Lamictal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMITRIL (LAMITRIL)

Composition:

Active substance: lamotrigine;

Tablets 25 mg:

Each tablet contains 25 mg of lamotrigine;

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

Tablets 100 mg:

Each tablet contains 100 mg of lamotrigine;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate (type A), povidone, magnesium stearate, yellow dye FCF (E 110);

Tablets 150 mg:

Each tablet contains 150 mg of lamotrigine;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate (type A), povidone, magnesium stearate, iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets 25 mg: white or almost white shield-shaped tablets with an imprint «P 25» on one side and a score line on the other.

Tablets 100 mg: light pink-colored tablets (fine orange specks are acceptable), shield-shaped, with an imprint «P 100» on one side and a score line on the other.

Tablets 150 mg: almost white or slightly yellowish tablets (fine light brown specks are acceptable), shield-shaped, with an imprint «P 150» on one side and a score line on the other.

Pharmacotherapeutic group.

Antiepileptic drugs. Lamotrigine. ATC code N03A X09.

Pharmacological Properties.

Pharmacodynamics.

Lamotrigine is an anticonvulsant agent whose mechanism of action is related to blockade of voltage-dependent sodium channels in presynaptic neuronal membranes during the phase of slow inactivation, and inhibition of excessive glutamate release (an amino acid that plays a significant role in the development of epileptic seizures).

Pharmacokinetics.

After oral administration, the drug is rapidly and completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached approximately 2.5 hours after intake.

Lamotrigine is actively metabolized, with the main metabolite being N-glucuronide. The average elimination half-life in adults is 29 hours. Lamictal has a linear pharmacokinetic profile. It is excreted primarily as metabolites and partially unchanged, mainly via the urine. In children, the elimination half-life is shorter than in adults.

Special patient groups.

Children.

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

Elderly patients.

In a study involving both elderly and younger patients with epilepsy, lamotrigine clearance did not change significantly. After single doses, apparent clearance decreased by 12%, from 35 ml/min/kg in 20-year-old patients to 31 ml/min/kg in 70-year-old patients. The reduction after 48 weeks of treatment was 10%, from 41 ml/min in younger patients to 37 ml/min in elderly patients. Additionally, the pharmacokinetics of lamotrigine were studied in 12 healthy elderly patients who received a single 150 mg dose. The mean clearance value in elderly patients (0.39 ml/min/kg) falls within the range of mean clearance values (0.31 to 0.65 ml/min/kg) observed in 9 studies conducted in younger patients receiving single doses of 30 to 450 mg.

Patients with renal impairment.

A single 100 mg dose of lamotrigine was administered to 12 volunteers with chronic renal impairment and to 6 patients undergoing hemodialysis. Mean apparent clearance values were 0.42 ml/min/kg (chronic renal impairment), 0.33 ml/min/kg (interdialytic period), and 1.57 ml/min/kg (during hemodialysis), compared to 0.58 ml/min/kg in healthy volunteers. Mean elimination half-life from plasma was 42.9 hours (chronic renal impairment), 57.4 hours (interdialytic period), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. Over a four-hour hemodialysis session, lamotrigine removal averaged 20% (ranging from 5.6 to 35.1%) of the total body amount. Initial dosing of Lamictal in this patient group should be based on the patient's concomitant antiepileptic medication regimen; reduction of maintenance dose may be effective in patients with significant functional renal impairment.

Patients with hepatic impairment.

A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy control subjects. Mean apparent clearance of lamotrigine was 0.31, 0.24, and 0.10 ml/min/kg in patients with Child-Pugh class A, B, and C hepatic impairment, respectively, compared to 0.34 ml/min/kg in healthy controls. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate hepatic impairment (Child-Pugh class B) and by 75% in patients with severe hepatic impairment (Child-Pugh class C). Escalation and maintenance doses should be adjusted according to individual response to treatment.

Clinical characteristics.

Indications.

Epilepsy.

Adults and children aged 13 years and older

For monotherapy and adjunctive therapy of epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures.

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

Children aged 2 to 12 years

For adjunctive therapy of epilepsy, particularly partial and generalized seizures, including tonic-clonic seizures, as well as seizures associated with Lennox–Gastaut syndrome.

For monotherapy of typical absence seizures.

Bipolar disorders (adults).

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Uridine-5’-diphosphate-glucuronosyltransferase (UGT) has been identified as the enzyme responsible for lamotrigine metabolism.

Therefore, drugs that induce or inhibit glucuronidation may affect lamotrigine clearance. Enzyme inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate intensity, which also induce UGT, may increase lamotrigine metabolism.

Medicinal products with clinically significant effects on lamotrigine metabolism are listed in Table 1 below. Specific dosage recommendations for these medicinal products are provided in the section “Method of administration and dosage.”

There is no evidence that lamotrigine causes clinically significant induction or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and not clinically significant.

Table 1.

Effect of other drugs on lamotrigine glucuronidation

* For detailed dosing information, see the section "General recommendations for Lamictal dosing in special patient populations" in the "Dosage and administration" section.

** Other oral contraceptives and hormone replacement therapies have not been studied, but they may similarly affect the pharmacokinetic properties of lamotrigine (see the section "General recommendations for Lamictal dosing in special patient populations" in the "Dosage and administration" section — dosing recommendations for women taking hormonal contraceptives, and the section "Hormonal contraceptives" in the "Special precautions" section).

Interaction with antiepileptic drugs (AEDs) (see also the section "Dosage and administration").

Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases the average elimination half-life by approximately two-fold.

Certain antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 enzymes, also induce UGT enzymes and thereby accelerate lamotrigine metabolism.

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

In a study in healthy adult volunteers receiving 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism.

In a study involving healthy volunteers, concomitant administration of felbamate 1200 mg twice daily and lamotrigine 100 mg twice daily for 10 days had no clinically significant effect on the pharmacokinetics of lamotrigine.

According to data from a retrospective analysis of plasma levels in patients receiving lamotrigine with gabapentin, gabapentin does not alter lamotrigine clearance.

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

Steady-state plasma concentration of lamotrigine is not altered by concomitant administration with pregabalin (200 mg three times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin.

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

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

Concomitant administration of lacosamide (200, 400, or 600 mg/day) did not affect lamotrigine plasma concentration in placebo-controlled clinical trials in patients with partial seizures. In a pooled analysis of data from three placebo-controlled clinical studies investigating adjunctive concomitant perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied dose of perampanel (12 mg/day) increased lamotrigine clearance by less than 10%. This effect is not considered clinically significant.

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

Interaction with other psychotropic agents.

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

Multiple oral doses of bupropion had no statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients—only a slight increase in lamotrigine glucuronide levels was observed.

In a study involving healthy adult volunteers, 15 mg olanzapine reduced the area under the concentration-time curve and Cmax of lamotrigine by an average of 24% and 20%, respectively. Such a pronounced effect is rarely encountered in clinical practice. 200 mg lamotrigine does not affect the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg daily did not cause a clinically significant effect on the pharmacokinetics of risperidone after a single 2 mg dose in studies involving 14 healthy adult volunteers. When 2 mg risperidone was co-administered with lamotrigine, 12 out of 14 volunteers experienced somnolence, compared to 1 out of 20 volunteers receiving risperidone alone. No cases of somnolence were observed with lamotrigine alone.

In a clinical study involving 18 adult patients with bipolar disorder receiving lamotrigine (≥100 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and continued for another 7 days. Overall, approximately a 10% reduction in Cmax and AUC of lamotrigine was observed. The clinical consequences of such changes are not expected.

In vitro experiments showed that amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam have only minimal effects on the formation of the primary metabolite of lamotrigine, N-glucuronide. Data from bufuralol metabolism studies in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs metabolized primarily by CYP2D6. In vitro data also suggest that clozapine, phenelzine, risperidone, sertraline, or trazodone are unlikely to affect lamotrigine clearance.

Interaction with hormonal contraceptives.

Effect of hormonal contraceptives on lamotrigine pharmacokinetics.

In a study involving 16 female volunteers taking a combined tablet containing "ethinylestradiol 30 µg/levonorgestrel 150 µg", lamotrigine clearance increased approximately two-fold, resulting in a mean reduction in the area under the concentration-time curve and Cmax of lamotrigine by 52% and 39%, respectively. During the weekly break from contraceptive use (the so-called "pill-free week"), lamotrigine serum concentration gradually increased over the week, reaching levels approximately two-fold higher than during concomitant use (see sections "Dosage and administration" and "Special precautions").

Effect of lamotrigine on hormonal contraceptive pharmacokinetics.

According to study data, a fixed dose of lamotrigine 300 mg did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptive tablets. A consistent slight increase in levonorgestrel clearance was observed, resulting in a mean reduction in the area under the concentration-time curve and Cmax of levonorgestrel by 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppression of ovarian hormonal activity in some women, although serum progesterone measurements revealed no hormonal signs of ovulation in any of the 16 women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the slight increase in levonorgestrel clearance on ovarian ovulatory activity is unknown (see the section "General recommendations for Lamictal dosing in special patient populations" in the "Dosage and administration" section — dosing recommendations for women taking hormonal contraceptives, and the section "Hormonal contraceptives" in the "Special precautions" section). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Studies of other hormonal contraceptives have also not been conducted.

Interaction with other medicinal products.

In a study involving 10 male volunteers, rifampicin increased lamotrigine elimination and reduced its elimination half-life due to induction of hepatic enzymes responsible for glucuronidation. For patients receiving concomitant rifampicin therapy, the treatment regimen recommended for lamotrigine and concomitant inducers of glucuronidation should be followed (see the "Dosage and administration" section).

According to studies in healthy volunteers, lopinavir/ritonavir reduce lamotrigine plasma concentration by approximately two-fold through induction of glucuronidation. For treatment of patients already taking lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and inducers of glucuronidation should be followed (see the "Dosage and administration" section).

According to studies in healthy volunteers, administration of atazanavir/ritonavir (300 mg/100 mg) reduced AUC and Cmax of lamotrigine (100 mg dose) in plasma by an average of 32% and 6%, respectively (see the "Dosage and administration" section).

According to in vitro studies on the effect of lamotrigine on organic cation transporter 2 (OCT2), lamotrigine, but not its metabolite N(2)-glucuronide, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2, with an IC50 value of 53.8 µM (see the "Special precautions" section).

Interaction in laboratory tests.

Interference of lamotrigine with urine screening tests used for rapid detection of certain drugs has been reported, potentially leading to false-positive results, particularly for phencyclidine. Alternative, more specific chemical methods are required to confirm positive results.

Special precautions for use.

Skin rashes.

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

Skin rashes may occur during the first 8 weeks of lamotrigine treatment. In most cases, rashes are mild and resolve without treatment; however, severe skin reactions requiring hospitalization and discontinuation of Lamictal have been reported. These include potentially life-threatening rashes such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Adverse reactions").

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

In adults receiving Lamictal at recommended doses, the incidence of severe skin rashes is approximately 1 in 500 patients with epilepsy. In about half of these cases, Stevens–Johnson syndrome was diagnosed (1 in 1,000).

The incidence of severe skin rashes in patients with bipolar disorder is 1 in 1,000.

The risk of serious skin rashes is higher in children than in adults.

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

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

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

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

Skin rashes require immediate patient evaluation (in both adults and children) and discontinuation of Lamictal if there is no evidence that the rash is unrelated to the drug. Reinitiating lamotrigine treatment after discontinuation due to a rash from prior lamotrigine therapy is not recommended. In such cases, the decision to re-prescribe the drug should carefully weigh the expected benefits against potential risks.

Skin rashes have also been reported as part of a hypersensitivity syndrome, characterized by various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, liver function disturbances, and aseptic meningitis (see section "Adverse reactions"). This syndrome may vary in severity and rarely may lead to disseminated intravascular coagulation and multiorgan failure. Importantly, early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rashes. If such symptoms occur, the patient should be evaluated immediately and Lamictal discontinued unless another cause is identified.

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

Hemophagocytic lymphohistiocytosis (HLH)

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

Patients should be informed about the symptoms associated with HLH and advised to seek immediate medical attention if they experience any of these symptoms during lamotrigine therapy.

Patients developing signs and symptoms suggestive of HLH should be evaluated immediately, and HLH should be considered in the differential diagnosis. Lamotrigine use should be discontinued immediately if no alternative etiology can be established.

Suicidal risk.

Depressive symptoms and/or bipolar disorder may occur in patients with epilepsy. Evidence indicates that patients with epilepsy and bipolar disorder have an increased risk of suicide.

Between 25% and 50% of patients with bipolar disorders have at least one suicide attempt and may experience worsening depression or emergence of suicidal thoughts and behaviors (suicidality), regardless of whether they are receiving treatment for bipolar disorder, including Lamictal.

Suicidal thoughts and behaviors have been reported in patients treated with antiepileptic drugs for various indications, including epilepsy. A meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, revealed a small increased risk of suicidal thoughts and behaviors. The mechanism of this risk is unknown, but available data do not rule out the possibility that lamotrigine may contribute to this risk. Therefore, patients should be closely monitored for signs of suicidal thoughts and behaviors. If such signs occur, patients and caregivers should seek immediate medical help.

Clinical worsening in bipolar disorder.

Patients treated with Lamictal for bipolar disorder should be closely monitored for clinical worsening (including new symptoms) and suicidality, particularly at the beginning of treatment or during dose adjustments. Patients with a history of suicidal behavior or ideation, younger patients, and those who demonstrated significant suicidal ideation prior to treatment initiation may be at higher risk of developing suicidal thoughts or attempts, requiring careful monitoring during treatment.

Patients (and caregivers) should be warned to seek immediate medical help if their condition worsens (including new symptoms) and/or if suicidal thoughts/behaviors or self-harm tendencies emerge.

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

Hormonal contraceptives.

Effect of hormonal contraceptives on lamotrigine efficacy.

Data indicate that the combination "ethinylestradiol 30 µg / levonorgestrel 150 µg" increases lamotrigine clearance by approximately two-fold, thereby reducing lamotrigine levels (see section "Interaction with other medicinal products and other forms of interaction"). To achieve optimal therapeutic effect, in most cases, the maintenance dose of lamotrigine will need to be increased (by titration), approximately doubled. In women not already taking lamotrigine glucuronidation inducers but using hormonal contraceptives with a weekly break between cycles, a gradual, temporary increase in lamotrigine levels may occur during the weekly break. This increase may be greater if the lamotrigine dose is increased one day before or during the weekly break (see section "Dosage and administration"). Therefore, women initiating or discontinuing oral contraceptives should remain under continuous medical supervision, and in most cases, dose adjustment of lamotrigine will be required.

Other oral contraceptives and hormone replacement therapies have not been studied but may similarly affect lamotrigine pharmacokinetics.

Effect of lamotrigine on hormonal contraceptive efficacy.

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

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

Lamotrigine is an inhibitor of renal tubular secretion via organic cation transporter proteins. This may lead to increased plasma levels of certain drugs primarily excreted via this pathway. Therefore, co-administration of Lamictal with OCT2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended.

Dihydrofolate reductase.

Lamictal is a weak inhibitor of dihydrofolate reductase, and thus prolonged use may affect folate metabolism. However, long-term use of Lamictal has not resulted in significant changes in hemoglobin levels, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentrations over 5 years.

Renal impairment.

In single-dose studies in patients with end-stage renal disease, lamotrigine plasma concentrations were not significantly altered. However, accumulation of the glucuronide metabolite is possible. Therefore, caution is required when treating patients with renal impairment.

Patients taking other lamotrigine-containing medications.

Lamictal should not be prescribed to patients already receiving any other medication containing lamotrigine without prior medical consultation.

ECG changes resembling Brugada syndrome.

Arrhythmogenic ST-T abnormalities and characteristic ECG patterns resembling Brugada syndrome have been reported in patients receiving lamotrigine. Prescribing lamotrigine to patients with Brugada syndrome should be done with caution.

Development in children.

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

Epilepsy.

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

According to scientific publications, severe epileptic seizures may lead to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes resulting in death. Similar cases may occur during Lamictal treatment.

A significant increase in seizure frequency may occur instead of improvement. If a patient has more than one seizure type, improvement in control of one seizure type should be carefully weighed against worsening control of another seizure type.

Lamotrigine treatment may exacerbate myoclonic seizures.

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

Therapeutic response is not achieved in all children treated for typical absence seizures.

Bipolar disorders.

Children (under 18 years of age)

Antidepressant treatment is associated with an increased risk of suicidal thoughts and behaviors in children (under 18 years of age) with major depressive disorders and other psychiatric disorders.

Fertility.

Lamictal did not impair fertility in reproductive studies in animals. There are no data on the effect of Lamictal on fertility in humans.

Teratogenicity.

Lamictal is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of congenital malformations in human fetuses if women are treated with folate inhibitors during pregnancy. However, reproductive toxicology studies of Lamictal in animals at doses exceeding human therapeutic doses did not reveal teratogenic effects.

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

Use during pregnancy or breastfeeding.

General risk associated with antiepileptic drugs

Women of childbearing potential require specialist consultation. The possibility of antiepileptic drug treatment should be reviewed when a woman plans pregnancy. If a woman is being treated for epilepsy, abrupt discontinuation of antiepileptic drugs should be avoided, as this may lead to seizure recurrence and have serious consequences for both the woman and the fetus. Monotherapy should be preferred whenever possible, as combination antiepileptic therapy is associated with a higher risk of congenital malformations compared to monotherapy, depending on the concomitant antiepileptic drugs used.

Risk associated with lamotrigine use.

Pregnancy.

Extensive data from pregnant women receiving lamotrigine monotherapy during the first trimester (over 8,700 cases) do not indicate a significant increase in the risk of serious congenital malformations, including cleft lip and palate. Animal studies showed embryofetal toxicity.

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

Lamotrigine has a mild inhibitory effect on dihydrofolate reductase and may theoretically increase the risk of embryofetal developmental abnormalities due to reduced folic acid levels (see section "Special precautions for use"). Folic acid supplementation should be considered during pregnancy planning and early pregnancy.

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

Breastfeeding period.

Lamotrigine has been reported to pass into breast milk at variable concentrations, and lamotrigine levels in infants may reach up to 50% of maternal levels. Therefore, in some breastfed infants, serum lamotrigine levels may reach concentrations at which a pharmacological effect is possible. Among the limited number of infants studied, no adverse effects were observed.

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

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

Data from two studies involving volunteers indicate that lamotrigine's effects on visual coordination, eye movement control, body control, and subjective sedation do not differ from placebo. However, dizziness and diplopia have been reported with lamotrigine use. Therefore, patients should first assess their individual response to lamotrigine before driving or operating machinery. Since individual responses to antiepileptic drugs vary, patients should consult their physician regarding specific driving considerations.

Method of administration and dosage.

Lamictal should be taken orally, independent of food intake.

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

Reinitiation of treatment.

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

Reinitiating Lamictal is not recommended in patients who discontinued treatment due to a rash associated with prior lamotrigine therapy, except in cases where the potential benefit clearly outweighs the risk.

Epilepsy.

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

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

Table 2.

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

Table 3.

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

To ensure maintenance of the therapeutic dose, it is necessary to monitor the child's body weight and adjust the dose in case of changes in body weight. It is quite likely that patients aged 2 to 6 years will require a maintenance dose approaching the upper limit of the recommended range.

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

Children under 2 years of age.

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

Bipolar disorder.

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

Table 4.

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

* Target maintenance dosage varies depending on clinical response.

Table 5.

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

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

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

Table 6.

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

There is no clinical experience regarding dose adjustment of lamotrigine when other drugs are co-administered.

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

Discontinuation of lamotrigine in patients with bipolar disorder.

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

Children (under 18 years of age).

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

General dosing recommendations for special patient groups.

Women taking hormonal contraceptives.

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

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

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

Measuring serum lamotrigine concentrations before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women using hormonal contraceptives with a one-week inactive treatment period (tablet-free week), serum lamotrigine monitoring should be performed during the third week of active treatment, i.e., from day 15 to day 21 of the tablet cycle. Consideration should be given to using contraceptive preparations without a weekly break in tablet intake as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

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

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

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

Initiation of lamotrigine therapy in women already taking hormonal contraceptives.

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

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

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

Concomitant use with atazanavir/ritonavir.

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

In patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation, dose increases of lamotrigine may be needed when atazanavir/ritonavir is added, and dose reductions may be necessary when atazanavir/ritonavir is discontinued.

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

Concomitant use with lopinavir/ritonavir.

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

In patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation, dose increases of lamotrigine may be needed when lopinavir/ritonavir is added, and dose reductions may be necessary when lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be performed before and within 2 weeks after starting or stopping lopinavir/ritonavir to determine the need for lamotrigine dose adjustment (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients (65 years and older).

Dose adjustment according to the recommended regimen is not required.

The pharmacokinetics of lamotrigine in this age group do not differ significantly from those in adult patients under 65 years of age.

Renal impairment.

Caution should be exercised when administering Lamictal to patients with renal impairment. In patients with end-stage renal disease, the initial lamotrigine dose should be established according to concomitant medications; dose reduction may be effective in patients with significant renal function impairment (see section "Special warnings and precautions for use").

Hepatic impairment.

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

Children.

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

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

Overdose.

Symptoms and signs

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

Treatment

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

Adverse reactions.

Adverse reactions reported during treatment of epilepsy and bipolar disorder, based on data from controlled clinical trials and other clinical experience, are listed in the table below. The frequency of reactions was determined from controlled clinical trials [monotherapy for epilepsy (denoted as †) and for bipolar disorder (denoted as §)]. If the frequency differs between clinical data from epilepsy and bipolar disorder studies, the lowest frequency is indicated. In the absence of data from controlled clinical trials, frequency was determined from other clinical experience.

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

1 Hematological abnormalities and lymphadenopathy may be either associated or not associated with hypersensitivity syndrome (see "Disorders of the immune system").

2 Skin rash has also been reported as part of a hypersensitivity syndrome accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, blood parameter abnormalities, and liver function impairment. The syndrome may vary in severity and, in rare cases, may lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early signs of hypersensitivity (e.g., fever and lymphadenopathy) may appear even in the absence of skin rash. If such symptoms occur, the patient should be examined immediately and, in the absence of other causes, Lamictal should be discontinued.

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

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

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

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

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

• high initial doses of lamotrigine and exceeding doses recommended in the dosing regimen

during lamotrigine therapy (see section "Dosage and administration");

• concomitant use of valproate (see section "Dosage and administration").

Skin rash has also been reported as part of a hypersensitivity syndrome accompanied by various systemic symptoms (see "Disorders of the immune system").

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

Shelf life. 5 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 25 °C, in the original packaging.

Packaging.

Tablets 25 mg – 30 tablets in bottles.

Tablets 100 mg or 150 mg – 60 tablets in bottles.

Prescription category. Prescription only.

Manufacturer. Pharmascience Inc.

Manufacturer's address and place of business

6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada /
6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada.