Lamal®

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

Composition:

Active substance: lamotrigine;

1 tablet contains lamotrigine 25 mg or 50 mg or 100 mg or 200 mg;

Excipients: low-substituted hydroxypropylcellulose, calcium carbonate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, aluminum-magnesium silicate, magnesium stearate, sodium saccharin, povidone, microcrystalline cellulose, blackcurrant flavor 501017 AP0551 (maltodextrin, flavoring agents, glycerol triacetate (E 1518), triethyl citrate (E 1505), ammonia-sulphite caramel (E 150D)).

Pharmaceutical form. Tablets.

Main physicochemical properties:

25 mg tablets: white, round, biconvex tablets;

50 mg or 100 mg or 200 mg tablets: white, round, biconvex tablets with a score line on one side.

Pharmacotherapeutic group.

Antiepileptic drugs. Lamotrigine. ATC code N03A X09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

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, and also caused a subjective sedative effect.

In another study, single oral doses 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 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 showed no 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 disorder type I was evaluated in two clinical trials.

Study SCAB2003 was a multicenter, double-blind, double-dummy, placebo- and lithium-controlled, randomized, fixed-dose trial 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 included additional pharmacotherapy or electroconvulsive therapy (ECT). Study SCAB2006 was conducted with a design similar to SCAB2003, but with a more flexible dosing regimen for 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

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., 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 the subsequent dose phase, reduced or not increased due to concentrations exceeding 0.41 \u00b5g/mL – 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 with therapeutic response (reduction in seizure frequency > 40%) 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 \u20132.6% < > 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 lamotrigine (IR) tablets as adjunctive maintenance therapy in 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, the 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 first-pass metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration is reached approximately within 2.5 hours. Time to maximum concentration is slightly prolonged when the drug is taken after food, but this does not affect the extent of absorption. There are substantial inter-individual 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.

Volume of distribution ranges from 0.92 to 1.22 L/kg.

Biotransformation

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

Lamotrigine induces its own metabolism to a minor, dose-dependent extent. However, the effect of lamotrigine on the pharmacokinetics of other anticonvulsants has not been demonstrated, 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 primarily 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 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, the pharmacokinetics of lamotrigine showed linear dependence.

Special patient populations

Children

Clearance, normalized per body weight, is higher in children than in adults, and highest in children under 5 years of age. The elimination half-life of lamotrigine in children is generally shorter than in adults. 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 weight ranging from 3 to 16 kg, oral administration of equivalent doses per kilogram of body weight resulted in lower clearance compared to children older than 2 years with similar body weight. The average elimination half-life in children under 26 months was 23 hours when enzyme-inducing therapy was administered, 136 hours when co-administered with valproate, and 38 hours without concomitant administration of enzyme inhibitors or inducers. Inter-individual variability in clearance following oral dosing in patients aged 2 to 26 months was high (47%). Predicted serum concentrations in this age group were within the range observed in older groups, although patients with body weight less than 10 kg had 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) obtained in 9 studies involving non-elderly adult patients after single doses of 30 to 450 mg.

Patients with impaired renal function

Twelve volunteers with chronic renal impairment and six patients on hemodialysis 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 in 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 impaired hepatic function

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 classes 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 group volunteers. Initial, titrated, and maintenance doses in patients with moderate to severe hepatic impairment should be reduced.

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 of partial and generalized seizures of epilepsy, including tonic-clonic seizures.

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

Children aged 2 to 12 years.

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

Monotherapy of typical absence seizures.

Bipolar disorder.

Adults (aged 18 years and older).

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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 the theoretical clearance of lamotrigine. Enzyme inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate intensity, which are known to induce UGT, may also enhance lamotrigine metabolism. There is no evidence that lamotrigine may cause clinically significant stimulation or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and has no significant clinical consequences.

Medicinal products that have been shown to have a relevant clinical effect on lamotrigine concentration are listed in Table 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, co-administration of such medicinal products is not expected to cause any clinical effect. However, patients with epilepsy whose condition is particularly sensitive to fluctuations in lamotrigine concentration should be cautioned.

Table 2

Effect of medicinal products on lamotrigine concentration

Detailed information on dosing can be found in the subsection "General dosing recommendations for special patient groups" of the section "Dosage and administration". For dosing instructions in women taking hormonal contraceptives, see the subsection "Hormonal contraceptives" of the section "Special instructions".

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases its average elimination half-life approximately two-fold. 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 enzymes, also induce UGT enzymes and thereby accelerate lamotrigine metabolism. 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. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.

In a study in healthy adult volunteers receiving 200 mg lamotrigine and 1200 mg 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 a study in healthy volunteers, concomitant administration of felbamate 1200 mg twice daily and lamotrigine 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 receiving lamotrigine with or without gabapentin, gabapentin does not alter the theoretical clearance of lamotrigine.

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

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

Topiramate does not affect 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 lamotrigine pharmacokinetics.

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 trials investigating add-on perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied dose of perampanel (12 mg/day) increased lamotrigine clearance by less than 10%.

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

Interaction with other psychotropic agents

When 100 mg/day lamotrigine and 2 g of anhydrous lithium gluconate administered twice daily for 6 days were co-administered to 20 healthy volunteers, the pharmacokinetics of lithium were not altered.

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 of lamotrigine glucuronide.

In a study in healthy adult volunteers, 15 mg of olanzapine reduced the area under the concentration-time curve and Cmax of lamotrigine by an average of 24% and 20%, respectively. Lamotrigine at a dose of 200 mg did not affect the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg/day did not cause a clinically significant effect on the pharmacokinetics of a single 2 mg dose of risperidone in studies involving 14 healthy adult volunteers. With concomitant administration of 2 mg risperidone and 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 observed with lamotrigine alone.

In a clinical study involving 18 adult patients with bipolar disorder receiving lamotrigine (100–400 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and continued for another 7 days. A decrease in Cmax and AUC of lamotrigine by approximately 10% was observed.

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 bufuralol metabolism studies 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.

In a study involving 16 female volunteers taking a tablet containing "ethinylestradiol 30 µg/levonorgestrel 150 µg", an approximately two-fold increase in lamotrigine clearance was observed, resulting in a mean reduction in the area under the concentration-time curve and Cmax of lamotrigine by 52% and 39%, respectively. During the weekly break from contraceptive use (the so-called "pill-free week"), lamotrigine serum concentration gradually increased, reaching levels approximately twice as high as during concomitant use (see section "Special instructions"). Dose adjustments of lamotrigine during the titration phase are not required when hormonal contraceptives are used concomitantly. 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 with 300 mg 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 the area under the concentration-time curve and Cmax of levonorgestrel by 19% and 12%, respectively. Serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol recorded in this study indicated reduced suppression of ovarian hormonal activity in some women, although serum progesterone levels indicated no hormonal signs of ovulation in all 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 subsection "General dosing recommendations for special patient groups" of the section "Dosage and administration" for dosing in women taking hormonal contraceptives and subsection "Hormonal contraceptives" of the section "Special instructions"). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Studies with other hormonal contraceptives have also not been conducted.

Interaction with other medicinal products.

In a study involving 10 male volunteers, rifampicin accelerated lamotrigine clearance and shortened its elimination half-life by inducing hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the dosing regimen recommended for lamotrigine and concomitant inducers of glucuronidation should be followed (see section "Dosage and administration").

According to studies in healthy volunteers, lopinavir/ritonavir reduce lamotrigine plasma concentration by approximately half by inducing glucuronidation. For treatment of patients already receiving lopinavir/ritonavir, the dosing regimen recommended for lamotrigine with inducers of glucuronidation should be followed (see section "Dosage and administration").

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

According to studies in healthy volunteers, administration of paracetamol 1 g four times daily reduced the 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 substrates of OCT2 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

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

In adult patients participating in clinical trials following current dosing recommendations, the incidence of severe skin rashes was approximately 1 in 500 patients with epilepsy. Approximately half of these cases were diagnosed as Stevens-Johnson syndrome (1 in 1,000). In patients with bipolar disorder, the incidence of severe skin rashes was 1 in 1,000.

The risk of serious skin rashes is higher in children than in adults. Available data indicate that the incidence of rashes leading to hospitalization in children ranges from 1 in 300 to 1 in 100 patients.

In children, early signs of skin rash may be mistaken for infection. Therefore, physicians should consider the possibility of this adverse reaction in children who develop rash and fever during the first 8 weeks of therapy.

The overall risk of skin rash appears closely related to high initial doses of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy (see section "Dosage and administration"), as well as 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 following 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 ancestry (primarily of Chinese and Thai descent) is associated with an increased risk of Stevens-Johnson syndrome and 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 should be discontinued unless there is clear evidence that the rash is unrelated to the drug. Reinitiating lamotrigine treatment after discontinuation due to rash following prior lamotrigine therapy is not recommended. In such cases, the potential benefits and risks should be carefully weighed when considering re-prescription. 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 may also be part of DRESS, also known as drug 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 rash. If such symptoms occur, the patient should be examined immediately and lamotrigine discontinued unless another cause is identified.

In most cases, aseptic meningitis resolves after discontinuation of the drug, but in some cases, symptoms may recur upon re-administration of lamotrigine. Reinitiating lamotrigine leads to rapid recurrence of symptoms, often with greater severity. 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, the reaction occurred with high-dose use (400 mg or more), dose increases, or rapid titration. If a patient presents with signs of photosensitivity (e.g., severe sunburn) suggestive of lamotrigine-related photosensitivity, discontinuation of treatment should be considered. If continuing lamotrigine therapy is clinically justified, patients should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g., wearing protective clothing and using sunscreen).

Hemophagocytic lymphohistiocytosis (HLH)

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

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

Patients presenting with these symptoms should be evaluated immediately, and HLH should be considered in the differential diagnosis. Lamotrigine therapy should be discontinued if an alternative etiology for the above symptoms cannot be established.

Clinical worsening and suicide risk

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications, including epilepsy. Meta-analysis of randomized placebo-controlled clinical trials of antiepileptic drugs 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 of increased risk with lamotrigine use.

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 disorders, 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 require careful monitoring for clinical worsening (including emergence of new symptoms) and suicidal behavior, particularly at the beginning of treatment or during dosage adjustments. Patients with a history of suicidal behavior or ideation, younger patients, and those who exhibited significant suicidal ideation prior to treatment initiation may be at higher risk of developing suicidal thoughts or suicide 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 existing symptomatology, 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 lead to loss of seizure control. To achieve optimal therapeutic effect, in most cases the maintenance dose of lamotrigine needs to be increased (by titration), typically doubled. 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 their physician.

In women who are not yet taking lamotrigine enzyme-inducing drugs 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).

The 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 involving 16 healthy volunteers demonstrated that lamotrigine co-administered with the hormonal contraceptive combination ethinylestradiol 30 µg/levonorgestrel 150 µg resulted in 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 ruled out that in some patients concurrently taking lamotrigine and hormonal contraceptives, these changes may lead to reduced contraceptive efficacy. 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 inhibits 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 Lamal® 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, prolonged use may potentially affect folate metabolism. However, during long-term lamotrigine treatment, no significant changes were 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 is possible. 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.

Brugada-type ECG and other cardiac rhythm disorders and conduction abnormalities

Arrhythmogenic ST-T abnormalities and Brugada-type 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 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 enhance 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.

Excipients

One tablet contains less than 1 mmol (23 mg) of sodium and can therefore be considered sodium-free.

Development in children

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

Epilepsy

Abrupt discontinuation of lamotrigine, as with other antiepileptic drugs, may provoke increased seizure frequency. Except in cases where the patient's condition requires immediate discontinuation (e.g., in case of rash), the lamotrigine dose 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 events 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 of another. Lamotrigine treatment may exacerbate myoclonic seizures.

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

In children with typical absence seizures, therapeutic effect 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.

Use during pregnancy or breastfeeding

General risk associated with antiepileptic drugs

Women of childbearing potential require specialist consultation. 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 with serious consequences for both the woman and the fetus. Monotherapy is preferred, as the use of combined antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the antiepileptic drugs used.

Risk associated with lamotrigine use

Pregnancy

A large amount of data from pregnant women receiving lamotrigine monotherapy during the first trimester of pregnancy (over 8,700 cases) does not indicate a significant increase in the risk of serious 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 mild inhibitory effect on dihydrofolate reductase and, therefore, theoretically may increase the risk of embryofetal developmental abnormalities due to reduced folic acid levels. Folic acid supplementation should be considered during pregnancy planning and early pregnancy.

Physiological changes during pregnancy may affect lamotrigine concentrations and/or its therapeutic effect. Reports indicate decreased plasma lamotrigine concentrations during pregnancy, with a potential risk of loss of seizure control. After delivery, lamotrigine levels may rapidly increase, increasing the risk of dose-dependent adverse events. Therefore, serum lamotrigine concentrations should be monitored before, during, and after pregnancy, and shortly after delivery. Dose adjustments may be necessary to maintain serum lamotrigine concentrations at pre-pregnancy levels or according to clinical response. Additionally, monitoring for dose-dependent adverse events is required after delivery.

Breastfeeding period

Lamotrigine is reported to pass into breast milk at various concentrations, resulting in infant lamotrigine levels reaching approximately 50% of maternal concentrations. Thus, in some breastfed infants, serum lamotrigine concentrations may reach levels at which pharmacological effects are observed.

The potential benefits of breastfeeding must be weighed against the possible 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

Data from two studies in volunteers showed that lamotrigine had no effect on visual 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. 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 driving suitability in such cases.

Method of Administration and Dosage

Lamal®, 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 whole tablets, the administered dose should correspond to the nearest lower number of whole tablets.

Restarting Treatment

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

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

Epilepsy

Recommended dose escalation regimens and maintenance doses for adults and children aged 13 years and older (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").

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

Table 3

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

Table 4

Children aged 2 to 12 years: recommended epilepsy treatment regimen

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

**If the calculated dose of lamotrigine cannot be achieved with whole tablets, the dose should be rounded to the nearest whole tablet.

To maintain therapeutic dosing, the child's body weight should be monitored and the dose adjusted as body weight changes. It is likely that patients aged two to six years will 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 monotherapy with Lamal® may be continued.

Children under 2 years of age.

Data on the efficacy and safety of lamotrigine for adjunctive treatment of partial seizures in children aged 1 month to 2 years are limited (see section "Special instructions"). There are no data on the use of lamotrigine in children under 1 month of age. Therefore, Lamal® is not recommended for use in children under 2 years of age. If, based on clinical need, treatment with Lamal® is considered, refer to sections "Special instructions" 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 dosing regimen 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 regimens when adding 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 "Special instructions").

Table 5

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

* Target maintenance dose varies depending on clinical response.

Table 6

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

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

* If necessary, the dose can be increased 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 dose adjustment of lamotrigine when other drugs are co-administered.

However, based on data concerning drug interactions, the following regimens may be recommended.

Discontinuation of lamotrigine in patients with bipolar disorders.

Clinical trial data showed no increase in the frequency, severity, or type of adverse reactions after rapid discontinuation of lamotrigine compared to placebo. Therefore, patients may discontinue Lamal® without tapering the dose.

Children (under 18 years of age).

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

General dosage recommendations for special patient groups.

Women taking hormonal contraceptives.

The use of a combination of ethinylestradiol/levonorgestrel (30 mcg/150 mcg) approximately doubles the clearance of lamotrigine, leading to reduced lamotrigine levels. After titration, higher maintenance doses of lamotrigine (almost twice as high) may be required to achieve optimal therapeutic response. A twofold increase in lamotrigine levels was observed during the week when the contraceptive was not taken. Dose-dependent adverse reactions cannot be excluded. Therefore, consideration should be given to using contraceptives that do not include a hormone-free week as first-line therapy (e.g., continuous hormonal contraceptives or non-hormonal methods; see sections «Special precautions» and «Interaction with other medicinal products and other forms of interaction»).

Initiation of hormonal contraceptives in patients receiving maintenance doses of lamotrigine who are NOT taking inducers of its glucuronidation.

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

Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women using hormonal contraceptives with a one-week hormone-free interval (tablet-free week), serum lamotrigine monitoring 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 regimens without a tablet-free week as first-line therapy (e.g., continuous hormonal contraceptives or non-hormonal methods; see sections «Special precautions» 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 drugs that induce lamotrigine glucuronidation.

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

Measurement of lamotrigine concentration in blood serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women wishing to discontinue hormonal contraceptives with a one-week hormone-free interval (tablet-free week), serum lamotrigine monitoring should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Blood samples for lamotrigine level assessment 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 dosage recommendations provided in the tables.

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

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 dose reduction when atazanavir/ritonavir is discontinued.

Plasma lamotrigine level monitoring 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.

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 dose reduction when lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be performed before and within 2 weeks after starting or stopping lopinavir/ritonavir to determine the need for lamotrigine dose adjustment (see section «Interaction with other medicinal products and other forms of interaction»).

Elderly patients (aged 65 years and older).

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

Renal impairment.

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

Hepatic impairment.

Initial, escalating, 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. Escalating and maintenance doses should be adjusted according to clinical response (see section «Pharmacokinetics»).

Children.

The efficacy of lamotrigine as monotherapy in children under 2 years of age or as adjunctive therapy in 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»).

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. Overdose has also been associated with QRS complex widening (intraventricular conduction delay) and QT interval prolongation. 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 care. Measures to reduce absorption (e.g., activated charcoal) should be administered if necessary. Further treatment should be based on clinical indications, considering the potential risks of effects on ventricular conduction. Intravenous lipid therapy may be considered for cardiotoxicity unresponsive to sodium bicarbonate. There is no experience with hemodialysis for treating lamotrigine overdose. In six volunteers with renal impairment, 20% of lamotrigine was removed during a 4-hour hemodialysis session (see section «Pharmacokinetics»).

Adverse reactions.

Adverse reactions for indications in the treatment of epilepsy and bipolar disorder, based on available data from controlled clinical trials and other clinical experience, are listed in Table 8. Frequency categories were derived from controlled clinical trials (epilepsy monotherapy (marked as †) and bipolar disorder (marked as §)). If frequency categories differ between epilepsy and bipolar disorder clinical data, the lowest frequency is applied. In the absence of data from controlled clinical trials, frequency categories were derived from other clinical experience.

Adverse reactions are categorized by frequency as follows:

very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Table 8

Description of individual 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 "Special precautions for use" and "Immune system disorders").

2 Skin rash has also been reported as part of this syndrome, also known as DRESS. This condition was accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, and hepatic and renal dysfunction. The syndrome may vary in severity and, in rare cases, may lead to disseminated intravascular coagulation and multiorgan 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 evaluated immediately and, in the absence of other causes, lamotrigine should be discontinued.

3 These reactions have been observed in clinical practice in other clinical conditions.

It has been noted that lamotrigine may exacerbate 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 Hepatic dysfunction is usually associated with hypersensitivity reactions, but isolated cases without prominent signs of hypersensitivity have been described.

5 In clinical trials in adults, skin rash was observed in 8–12% of patients treated with lamotrigine and in 5–6% of patients treated with placebo. Rash led to drug discontinuation in 2% of patients. The rash was maculopapular in nature, most commonly occurring within eight weeks of starting treatment and resolving after discontinuation of lamotrigine (see section "Special 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 have persistent scarring; in rare cases, these syndromes have been fatal (see section "Special precautions for use").

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

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

There are 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 of adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging.

Tablets 25 mg and 50 mg: 10 tablets in a blister pack made of aluminum foil and polyvinyl chloride film; 3 blisters (30 tablets) in a cardboard box.

Tablets 100 mg and 200 mg: 15 tablets in a blister pack made of aluminum foil and polyvinyl chloride film; 2 blisters (30 tablets) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and location of its operations.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.