Lamotrin 50mg 60 tablets

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LAMICTAL 25 LAMICTAL 50 LAMICTAL 100 Trade name of the medicinal product: LAMICTAL. International nonproprietary name: Lamotrigine. Dosage form: Tablets. General characteristics: 1 tablet contains: Active substance: Lamotrigine 25 mg or 50 mg, 100 mg; Excipients: Microcrystalline cellulose, colloidal anhydrous silica, povidone, sodium starch glycolate (type A), lactose monohydrate, magnesium stearate. Description: White or almost white tablets, round, biconvex, with a score line (LAMICTAL 50 and LAMICTAL 100), without a score line (LAMICTAL 25). Pharmacotherapeutic group: Antiepileptic agents. Lamotrigine. ATC code N03AX09. Pharmacological properties. Pharmacodynamics. Lamotrigine is an anticonvulsant whose mechanism of action is related to the blockade of voltage-dependent sodium channels in the presynaptic membranes of neurons in the slow inactivation phase and the suppression of excessive glutamate release (amino acids that play an important role in the development of epileptic seizures). Pharmacokinetics. After oral administration, the drug is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration is reached approximately 2.5 hours later. Lamotrigine undergoes active metabolism, the main metabolite being N-glucuronide. The half-life in adults averages 29 hours. Lamotrigine has a linear pharmacokinetic profile. It is excreted mainly in the form of metabolites and partly unchanged, predominantly in the urine. The half-life in children is shorter than in adults. Special patient groups. Children. Clearance dependent on body weight is higher in children than in adults, with the highest values in children under 5 years of age. The half-life of lamotrigine in children is generally shorter than in adults, with an average value of approximately 7 hours when co-administered with enzyme inducers such as carbamazepine and phenytoin, and an increase to an average period of 45 to 50 hours when co-administered with valproate alone. Elderly patients. Information is provided that pharmacokinetic analysis results in patient groups including both elderly and young epileptic patients participating in the study showed that lamotrigine clearance did not change to a clinically significant extent. After single doses, apparent clearance decreased by 12% from 35 ml/min/kg in patients aged 20 years to 31 ml/min/kg in patients aged 70 years. After 48 weeks of treatment, the decrease was 10% from 41 ml/min in young patients to 37 ml/min in elderly patients. Information is provided that the pharmacokinetics of lamotrigine were studied in 12 healthy elderly patients who received a single dose of 150 mg. The mean clearance in elderly patients (0.39 ml/min/kg) falls within the range of mean clearance (0.31 to 0.65 ml/min/kg) obtained in 9 studies conducted in non-elderly adult patients after receiving single doses from 30 to 450 mg. Patients with renal impairment. 12 volunteers with chronic renal impairment and 6 patients on hemodialysis received a single dose of 100 mg of lamotrigine. Mean CL/F values were 0.42 ml/min/kg (chronic renal impairment), 0.33 ml/min/kg (interdialytic period), and 1.57 ml/min/kg (during hemodialysis), compared to 0.58 ml/min/kg in healthy patients. The mean plasma half-life was 42.9 hours (chronic renal impairment), 57.4 hours (interdialytic period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy patients. During a four-hour hemodialysis session, the amount of lamotrigine decreased by approximately 20% (from 5.6 to 35.1). The initial dose for patients in this group should be based on the patient's antiepileptic drug regimen; a reduction in the maintenance dose may be effective for patients with significant renal impairment. Patients with hepatic impairment. Single-dose pharmacokinetic studies were conducted in patients with varying degrees of hepatic impairment and in healthy volunteers. The mean apparent clearance of lamotrigine was 0.31 ml/min/kg, 0.24 ml/min/kg, and 0.10 ml/min/kg in patients with hepatic impairment of grades A, B, and C (Child-Pugh classification), respectively, compared to 0.34 ml/min/kg in healthy patients. Generally, initial, titration, and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh grade B) and by 75% in patients with severe hepatic impairment (Child-Pugh grade C). Titration and maintenance doses should be adjusted according to the response to treatment. Indications for use. Epilepsy. Adults and children aged 13 years and older: Monotherapy and adjunctive therapy for partial and generalized epileptic seizures, including tonic-clonic seizures, and also seizures associated with Lennox-Gastaut syndrome. LAMICTAL is indicated as adjunctive therapy, but in Lennox-Gastaut syndrome, it can be prescribed as an initial antiepileptic drug (AED). Children aged 2 to 12 years: Adjunctive therapy for epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures, and also seizures associated with Lennox-Gastaut syndrome. Monotherapy for typical absence seizures. Bipolar disorder in adults. Adults (from 18 years of age). For the prevention of depressive episodes in patients with bipolar I disorder who predominantly experience depressive episodes. Lamotrigine is not indicated for the emergency treatment of manic or depressive episodes. Method of administration and dosage. LAMICTAL tablets should be taken whole, without chewing or crushing. If the calculated dose of lamotrigine (e.g., for the treatment of children with epilepsy or patients with hepatic impairment) is not a multiple of whole tablets, the dose should correspond to the nearest lower whole tablet quantity. If lamotrigine dosage is not possible in children, other dosage forms of lamotrigine with appropriate dosing should be used. Resumption of treatment. Physicians should assess the need to increase the dose to the maintenance dose when resuming lamotrigine in patients who have discontinued lamotrigine for any reason, as the risk of developing severe rash is associated with high initial doses and exceeding the recommended lamotrigine dose titration regimen (see section "Special Warnings"). The longer the interval since the last dose, the more attention should be paid to the dose titration regimen to the maintenance dose. When the interval after discontinuation of lamotrigine exceeds 5 times the half-life (see section "Pharmacokinetics"), the lamotrigine dose should be increased to the maintenance dose according to the existing schedule. Resumption of lamotrigine treatment is not recommended if treatment was discontinued due to rash caused by previous treatment. In this case, when deciding on re-prescription, the expected benefit and potential risk of treatment should be assessed. Epilepsy. The recommended dose titration regimen and maintenance dose levels for adults and adolescents aged 13 years and older (Table 1), as well as for children and adolescents aged 2 to 12 years (Table 2) are provided below. Do not exceed the initial dose, and the dose titration regimen should not be exceeded due to the risk of developing skin rash (see section "Special Warnings"). The possible impact of withdrawal or addition of other concomitant anticonvulsants and other medications on the pharmacokinetics of lamotrigine should be considered (see section "Interactions with other medicinal products and other types of interactions"). Table 1: Dosing regimen for epilepsy in adults and children aged 13 years and older. Treatment regimen Weeks I-II Weeks III-IV Usual maintenance dose Monotherapy 25 mg/day (once daily) 50 mg/day (once daily) 100-200 mg/day (in 1 or 2 doses). The dose can be increased by 50-100 mg every 1-2 weeks to the maintenance dose until therapeutic effect is achieved. Some patients may require a dose of 500 mg/day to achieve the desired therapeutic effect. Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") The specified dosing regimen should be used, regardless of concomitant therapy with other medications 12.5 mg/day (25 mg every other day) 25 mg/day (once daily) 100-200 mg daily (in 1 or 2 doses). The dose can be increased by 25-50 mg every 1-2 weeks until therapeutic effect is achieved. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 50 mg/day (once daily) 100 mg/day (in 2 doses) 200-400 mg daily (in 2 doses). The dose can be increased by 100 mg every 1-2 weeks to the maintenance dose until therapeutic effect is achieved. Some patients may require a dose of 700 mg/day to achieve the desired therapeutic effect. Adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 25 mg/day (once daily) 50 mg/day (once daily) 100-200 mg daily (once daily or in 2 doses). The dose can be increased by a maximum of 50-100 mg every 1-2 weeks until therapeutic effect is achieved. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 2. Children aged 2 to 12 years: Recommended dosing regimen for epilepsy treatment (total daily dose, mg/kg body weight)**. Treatment regimen Weeks I-II Weeks III-IV Usual maintenance dose Monotherapy for typical absence seizures 0.3 mg/kg/day (once daily or divided into 2 doses) 0.6 mg/kg/day (once daily or divided into 2 doses) 1-15 mg/kg/day (in 1 or 2 doses). To achieve the maintenance regimen, the dose can be increased by no more than 0.6 mg/kg/day every 1-2 weeks until therapeutic effect is achieved. The maximum maintenance dose is 200 mg/day. Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used, regardless of concomitant therapy with other medications. 0.15 mg/kg/day * (once daily) 0.3 mg/kg/day (once daily) 1-5 mg/kg/day (once daily or divided into 2 doses). To achieve the maintenance regimen, the dose can be increased by no more than 0.3 mg/kg/day every 1-2 weeks until optimal effect is achieved. The maximum maintenance dose is 200 mg/day. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 0.6 mg/kg/day (divided into 2 doses) 1.2 mg/kg/day (divided into 2 doses) 5-15 mg/kg/day (once daily or in 2 doses). The dose can be increased by no more than 1.2 mg/kg every 1-2 weeks until the maintenance dose is reached. The maximum maintenance dose is 400 mg/day. Adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 0.3 mg/kg/day (once daily or divided into 2 doses) 0.6 mg/kg/day (once daily or divided into 2 doses) 1-10 mg/kg/day (once daily or divided into 2 doses). The dose can be increased by no more than 0.6 mg/kg every 1-2 weeks until the maintenance dose is reached. The maximum maintenance dose is 200 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. * If the calculated daily dose in patients receiving valproate is 1 mg or more, but not more than 2 mg, it is permissible to take 2 mg of lamotrigine in the form of dispersible tablets every other day for the first 2 weeks. If the calculated daily dose in patients receiving valproate is less than 1 mg, lamotrigine intake is not recommended. Lamotrigine withdrawal in patients with bipolar disorder. No increase in the frequency, severity, or type of adverse reactions was observed after abrupt discontinuation of the drug compared to placebo. Therefore, discontinuation of the drug is possible abruptly, without gradual dose reduction. Children (under 18 years of age). Lamotrigine is not recommended for use in children (under 18 years of age) with bipolar disorder, as randomized discontinuation studies have not shown its significant efficacy and have shown an increase in suicidal ideation (see section "Special Warnings"). Table 3. Recommended maintenance daily doses and titration regimens for bipolar disorder treatment - in patients aged 18 years and older. Treatment regimen Weeks I-II Weeks III-IV Week V Target maintenance dose (Week VI)* Dose (Week VI)* Monotherapy with lamotrigine or adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day (once daily or divided into 2 doses) 200 mg/day - usual maintenance dose (once daily or divided into 2 doses). Doses in the range of 100-400 mg/day have been used in clinical trials. Adjunctive therapy with valproates (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with valproates, regardless of concomitant therapy with other medications. 12.5 mg/day (taken 25 mg every other day) 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day is the usual maintenance dose (once daily or divided into 2 doses). 200 mg/day is the maximum dose that can be prescribed according to clinical response. Adjunctive therapy with valproates (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with valproates, regardless of concomitant therapy with other medications. 12.5 mg/day (taken 25 mg every other day) 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day is the usual maintenance dose (once daily or divided into 2 doses). 200 mg/day is the maximum dose that can be prescribed according to clinical response. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 50 mg/day (once daily) 100 mg/day (divided into 2 doses) 200 mg/day (divided into 2 doses) 300 mg/day on the 6th week of administration. If necessary, the dose can be increased to 400 mg/day on the 7th week (divided into 2 doses) to achieve optimal effect. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 4. Adults (over 18 years of age): Maintenance stabilizing daily doses for bipolar disorder treatment after withdrawal of concomitant medications. Treatment regimen Current stabilizing dose of lamotrigine (before withdrawal) Week I (start of withdrawal) Week II Weeks III and subsequent * Withdrawal of valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine When withdrawing valproates, the stabilizing dose needs to be doubled, but not more than 100 mg/week. 100 mg/day 200 mg/day 200 mg/day 300 mg/day 200 mg/day, divided into 2 doses 400 mg/day 400 mg/day Withdrawal of lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine This dosing regimen should be used when discontinuing phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir. 400 mg/day 300 mg/day 200 mg/day 400 mg/day 300 mg/day 200 mg/day 300 mg/day 225 mg/day 150 mg/day 200 mg/day 150 mg/day 100 mg/day Withdrawal of medications that do not significantly affect lamotrigine glucuronidation (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when discontinuing medications that do not have a significant inhibitory or inducing effect on lamotrigine glucuronidation. Maintain the target dose achieved during titration (200 mg/day, divided into 2 doses). The dose range is 100-400 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 5: Maintenance stabilizing daily doses of lamotrigine for bipolar disorder treatment with subsequent addition of other medications - in patients aged 18 years and older. Clinical experience of lamotrigine daily dose adjustment when adding other medications is not available. However, based on drug interaction studies, the following recommendations can be made: Treatment regimen Current stabilizing dose of lamotrigine (before adding new medication) Week I (start of adding new medication) Week II Weeks III and subsequent Addition of valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine This dosing regimen should be used when adding valproate, regardless of concomitant therapy with other medications. 200 mg/day 300 mg/day 400 mg/day 100 mg/day 150 mg/day 200 mg/day Maintain this dose (100 mg/day) Maintain this dose (150 mg/day) Maintain this dose (200 mg/day) Addition of lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") In patients not taking valproates (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir. 200 mg/day 150 mg/day 100 mg/day 200 mg/day 150 mg/day 100 mg/day 300 mg/day 225 mg/day 150 mg/day 400 mg/day 300 mg/day 200 mg/day Addition of medications that do not significantly affect lamotrigine glucuronidation (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when adding other medications that do not significantly affect lamotrigine glucuronidation. Maintain the target dose achieved during titration (200 mg/day). The dose range is 100-400 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Recommendations for special patient groups. Women taking hormonal contraceptives. It is known that the use of the combination ethinylestradiol/levonorgestrel (30 mcg/150 mcg) doubles the clearance of lamotrigine, leading to a decrease in lamotrigine levels. Higher (approximately double) maintenance doses of lamotrigine may be required after titration to achieve maximum therapeutic response. During the week when the drug was not taken, a twofold increase in lamotrigine levels was observed. Dose-dependent adverse reactions cannot be ruled out. Therefore, the use of contraception that does not involve weeks without medication should be considered as a first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). Initiation of hormonal contraceptive therapy in patients already receiving maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers. In most cases, a twofold increase in the maintenance dose of lamotrigine will be necessary. It is recommended to increase the lamotrigine dose by 50 to 100 mg/day every week after starting hormonal contraceptive therapy, according to the individual clinical response to treatment. The dose increase should not exceed the indicated level, unless such a dose increase is necessary according to the clinical response to treatment. Measurement of lamotrigine levels in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include a week of inactive treatment (a week without taking tablets), lamotrigine levels in serum should be monitored during the 3rd week of active treatment, i.e., from day 15 to 21 of the tablet intake cycle. The possibility of using contraceptive preparations that do not include a week without tablet intake should be considered as a first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods: see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). Discontinuation of hormonal contraceptive therapy in patients already receiving maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers. In most cases, it will be necessary to reduce the maintenance dose of lamotrigine by up to 50% (see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). It is recommended that the daily dose of lamotrigine be gradually reduced by 50 to 100 mg weekly (not more than 25% of the total dose per week) over 3 weeks, unless otherwise indicated by the individual clinical response to treatment. Measurement of lamotrigine levels in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include a week of inactive treatment (a week without taking tablets), lamotrigine levels in serum should be monitored during the 3rd week of active treatment, i.e., from day 15 to 21 of the tablet intake cycle. Samples for lamotrigine level assessment should not be taken within 1 week of discontinuing contraceptive intake. Initiation of lamotrigine therapy in women already taking hormonal contraceptives. Dose titration should follow the standard dose recommendations given in the tables. Initiation and discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine, and also taking lamotrigine glucuronidation inducers. Correction of the recommended maintenance dose of lamotrigine is not mandatory. Use with atazanavir/ritonavir. Correction of the recommended dose of lamotrigine when adding it to atazanavir/ritonavir therapy is not mandatory. In patients already using maintenance doses of lamotrigine and not using glucuronidation inducers, the dose of lamotrigine may need to be increased if treatment with atazanavir/ritonavir is added, or decreased if treatment with atazanavir/ritonavir is discontinued. Lamotrigine plasma levels should be monitored for 2 weeks after starting or discontinuing atazanavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interactions with other medicinal products and other types of interactions"). Concomitant use with lopinavir/ritonavir. Correction of the recommended dose of lamotrigine when adding it to lopinavir/ritonavir therapy is not mandatory. For patients already receiving maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased when lopinavir/ritonavir is added, and decreased when lopinavir/ritonavir is discontinued. Lamotrigine plasma levels should be monitored for 2 weeks after starting or discontinuing lopinavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interactions with other medicinal products and other types of interactions"). Elderly patients (from 65 years of age). Dose adjustment of the drug according to the recommended regimen is not necessary. The pharmacokinetics of lamotrigine in this age group do not differ from those in patients under 65 years of age. Hepatic insufficiency. It is necessary to reduce the initial, titration, and maintenance doses, generally by 50% in patients with moderate hepatic impairment (Child-Pugh grade B) and by 75% in patients with severe hepatic impairment (Child-Pugh grade C). Titration and maintenance doses should be adjusted according to clinical effect. Renal insufficiency. Caution should be exercised when prescribing lamotrigine to patients with renal impairment. For patients with end-stage renal failure, the initial dose of lamotrigine is determined based on the prescribed concomitant medications; a reduction in the maintenance dose may be effective in patients with significant renal impairment (see section "Special Warnings"). Adverse reactions. The list of adverse reactions associated with the use of medicinal products for epilepsy and bipolar disorder has been compiled based on available data from controlled clinical trials and clinical experience with the medicinal product. Adverse reactions are listed in the table below. The frequency of adverse reactions was determined in controlled clinical trials of lamotrigine monotherapy (marked with "*") and bipolar disorder (marked with "§"). In case of differences in the frequency of adverse reactions observed in clinical trials in patients with epilepsy and bipolar disorder, the highest frequency category is given. In the absence of controlled clinical trial data, the frequency of adverse reactions is inferred from clinical experience with the use of the medicinal product. The following classification was used to assess the frequency of adverse events: very common (≥1/10), common (≥1/100 - <1/10), uncommon (≥1/1000 - <1/100), rare (≥1/10,000 - <1/1000), very rare (<1/10,000), unknown (cannot be estimated from available data). Skin and subcutaneous tissue disorders. Very common - rash5*§; Uncommon - alopecia, photosensitivity reactions; Rare - Stevens-Johnson syndrome§; Very rare - toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms. Blood and lymphatic system disorders. Very rare - hematological abnormalities1 (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), hemophagocytic lymphohistiocytosis (see section "Special Warnings"); Frequency unknown - lymphadenopathy1. Immune system disorders. Very rare - hypersensitivity syndrome2; Frequency unknown - hypogammaglobulinemia. Psychiatric disorders. Common - irritability, aggression; Very rare - tics, hallucinations, and confusion of consciousness; Frequency unknown - nightmares. Nervous system disorders. Very common - headache§; Common - somnolence*§, insomnia*, dizziness*§, tremor*, anxiety§; Uncommon - ataxia*; Rare: nystagmus*, aseptic meningitis (see section "Special Warnings"); Very rare - instability, movement disorders, exacerbation of Parkinson's disease3, extrapyramidal effects, choreoathetosis*, increased seizure frequency. Eye disorders. Uncommon - diplopia*, blurred vision*; Rare - conjunctivitis. Gastrointestinal disorders. Common - nausea*, vomiting* and diarrhea*, dry mouth§. Hepatobiliary system disorders. Very rare - increased liver function test results, hepatic dysfunction4, liver failure. Musculoskeletal and connective tissue disorders. Common - arthralgia§; Very rare - symptoms of systemic lupus erythematosus. Kidney and urinary system disorders. Frequency unknown - tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis. General disorders. Common - fatigue*, pain§, back pain§. Description of individual adverse reactions. 1 Hematological disorders and lymphadenopathy may be associated with, and not associated with, drug reaction with eosinophilia and systemic symptoms (DRESS) / hypersensitivity syndrome (see sections "Special Warnings" and "Immune system disorders"). 2 Information is also provided that rash is part of hypersensitivity syndrome (DRESS), which is associated with various systemic manifestations, including fever, lymphadenopathy, facial edema, blood, liver, and kidney dysfunction. The syndrome occurs with varying degrees of severity and in rare cases can lead to DIC (disseminated intravascular coagulation) syndrome and multiple organ failure. It is important to note that early manifestations of hypersensitivity (i.e., fever, lymphadenopathy) may occur even in the absence of obvious signs of rash. If such symptoms develop, the patient should be immediately examined by a doctor, and if no other cause for the symptoms is identified, lamotrigine should be discontinued. 3 These reactions were observed in clinical practice in other clinical conditions. It has been noted that lamotrigine can worsen the symptoms of parkinsonism in patients with Parkinson's disease, and there is isolated information about extrapyramidal effects and choreoathetosis in patients without this condition. 4 Hepatic dysfunction usually develops with hypersensitivity symptoms, but in isolated cases, it has been observed even in the absence of obvious signs of hypersensitivity. 5 Information is provided that in clinical trials in adults, the incidence of skin rash in patients taking lamotrigine was 8-12%, while in patients taking placebo, it was 5-6%. In 2% of cases, the development of rash led to discontinuation of lamotrigine. Rash, mainly maculopapular, usually appears within the first 8 weeks of starting therapy and resolves after discontinuation of lamotrigine (see section "Special Warnings"). There are reports of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Although symptoms are usually reversible upon discontinuation of lamotrigine, some patients have persistent irreversible scarring, and in rare cases, a fatal outcome has been recorded (see section "Special Warnings"). The overall risk of rash development is significantly associated with: - high initial dose of lamotrigine and exceeding the recommended dose titration rates (see section "Method of administration and dosage"); - concomitant use of valproate (see section "Method of administration and dosage"). Rash development was also considered a manifestation of hypersensitivity syndrome associated with various systemic manifestations (see "Immune system disorders"). There are reports of reduced bone mineral density, osteopenia, osteoporosis, and fractures in patients on long-term lamotrigine therapy. The mechanism of lamotrigine's effect on bone metabolism is not determined. Contraindications. Hypersensitivity to lamotrigine or other components of the preparation. Overdose. Symptoms and manifestations. There are reports of cases of acute overdose with doses 10-20 times the maximum therapeutic dose, including fatal cases. Symptoms of overdose: ataxia, nystagmus, impaired consciousness, generalized epileptic seizures, coma, widening of the QRS complex (intraventricular conduction delay). Widening of the QRS complex to over 100 ms may be associated with a more severe toxic effect of the drug. Treatment: Hospitalization of the patient in an intensive care unit with appropriate symptomatic and supportive therapy is necessary. Activated charcoal is recommended to reduce lamotrigine absorption. Further treatment is carried out according to the clinical situation. There is no experience with the use of hemodialysis for overdose treatment. In a study of 6 volunteers with renal failure, 20% of lamotrigine was eliminated from the body during a four-hour hemodialysis session. Special warnings. Skin rash. A skin side reaction in the form of rash may develop within the first 8 weeks of starting lamotrigine treatment. In most cases, the rash is mild and resolves without treatment, however, reports of severe skin reactions requiring hospitalization and discontinuation of the drug have been provided. These include the development of potentially life-threatening rashes, specifically Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as drug reaction with eosinophilia and systemic symptoms (DRESS); also known as hypersensitivity syndrome (HSS) (see section "Adverse reactions"). Patients who have developed Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic manifestations (DRESS) after using lamotrigine cannot be re-prescribed lamotrigine. It is known that in adults participating in studies using current recommended lamotrigine dosing, the incidence of severe skin rash was approximately 1 in 500 patients with epilepsy. About half of these cases were diagnosed with Stevens-Johnson syndrome (1 in 1000). The incidence of severe skin rash in patients with bipolar disorder is 1 in 1000. The risk of serious skin rash is higher in children than in adults. It is known that according to data from lamotrigine use studies, the incidence of rash requiring hospitalization in children ranges from 1 in 300 to 1 in 100 patients. In children, the first signs of skin rash may be mistaken for an infection, so doctors should be aware of the possibility of developing a drug reaction in children who develop rash and fever within the first 8 weeks of therapy. The overall risk of rash development is clearly closely related to high initial doses of lamotrigine and exceeding the recommended dose titration regimen during lamotrigine therapy (see section "Method of administration and dosage"), as well as concomitant use of valproate (see section "Method of administration and dosage"). Lamotrigine should be prescribed with caution to patients with a history of allergy or rash with other antiepileptic drugs, as the incidence of mild rash after lamotrigine treatment in this group of patients was 3 times higher than in the group without such a history. All patients (adults and children) who develop a rash should be immediately examined by a doctor, and treatment with lamotrigine should be immediately discontinued, unless the rash is not related to lamotrigine intake. Resumption of lamotrigine intake is not recommended in cases where its previous prescription was discontinued due to the development of skin reactions. In this case, when deciding on re-prescription, the expected benefit and potential risk of treatment should be considered. Information is provided that rash is part of DRESS syndrome, also known as hypersensitivity syndrome. This condition is accompanied by various systemic symptoms, including fever, lymphadenopathy, facial edema, blood changes, liver and kidney dysfunction, aseptic meningitis (see section "Adverse reactions"). The syndrome can have varying degrees of severity and can sometimes lead to disseminated intravascular coagulation and multiple organ failure. Early signs of hypersensitivity (e.g., fever, lymphadenopathy) may occur even in the absence of rash. If such symptoms occur, the patient should be immediately examined, and if no other cause is identified, lamotrigine intake should be discontinued. In most cases, aseptic meningitis is reversible after discontinuation of the drug, but in some cases it may recur upon re-administration of lamotrigine. Re-administration of lamotrigine leads to a rapid return of symptoms, which are often more severe. Patients should not resume lamotrigine therapy after its discontinuation due to the development of aseptic meningitis. Reports of photosensitivity reactions associated with lamotrigine intake have also been received (see section "Adverse reactions"). In some cases, the reaction occurred at high doses of lamotrigine (400 mg or more), during dose titration, or at increased dose titration rates. If photosensitivity reaction is suspected, associated with lamotrigine intake (e.g., severe sunburn), it is necessary to discontinue treatment with the drug. If continuation of lamotrigine treatment is considered clinically appropriate, the patient is advised to avoid sun exposure and artificial UV radiation and use protective measures (e.g., protective clothing and sunscreen). Hemophagocytic lymphohistiocytosis (HLH). HLH has been reported in patients taking lamotrigine (see Adverse Reactions). HLH is characterized by the following signs and symptoms: fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, increased serum ferritin levels, hypertriglyceridemia, and liver and blood coagulation disorders. Symptoms usually appear within 4 weeks of starting treatment. Patients should be informed about the symptoms associated with HLH and advised to seek immediate medical attention if these symptoms develop during lamotrigine treatment. Patients presenting with these signs and symptoms should be immediately evaluated, and the diagnosis of HLH should be considered. Lamotrigine treatment should be immediately discontinued if no other cause for the development of symptoms can be identified. Suicidal risk. Patients with epilepsy may experience symptoms of depression and/or bipolar disorder, and there is evidence that patients with epilepsy and bipolar disorder have an increased risk of suicidality. 25% to 50% of patients with bipolar disorder have experienced at least one suicide attempt. They may experience worsening of depressive symptoms and/or manifestation of suicidal impulses and behavior (suicide), regardless of whether they are taking medications for bipolar disorder, such as lamotrigine. Suicidal ideation and behavior have been reported in patients with various indications, including epilepsy, treated with antiepileptic drugs. Meta-analysis data on the use of antiepileptic drugs, including lamotrigine, have demonstrated a small increase in the risk of suicidal ideation and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility of an increased risk associated with lamotrigine use. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior. If such signs are detected, patients and their caregivers should seek medical attention. Clinical worsening in bipolar disorder. Patients taking lamotrigine for bipolar disorder should be closely monitored to avoid missing clinical worsening (including the emergence of new symptoms) or suicidality, especially at the beginning of treatment or during dose changes. In patients with a history of suicidal behavior or thoughts, as well as in those who exhibit suicidal ideation before starting treatment, there may be a higher risk of suicidal thoughts or suicide attempts, requiring close monitoring during treatment. Patients and their caregivers should be warned about the need to monitor for any worsening of their condition (including the emergence of new symptoms) and/or the occurrence of suicidal ideation/attempts or self-harm, so that they can seek medical attention promptly if these symptoms occur. At the same time, it is necessary to assess the situation and make appropriate changes to the therapeutic regimen, including possible discontinuation of treatment for patients if clinical worsening (including the emergence of new symptoms) and/or suicidal ideation/behavior occurs, especially if these symptoms are severe, appear suddenly, and are not part of existing symptoms. Hormonal contraceptives. Effect of hormonal contraceptives on the efficacy of lamotrigine. Data have been received indicating that the combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg doubles the elimination of lamotrigine, which in turn reduces lamotrigine levels (see section "Interactions with other medicinal products and other types of interactions"). In most cases, an increase in the maintenance dose of lamotrigine (through titration) (doubled) will be necessary to achieve maximum therapeutic effect. In women who have not yet taken enzyme-inducing drugs and are already using hormonal contraceptives with a one-week break between cycles (so-called pill-free week), a gradual temporary increase in lamotrigine levels may be observed during the pill-free week. This increase will be greater if the lamotrigine dose is increased a few days before or during the one-week break. For detailed information on dosing, see section "General dosing recommendations for special patient groups" in the "Method of administration and dosage" section. Accordingly, women who start oral contraceptives or complete a course of oral contraceptives should be under constant medical supervision, and in most cases, they will require lamotrigine dose adjustment. Other oral contraceptives and hormone replacement preparations have not been studied, but they may have a similar effect on the pharmacokinetics of lamotrigine. Effect of lamotrigine on the efficacy of oral contraceptives. Information has been provided that according to the results of interaction clinical studies involving 16 healthy volunteers, a slight increase in levonorgestrel release and changes in serum levels of follicle-stimulating and luteinizing hormones were observed when lamotrigine was used with hormonal contraceptives (ethinylestradiol 30 mcg/levonorgestrel 150 mcg combination) (see section "Interactions with other medicinal products and other types of interactions"). The effect of these changes on ovulation is unknown. However, the possibility cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives concurrently, these changes may lead to a decrease in the efficacy of the latter. Therefore, patients should promptly report changes in their menstrual cycle, such as the occurrence of sudden bleeding. Effect of lamotrigine on organic cation transporter 2 (OCT 2) substrates. Lamotrigine is an inhibitor of renal tubular secretion via organic protein transporters for cations (see section "Interactions with other medicinal products and other types of interactions"). This may lead to an increase in plasma levels of some drugs that are primarily excreted via the above pathway. Therefore, the use of lamotrigine with OCT 2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended. Dihydrofolate reductase. Lamotrigine is a weak inhibitor of dihydrofolate reductase, therefore, with prolonged use of lamotrigine, its metabolism of folates may be affected. However, with prolonged use of lamotrigine, no significant changes in hemoglobin levels, mean red blood cell volume, serum and red blood cell folate concentrations are observed within 1 year, and also in red blood cell folate concentrations within 5 years. Renal insufficiency. In a single-dose study in patients with end-stage renal failure, plasma lamotrigine concentration did not change significantly. However, accumulation of the glucuronide metabolite is possible. Use of the preparation in patients with kidney damage requires caution. Patients taking other preparations containing lamotrigine. Patients taking other preparations containing lamotrigine should not take lamotrigine without consulting a doctor. Brugada-like changes on ECG. Arrhythmogenic ST-T anomalies and typical Brugada ECG were observed on ECG in patients taking lamotrigine. In this regard, before using lamotrigine in patients with Brugada syndrome, the possibility of such treatment should be thoroughly considered. Development in children. There is no information on the effect of lamotrigine on growth, sexual maturation, as well as cognitive, emotional, and behavioral development in children. Epilepsy. Abrupt discontinuation of lamotrigine, like other antiepileptic drugs, can provoke an increase in seizure frequency. Except in cases where the patient's condition requires abrupt discontinuation of the drug (e.g., in case of rash), the lamotrigine dose should be gradually reduced over at least 2 weeks. According to published data, severe epileptic seizures can cause rhabdomyolysis, multiple organ failure, and disseminated intravascular coagulation syndrome, sometimes with a fatal outcome. Similar cases are possible during lamotrigine treatment. Significant clinical worsening of seizure frequency may be observed instead of improvement in condition. In patients with more than one type of seizure, improvement in control of one type of seizure should be carefully assessed for worsening of control of other types of seizures. Lamotrigine treatment may exacerbate myoclonic seizures. There is data that the response to treatment with enzyme inducers is weaker than with treatment with antiepileptic drugs that do not induce enzymes. The reason for this is unknown. In the treatment of children with typical absence seizures, efficacy is not achieved in all patients. Bipolar disorders. Children (under 18 years of age). Antidepressant treatment is associated with an increased risk of suicidal ideation and behavior in children (under 18 years of age) with major depressive disorder and other mental disorders. Fertility. Lamotrigine use has been known not to impair fertility in animal reproductive studies. There is no data on the effect of lamotrigine on human fertility. Teratogenicity. Lamotrigine is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of congenital malformations in the human fetus if a woman is treated with folate inhibitors during pregnancy. However, reproductive toxicology studies in animals using lamotrigine at doses lower than the human dose of 400 mg/day [calculated on body surface area (mg/m2)] showed toxic effects on offspring development (increased mortality, decreased body weight, increased structural changes, neurobehavioral disorders), but no teratogenic effect was detected. The preparation contains lactose, so it is not recommended for patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free. Use during pregnancy and breastfeeding. Risks associated with the use of antiepileptic drugs in general. Women of reproductive age require specialist consultation. The issue of antiepileptic drug (AED) treatment should be discussed when a woman plans pregnancy. Women undergoing treatment for epilepsy should avoid abrupt discontinuation of AEDs, as this can lead to recurrence of epileptic seizures and may have serious consequences for the woman and the fetus. In all cases, monotherapy should be preferred, as the use of combination therapy with AEDs may be associated with an increased risk of congenital malformations compared to monotherapy, depending on the AED used. Risks associated with lamotrigine use. Pregnancy. A large amount of data on pregnant women undergoing lamotrigine monotherapy in the first trimester (over 8700) 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 weak inhibitory effect on dihydrofolate reductase and, therefore, can theoretically increase the risk of embryonic developmental disorders by reducing folic acid levels (see section "Special Warnings"). Therefore, attention should be paid to the need for folic acid intake when planning pregnancy and in its early stages. Physiological changes during pregnancy can affect lamotrigine levels and/or its therapeutic effect. Cases of decreased lamotrigine levels during pregnancy have been reported, potentially increasing the risk of loss of seizure control. After childbirth, lamotrigine levels can rapidly increase with the potential risk of dose-dependent adverse reactions. Therefore, lamotrigine levels in serum should be checked before, during, and after childbirth. If necessary, the lamotrigine dose should be modified to maintain lamotrigine levels in serum at pre-pregnancy levels, or adjusted according to the clinical situation. Dose-dependent adverse reactions should also be monitored after childbirth. Breastfeeding. Information is available that lamotrigine is excreted in breast milk at variable concentrations. At the same time, the level of lamotrigine in the newborn can reach 50% of the corresponding maternal level. Therefore, in some breastfed infants, lamotrigine levels in serum may reach levels at which pharmacological effects are possible. In this regard, the benefits of breastfeeding should be weighed against the potential risk of adverse reactions in the infant. If a woman undergoing lamotrigine treatment decides to breastfeed, the infant should be closely monitored for adverse events such as sedation, rash, and insufficient weight gain. Fertility. Animal studies have not revealed any effect of lamotrigine on fertility. Children. The effect of lamotrigine in children under 2 years of age as monotherapy or in children under 1 month of age as adjunctive therapy 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, it is not recommended for children in this age group. Lamotrigine is not indicated in children and adolescents (under 18 years of age) with bipolar disorder, as the efficacy of the drug has not been established, and also due to the increased risk of suicidal ideation (see section "Special Warnings"). Effect on ability to drive or operate machinery. Available data indicate that the effect of lamotrigine related to visual coordination, eye movements, body control, and subjective sedative effect does not differ from placebo. In clinical studies using lamotrigine, neurological side effects such as dizziness and diplopia were observed, so patients should first assess their own reaction to lamotrigine treatment before starting to drive or operate machinery. Since there is an individual response to antiepileptic drugs, the patient should consult a doctor for advice on driving a car in these cases. Interactions with other medicinal products and other types of interactions. It has been established that uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for the metabolism of lamotrigine. Thus, drugs that induce or inhibit glucuronidation can affect lamotrigine clearance. Strong or moderate inducers of the cytochrome P450 (CYP3A4) enzyme, known to induce UGT, can also enhance lamotrigine metabolism. There is no evidence that lamotrigine can cause clinically significant stimulation or inhibition of cytochrome P450 oxidizing enzymes. Lamotrigine can induce its own metabolism, but this effect is moderate and has no clinically significant consequences. Drugs proven to have a clinically significant effect on lamotrigine concentration are listed in Table 6. Special dosing recommendations for these drugs are presented in the "General dosing recommendations for special patient groups" section of the "Method of administration and dosage" section. Table 6 also lists drugs that have been shown to have little or no effect on lamotrigine concentration. Generally, no clinical effect is expected with concomitant use of these drugs. However, caution should be exercised in patients with epilepsy whose disease state is particularly sensitive to fluctuations in lamotrigine concentration. Table 6. Effect of other medicinal products on lamotrigine glucuronidation. Medicinal products that increase lamotrigine concentration Medicinal products that decrease lamotrigine concentration Medicinal products that have little or no effect on lamotrigine concentration Valproate Atazanavir/ritonavir Carbamazepine Combination "ethinylestradiol/levonorgestrel" Lopinavir/ritonavir Phenobarbital Phenytoin Primidone Rifampicin Aripiprazole Bupropion Felbamate Gabapentin Lacosamide Levetiracetam Lithium Olanzapine Oxcarbazepine Paracetamol Perampanel Pregabalin Topiramate Zonisamide Detailed dosing information can be found in the subsection "General dosing recommendations for special patient groups" of the section "Method of administration and dosage". Dosing instructions for women taking hormonal contraceptives can be found in the subsection "Hormonal contraceptives" of the section "Special Warnings"). Interactions with antiepileptic drugs (see also section "Method of administration and dosage"). Valproate, which inhibits lamotrigine glucuronidation, slows down lamotrigine metabolism and approximately doubles its mean half-life. Some antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 microsomal enzymes, induce UGT and accelerate lamotrigine metabolism. There are reports of central nervous system side effects, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients taking carbamazepine concurrently with lamotrigine. These events usually resolve with a reduction in carbamazepine dose. Similar effects were observed in a study of lamotrigine and oxcarbazepine involving healthy adult volunteers, but a dose reduction study was not conducted. It is known that in a study involving healthy adult volunteers who received a dose of 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not change lamotrigine metabolism, and lamotrigine, in turn, did not change oxcarbazepine metabolism. There are reports that a study in healthy volunteers found that co-administration of felbamate 1200 mg twice daily and lamotrigine 100 mg twice daily for 10 days did not have a clinically significant effect on the pharmacokinetics of the latter. According to retrospective analysis of plasma levels in patients taking lamotrigine with or without gabapentin, gabapentin did not change the apparent clearance of lamotrigine. It is known that the potential drug interaction between levetiracetam and lamotrigine was studied by assessing the serum concentrations of both drugs in placebo-controlled clinical trials. According to this data, the substances do not change each other's pharmacokinetics. Stable plasma lamotrigine concentration is not changed with concomitant use of pregabalin (200 mg three times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin. Topiramate does not affect lamotrigine plasma concentrations. Lamotrigine use increases topiramate concentration by 15%. It is known that according to study data, the use of zonisamide (200-400 mg/day) with lamotrigine (150-500 mg/day) for 35 days for epilepsy treatment did not significantly affect the pharmacokinetics of lamotrigine. Plasma lamotrigine concentration was not affected by its co-administration with lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial seizures. Additionally, according to data from three placebo-controlled clinical trials of concomitant perampanel use in patients with partial and primary generalized tonic-clonic seizures, the highest dose of perampanel studied (12 mg/day) increased lamotrigine clearance by less than 10%. Although changes in plasma concentrations of other antiepileptic drugs have been described, available study data indicate that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic drugs. In vitro study results showed that lamotrigine does not affect the binding of other antiepileptic drugs to plasma proteins. Interactions with other psychotropic substances (see section "Method of administration and dosage"). It is known that in a study of 20 patients taking lamotrigine 100 mg daily and lithium gluconate 2 g twice daily for 6 days, lithium pharmacokinetics did not change. Multiple oral doses of bupropion did not have a statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients, with only a slight increase in lamotrigine glucuronide levels observed. It is known that in studies involving healthy volunteers, 15 mg of olanzapine reduced the area under the lamotrigine concentration-time curve (AUC) and maximum concentration (Cmax) by an average of 24% and 20%, respectively. Lamotrigine 200 mg did not affect olanzapine pharmacokinetics. Multiple oral doses of lamotrigine 400 mg/day did not have a clinically significant effect on the pharmacokinetics of risperidone at a single dose of 2 mg. When risperidone 2 mg was used with lamotrigine, somnolence was observed. Available data indicate that no cases of somnolence were observed with lamotrigine alone. It is known that in a clinical study involving 18 adult patients with bipolar disorder taking lamotrigine (≥100 mg/day) and aripiprazole with gradual dose increase from 10 mg/kg to 30 mg/kg over 7 days, and then for the next 7 days, a decrease in lamotrigine AUC and Cmax by approximately 10% was observed. Such changes are not expected to have clinical consequences. In vitro experimental results showed that amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam had only a minimal effect on the formation of lamotrigine's primary metabolite, 2-N-glucuronide. Based on data from studies of bufuralol metabolism in human liver microsomes, it can be determined that lamotrigine does not reduce the clearance of drugs that are primarily metabolized by CYP 2D6. In vitro experimental results allow to confirm that clozapine, phenelzine, risperidone, sertraline, or trazodone cannot affect lamotrigine clearance. Interactions with hormonal contraceptives. Effect of hormonal contraceptives on lamotrigine pharmacokinetics. Data indicate that the combination "ethinylestradiol 30 mcg/levonorgestrel 150 mcg" doubles the elimination of lamotrigine, which in turn reduces the area under the lamotrigine curve (AUC) and Cmax by an average of 52% and 39%, respectively. In the case of a one-week break in contraceptive use (so-called pill-free week), serum lamotrigine concentrations steadily increased, reaching concentrations approximately twice as high as during combined drug use (see sections "Method of administration and dosage" and "Special Warnings"). Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives. It is known that, according to studies, an unchanged dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinylestradiol, which is part of a combined oral contraceptive tablet. A slight, constant increase in levonorgestrel release was observed, which in turn led to a decrease in levonorgestrel AUC and Cmax by an average of 19% and 12%, respectively. Measurements of serum levels of follicle-stimulating hormone and luteinizing hormone and estradiol during the studies showed suppression of ovarian hormonal activity in some women, however, progesterone levels in serum showed that no woman had any hormonal symptoms of ovulation. The effect of changes in serum levels of follicle-stimulating and luteinizing hormones and a slight increase in levonorgestrel release on ovarian ovulatory activity is unknown (see section "General dosing recommendations for special patient groups" in the section "Method of administration and dosage" for dosing in women taking hormonal contraceptives and subsection "Hormonal contraceptives" in the section "Special Warnings"). It is known that the effect of a daily dose of lamotrigine 300 mg has not been studied. Information is provided that studies of other hormonal contraceptives have also not been conducted. Interactions with other medicinal products. It is known that in studies involving 10 male volunteers taking rifampicin, the level of lamotrigine elimination increased and its half-life decreased, as a result of induction of liver enzymes responsible for glucuronidation. In patients receiving rifampicin therapy, the treatment regimen recommended for lamotrigine with appropriate glucuronidation inducers should be used (see section "Method of administration and dosage"). According to studies involving healthy volunteers, lopinavir/ritonavir approximately halves plasma lamotrigine concentrations through glucuronidation induction. For patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for lamotrigine with appropriate glucuronidation inducers should be used (see section "Method of administration and dosage"). Use of atazanavir/ritonavir (300 mg/100 mg) reduces lamotrigine AUC and Cmax in plasma (at a dose of 100 mg) by an average of 32% and 6%, respectively. (see subsection "General dosing recommendations for special patient groups" in the section "Method of administration and dosage"). According to data from studies in healthy volunteers, paracetamol 1g dose (4 times daily) reduced lamotrigine AUC and Cmin in plasma by an average of 20% and 25%, respectively. In vitro study data on the effect of lamotrigine on organic cation transporters 2 (OCT 2) showed that lamotrigine, but not the N(2)-glucuronide metabolite, is an OCT 2 inhibitor at potentially clinically significant concentrations. Lamotrigine is a stronger inhibitor of OCT 2 with IC50 values of 53.8 μM and 186 μM, respectively (see section "Special Warnings"). Interactions using laboratory tests. Information is provided on the effect of lamotrigine on tests used for rapid determination of certain drugs in urine, which may result in false-positive results, especially for phencyclidine. To confirm positive results, an alternative, more specific chemical method should be used. Dosage form. 10 tablets in a blister; 3 or 6 blisters in a cardboard box. Storage conditions Store in the original packaging, protected from light and moisture, at a temperature not exceeding 250C. Keep out of reach of children. Shelf life 3 years. Dispensing category: Pharmaceutical product group - II. Dispensed with prescription form №3. Manufacturer. Pharmastart LLC, Ukraine, 03124, Kyiv, V. Haveli Blvd #8.

Active

lamotrigine

What is it?

LAMICTAL 25 LAMICTAL 50 LAMICTAL 100 Trade name of the medicinal product: LAMICTAL. International nonproprietary name: Lamotrigine. Dosage form: Tablets. General characteristics: 1 tablet contains: Active substance: Lamotrigine 25 mg or 50 mg, 100 mg; Excipients: Microcrystalline cellulose, colloidal anhydrous silica, povidone, sodium starch glycolate (type A), lactose monohydrate, magnesium stearate. Description: White or almost white tablets, round, biconvex, with a score line (LAMICTAL 50 and LAMICTAL 100), without a score line (LAMICTAL 25). Pharmacotherapeutic group: Antiepileptic agents. Lamotrigine. ATC code N03AX09. Pharmacological properties. Pharmacodynamics. Lamotrigine is an anticonvulsant whose mechanism of action is related to the blockade of voltage-dependent sodium channels in the presynaptic membranes of neurons in the slow inactivation phase and the suppression of excessive glutamate release (amino acids that play an important role in the development of epileptic seizures). Pharmacokinetics. After oral administration, the drug is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration is reached approximately 2.5 hours later. Lamotrigine undergoes active metabolism, the main metabolite being N-glucuronide. The half-life in adults averages 29 hours. Lamotrigine has a linear pharmacokinetic profile. It is excreted mainly in the form of metabolites and partly unchanged, predominantly in the urine. The half-life in children is shorter than in adults. Special patient groups. Children. Clearance dependent on body weight is higher in children than in adults, with the highest values in children under 5 years of age. The half-life of lamotrigine in children is generally shorter than in adults, with an average value of approximately 7 hours when co-administered with enzyme inducers such as carbamazepine and phenytoin, and an increase to an average period of 45 to 50 hours when co-administered with valproate alone. Elderly patients. Information is provided that pharmacokinetic analysis results in patient groups including both elderly and young epileptic patients participating in the study showed that lamotrigine clearance did not change to a clinically significant extent. After single doses, apparent clearance decreased by 12% from 35 ml/min/kg in patients aged 20 years to 31 ml/min/kg in patients aged 70 years. After 48 weeks of treatment, the decrease was 10% from 41 ml/min in young patients to 37 ml/min in elderly patients. Information is provided that the pharmacokinetics of lamotrigine were studied in 12 healthy elderly patients who received a single dose of 150 mg. The mean clearance in elderly patients (0.39 ml/min/kg) falls within the range of mean clearance (0.31 to 0.65 ml/min/kg) obtained in 9 studies conducted in non-elderly adult patients after receiving single doses from 30 to 450 mg. Patients with renal impairment. 12 volunteers with chronic renal impairment and 6 patients on hemodialysis received a single dose of 100 mg of lamotrigine. Mean CL/F values were 0.42 ml/min/kg (chronic renal impairment), 0.33 ml/min/kg (interdialytic period), and 1.57 ml/min/kg (during hemodialysis), compared to 0.58 ml/min/kg in healthy patients. The mean plasma half-life was 42.9 hours (chronic renal impairment), 57.4 hours (interdialytic period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy patients. During a four-hour hemodialysis session, the amount of lamotrigine decreased by approximately 20% (from 5.6 to 35.1). The initial dose for patients in this group should be based on the patient's antiepileptic drug regimen; a reduction in the maintenance dose may be effective for patients with significant renal impairment. Patients with hepatic impairment. Single-dose pharmacokinetic studies were conducted in patients with varying degrees of hepatic impairment and in healthy volunteers. The mean apparent clearance of lamotrigine was 0.31 ml/min/kg, 0.24 ml/min/kg, and 0.10 ml/min/kg in patients with hepatic impairment of grades A, B, and C (Child-Pugh classification), respectively, compared to 0.34 ml/min/kg in healthy patients. Generally, initial, titration, and maintenance doses should be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh grade B) and by 75% in patients with severe hepatic impairment (Child-Pugh grade C). Titration and maintenance doses should be adjusted according to the response to treatment. Indications for use. Epilepsy. Adults and children aged 13 years and older: Monotherapy and adjunctive therapy for partial and generalized epileptic seizures, including tonic-clonic seizures, and also seizures associated with Lennox-Gastaut syndrome. LAMICTAL is indicated as adjunctive therapy, but in Lennox-Gastaut syndrome, it can be prescribed as an initial antiepileptic drug (AED). Children aged 2 to 12 years: Adjunctive therapy for epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures, and also seizures associated with Lennox-Gastaut syndrome. Monotherapy for typical absence seizures. Bipolar disorder in adults. Adults (from 18 years of age). For the prevention of depressive episodes in patients with bipolar I disorder who predominantly experience depressive episodes. Lamotrigine is not indicated for the emergency treatment of manic or depressive episodes. Method of administration and dosage. LAMICTAL tablets should be taken whole, without chewing or crushing. If the calculated dose of lamotrigine (e.g., for the treatment of children with epilepsy or patients with hepatic impairment) is not a multiple of whole tablets, the dose should correspond to the nearest lower whole tablet quantity. If lamotrigine dosage is not possible in children, other dosage forms of lamotrigine with appropriate dosing should be used. Resumption of treatment. Physicians should assess the need to increase the dose to the maintenance dose when resuming lamotrigine in patients who have discontinued lamotrigine for any reason, as the risk of developing severe rash is associated with high initial doses and exceeding the recommended lamotrigine dose titration regimen (see section "Special Warnings"). The longer the interval since the last dose, the more attention should be paid to the dose titration regimen to the maintenance dose. When the interval after discontinuation of lamotrigine exceeds 5 times the half-life (see section "Pharmacokinetics"), the lamotrigine dose should be increased to the maintenance dose according to the existing schedule. Resumption of lamotrigine treatment is not recommended if treatment was discontinued due to rash caused by previous treatment. In this case, when deciding on re-prescription, the expected benefit and potential risk of treatment should be assessed. Epilepsy. The recommended dose titration regimen and maintenance dose levels for adults and adolescents aged 13 years and older (Table 1), as well as for children and adolescents aged 2 to 12 years (Table 2) are provided below. Do not exceed the initial dose, and the dose titration regimen should not be exceeded due to the risk of developing skin rash (see section "Special Warnings"). The possible impact of withdrawal or addition of other concomitant anticonvulsants and other medications on the pharmacokinetics of lamotrigine should be considered (see section "Interactions with other medicinal products and other types of interactions"). Table 1: Dosing regimen for epilepsy in adults and children aged 13 years and older. Treatment regimen Weeks I-II Weeks III-IV Usual maintenance dose Monotherapy 25 mg/day (once daily) 50 mg/day (once daily) 100-200 mg/day (in 1 or 2 doses). The dose can be increased by 50-100 mg every 1-2 weeks to the maintenance dose until therapeutic effect is achieved. Some patients may require a dose of 500 mg/day to achieve the desired therapeutic effect. Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") The specified dosing regimen should be used, regardless of concomitant therapy with other medications 12.5 mg/day (25 mg every other day) 25 mg/day (once daily) 100-200 mg daily (in 1 or 2 doses). The dose can be increased by 25-50 mg every 1-2 weeks until therapeutic effect is achieved. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 50 mg/day (once daily) 100 mg/day (in 2 doses) 200-400 mg daily (in 2 doses). The dose can be increased by 100 mg every 1-2 weeks to the maintenance dose until therapeutic effect is achieved. Some patients may require a dose of 700 mg/day to achieve the desired therapeutic effect. Adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 25 mg/day (once daily) 50 mg/day (once daily) 100-200 mg daily (once daily or in 2 doses). The dose can be increased by a maximum of 50-100 mg every 1-2 weeks until therapeutic effect is achieved. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 2. Children aged 2 to 12 years: Recommended dosing regimen for epilepsy treatment (total daily dose, mg/kg body weight)**. Treatment regimen Weeks I-II Weeks III-IV Usual maintenance dose Monotherapy for typical absence seizures 0.3 mg/kg/day (once daily or divided into 2 doses) 0.6 mg/kg/day (once daily or divided into 2 doses) 1-15 mg/kg/day (in 1 or 2 doses). To achieve the maintenance regimen, the dose can be increased by no more than 0.6 mg/kg/day every 1-2 weeks until therapeutic effect is achieved. The maximum maintenance dose is 200 mg/day. Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used, regardless of concomitant therapy with other medications. 0.15 mg/kg/day * (once daily) 0.3 mg/kg/day (once daily) 1-5 mg/kg/day (once daily or divided into 2 doses). To achieve the maintenance regimen, the dose can be increased by no more than 0.3 mg/kg/day every 1-2 weeks until optimal effect is achieved. The maximum maintenance dose is 200 mg/day. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 0.6 mg/kg/day (divided into 2 doses) 1.2 mg/kg/day (divided into 2 doses) 5-15 mg/kg/day (once daily or in 2 doses). The dose can be increased by no more than 1.2 mg/kg every 1-2 weeks until the maintenance dose is reached. The maximum maintenance dose is 400 mg/day. Adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 0.3 mg/kg/day (once daily or divided into 2 doses) 0.6 mg/kg/day (once daily or divided into 2 doses) 1-10 mg/kg/day (once daily or divided into 2 doses). The dose can be increased by no more than 0.6 mg/kg every 1-2 weeks until the maintenance dose is reached. The maximum maintenance dose is 200 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. * If the calculated daily dose in patients receiving valproate is 1 mg or more, but not more than 2 mg, it is permissible to take 2 mg of lamotrigine in the form of dispersible tablets every other day for the first 2 weeks. If the calculated daily dose in patients receiving valproate is less than 1 mg, lamotrigine intake is not recommended. Lamotrigine withdrawal in patients with bipolar disorder. No increase in the frequency, severity, or type of adverse reactions was observed after abrupt discontinuation of the drug compared to placebo. Therefore, discontinuation of the drug is possible abruptly, without gradual dose reduction. Children (under 18 years of age). Lamotrigine is not recommended for use in children (under 18 years of age) with bipolar disorder, as randomized discontinuation studies have not shown its significant efficacy and have shown an increase in suicidal ideation (see section "Special Warnings"). Table 3. Recommended maintenance daily doses and titration regimens for bipolar disorder treatment - in patients aged 18 years and older. Treatment regimen Weeks I-II Weeks III-IV Week V Target maintenance dose (Week VI)* Dose (Week VI)* Monotherapy with lamotrigine or adjunctive therapy without valproates and lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with other medications that do not significantly affect the glucuronidation process of lamotrigine. 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day (once daily or divided into 2 doses) 200 mg/day - usual maintenance dose (once daily or divided into 2 doses). Doses in the range of 100-400 mg/day have been used in clinical trials. Adjunctive therapy with valproates (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with valproates, regardless of concomitant therapy with other medications. 12.5 mg/day (taken 25 mg every other day) 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day is the usual maintenance dose (once daily or divided into 2 doses). 200 mg/day is the maximum dose that can be prescribed according to clinical response. Adjunctive therapy with valproates (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when co-administered with valproates, regardless of concomitant therapy with other medications. 12.5 mg/day (taken 25 mg every other day) 25 mg/day (once daily) 50 mg/day (once daily or divided into 2 doses) 100 mg/day is the usual maintenance dose (once daily or divided into 2 doses). 200 mg/day is the maximum dose that can be prescribed according to clinical response. Adjunctive therapy without valproates, but with lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir 50 mg/day (once daily) 100 mg/day (divided into 2 doses) 200 mg/day (divided into 2 doses) 300 mg/day on the 6th week of administration. If necessary, the dose can be increased to 400 mg/day on the 7th week (divided into 2 doses) to achieve optimal effect. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 4. Adults (over 18 years of age): Maintenance stabilizing daily doses for bipolar disorder treatment after withdrawal of concomitant medications. Treatment regimen Current stabilizing dose of lamotrigine (before withdrawal) Week I (start of withdrawal) Week II Weeks III and subsequent * Withdrawal of valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine When withdrawing valproates, the stabilizing dose needs to be doubled, but not more than 100 mg/week. 100 mg/day 200 mg/day 200 mg/day 300 mg/day 200 mg/day, divided into 2 doses 400 mg/day 400 mg/day Withdrawal of lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine This dosing regimen should be used when discontinuing phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir. 400 mg/day 300 mg/day 200 mg/day 400 mg/day 300 mg/day 200 mg/day 300 mg/day 225 mg/day 150 mg/day 200 mg/day 150 mg/day 100 mg/day Withdrawal of medications that do not significantly affect lamotrigine glucuronidation (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when discontinuing medications that do not have a significant inhibitory or inducing effect on lamotrigine glucuronidation. Maintain the target dose achieved during titration (200 mg/day, divided into 2 doses). The dose range is 100-400 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Table 5: Maintenance stabilizing daily doses of lamotrigine for bipolar disorder treatment with subsequent addition of other medications - in patients aged 18 years and older. Clinical experience of lamotrigine daily dose adjustment when adding other medications is not available. However, based on drug interaction studies, the following recommendations can be made: Treatment regimen Current stabilizing dose of lamotrigine (before adding new medication) Week I (start of adding new medication) Week II Weeks III and subsequent Addition of valproate (inhibitor of lamotrigine glucuronidation - see section "Interactions with other medicinal products and other types of interactions") According to the initial dose of lamotrigine This dosing regimen should be used when adding valproate, regardless of concomitant therapy with other medications. 200 mg/day 300 mg/day 400 mg/day 100 mg/day 150 mg/day 200 mg/day Maintain this dose (100 mg/day) Maintain this dose (150 mg/day) Maintain this dose (200 mg/day) Addition of lamotrigine glucuronidation inducers (see section "Interactions with other medicinal products and other types of interactions") In patients not taking valproates (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used if valproates are not used, but the following medications are prescribed: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir. 200 mg/day 150 mg/day 100 mg/day 200 mg/day 150 mg/day 100 mg/day 300 mg/day 225 mg/day 150 mg/day 400 mg/day 300 mg/day 200 mg/day Addition of medications that do not significantly affect lamotrigine glucuronidation (see section "Interactions with other medicinal products and other types of interactions") This dosing regimen should be used when adding other medications that do not significantly affect lamotrigine glucuronidation. Maintain the target dose achieved during titration (200 mg/day). The dose range is 100-400 mg/day. Note: In patients taking medications whose pharmacokinetic interaction with lamotrigine is unknown (see section "Interactions with other medicinal products and other types of interactions"), the same dosing regimen as for valproate use should be used. Recommendations for special patient groups. Women taking hormonal contraceptives. It is known that the use of the combination ethinylestradiol/levonorgestrel (30 mcg/150 mcg) doubles the clearance of lamotrigine, leading to a decrease in lamotrigine levels. Higher (approximately double) maintenance doses of lamotrigine may be required after titration to achieve maximum therapeutic response. During the week when the drug was not taken, a twofold increase in lamotrigine levels was observed. Dose-dependent adverse reactions cannot be ruled out. Therefore, the use of contraception that does not involve weeks without medication should be considered as a first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). Initiation of hormonal contraceptive therapy in patients already receiving maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers. In most cases, a twofold increase in the maintenance dose of lamotrigine will be necessary. It is recommended to increase the lamotrigine dose by 50 to 100 mg/day every week after starting hormonal contraceptive therapy, according to the individual clinical response to treatment. The dose increase should not exceed the indicated level, unless such a dose increase is necessary according to the clinical response to treatment. Measurement of lamotrigine levels in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include a week of inactive treatment (a week without taking tablets), lamotrigine levels in serum should be monitored during the 3rd week of active treatment, i.e., from day 15 to 21 of the tablet intake cycle. The possibility of using contraceptive preparations that do not include a week without tablet intake should be considered as a first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods: see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). Discontinuation of hormonal contraceptive therapy in patients already receiving maintenance doses of lamotrigine and not taking lamotrigine glucuronidation inducers. In most cases, it will be necessary to reduce the maintenance dose of lamotrigine by up to 50% (see section "Special Warnings" and "Interactions with other medicinal products and other types of interactions"). It is recommended that the daily dose of lamotrigine be gradually reduced by 50 to 100 mg weekly (not more than 25% of the total dose per week) over 3 weeks, unless otherwise indicated by the individual clinical response to treatment. Measurement of lamotrigine levels in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. If necessary, the dose should be adjusted. In women taking hormonal contraceptives that include a week of inactive treatment (a week without taking tablets), lamotrigine levels in serum should be monitored during the 3rd week of active treatment, i.e., from day 15 to 21 of the tablet intake cycle. Samples for lamotrigine level assessment should not be taken within 1 week of discontinuing contraceptive intake. Initiation of lamotrigine therapy in women already taking hormonal contraceptives. Dose titration should follow the standard dose recommendations given in the tables. Initiation and discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine, and also taking lamotrigine glucuronidation inducers. Correction of the recommended maintenance dose of lamotrigine is not mandatory. Use with atazanavir/ritonavir. Correction of the recommended dose of lamotrigine when adding it to atazanavir/ritonavir therapy is not mandatory. In patients already using maintenance doses of lamotrigine and not using glucuronidation inducers, the dose of lamotrigine may need to be increased if treatment with atazanavir/ritonavir is added, or decreased if treatment with atazanavir/ritonavir is discontinued. Lamotrigine plasma levels should be monitored for 2 weeks after starting or discontinuing atazanavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interactions with other medicinal products and other types of interactions"). Concomitant use with lopinavir/ritonavir. Correction of the recommended dose of lamotrigine when adding it to lopinavir/ritonavir therapy is not mandatory. For patients already receiving maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased when lopinavir/ritonavir is added, and decreased when lopinavir/ritonavir is discontinued. Lamotrigine plasma levels should be monitored for 2 weeks after starting or discontinuing lopinavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interactions with other medicinal products and other types of interactions"). Elderly patients (from 65 years of age). Dose adjustment of the drug according to the recommended regimen is not necessary. The pharmacokinetics of lamotrigine in this age group do not differ from those in patients under 65 years of age. Hepatic insufficiency. It is necessary to reduce the initial, titration, and maintenance doses, generally by 50% in patients with moderate hepatic impairment (Child-Pugh grade B) and by 75% in patients with severe hepatic impairment (Child-Pugh grade C). Titration and maintenance doses should be adjusted according to clinical effect. Renal insufficiency. Caution should be exercised when prescribing lamotrigine to patients with renal impairment. For patients with end-stage renal failure, the initial dose of lamotrigine is determined based on the prescribed concomitant medications; a reduction in the maintenance dose may be effective in patients with significant renal impairment (see section "Special Warnings"). Adverse reactions. The list of adverse reactions associated with the use of medicinal products for epilepsy and bipolar disorder has been compiled based on available data from controlled clinical trials and clinical experience with the medicinal product. Adverse reactions are listed in the table below. The frequency of adverse reactions was determined in controlled clinical trials of lamotrigine monotherapy (marked with "*") and bipolar disorder (marked with "§"). In case of differences in the frequency of adverse reactions observed in clinical trials in patients with epilepsy and bipolar disorder, the highest frequency category is given. In the absence of controlled clinical trial data, the frequency of adverse reactions is inferred from clinical experience with the use of the medicinal product. The following classification was used to assess the frequency of adverse events: very common (≥1/10), common (≥1/100 - <1/10), uncommon (≥1/1000 - <1/100), rare (≥1/10,000 - <1/1000), very rare (<1/10,000), unknown (cannot be estimated from available data). Skin and subcutaneous tissue disorders. Very common - rash5*§; Uncommon - alopecia, photosensitivity reactions; Rare - Stevens-Johnson syndrome§; Very rare - toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms. Blood and lymphatic system disorders. Very rare - hematological abnormalities1 (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), hemophagocytic lymphohistiocytosis (see section "Special Warnings"); Frequency unknown - lymphadenopathy1. Immune system disorders. Very rare - hypersensitivity syndrome2; Frequency unknown - hypogammaglobulinemia. Psychiatric disorders. Common - irritability, aggression; Very rare - tics, hallucinations, and confusion of consciousness; Frequency unknown - nightmares. Nervous system disorders. Very common - headache§; Common - somnolence*§, insomnia*, dizziness*§, tremor*, anxiety§; Uncommon - ataxia*; Rare: nystagmus*, aseptic meningitis (see section "Special Warnings"); Very rare - instability, movement disorders, exacerbation of Parkinson's disease3, extrapyramidal effects, choreoathetosis*, increased seizure frequency. Eye disorders. Uncommon - diplopia*, blurred vision*; Rare - conjunctivitis. Gastrointestinal disorders. Common - nausea*, vomiting* and diarrhea*, dry mouth§. Hepatobiliary system disorders. Very rare - increased liver function test results, hepatic dysfunction4, liver failure. Musculoskeletal and connective tissue disorders. Common - arthralgia§; Very rare - symptoms of systemic lupus erythematosus. Kidney and urinary system disorders. Frequency unknown - tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis. General disorders. Common - fatigue*, pain§, back pain§. Description of individual adverse reactions. 1 Hematological disorders and lymphadenopathy may be associated with, and not associated with, drug reaction with eosinophilia and systemic symptoms (DRESS) / hypersensitivity syndrome (see sections "Special Warnings" and "Immune system disorders"). 2 Information is also provided that rash is part of hypersensitivity syndrome (DRESS), which is associated with various systemic manifestations, including fever, lymphadenopathy, facial edema, blood, liver, and kidney dysfunction. The syndrome occurs with varying degrees of severity and in rare cases can lead to DIC (disseminated intravascular coagulation) syndrome and multiple organ failure. It is important to note that early manifestations of hypersensitivity (i.e., fever, lymphadenopathy) may occur even in the absence of obvious signs of rash. If such symptoms develop, the patient should be immediately examined by a doctor, and if no other cause for the symptoms is identified, lamotrigine should be discontinued. 3 These reactions were observed in clinical practice in other clinical conditions. It has been noted that lamotrigine can worsen the symptoms of parkinsonism in patients with Parkinson's disease, and there is isolated information about extrapyramidal effects and choreoathetosis in patients without this condition. 4 Hepatic dysfunction usually develops with hypersensitivity symptoms, but in isolated cases, it has been observed even in the absence of obvious signs of hypersensitivity. 5 Information is provided that in clinical trials in adults, the incidence of skin rash in patients taking lamotrigine was 8-12%, while in patients taking placebo, it was 5-6%. In 2% of cases, the development of rash led to discontinuation of lamotrigine. Rash, mainly maculopapular, usually appears within the first 8 weeks of starting therapy and resolves after discontinuation of lamotrigine (see section "Special Warnings"). There are reports of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Although symptoms are usually reversible upon discontinuation of lamotrigine, some patients have persistent irreversible scarring, and in rare cases, a fatal outcome has been recorded (see section "Special Warnings"). The overall risk of rash development is significantly associated with: - high initial dose of lamotrigine and exceeding the recommended dose titration rates (see section "Method of administration and dosage"); - concomitant use of valproate (see section "Method of administration and dosage"). Rash development was also considered a manifestation of hypersensitivity syndrome associated with various systemic manifestations (see "Immune system disorders"). There are reports of reduced bone mineral density, osteopenia, osteoporosis, and fractures in patients on long-term lamotrigine therapy. The mechanism of lamotrigine's effect on bone metabolism is not determined. Contraindications. Hypersensitivity to lamotrigine or other components of the preparation. Overdose. Symptoms and manifestations. There are reports of cases of acute overdose with doses 10-20 times the maximum therapeutic dose, including fatal cases. Symptoms of overdose: ataxia, nystagmus, impaired consciousness, generalized epileptic seizures, coma, widening of the QRS complex (intraventricular conduction delay). Widening of the QRS complex to over 100 ms may be associated with a more severe toxic effect of the drug. Treatment: Hospitalization of the patient in an intensive care unit with appropriate symptomatic and supportive therapy is necessary. Activated charcoal is recommended to reduce lamotrigine absorption. Further treatment is carried out according to the clinical situation. There is no experience with the use of hemodialysis for overdose treatment. In a study of 6 volunteers with renal failure, 20% of lamotrigine was eliminated from the body during a four-hour hemodialysis session. Special warnings. Skin rash. A skin side reaction in the form of rash may develop within the first 8 weeks of starting lamotrigine treatment. In most cases, the rash is mild and resolves without treatment, however, reports of severe skin reactions requiring hospitalization and discontinuation of the drug have been provided. These include the development of potentially life-threatening rashes, specifically Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as drug reaction with eosinophilia and systemic symptoms (DRESS); also known as hypersensitivity syndrome (HSS) (see section "Adverse reactions"). Patients who have developed Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic manifestations (DRESS) after using lamotrigine cannot be re-prescribed lamotrigine. It is known that in adults participating in studies using current recommended lamotrigine dosing, the incidence of severe skin rash was approximately 1 in 500 patients with epilepsy. About half of these cases were diagnosed with Stevens-Johnson syndrome (1 in 1000). The incidence of severe skin rash in patients with bipolar disorder is 1 in 1000. The risk of serious skin rash is higher in children than in adults. It is known that according to data from lamotrigine use studies, the incidence of rash requiring hospitalization in children ranges from 1 in 300 to 1 in 100 patients. In children, the first signs of skin rash may be mistaken for an infection, so doctors should be aware of the possibility of developing a drug reaction in children who develop rash and fever within the first 8 weeks of therapy. The overall risk of rash development is clearly closely related to high initial doses of lamotrigine and exceeding the recommended dose titration regimen during lamotrigine therapy (see section "Method of administration and dosage"), as well as concomitant use of valproate (see section "Method of administration and dosage"). Lamotrigine should be prescribed with caution to patients with a history of allergy or rash with other antiepileptic drugs, as the incidence of mild rash after lamotrigine treatment in this group of patients was 3 times higher than in the group without such a history. All patients (adults and children) who develop a rash should be immediately examined by a doctor, and treatment with lamotrigine should be immediately discontinued, unless the rash is not related to lamotrigine intake. Resumption of lamotrigine intake is not recommended in cases where its previous prescription was discontinued due to the development of skin reactions. In this case, when deciding on re-prescription, the expected benefit and potential risk of treatment should be considered. Information is provided that rash is part of DRESS syndrome, also known as hypersensitivity syndrome. This condition is accompanied by various systemic symptoms, including fever, lymphadenopathy, facial edema, blood changes, liver and kidney dysfunction, aseptic meningitis (see section "Adverse reactions"). The syndrome can have varying degrees of severity and can sometimes lead to disseminated intravascular coagulation and multiple organ failure. Early signs of hypersensitivity (e.g., fever, lymphadenopathy) may occur even in the absence of rash. If such symptoms occur, the patient should be immediately examined, and if no other cause is identified, lamotrigine intake should be discontinued. In most cases, aseptic meningitis is reversible after discontinuation of the drug, but in some cases it may recur upon re-administration of lamotrigine. Re-administration of lamotrigine leads to a rapid return of symptoms, which are often more severe. Patients should not resume lamotrigine therapy after its discontinuation due to the development of aseptic meningitis. Reports of photosensitivity reactions associated with lamotrigine intake have also been received (see section "Adverse reactions"). In some cases, the reaction occurred at high doses of lamotrigine (400 mg or more), during dose titration, or at increased dose titration rates. If photosensitivity reaction is suspected, associated with lamotrigine intake (e.g., severe sunburn), it is necessary to discontinue treatment with the drug. If continuation of lamotrigine treatment is considered clinically appropriate, the patient is advised to avoid sun exposure and artificial UV radiation and use protective measures (e.g., protective clothing and sunscreen). Hemophagocytic lymphohistiocytosis (HLH). HLH has been reported in patients taking lamotrigine (see Adverse Reactions). HLH is characterized by the following signs and symptoms: fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, increased serum ferritin levels, hypertriglyceridemia, and liver and blood coagulation disorders. Symptoms usually appear within 4 weeks of starting treatment. Patients should be informed about the symptoms associated with HLH and advised to seek immediate medical attention if these symptoms develop during lamotrigine treatment. Patients presenting with these signs and symptoms should be immediately evaluated, and the diagnosis of HLH should be considered. Lamotrigine treatment should be immediately discontinued if no other cause for the development of symptoms can be identified. Suicidal risk. Patients with epilepsy may experience symptoms of depression and/or bipolar disorder, and there is evidence that patients with epilepsy and bipolar disorder have an increased risk of suicidality. 25% to 50% of patients with bipolar disorder have experienced at least one suicide attempt. They may experience worsening of depressive symptoms and/or manifestation of suicidal impulses and behavior (suicide), regardless of whether they are taking medications for bipolar disorder, such as lamotrigine. Suicidal ideation and behavior have been reported in patients with various indications, including epilepsy, treated with antiepileptic drugs. Meta-analysis data on the use of antiepileptic drugs, including lamotrigine, have demonstrated a small increase in the risk of suicidal ideation and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility of an increased risk associated with lamotrigine use. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior. If such signs are detected, patients and their caregivers should seek medical attention. Clinical worsening in bipolar disorder. Patients taking lamotrigine for bipolar disorder should be closely monitored to avoid missing clinical worsening (including the emergence of new symptoms) or suicidality, especially at the beginning of treatment or during dose changes. In patients with a history of suicidal behavior or thoughts, as well as in those who exhibit suicidal ideation before starting treatment, there may be a higher risk of suicidal thoughts or suicide attempts, requiring close monitoring during treatment. Patients and their caregivers should be warned about the need to monitor for any worsening of their condition (including the emergence of new symptoms) and/or the occurrence of suicidal ideation/attempts or self-harm, so that they can seek medical attention promptly if these symptoms occur. At the same time, it is necessary to assess the situation and make appropriate changes to the therapeutic regimen, including possible discontinuation of treatment for patients if clinical worsening (including the emergence of new symptoms) and/or suicidal ideation/behavior occurs, especially if these symptoms are severe, appear suddenly, and are not part of existing symptoms. Hormonal contraceptives. Effect of hormonal contraceptives on the efficacy of lamotrigine. Data have been received indicating that the combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg doubles the elimination of lamotrigine, which in turn reduces lamotrigine levels (see section "Interactions with other medicinal products and other types of interactions"). In most cases, an increase in the maintenance dose of lamotrigine (through titration) (doubled) will be necessary to achieve maximum therapeutic effect. In women who have not yet taken enzyme-inducing drugs and are already using hormonal contraceptives with a one-week break between cycles (so-called pill-free week), a gradual temporary increase in lamotrigine levels may be observed during the pill-free week. This increase will be greater if the lamotrigine dose is increased a few days before or during the one-week break. For detailed information on dosing, see section "General dosing recommendations for special patient groups" in the "Method of administration and dosage" section. Accordingly, women who start oral contraceptives or complete a course of oral contraceptives should be under constant medical supervision, and in most cases, they will require lamotrigine dose adjustment. Other oral contraceptives and hormone replacement preparations have not been studied, but they may have a similar effect on the pharmacokinetics of lamotrigine. Effect of lamotrigine on the efficacy of oral contraceptives. Information has been provided that according to the results of interaction clinical studies involving 16 healthy volunteers, a slight increase in levonorgestrel release and changes in serum levels of follicle-stimulating and luteinizing hormones were observed when lamotrigine was used with hormonal contraceptives (ethinylestradiol 30 mcg/levonorgestrel 150 mcg combination) (see section "Interactions with other medicinal products and other types of interactions"). The effect of these changes on ovulation is unknown. However, the possibility cannot be excluded that in some patients taking lamotrigine and hormonal contraceptives concurrently, these changes may lead to a decrease in the efficacy of the latter. Therefore, patients should promptly report changes in their menstrual cycle, such as the occurrence of sudden bleeding. Effect of lamotrigine on organic cation transporter 2 (OCT 2) substrates. Lamotrigine is an inhibitor of renal tubular secretion via organic protein transporters for cations (see section "Interactions with other medicinal products and other types of interactions"). This may lead to an increase in plasma levels of some drugs that are primarily excreted via the above pathway. Therefore, the use of lamotrigine with OCT 2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended. Dihydrofolate reductase. Lamotrigine is a weak inhibitor of dihydrofolate reductase, therefore, with prolonged use of lamotrigine, its metabolism of folates may be affected. However, with prolonged use of lamotrigine, no significant changes in hemoglobin levels, mean red blood cell volume, serum and red blood cell folate concentrations are observed within 1 year, and also in red blood cell folate concentrations within 5 years. Renal insufficiency. In a single-dose study in patients with end-stage renal failure, plasma lamotrigine concentration did not change significantly. However, accumulation of the glucuronide metabolite is possible. Use of the preparation in patients with kidney damage requires caution. Patients taking other preparations containing lamotrigine. Patients taking other preparations containing lamotrigine should not take lamotrigine without consulting a doctor. Brugada-like changes on ECG. Arrhythmogenic ST-T anomalies and typical Brugada ECG were observed on ECG in patients taking lamotrigine. In this regard, before using lamotrigine in patients with Brugada syndrome, the possibility of such treatment should be thoroughly considered. Development in children. There is no information on the effect of lamotrigine on growth, sexual maturation, as well as cognitive, emotional, and behavioral development in children. Epilepsy. Abrupt discontinuation of lamotrigine, like other antiepileptic drugs, can provoke an increase in seizure frequency. Except in cases where the patient's condition requires abrupt discontinuation of the drug (e.g., in case of rash), the lamotrigine dose should be gradually reduced over at least 2 weeks. According to published data, severe epileptic seizures can cause rhabdomyolysis, multiple organ failure, and disseminated intravascular coagulation syndrome, sometimes with a fatal outcome. Similar cases are possible during lamotrigine treatment. Significant clinical worsening of seizure frequency may be observed instead of improvement in condition. In patients with more than one type of seizure, improvement in control of one type of seizure should be carefully assessed for worsening of control of other types of seizures. Lamotrigine treatment may exacerbate myoclonic seizures. There is data that the response to treatment with enzyme inducers is weaker than with treatment with antiepileptic drugs that do not induce enzymes. The reason for this is unknown. In the treatment of children with typical absence seizures, efficacy is not achieved in all patients. Bipolar disorders. Children (under 18 years of age). Antidepressant treatment is associated with an increased risk of suicidal ideation and behavior in children (under 18 years of age) with major depressive disorder and other mental disorders. Fertility. Lamotrigine use has been known not to impair fertility in animal reproductive studies. There is no data on the effect of lamotrigine on human fertility. Teratogenicity. Lamotrigine is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of congenital malformations in the human fetus if a woman is treated with folate inhibitors during pregnancy. However, reproductive toxicology studies in animals using lamotrigine at doses lower than the human dose of 400 mg/day [calculated on body surface area (mg/m2)] showed toxic effects on offspring development (increased mortality, decreased body weight, increased structural changes, neurobehavioral disorders), but no teratogenic effect was detected. The preparation contains lactose, so it is not recommended for patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free. Use during pregnancy and breastfeeding. Risks associated with the use of antiepileptic drugs in general. Women of reproductive age require specialist consultation. The issue of antiepileptic drug (AED) treatment should be discussed when a woman plans pregnancy. Women undergoing treatment for epilepsy should avoid abrupt discontinuation of AEDs, as this can lead to recurrence of epileptic seizures and may have serious consequences for the woman and the fetus. In all cases, monotherapy should be preferred, as the use of combination therapy with AEDs may be associated with an increased risk of congenital malformations compared to monotherapy, depending on the AED used. Risks associated with lamotrigine use. Pregnancy. A large amount of data on pregnant women undergoing lamotrigine monotherapy in the first trimester (over 8700) 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 weak inhibitory effect on dihydrofolate reductase and, therefore, can theoretically increase the risk of embryonic developmental disorders by reducing folic acid levels (see section "Special Warnings"). Therefore, attention should be paid to the need for folic acid intake when planning pregnancy and in its early stages. Physiological changes during pregnancy can affect lamotrigine levels and/or its therapeutic effect. Cases of decreased lamotrigine levels during pregnancy have been reported, potentially increasing the risk of loss of seizure control. After childbirth, lamotrigine levels can rapidly increase with the potential risk of dose-dependent adverse reactions. Therefore, lamotrigine levels in serum should be checked before, during, and after childbirth. If necessary, the lamotrigine dose should be modified to maintain lamotrigine levels in serum at pre-pregnancy levels, or adjusted according to the clinical situation. Dose-dependent adverse reactions should also be monitored after childbirth. Breastfeeding. Information is available that lamotrigine is excreted in breast milk at variable concentrations. At the same time, the level of lamotrigine in the newborn can reach 50% of the corresponding maternal level. Therefore, in some breastfed infants, lamotrigine levels in serum may reach levels at which pharmacological effects are possible. In this regard, the benefits of breastfeeding should be weighed against the potential risk of adverse reactions in the infant. If a woman undergoing lamotrigine treatment decides to breastfeed, the infant should be closely monitored for adverse events such as sedation, rash, and insufficient weight gain. Fertility. Animal studies have not revealed any effect of lamotrigine on fertility. Children. The effect of lamotrigine in children under 2 years of age as monotherapy or in children under 1 month of age as adjunctive therapy 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, it is not recommended for children in this age group. Lamotrigine is not indicated in children and adolescents (under 18 years of age) with bipolar disorder, as the efficacy of the drug has not been established, and also due to the increased risk of suicidal ideation (see section "Special Warnings"). Effect on ability to drive or operate machinery. Available data indicate that the effect of lamotrigine related to visual coordination, eye movements, body control, and subjective sedative effect does not differ from placebo. In clinical studies using lamotrigine, neurological side effects such as dizziness and diplopia were observed, so patients should first assess their own reaction to lamotrigine treatment before starting to drive or operate machinery. Since there is an individual response to antiepileptic drugs, the patient should consult a doctor for advice on driving a car in these cases. Interactions with other medicinal products and other types of interactions. It has been established that uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for the metabolism of lamotrigine. Thus, drugs that induce or inhibit glucuronidation can affect lamotrigine clearance. Strong or moderate inducers of the cytochrome P450 (CYP3A4) enzyme, known to induce UGT, can also enhance lamotrigine metabolism. There is no evidence that lamotrigine can cause clinically significant stimulation or inhibition of cytochrome P450 oxidizing enzymes. Lamotrigine can induce its own metabolism, but this effect is moderate and has no clinically significant consequences. Drugs proven to have a clinically significant effect on lamotrigine concentration are listed in Table 6. Special dosing recommendations for these drugs are presented in the "General dosing recommendations for special patient groups" section of the "Method of administration and dosage" section. Table 6 also lists drugs that have been shown to have little or no effect on lamotrigine concentration. Generally, no clinical effect is expected with concomitant use of these drugs. However, caution should be exercised in patients with epilepsy whose disease state is particularly sensitive to fluctuations in lamotrigine concentration. Table 6. Effect of other medicinal products on lamotrigine glucuronidation. Medicinal products that increase lamotrigine concentration Medicinal products that decrease lamotrigine concentration Medicinal products that have little or no effect on lamotrigine concentration Valproate Atazanavir/ritonavir Carbamazepine Combination "ethinylestradiol/levonorgestrel" Lopinavir/ritonavir Phenobarbital Phenytoin Primidone Rifampicin Aripiprazole Bupropion Felbamate Gabapentin Lacosamide Levetiracetam Lithium Olanzapine Oxcarbazepine Paracetamol Perampanel Pregabalin Topiramate Zonisamide Detailed dosing information can be found in the subsection "General dosing recommendations for special patient groups" of the section "Method of administration and dosage". Dosing instructions for women taking hormonal contraceptives can be found in the subsection "Hormonal contraceptives" of the section "Special Warnings"). Interactions with antiepileptic drugs (see also section "Method of administration and dosage"). Valproate, which inhibits lamotrigine glucuronidation, slows down lamotrigine metabolism and approximately doubles its mean half-life. Some antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 microsomal enzymes, induce UGT and accelerate lamotrigine metabolism. There are reports of central nervous system side effects, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients taking carbamazepine concurrently with lamotrigine. These events usually resolve with a reduction in carbamazepine dose. Similar effects were observed in a study of lamotrigine and oxcarbazepine involving healthy adult volunteers, but a dose reduction study was not conducted. It is known that in a study involving healthy adult volunteers who received a dose of 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not change lamotrigine metabolism, and lamotrigine, in turn, did not change oxcarbazepine metabolism. There are reports that a study in healthy volunteers found that co-administration of felbamate 1200 mg twice daily and lamotrigine 100 mg twice daily for 10 days did not have a clinically significant effect on the pharmacokinetics of the latter. According to retrospective analysis of plasma levels in patients taking lamotrigine with or without gabapentin, gabapentin did not change the apparent clearance of lamotrigine. It is known that the potential drug interaction between levetiracetam and lamotrigine was studied by assessing the serum concentrations of both drugs in placebo-controlled clinical trials. According to this data, the substances do not change each other's pharmacokinetics. Stable plasma lamotrigine concentration is not changed with concomitant use of pregabalin (200 mg three times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin. Topiramate does not affect lamotrigine plasma concentrations. Lamotrigine use increases topiramate concentration by 15%. It is known that according to study data, the use of zonisamide (200-400 mg/day) with lamotrigine (150-500 mg/day) for 35 days for epilepsy treatment did not significantly affect the pharmacokinetics of lamotrigine. Plasma lamotrigine concentration was not affected by its co-administration with lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial seizures. Additionally, according to data from three placebo-controlled clinical trials of concomitant perampanel use in patients with partial and primary generalized tonic-clonic seizures, the highest dose of perampanel studied (12 mg/day) increased lamotrigine clearance by less than 10%. Although changes in plasma concentrations of other antiepileptic drugs have been described, available study data indicate that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic drugs. In vitro study results showed that lamotrigine does not affect the binding of other antiepileptic drugs to plasma proteins. Interactions with other psychotropic substances (see section "Method of administration and dosage"). It is known that in a study of 20 patients taking lamotrigine 100 mg daily and lithium gluconate 2 g twice daily for 6 days, lithium pharmacokinetics did not change. Multiple oral doses of bupropion did not have a statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients, with only a slight increase in lamotrigine glucuronide levels observed. It is known that in studies involving healthy volunteers, 15 mg of olanzapine reduced the area under the lamotrigine concentration-time curve (AUC) and maximum concentration (Cmax) by an average of 24% and 20%, respectively. Lamotrigine 200 mg did not affect olanzapine pharmacokinetics. Multiple oral doses of lamotrigine 400 mg/day did not have a clinically significant effect on the pharmacokinetics of risperidone at a single dose of 2 mg. When risperidone 2 mg was used with lamotrigine, somnolence was observed. Available data indicate that no cases of somnolence were observed with lamotrigine alone. It is known that in a clinical study involving 18 adult patients with bipolar disorder taking lamotrigine (≥100 mg/day) and aripiprazole with gradual dose increase from 10 mg/kg to 30 mg/kg over 7 days, and then for the next 7 days, a decrease in lamotrigine AUC and Cmax by approximately 10% was observed. Such changes are not expected to have clinical consequences. In vitro experimental results showed that amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam had only a minimal effect on the formation of lamotrigine's primary metabolite, 2-N-glucuronide. Based on data from studies of bufuralol metabolism in human liver microsomes, it can be determined that lamotrigine does not reduce the clearance of drugs that are primarily metabolized by CYP 2D6. In vitro experimental results allow to confirm that clozapine, phenelzine, risperidone, sertraline, or trazodone cannot affect lamotrigine clearance. Interactions with hormonal contraceptives. Effect of hormonal contraceptives on lamotrigine pharmacokinetics. Data indicate that the combination "ethinylestradiol 30 mcg/levonorgestrel 150 mcg" doubles the elimination of lamotrigine, which in turn reduces the area under the lamotrigine curve (AUC) and Cmax by an average of 52% and 39%, respectively. In the case of a one-week break in contraceptive use (so-called pill-free week), serum lamotrigine concentrations steadily increased, reaching concentrations approximately twice as high as during combined drug use (see sections "Method of administration and dosage" and "Special Warnings"). Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives. It is known that, according to studies, an unchanged dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinylestradiol, which is part of a combined oral contraceptive tablet. A slight, constant increase in levonorgestrel release was observed, which in turn led to a decrease in levonorgestrel AUC and Cmax by an average of 19% and 12%, respectively. Measurements of serum levels of follicle-stimulating hormone and luteinizing hormone and estradiol during the studies showed suppression of ovarian hormonal activity in some women, however, progesterone levels in serum showed that no woman had any hormonal symptoms of ovulation. The effect of changes in serum levels of follicle-stimulating and luteinizing hormones and a slight increase in levonorgestrel release on ovarian ovulatory activity is unknown (see section "General dosing recommendations for special patient groups" in the section "Method of administration and dosage" for dosing in women taking hormonal contraceptives and subsection "Hormonal contraceptives" in the section "Special Warnings"). It is known that the effect of a daily dose of lamotrigine 300 mg has not been studied. Information is provided that studies of other hormonal contraceptives have also not been conducted. Interactions with other medicinal products. It is known that in studies involving 10 male volunteers taking rifampicin, the level of lamotrigine elimination increased and its half-life decreased, as a result of induction of liver enzymes responsible for glucuronidation. In patients receiving rifampicin therapy, the treatment regimen recommended for lamotrigine with appropriate glucuronidation inducers should be used (see section "Method of administration and dosage"). According to studies involving healthy volunteers, lopinavir/ritonavir approximately halves plasma lamotrigine concentrations through glucuronidation induction. For patients receiving concomitant therapy with lopinavir/ritonavir, the treatment regimen recommended for lamotrigine with appropriate glucuronidation inducers should be used (see section "Method of administration and dosage"). Use of atazanavir/ritonavir (300 mg/100 mg) reduces lamotrigine AUC and Cmax in plasma (at a dose of 100 mg) by an average of 32% and 6%, respectively. (see subsection "General dosing recommendations for special patient groups" in the section "Method of administration and dosage"). According to data from studies in healthy volunteers, paracetamol 1g dose (4 times daily) reduced lamotrigine AUC and Cmin in plasma by an average of 20% and 25%, respectively. In vitro study data on the effect of lamotrigine on organic cation transporters 2 (OCT 2) showed that lamotrigine, but not the N(2)-glucuronide metabolite, is an OCT 2 inhibitor at potentially clinically significant concentrations. Lamotrigine is a stronger inhibitor of OCT 2 with IC50 values of 53.8 μM and 186 μM, respectively (see section "Special Warnings"). Interactions using laboratory tests. Information is provided on the effect of lamotrigine on tests used for rapid determination of certain drugs in urine, which may result in false-positive results, especially for phencyclidine. To confirm positive results, an alternative, more specific chemical method should be used. Dosage form. 10 tablets in a blister; 3 or 6 blisters in a cardboard box. Storage conditions Store in the original packaging, protected from light and moisture, at a temperature not exceeding 250C. Keep out of reach of children. Shelf life 3 years. Dispensing category: Pharmaceutical product group - II. Dispensed with prescription form №3. Manufacturer. Pharmastart LLC, Ukraine, 03124, Kyiv, V. Haveli Blvd #8.