Lamotrigine

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMOTRIN® (LAMOTRIN)

Composition:

Active substance: lamotrigine;

One dispersible tablet contains 25 mg, 50 mg, or 100 mg of lamotrigine;

Excipients: heavy magnesium carbonate, microcrystalline cellulose, povidone, low-substituted hydroxypropylcellulose, sodium saccharin, crospovidone, microcrystalline cellulose and guar gum, flavoring agent "Black Currant" (Silarom 1202002208), magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties:

25 mg dispersible tablets: white or almost white, round flat cylindrical tablets with beveled edges, uncoated, marked with "25", tablet diameter 5.5 mm;

50 mg dispersible tablets: white or almost white, round flat cylindrical tablets with beveled edges, uncoated, marked with "50", tablet diameter 7 mm;

100 mg dispersible tablets: white or almost white, round flat cylindrical tablets with beveled edges, uncoated, marked with "100", tablet diameter 9 mm.

Pharmacotherapeutic group. Antiepileptic agents. Lamotrigine.

ATC code N03A X09.

Pharmacological Properties

Mechanism of Action

Pharmacological studies indicate that lamotrigine is a use-dependent and voltage-dependent blocker of voltage-gated sodium channels. It suppresses sustained neuronal repetitive firing and inhibits the release of glutamate (a neurotransmitter playing a key role in the development 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.

Pharmacodynamics

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

In another study, a single oral dose of 600 mg of carbamazepine significantly impaired fine visuomotor coordination, eye movements, and body balance, and increased heart rate. In contrast, the effects of lamotrigine at doses of 150 mg and 300 mg did not differ from those of 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 for the prevention of mood episodes in patients with bipolar I disorder 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 I disorder 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 of 0.8 to 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 with a design similar to SCAB2003 but used a more flexible dosing regimen of lamotrigine (100 to 400 mg/day) and included patients with bipolar I disorder who had a current or recent manic episode. Results are presented in Table 1.

Summary of Results from Efficacy Studies of Lamotrigine in the Prevention of Mood Episodes in Patients with Bipolar I Disorder

Table 1

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

The 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 titration regimen recommended for children aged 2 to 12 years. The lowest available lamotrigine dose is contained in 2 mg tablets. Therefore, in some cases, the standard dosing regimen during the titration phase was appropriately adjusted (e.g., administration of a 2 mg tablet every other day when the calculated dose was less than 2 mg). Serum concentrations were measured at the end of week 2 of the titration phase and during the maintenance phase, with dose reduction or no increase implemented upon reaching concentrations exceeding 0.41 mcg/mL – predicted concentrations in adult patients at this time point of therapy. By the end of week 2, some patients required a 90% dose reduction. Thirty-eight patients with therapeutic response (seizure frequency reduction > 40%) were randomized into two groups: placebo or continued lamotrigine treatment. Treatment failure was observed in 84% of patients in the placebo group (16 of 19) and in 54% of patients in the lamotrigine group (11 of 19). The difference was not statistically significant: 26.3%, 95% CI –2.6% < > 50.2%, p = 0.07.

Overall, up to 72 weeks, 256 children aged 1 to 24 months received lamotrigine at doses ranging from 1 to 15 mg/kg/day. The safety profile of lamotrigine in this age group was similar to that in older children, except for seizure worsening (≥ 50%), which was observed 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 lamotrigine (lamotrigine IR) tablets as adjunctive maintenance therapy for delaying mood episodes were evaluated in children and adolescents (10–17 years) 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 bipolar event) did not show a statistically significant result (p = 0.0717), indicating lack of efficacy. Additionally, safety analysis revealed an increased 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 presystemic metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration is reached approximately 2.5 hours post-dose. Time to maximum concentration is slightly prolonged when the drug is administered after food, but this does not affect the extent of absorption. There are substantial interindividual variations in steady-state maximum concentrations, although individual patient values 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 only 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 via 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, the average theoretical clearance in these subjects was 32% lower than in the control group but remained within the range defined for 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 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, lamotrigine pharmacokinetics demonstrated linear behavior.

Special patient populations

Children

Clearance, normalized to 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. When co-administered with enzyme inducers such as carbamazepine and phenytoin, the half-life averages approximately 7 hours, increasing to 45–50 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 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 average elimination half-life in children under 26 months was 23 hours with enzyme-inducing therapy, 136 hours with concomitant valproate, and 38 hours without concomitant enzyme-inducing or enzyme-inhibiting drugs. Interindividual 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 results from one study in patients with epilepsy did not show clinically significant differences in lamotrigine clearance between elderly and younger patients. After single doses, theoretical clearance decreased by 12%: from 35 mL/min/kg in patients aged 20 years to 31 mL/min/kg in patients aged 70 years. After 48 weeks of treatment, the reduction was 10%: from 41 mL/min in younger patients to 37 mL/min in elderly patients. Lamotrigine pharmacokinetics were also 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 (0.31–0.65 mL/min/kg) observed in 9 studies involving non-elderly adult patients after single doses of 30 to 450 mg.

Patients with renal impairment

Twelve volunteers with chronic renal impairment and six hemodialysis patients received a single 100 mg dose of lamotrigine. Mean clearance was 0.42 mL/min/kg (in chronic renal impairment), 0.33 mL/min/kg (between hemodialysis sessions), and 1.57 mL/min/kg (during hemodialysis), compared to 0.58 mL/min/kg in healthy volunteers. Mean plasma elimination half-life was 42.9 hours (in chronic renal impairment), 57.4 hours (between hemodialysis sessions), 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's lamotrigine was removed during a four-hour hemodialysis session. Initial doses of lamotrigine for this patient group should be determined based on concomitantly administered medications. Reduction of maintenance dose may be effective in patients with significant renal impairment.

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. In patients with Child-Pugh class A, B, and C hepatic impairment, mean theoretical lamotrigine clearance was 0.31 mL/min/kg, 0.24 mL/min/kg, and 0.10 mL/min/kg, respectively, compared to 0.34 mL/min/kg in control volunteers. Initial, titrated, and maintenance doses should be reduced in patients with moderate to severe hepatic impairment.

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 warnings and precautions for use").

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. Lamictal® is indicated as adjunctive therapy, but in Lennox-Gastaut syndrome it may be used as an 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 are predominantly affected by depressive episodes.

Lamictal® is not indicated for acute treatment of manic or depressive episodes.

Contraindications.

Lamictal® 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 adult patients.

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 lamotrigine clearance. Enzyme inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate activity, which are known to induce glucuronosyltransferase, 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 modest and not of major clinical consequence.

Medicinal products that have been shown to have a clinically significant 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." In addition, this table lists medicinal products that have been shown to have little or no effect on lamotrigine concentration. Generally, concomitant administration of such products is not expected to have any clinical impact. However, patients with epilepsy, whose condition is particularly sensitive to fluctuations in lamotrigine concentration, should be cautioned.

Effect of medicinal products on lamotrigine concentration

Table 2

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

*For detailed dosing information, see the section "General Dosing Recommendations for Special Patient Populations" in the "Dosage and Administration" section. For dosing recommendations in women taking hormonal contraceptives, see the "Hormonal Contraceptives" subsection in the "Special Warnings and Precautions for Use" section.

Interaction with antiepileptic drugs (AEDs) (see section "Dosage and Administration").

Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases its mean elimination half-life approximately two-fold. Patients receiving valproate concomitantly require an appropriate dosing regimen (see section "Dosage and Administration").

Some AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 enzymes, also induce UGT and accelerate lamotrigine metabolism. Patients receiving phenytoin, carbamazepine, phenobarbital, or primidone concomitantly require 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 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.

In studies involving healthy adult volunteers receiving a 200 mg dose of lamotrigine and a 1200 mg dose of oxcarbazepine, oxcarbazepine was found not to alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism. 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").

In studies involving 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 theoretical clearance 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 alter 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%.

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 the pharmacokinetics of lamotrigine.

Concomitant administration of lacosamide (200, 400, or 600 mg/day) did not affect lamotrigine plasma concentration in placebo-controlled clinical trials in patients with partial seizures. In a pooled analysis of data from three placebo-controlled clinical studies 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 antiepileptic drugs have been described, controlled studies have shown that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic agents. In vitro study results demonstrated that lamotrigine does not displace other antiepileptic drugs from their plasma protein binding sites.

Interaction with other psychotropic agents (see section "Dosage and Administration")

When 100 mg/day lamotrigine and 2 g of anhydrous lithium gluconate administered twice daily for 6 days were coadministered to 20 healthy volunteers, 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.

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

Multiple oral doses of lamotrigine at 400 mg/day did not cause clinically significant effects on the pharmacokinetics of a single 2 mg dose of risperidone in a study involving 14 healthy adult volunteers. When 2 mg risperidone was administered concomitantly 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), the dose of aripiprazole was increased from 10 mg/day to 30 mg/day over 7 days and maintained for another 7 days. Overall, there was approximately a 10% decrease in Cmax and AUC of lamotrigine.

In vitro experiments showed that the presence of amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam may minimally slow the formation of the primary lamotrigine metabolite, 2-N-glucuronide. These experiments also demonstrated that lamotrigine metabolism is not inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone. Data from studies on 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 lamotrigine pharmacokinetics

It is known that in a study involving 16 female volunteers receiving lamotrigine tablets together with a combination of 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 concentration gradually increased, reaching on average approximately twice the level observed during concomitant administration (see "Special Warnings and Precautions for Use" section). Dose adjustments of lamotrigine during the titration phase are not required when hormonal contraceptives are initiated. However, maintenance doses of lamotrigine should be increased or decreased each time a patient 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 levonorgestrel clearance was observed, resulting in a mean reduction in AUC and Cmax of levonorgestrel by 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol levels 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 the "General Dosing Recommendations for Special Patient Populations" subsection in the "Special Warnings and Precautions for Use" section regarding dosing in women taking hormonal contraceptives, and the "Hormonal Contraceptives" subsection in the "Special Warnings and Precautions for Use" section). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Other hormonal contraceptives have also not been investigated.

Interaction with other medicinal products

It is known that in studies involving 10 male volunteers receiving rifampicin, lamotrigine clearance increased and its half-life decreased due to induction of hepatic enzymes responsible for glucuronidation. Patients receiving concomitant therapy with rifampicin should follow the treatment regimen recommended for lamotrigine use with inducers of glucuronidation (see section "Dosage and Administration").

According to studies in healthy volunteers, lopinavir/ritonavir reduces lamotrigine plasma concentration by approximately two-fold via induction of glucuronidation. Patients already taking lopinavir/ritonavir should follow the treatment regimen recommended for use of lamotrigine with inducers of glucuronidation (see section "Dosage and Administration").

According to studies in healthy volunteers, administration of atazanavir/ritonavir (300 mg/100 mg) reduced AUC and Cmax of lamotrigine (100 mg dose) in plasma by an average of 32% and 6%, respectively. Patients taking atazanavir/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 AUC and Cmin of lamotrigine in plasma by an average of 20% and 25%, respectively.

In vitro studies demonstrated that only lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT2) at potentially clinically relevant concentrations. These data indicate that lamotrigine is an inhibitor of OCT2 with an IC50 value of 53.8 µM. Concomitant administration of lamotrigine with medicinal products that are OCT2 substrates and renally excreted (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

Special warnings

Skin rashes

Skin reactions in the form of rashes 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 have been reported, requiring hospitalization and discontinuation of lamotrigine. 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 (HSS) (see section "Adverse reactions").

Lamotrigine must not be re-administered to patients who previously experienced Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS following lamotrigine use.

In adults participating in clinical trials following current 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).

The incidence of severe skin rashes in patients with bipolar disorder is 1 in 1000.

Children have a higher risk of developing serious skin rashes compared to adults.

According to studies using lamotrigine, 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 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 used with caution in patients with a history of allergy or rash to other antiepileptic drugs, 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 Stevens-Johnson syndrome / toxic epidermal necrolysis when taking lamotrigine. If a patient tests positive for the HLA-B*1502 allele, the decision to use lamotrigine should be carefully considered.

If a skin rash develops, the patient (adult or child) should be examined immediately, and lamotrigine therapy should be discontinued if there is no evidence that the rash is unrelated to the drug. Reinitiating lamotrigine is not recommended in cases where prior treatment was discontinued due to rash. In such cases, the potential benefits of treatment must be weighed against the possible risks when considering re-administration.

Skin rashes have also been reported as part 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. Importantly, early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rashes. If such symptoms occur, the patient should be examined immediately, and lamotrigine should be discontinued if no other cause is identified.

In most cases, aseptic meningitis resolves after discontinuation of the drug, but it may recur upon re-exposure to lamotrigine. Re-administration of lamotrigine often leads to rapid recurrence of symptoms, which may be more severe. Lamotrigine must not be re-administered to patients in whom it was previously discontinued due to aseptic meningitis.

Photosensitivity reactions associated with lamotrigine use have also been reported (see section "Adverse reactions"). In several cases, such reactions 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), 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)

HLH has 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 levels, hypertriglyceridemia, and liver dysfunction and coagulopathy. Symptoms typically develop within 4 weeks of starting treatment. HLH can be life-threatening.

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

Patients developing 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

In patients treated for various conditions, including epilepsy, antiepileptic drugs have been associated with suicidal thoughts and behavior. Data from a meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, demonstrated 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 signs of suicidal thoughts and behavior. If such signs occur, patients and caregivers should seek immediate medical help.

In patients with bipolar disorder, worsening of depressive symptoms and/or suicidal behavior may occur regardless of whether they are receiving treatment for bipolar disorder, including lamotrigine.

Patients treated with lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including emergence of new symptoms) and suicidal ideation, particularly at the beginning of treatment or during dosage adjustments. Patients with a history of suicidal behavior or ideation, younger patients, and those who demonstrated significant suicidal ideation prior to treatment initiation may be 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, especially 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 by approximately two-fold, thereby reducing lamotrigine levels (see section "Interaction with other medicinal products and other forms of interaction"). Reduced lamotrigine levels may lead to loss of seizure control. To achieve maximum therapeutic effect, in most cases the maintenance dose of lamotrigine needs to be increased (via titration), often by two-fold. After discontinuation of hormonal contraceptives, lamotrigine clearance may double. Increased lamotrigine concentrations may provoke dose-dependent adverse reactions; therefore, patients should be closely monitored by a physician. In women not already taking lamotrigine-inducing drugs and who are using hormonal contraceptives with a weekly break between cycles, a gradual temporary increase in lamotrigine levels may occur during the weekly break. 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).

Interactions between lamotrigine and other oral contraceptives or hormone replacement therapies 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 levels of follicle-stimulating hormone and luteinizing hormone 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, these changes may lead to reduced contraceptive efficacy when lamotrigine is taken concomitantly with hormonal contraceptives. Therefore, patients should promptly report changes in their menstrual cycle, such as sudden breakthrough bleeding.

Effect of lamotrigine on substrates of organic cation transporter 2 (OCT2)

Lamotrigine is an inhibitor of renal tubular secretion via organic cation transporter proteins (see section "Interaction with other medicinal products and other forms of interaction"). This may lead to increased plasma levels of certain drugs primarily excreted via this pathway. Therefore, co-administration of lamotrigine with OCT2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase; therefore, long-term use may potentially affect folate metabolism. However, during long-term lamotrigine therapy, no significant changes were observed in hemoglobin levels, mean corpuscular volume, serum and erythrocyte folate concentrations over one year, or erythrocyte folate concentrations over five 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. Therefore, caution is required when treating patients with renal impairment.

Patients taking other lamotrigine-containing products

Lamotrigine should not be prescribed to patients already receiving any other lamotrigine-containing medication without prior physician consultation.

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.

Brugada syndrome – ECG type and other cardiac rhythm disorders and conduction abnormalities

Arrhythmogenic ST-T changes and typical Brugada syndrome ECG patterns have been observed in patients taking lamotrigine. In vitro studies have shown that lamotrigine at concentrations corresponding to therapeutic doses may slow ventricular conduction (with QRS complex widening) and may provoke proarrhythmic effects 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. In a thorough QT interval study in healthy volunteers, lamotrigine at therapeutic doses up to 400 mg/day did not slow ventricular conduction (no QRS widening) and did not 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.

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 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 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 control of another. Lamotrigine treatment may exacerbate myoclonic seizures.

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

Not all children with typical absence seizures respond to treatment.

Bipolar disorders

Children (under 18 years)

Antidepressant treatment has been associated with increased risk of suicidal thoughts and behavior in children and adolescents (under 18 years) with major depressive disorders and other psychiatric disorders.

Use during pregnancy or breastfeeding

General risk associated with antiepileptic drug use

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 and serious consequences for both mother and fetus. Monotherapy is preferred, as combination antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the antiepileptic drugs used.

Risk associated with lamotrigine use

Pregnancy

Large data from pregnant women receiving lamotrigine monotherapy during the first trimester (over 8,700 cases) do 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 effective dose.

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

Physiological changes during pregnancy may affect lamotrigine levels and/or its therapeutic effect. Reports indicate decreased lamotrigine plasma concentrations during pregnancy, with a potential 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 concentrations should be monitored before, during, and after pregnancy and shortly after delivery. Dose adjustments should be made as necessary to maintain serum lamotrigine concentrations at the same level as before pregnancy or according to clinical response. Additionally, patients should be monitored for dose-dependent adverse effects after delivery.

Breastfeeding period

Lamotrigine has been reported to pass into breast milk at various concentrations, resulting in infant lamotrigine levels reaching approximately 50% of maternal serum concentrations. Therefore, in some breastfed infants, serum lamotrigine levels may reach levels associated with pharmacological effects.

The potential benefit of breastfeeding should be weighed against the possible risk of adverse effects in the infant. If a woman receiving lamotrigine therapy 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 influence reaction speed when driving or operating machinery

Data from two studies in volunteers showed that lamotrigine had no effect on visual-motor coordination, eye movement, body control, or subjective sedation compared to placebo. However, in clinical trials, neurological adverse reactions such as dizziness and diplopia have been reported with lamotrigine use. Therefore, patients should first assess their individual response to lamotrigine before driving or operating machinery. Since individual responses to antiepileptic drugs may vary, patients should consult their physician regarding their ability to drive in such cases.

Method of administration and dosage.

Lamotrigine dispersible tablets may be chewed, dissolved in a small amount of water (at least sufficient to cover the entire tablet), or swallowed whole with a small amount of water. There is no need to attempt dividing the chewable tablet for administration.

If the required lamotrigine dose (e.g., for treating 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.

Reinitiation of treatment.

Physicians should assess the need for dose escalation to maintenance levels when resuming lamotrigine in patients who have discontinued lamotrigine 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 in escalating the dose to the maintenance level. If the interval since discontinuation of lamotrigine exceeds five half-lives, the dose of Lamotrin® should be increased to the maintenance dose according to the established regimen.

Reinitiating lamotrigine is not recommended in patients who previously discontinued due to a rash related to prior lamotrigine therapy, except when the potential benefit clearly outweighs the risk.

Epilepsy.

Recommended dosage escalation regimens and maintenance doses for adults and children aged 13 years and older (see Table 3), as well as for children aged 2 to 12 years (see Table 4), 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 concomitant antiepileptic drugs (AEDs) are discontinued or other AEDs/medications are added to regimens containing lamotrigine, the potential impact on lamotrigine pharmacokinetics should be considered (see section "Interaction with other medicinal products and other forms of interaction").

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

Table 3

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 (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction")
This treatment regimen applies when valproate is used, regardless of the use 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.

Additional therapy without the use of valproate and with the use of inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction")
This treatment regimen does not include the use of valproate, but includes the use of: 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, it should be increased 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.
Additional therapy without the use of valproate and inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction")
This treatment regimen includes 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, it should be increased by no more than 50–100 mg every one or two 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 interaction") should follow the dosing regimen recommended for concomitant use of lamotrigine and valproate.

Children aged 2 to 12 years: recommended epilepsy treatment regimen

(total daily dose in mg/kg body weight/day)**

Table 4

Treatment regimen		Weeks 1 and 2	Weeks 3 and 4	Usual maintenance dose
Monotherapy for 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, increase by no more than 0.6 mg/kg/day every one or two 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 includes valproate, regardless 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, increase by no more than 0.3 mg/kg/day every one or two 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 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, increase by no more than 1.2 mg/kg/day every one or two 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 have significant inhibitory or inductive effects on 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, increase by no more than 0.6 mg/kg/day every one or two 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 cannot be achieved with whole tablets, the dose should be rounded to the nearest whole tablet dose.

To maintain the therapeutic dose, the child's body weight should be monitored and the dose adjusted if the 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 AEDs may be discontinued, and monotherapy with Lamotrigine® may be continued.

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. 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 treatment with lamotrigine is considered necessary based on clinical need, see section "Dosage and administration".

Bipolar disorder.

Recommended dose escalation and maintenance doses for adults aged 18 years and older are presented in the tables below. The conversion scheme includes increasing the lamotrigine dose to a 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 schemes following the addition of other psychotropic medications and/or AEDs 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").

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

Table 5

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 significantly inhibit or induce 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 includes valproate, regardless of other concomitant medications	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 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 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 interaction"), the dose escalation regimen recommended for concomitant use of lamotrigine with valproate should be used.

* Target maintenance dose varies depending on clinical response.

Adults (aged 18 years and older): maintenance stabilizing daily dose after discontinuation of concomitant medicinal products 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.

Table 6

Treatment regimen	Current maintenance dose of lamotrigine (prior to discontinuation)		Week 1 (starting with 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 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 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 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.

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

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

Table 7

Treatment regimen	Current maintenance dose (prior to add-on therapy)		Week 1 (start of add-on therapy)	Week 2	Week 3 and onwards
Add-on valproate (inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") depending on initial lamotrigine dose
This treatment regimen should be used when adding valproate regardless of concomitant medication	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 this dose of 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 initial lamotrigine dose:
This treatment regimen should be used when adding the following drugs 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 do not have significant inhibitory or inductive effects 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 do not have significant inhibitory or inductive effects on lamotrigine glucuronidation		Maintain target dose achieved during titration (200 mg/day; dose range 100–400 mg/day)
In 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.

Discontinuation of lamotrigine in patients with bipolar disorder

Clinical studies have shown no increase in the frequency, severity, or type of adverse reactions following rapid discontinuation of lamotrigine compared to placebo. Therefore, patients may discontinue lamotrigine without tapering the dose.

Children (under 18 years of age)

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

General dosage recommendations for special patient groups

Women taking hormonal contraceptives

The use of the combination ethinylestradiol/levonorgestrel (30 mcg/150 mcg) increases lamotrigine clearance by approximately two-fold, resulting in 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 contraceptive is not taken, lamotrigine levels increased by a factor of 2. 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 already receiving maintenance doses of lamotrigine and NOT taking inducers of its glucuronidation

The maintenance dose of lamotrigine will generally 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 lamotrigine dose be increased by 50–100 mg/day each week starting from the initiation of hormonal contraceptives, according to individual clinical response. Dose increases should not exceed this rate unless clinically indicated.

Measurement of lamotrigine plasma concentrations before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women using hormonal contraceptives with one week of inactive treatment (tablet-free week), monitoring of lamotrigine plasma 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 methods 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 generally need to be reduced by 50% (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). The daily dose of lamotrigine should be gradually reduced by 50–100 mg per week (not more than 25% of the total dose per week) over 3 weeks, unless otherwise indicated based on individual clinical response.

Measurement of lamotrigine plasma concentrations before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women wishing to discontinue hormonal contraceptives that include one week of inactive treatment (tablet-free week), monitoring of lamotrigine plasma levels should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Plasma samples to assess lamotrigine levels after permanent discontinuation of the contraceptive should not be collected during the first week after stopping.

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

Dose adjustment of the recommended maintenance dose of lamotrigine is not required.

Concomitant use with atazanavir/ritonavir

Dose adjustment of lamotrigine when added to existing atazanavir/ritonavir therapy is not required.

Patients already receiving maintenance doses of lamotrigine and not taking glucuronidation inducers may require an increase in lamotrigine dose when atazanavir/ritonavir is added, and a reduction 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 dose adjustment (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with lopinavir/ritonavir

Dose adjustment of lamotrigine when added to existing lopinavir/ritonavir therapy is not required.

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

Renal impairment

Caution should be exercised when administering the drug 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 dysfunction (see section "Special precautions for use").

Hepatic impairment

The 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.

Children

The use of lamotrigine as monotherapy for 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 (under 18 years) 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

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 complex (intraventricular conduction delay) and QT interval prolongation have also been reported in overdose. QRS widening exceeding 100 msec may be associated with more severe toxicity.

Treatment

In case of overdose, the patient should be hospitalized for appropriate supportive therapy. Measures to reduce absorption (e.g., activated charcoal) should be used if indicated. Additional treatment should be based on clinical indications, considering potential risks related to ventricular conduction. There is no experience with hemodialysis for 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 by †) and bipolar disorder (denoted by §)). 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, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <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 reaction;
Rare – Stevens-Johnson syndrome§;
Very rare – toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS).

Blood and lymphatic system disorders:
Very rare – hematological abnormalities*1 (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), hemophagocytic lymphohistiocytosis (see section "Special precautions");
Frequency not known – lymphadenopathy*1, cutaneous pseudolymphoma.

Immune system disorders:
Very rare – hypersensitivity syndrome*2;
Frequency not known – hypogammaglobulinemia.

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 precautions");
Very rare – instability, movement disorders, exacerbation of Parkinson’s disease*3, 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 tests, liver function impairment*4, 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 with uveitis syndrome.

General disorders:
Common – fatigue, pain§, back pain§.

Description of selected adverse reactions

1 Hematological abnormalities and lymphadenopathy may be associated with drug reaction with eosinophilia and systemic symptoms (DRESS)/hypersensitivity syndrome (see section "Special precautions" and "Immune system disorders").

2 Skin rash has also been reported as part of a syndrome also known as DRESS. This condition is associated with various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, 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 examined immediately and, in the absence of other causes, lamotrigine should be discontinued.

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

Worsening of Parkinsonism symptoms has been reported in patients with Parkinson’s disease, and isolated reports of extrapyramidal effects and choreoathetosis have been reported 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 occurred 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 appearing within eight weeks of starting treatment and resolving after lamotrigine discontinuation (see section "Special precautions"). 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 irreversible scarring; in rare cases, these syndromes have led to fatal outcomes (see section "Special precautions").

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 of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or 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 reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

PharmaPath S.A.

Manufacturer's address.

28is Oktovriou 1, Agia Varvara, 123 51, Greece.

Marketing Authorization Holder.

LLC "ASINO UKRAINE"

Address of Marketing Authorization Holder.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse effects or questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel./Fax: +38 044 281 23 33.