (see section "Dosage and Administration").

Table 5

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 + 2	Weeks 3 + 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 interaction")
This treatment regimen involves 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 interaction")
This treatment regimen involves the use of valproate, regardless of concomitant use of other 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 interaction")
This treatment regimen does not involve the use of valproate, but includes use of 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 may be increased in week 7 to achieve optimal response (twice daily)
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 dose escalation regimen recommended for concomitant use of lamotrigine with valproate.

• The maintenance dose may be adjusted depending on the clinical response.

Table 6

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

After achieving 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, double the maintenance dose, without increasing by more than 100 mg/week	100 mg/day		200 mg/day	Maintain dose of 200 mg/day (two doses)
	200 mg/day		300 mg/day	400 mg/day	Maintain dose of 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 when discontinuing 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.

* The dose may be increased as necessary up to 400 mg/day.

Table 7

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 dosage adjustments 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 (starting with add-on therapy)	Week 2	Week 3 and onwards
Add-on valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interactions") depending on the initial dose of lamotrigine
This treatment regimen should be used when adding valproate regardless of the use of any concomitant medicinal products	200 mg/day		100 mg/day	Maintain dose of 100 mg/day
	300 mg/day		150 mg/day	Maintain dose of 150 mg/day
	400 mg/day		200 mg/day	Maintain dose of 200 mg/day
Add-on inducers of lamotrigine glucuronidation in patients not taking valproate (see section "Interaction with other medicinal products and other forms of interactions"), depending on the initial dose of lamotrigine:
This treatment regimen should be used when adding the following medicinal products 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 medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions")
This treatment regimen should be used when adding other medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation		Maintain the target dose achieved during titration (200 mg/day; dose range 100–400 mg/day)
In patients taking medicinal products with unknown effect on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interactions"), the treatment regimen recommended for concomitant use of lamotrigine and valproate should be applied.

Discontinuation of lamotrigine in patients with bipolar disorder.

According to clinical studies, there was no increase in the frequency, severity, or type of adverse reactions after abrupt discontinuation of the drug compared to placebo. Therefore, the medication may be stopped immediately without gradual dose reduction.

Children (under 18 years of age).

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

General dosing recommendations for special patient groups.

Women using hormonal contraceptives.

It is known that the use of the combination ethinylestradiol/levonorgestrel (30 mcg/150 mcg) increases lamotrigine clearance approximately twofold, leading to reduced lamotrigine levels. After titration, higher maintenance doses of lamotrigine (almost twice as high) may be required to achieve optimal therapeutic response. During the week when the drug is not taken, a twofold increase in lamotrigine levels has been observed. Dose-dependent adverse reactions cannot be excluded. Therefore, consideration should be given to using contraception that does not include a pill-free week as first-line therapy (e.g., continuous hormonal contraceptives or non-hormonal methods; see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

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 generally need to be doubled. It is recommended that, starting from the initiation of hormonal contraceptives, the lamotrigine dose be increased by 50 to 100 mg/day each week according to individual clinical response to treatment. Dose increases should not exceed this level unless clinically indicated.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. Dose adjustments should be made as necessary. In women using hormonal contraceptives that include one week of inactive treatment (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 hormonal contraceptives or non-hormonal methods; see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation. The maintenance dose of lamotrigine will generally need to be reduced to 50% (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). It is recommended that the daily dose of lamotrigine be gradually reduced by 50 to 100 mg each week (not more than 25% of the total dose per week) over 3 weeks, unless otherwise indicated by individual clinical response.

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. Dose adjustments should be made as necessary. In women using hormonal contraceptives that include one week of inactive treatment (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. 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 using hormonal contraceptives.

Dose escalation should follow the standard dosage 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.

Use in combination with atazanavir/ritonavir.

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

In patients already receiving maintenance doses of Lamotrigine and not taking inducers of lamotrigine glucuronidation, the dose of Lamotrigine may need to be increased when atazanavir/ritonavir is added, or decreased when atazanavir/ritonavir is discontinued. Monitoring of lamotrigine plasma levels 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 lopinavir/ritonavir to therapy is not required.

In patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation, dose increases of lamotrigine may be required when lopinavir/ritonavir is added, and dose reductions when lopinavir/ritonavir is discontinued. Monitoring of lamotrigine plasma levels 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 from those in patients under 65 years of age (see section "Pharmacokinetics").

Hepatic impairment.

The initial dose, dose escalation, and maintenance dose should be reduced by 50% in patients with moderate (Child-Pugh class B) and by 75% in patients with severe (Child-Pugh class C) hepatic impairment. Dose escalation and maintenance dose should be adjusted according to clinical effect (see section "Pharmacokinetics").

Renal impairment.

Caution should be exercised when prescribing lamotrigine to patients with renal impairment. In 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 section "Special precautions for use").

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 this age group.

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

Overdose.

Symptoms and signs

Cases of acute overdose (with doses 10–20 times higher than the maximum therapeutic doses) have been reported, including fatal cases. Symptoms of overdose included ataxia, nystagmus, impaired consciousness, generalized seizures, and coma. Overdose has also been associated with QRS complex widening (intraventricular conduction delay) and QT interval prolongation. QRS complex widening exceeding 100 msec may be associated with more severe toxicity.

Treatment: The patient should be hospitalized in an intensive care unit for appropriate symptomatic and supportive treatment. Therapy aimed at reducing absorption (activated charcoal) should be administered if necessary. Further treatment should be guided by clinical findings, with attention to potential effects on cardiac conduction (see section "Special precautions for use"). Intravenous lipid therapy may be considered for cardiotoxicity unresponsive to sodium bicarbonate. There is no experience with hemodialysis for the treatment of overdose. In six volunteers with renal impairment, 20% of lamotrigine was eliminated during a 4-hour hemodialysis session.

Adverse reactions.

Adverse reactions for indications in epilepsy and bipolar disorder, based on available data from controlled clinical trials and other clinical experience, are listed in the table 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 rashes⁵†§; uncommon – alopecia, photosensitivity reaction; 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 – hematological abnormalities¹ (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), hemophagocytic lymphohistiocytosis (see section "Special precautions for use"); frequency not known – lymphadenopathy¹, pseudolymphoma.

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

Psychiatric disorders: common – aggression, irritability; very rare – tics (motor and/or vocal), 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 precautions for use"); very rare – restlessness, 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†, and diarrhea†, dry mouth§.

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

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

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

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

Description of selected adverse reactions

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

2 Skin rash has also been reported as part of a syndrome also known as DRESS. This condition was accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, and liver and kidney function impairment. The syndrome may vary in severity and, in isolated 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 immediately evaluated and, in the absence of other causes, lamotrigine should be discontinued.

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

It has been reported 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 in 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 often occurring within eight weeks of starting treatment and resolving after discontinuation of lamotrigine (see section "Special 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 discontinuation of lamotrigine, some patients may have irreversible scarring; in rare cases, these syndromes have led to death (see section "Special 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.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1, 3, or 6 blisters in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

LLC "Pharma Start".

Manufacturer's address.

8 Vatslava Havela Boulevard, Kyiv, Ukraine, 03124.