Lamictal

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMITOR

Composition:

Active substance: lamotrigine;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat, light-yellow tablets with a score line on one side.

Pharmacotherapeutic group.

Antiepileptic drugs. Lamotrigine. ATC code N03AX09.

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 (under monotherapy). Lamitor has a linear pharmacokinetic profile. It is excreted mainly as metabolites and partially unchanged, primarily via urine. In children, the elimination half-life is shorter than in adults.

Clinical characteristics.

Indications.

Epilepsy

Adults and children aged 12 years and older: monotherapy and adjunctive therapy for epilepsy, including partial and generalized seizures, tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome.

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

After seizure control is achieved, adjunctive medications may be discontinued, and monotherapy with lamotrigine may be continued.

Monotherapy for typical absence seizures.

Bipolar disorders (adults)

For prevention of mood episodes (depression, mania, hypomania, mixed states) in patients with bipolar disorders.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Uridine diphosphate glucuronosyltransferase (UGT) has been identified as the enzyme responsible for lamotrigine metabolism. There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative enzymes involved in drug metabolism, and it is unlikely that interactions will occur between lamotrigine and drugs metabolized by cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and has no significant clinical consequences.

Medicinal products that strongly inhibit hepatic enzymes: valproate.

Medicinal products that strongly induce hepatic enzymes: carbamazepine, phenytoin, primidone, phenobarbital, rifampicin, lopinavir/ritonavir, atazanavir/ritonavir, ethinylestradiol/levonorgestrel combination (other oral contraceptives and hormonal agents have not been studied, but they may similarly affect lamotrigine pharmacokinetics).

Medicinal products that neither inhibit nor induce hepatic enzymes: lithium, bupropion, olanzapine, oxcarbazepine, felbamate, gabapentin, levetiracetam, pregabalin, topiramate, zonisamide, aripiprazole.

Interaction with antiepileptic drugs

Valproate, which inhibits lamotrigine glucuronidation, reduces lamotrigine metabolism and approximately doubles the mean elimination half-life.

Certain antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce hepatic enzymes, enhance the glucuronidation metabolism of lamotrigine and accelerate its elimination.

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 carbamazepine dosage. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.

In studies involving healthy adult volunteers receiving 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism.

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

According to data from a retrospective analysis of plasma levels in patients receiving lamotrigine with or without gabapentin, gabapentin does not alter the existing clearance rate of lamotrigine.

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

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

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

Studies have shown that 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.

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

Interaction with other psychotropic agents

Data indicate that co-administration of 100 mg/day lamotrigine and 2 g lithium gluconate twice daily for 6 days did not alter lithium pharmacokinetics.

Multiple oral doses of bupropion had no statistically significant effect on lamotrigine pharmacokinetics in a study, only causing a slight increase in lamotrigine glucuronide levels.

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

Multiple oral doses of lamotrigine 400 mg/day did not cause clinically significant effects on risperidone pharmacokinetics after a single 2 mg dose in studies involving healthy adult volunteers. Drowsiness was reported when 2 mg risperidone was administered alone. No cases of drowsiness were observed with lamotrigine alone.

In studies involving patients with bipolar disorder receiving lamotrigine (≥100 mg/day), the dose of aripiprazole was increased from 10 mg/day to 30 mg/day over 7 days. Overall, a decrease of approximately 10% in Cmax and AUC of lamotrigine was observed. Such changes are not expected to have clinical consequences.

In vitro experiments showed that the formation of lamotrigine's primary metabolite, 2-N-glucuronide, is minimally affected by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Studies on bufuralol metabolism in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs primarily metabolized by CYP2D6. In vitro data also suggest that the clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline, or trazodone.

Interaction with hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine pharmacokinetics

In patients receiving a tablet containing ethinylestradiol 30 µg/levonorgestrel 150 µg, lamotrigine clearance approximately doubled, resulting in a mean reduction of AUC and Cmax of lamotrigine by 52% and 39%, respectively. Serum lamotrigine concentrations gradually increased during the weekly contraceptive-free interval, reaching levels approximately twice as high by the end of the interval compared to levels during combined administration.

Effect of lamotrigine on hormonal contraceptive pharmacokinetics

In studies involving female volunteers, a single 300 mg dose of lamotrigine did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptives. A consistent slight increase in levonorgestrel clearance was observed, resulting in mean reductions in AUC and Cmax of levonorgestrel by 19% and 12%, respectively. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed suppressed ovarian hormonal activity in some women, although serum progesterone measurements indicated no hormonal signs of ovulation. 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. The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Other hormonal contraceptives have also not been investigated.

Interaction with other medicinal products

In male volunteers receiving rifampicin, lamotrigine clearance increased and elimination half-life decreased due to induction of hepatic enzymes responsible for glucuronidation. Patients concurrently taking rifampicin should follow the dosing regimen recommended for lamotrigine therapy in combination with glucuronidation inducers.

Data from studies in healthy volunteers show that lopinavir/ritonavir reduce lamotrigine plasma concentrations by approximately half through induction of glucuronidation. For patients already taking lopinavir/ritonavir, the recommended dosing regimen for lamotrigine in combination with glucuronidation inducers should be followed.

Data from studies in healthy volunteers show that administration of atazanavir/ritonavir (300 mg/100 mg) reduced AUC and Cmax of lamotrigine (100 mg dose) in plasma by 32% and 6%, respectively, on average.

In vitro data on the effect of lamotrigine on organic cation transporter 2 (OCT2) demonstrated that lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data indicate that lamotrigine is a more potent inhibitor of OCT2 than cimetidine, with IC50 values of 53.8 µM and 186 µM, respectively.

Interaction in laboratory tests

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

Special precautions for use.

Skin rashes

Skin rash 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 lamotrigine have been reported. These include potentially life-threatening rashes such as Stevens–Johnson syndrome and toxic epidermal necrolysis.

In adults receiving lamotrigine 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 1000).

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

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

According to study data, 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 developing skin rashes appears to be closely related to high initial doses of lamotrigine, exceeding the recommended dosing escalation regimen, and concomitant use of valproate.

Lamotrigine should be used with caution in patients who previously experienced allergy or rashes during treatment with other antiepileptic drugs, as the frequency of mild rashes after lamotrigine treatment in this patient group was three times higher than in those without such history.

If a skin rash develops, the patient (adult or child) should be examined immediately and lamotrigine discontinued unless there is evidence that the rash is unrelated to the drug. Reinitiating lamotrigine treatment after discontinuation due to rash from prior lamotrigine therapy is not recommended. In such cases, the decision on re-prescribing the drug should carefully weigh the expected benefit against the potential risk.

Skin rashes have also been reported as part of a hypersensitivity syndrome, characterized by various systemic symptoms including fever, lymphadenopathy, facial swelling, blood abnormalities, liver function disturbances, and aseptic meningitis. 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. In the presence of such symptoms, the patient should be examined immediately and lamotrigine discontinued if no other cause is identified.

In most cases, aseptic meningitis resolves after discontinuation of the drug, but in some cases may recur upon re-challenge with lamotrigine. Reinitiating lamotrigine leads to rapid recurrence of symptoms, often with greater severity. Lamotrigine should not be re-administered to patients who previously discontinued it due to aseptic meningitis.

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

Hemophagocytic lymphohistiocytosis (HLH)

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

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

Patients presenting with such symptoms should be evaluated immediately, and the possibility of HLH should be considered. Lamotrigine therapy should be discontinued if an alternative etiology for the above symptoms cannot 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. They may experience worsening of depressive symptoms and/or emergence of suicidal thoughts and behaviors (suicidality), regardless of whether they are treated with medications for bipolar disorder, including lamotrigine.

Suicidal thoughts and behaviors have been reported in patients treated with antiepileptic drugs for various indications, including epilepsy. Data indicate a small increased risk of suicidal thoughts and behaviors. The mechanism of this risk is unknown, but available data do not exclude the possibility that lamotrigine may contribute to this risk. Therefore, patients should be closely monitored for signs of suicidal thoughts and behaviors. If such signs occur, patients and caregivers should seek immediate medical help.

Clinical worsening in bipolar disorder

Patients receiving lamotrigine for bipolar disorder should be closely monitored for clinical worsening (including new symptoms) and suicidality, especially 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 before 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 monitor for any worsening of condition (including new symptoms) and/or emergence of suicidal thoughts/behaviors or self-harming tendencies, and to seek immediate medical help if these symptoms occur.

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

Hormonal contraceptives

Effect of hormonal contraceptives on lamotrigine efficacy

Data indicate that the combination of ethinylestradiol 30 mcg/levonorgestrel 150 mcg increases lamotrigine clearance approximately two-fold, thereby reducing lamotrigine levels. To achieve maximum therapeutic effect, in most cases the maintenance dose of lamotrigine needs to be increased (by titration), typically doubled. In women not taking other glucuronidation-inducing drugs who are already 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. Therefore, women starting or stopping oral contraceptives should be under continuous medical supervision, and in most cases will require dose adjustment of lamotrigine.

Other oral contraceptives and hormone replacement therapies have not been studied but may similarly affect the pharmacokinetic properties of lamotrigine.

Effect of lamotrigine on hormonal contraceptive efficacy

Studies have shown a slight increase in levonorgestrel clearance and changes in serum levels of follicle-stimulating and luteinizing hormones when lamotrigine is used concomitantly with hormonal contraceptives (ethinylestradiol 30 mcg/levonorgestrel 150 mcg). The impact of these changes on ovulation is unknown. However, it cannot be ruled out that in some patients taking lamotrigine and hormonal contraceptives simultaneously, these changes may lead to reduced contraceptive efficacy. Therefore, patients should promptly report any changes in menstrual cycle, such as sudden breakthrough bleeding.

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

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

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase, so prolonged use may potentially affect folate metabolism. However, no significant changes in hemoglobin concentration, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentration over 5 years were observed during long-term lamotrigine treatment.

Renal impairment

In studies of single-dose administration 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

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

ECG pattern of Brugada syndrome

Arrhythmogenic ST-T abnormalities and ECG patterns typical of Brugada syndrome have been observed in patients taking lamotrigine. Lamotrigine should be prescribed cautiously in patients with Brugada syndrome.

Development in children

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

Epilepsy

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

Severe epileptic seizures may cause rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes with fatal outcomes. Similar cases may occur during lamotrigine treatment.

Significant clinical worsening in seizure frequency instead of improvement may occur. In patients with more than one seizure type, improvement in control of one seizure type should be carefully weighed against worsening control of another. Lamotrigine treatment may exacerbate myoclonic seizures.

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

Not all children with typical absence seizures respond to lamotrigine treatment.

Bipolar disorders

Children

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

Fertility

There are no data on the effect of the drug on fertility in humans.

Teratogenicity

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of fetal congenital malformations if women are treated with folate inhibitors during pregnancy.

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

Use during pregnancy or breastfeeding.

Pregnancy.

General risk associated with antiepileptic drugs

Women of reproductive age should seek medical advice. The need for antiepileptic treatment should be reviewed when planning pregnancy. Women with epilepsy who are already being treated should avoid abrupt discontinuation of antiepileptic therapy, as this may provoke seizure exacerbation and have serious consequences for both mother and child.

The risk of congenital abnormalities in children whose mothers were treated with antiepileptic drugs is approximately 3% higher than in the general population. The most commonly reported defects include cleft lip ("hare lip"), cardiovascular malformations, and neural tube defects. The risk of congenital malformations is higher with combination antiepileptic therapy compared to monotherapy; therefore, monotherapy should be used whenever possible.

Risk associated with lamotrigine use

Studies have been conducted in women who received lamotrigine monotherapy during the first trimester of pregnancy. Overall, there was no substantial evidence of increased risk of major congenital malformations; however, limited registry data have reported an increased risk of cleft palate. A controlled case study did not demonstrate an increased risk of isolated cleft palate compared to other malformations after lamotrigine use. If lamotrigine therapy is necessary during pregnancy, the lowest effective doses should be used.

Data on lamotrigine use in combination therapy are insufficient to conclude whether lamotrigine affects the risk of developmental abnormalities associated with other drugs.

Like other drugs, Lamitor should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

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

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

Period of breastfeeding

Lamotrigine has been reported to pass into breast milk in variable concentrations. Infant lamotrigine levels may reach up to 50% of maternal levels. Therefore, in some breastfed infants, serum lamotrigine levels may reach concentrations at which pharmacological effects are possible.

If lamotrigine treatment is necessary, the decision whether to discontinue breastfeeding should be made, weighing the benefit of treatment for the mother against the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery.

Study data indicate that lamotrigine's effects on visual coordination, eye movement, body control, and subjective sedative effects do not differ from placebo. Dizziness and diplopia have been reported during lamotrigine treatment; therefore, patients should assess their individual response to lamotrigine before driving or operating machinery. Since individual responses to antiepileptic drugs vary, patients should consult their physician regarding specific recommendations for driving in these cases.

Method of administration and dosing

Tablets should be dissolved in a small amount of water (sufficient to cover the entire tablet) or swallowed whole with water. If the calculated dose of lamotrigine, for example for children (epilepsy only) or for patients with impaired liver function, does not correspond to the dose of a whole tablet, the smallest dose corresponding to a whole tablet should be administered.

Epilepsy

Monotherapy

Adults and children aged 12 years and older (see Table 1).

The initial dose is 25 mg once daily for 2 weeks, followed by 50 mg once daily for the next 2 weeks. Thereafter, the dose should be increased by 50–100 mg every 1–2 weeks until the optimal effect is achieved. The usual maintenance dose is 100–200 mg daily in 1 or 2 divided doses. Some patients may require a dose of up to 500 mg daily.

Children aged 2 to 12 years (see Table 3).

The initial dose of lamotrigine for the treatment of typical absence seizures is 0.3 mg/kg body weight per day in 1 or 2 divided doses for 2 weeks, followed by 0.6 mg/kg per day in 1 or 2 divided doses for the next 2 weeks. Thereafter, the dose should be increased by 0.6 mg/kg every 1–2 weeks until the optimal effect is achieved. The usual maintenance dose is 1–10 mg/kg/day in 1 or 2 divided doses. Some patients may require higher doses.

Due to the risk of rash, the initial dose and the rate of subsequent dose escalation should not be exceeded.

Adjunctive therapy

Adults and children aged 12 years and older (see Table 1).

For patients taking valproate (with or without other antiepileptic drugs), the initial dose of lamotrigine is 25 mg every other day for 2 weeks, followed by 25 mg daily for the next 2 weeks. Thereafter, the dose should be increased (by a maximum of 25–50 mg/day) every 1–2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 100–200 mg daily in 1 or 2 divided doses.

For patients taking other antiepileptic drugs or other medicinal products that are inducers of lamotrigine glucuronidation, either alone or in combination with other antiepileptic drugs (except sodium valproate), the initial dose is 50 mg once daily for 2 weeks, followed by 100 mg daily in two divided doses for the next 2 weeks. Thereafter, the dose should be increased (by a maximum of 100 mg) every 1–2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 200–400 mg daily in two divided doses. Some patients may require a dose of up to 700 mg daily.

For patients taking other medicinal products that do not significantly induce or inhibit lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction"), the initial dose is 25 mg once daily for 2 weeks, followed by 50 mg once daily for the next 2 weeks. Thereafter, the dose should be increased (by a maximum of 50–100 mg/day) every 1–2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 100–200 mg daily in 1 or 2 divided doses.

Table 1

Recommended treatment regimen for epilepsy in adults and children aged 12 years and older

For patients taking antiepileptic drugs whose interaction with lamotrigine is unknown, it is recommended to follow the same dosing regimen as for patients taking lamotrigine with valproate.

Due to the risk of developing rashes, the initial dose and rate of subsequent dose escalation should not be exceeded.

Children aged 2 to 12 years (see Table 2).

For children receiving sodium valproate, either in combination with other antiepileptic drugs or alone, the initial dose of lamotrigine is 0.15 mg/kg body weight once daily for 2 weeks, followed by 0.3 mg/kg body weight once daily for the next 2 weeks. Thereafter, the dose should be increased (by up to 0.3 mg/kg body weight) every 1–2 weeks until the optimal therapeutic effect is achieved. The maintenance dose is 1–5 mg/kg body weight once or twice daily (maximum 200 mg per day).

For children taking other antiepileptic drugs or other medicinal products that are inducers of lamotrigine glucuronidation, either in combination with other antiepileptic drugs or alone (excluding sodium valproate), the initial dose of lamotrigine is 0.6 mg/kg body weight per day given in two divided doses for 2 weeks, followed by 1.2 mg/kg body weight per day in two divided doses for the next 2 weeks. Thereafter, the dose should be increased (by up to 1.2 mg/kg body weight) every 1–2 weeks until the optimal therapeutic effect is achieved. The average maintenance dose is 5–15 mg/kg body weight per day in two divided doses (maximum 400 mg per day).

For children taking other medicinal products that do not significantly induce or inhibit lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction"), the initial dose of lamotrigine is 0.3 mg/kg body weight per day given once or twice daily for 2 weeks, followed by 0.6 mg/kg body weight per day once or twice daily for the next 2 weeks. Thereafter, the dose should be increased (by up to 0.6 mg/kg body weight) every 1–2 weeks until the optimal therapeutic effect is achieved. The usual maintenance dose is 1–10 mg/kg per day given once or twice daily. The maximum dose is 200 mg per day.

To ensure correct calculation of the maintenance dose, the child's body weight should be monitored.

Table 2

Recommended dosing regimen for epilepsy in children aged 2 to 12 years (total daily dose in mg/kg body weight per day)

* If a calculated dose of 2.5–5 mg is required, administration of 5 mg lamotrigine every other day may be permitted during the first 2 weeks. If the calculated dose is less than 2.5 mg, administration of the medicinal product is not recommended.

For children receiving antiepileptic drugs whose interaction with lamotrigine is unknown, the same dosing regimen as for patients receiving lamotrigine with valproate is recommended.

Due to the risk of rash, the initial dose and the rate of subsequent dose escalation must not be exceeded.

It should be noted that in the absence of Lamictal 2 mg tablets, correct initiation of treatment in children with body weight below 17 kg is not possible.

General recommendations for epilepsy treatment

When discontinuing concomitant antiepileptic drugs to achieve lamotrigine monotherapy, or when adding other antiepileptic drugs to lamotrigine therapy, the potential effects on the pharmacokinetics of lamotrigine should be taken into account.

Bipolar disorders

Adults

Due to the risk of rash, the initial dose and the rate of subsequent dose escalation must not be exceeded.

The transition regimen outlined below should be followed. This regimen includes increasing the dose of lamotrigine to reach a maintenance stabilizing dose over 6 weeks (see Table 3), after which other psychotropic and/or antiepileptic drugs may be discontinued if clinically appropriate (see Table 4).

Table 3

Recommended dosage escalation regimen for lamotrigine to achieve a maintenance stabilizing daily dose in the treatment of adult patients with bipolar disorders

Note. For patients taking antiepileptic drugs with unknown effects on lamotrigine pharmacokinetics, the dose escalation regimen recommended for concomitant use with valproate should be applied.

∗ The maintenance dose may be adjusted depending on clinical response.

Adjunctive therapy with inhibitors of lamotrigine glucuronidation, for example, valproate.

The initial dose for patients receiving concomitant therapy with such an inhibitor of glucuronidation (e.g., valproate) is 25 mg every other day for 2 weeks, followed by 25 mg once daily for the next 2 weeks. The dose should then be increased to 50 mg daily (in 1 or 2 divided doses) by week 5. The usual dose to achieve optimal response is 100 mg daily (in 1 or 2 divided doses). However, the dose may be increased up to a maximum of 200 mg daily depending on clinical response.

Adjunctive therapy with inducers of lamotrigine glucuronidation in patients not taking inhibitors such as valproate. This regimen should be used with phenytoin, carbamazepine, phenobarbital, primidone, or other inducers of lamotrigine glucuronidation.

The initial dose for patients taking drugs that induce lamotrigine glucuronidation and who are not taking valproate is 50 mg once daily for 2 weeks, followed by 100 mg daily (divided into 2 doses) for the next 2 weeks. The dose should then be increased to 200 mg daily (in 2 divided doses) by week 5. The dose may be further increased to 300 mg daily by week 6; however, the usual dose to achieve optimal response is 400 mg daily (in 2 divided doses), which may be prescribed starting from week 7.

Monotherapy with lamotrigine or adjunctive therapy in patients taking other medications that do not significantly induce or inhibit lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").

The initial dose for these patients is 25 mg once daily for 2 weeks, followed by 50 mg daily (in 1 or 2 divided doses) for the next 2 weeks. The dose should then be increased to 100 mg daily by week 5. The usual dose to achieve optimal response is 200 mg daily (in 1 or 2 divided doses); however, doses ranging from 100–400 mg have been used in clinical studies.

After reaching the required maintenance dose, other psychotropic medications may be discontinued according to the schedule provided below (see Table 4).

Table 4

Maintenance dose in bipolar disorders with subsequent discontinuation of concomitant psychotropic or antiepileptic agents

∗ The dose may be increased if necessary up to 400 mg/day.

Note. For patients taking antiepileptic drugs with unknown effects on lamotrigine pharmacokinetics, a treatment regimen should be used whereby the current dose of the drug is maintained, with dose adjustments based on clinical status.

Following discontinuation of inhibitors of lamotrigine glucuronidation, e.g., valproate

The required maintenance dose of lamotrigine should be doubled and maintained at this level after stopping valproate.

Following discontinuation of inducers of lamotrigine glucuronidation, depending on the initial maintenance dose. This treatment regimen should be applied with phenytoin, carbamazepine, phenobarbital, primidone, or other inducers of lamotrigine glucuronidation.

The dose of lamotrigine should be gradually reduced over 3 weeks after discontinuation of drugs that induce glucuronidation.

Following discontinuation of other drugs that do not significantly induce or inhibit lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction").

The dose achieved after the upward titration regimen should be maintained.

Adjustment of lamotrigine dosage in patients with bipolar disorder when other drugs are added

There is no clinical experience regarding dosage adjustment of lamotrigine when other drugs are added; however, based on data on drug interactions, the following scheme may be recommended (Table 5).

Table 5

Adjustment of lamotrigine dosage in patients with bipolar disorder when other drugs are added

Note. For patients taking antiepileptic drugs with unknown effects on lamotrigine pharmacokinetics, a dosing regimen recommended for concomitant use with valproate should be applied.

Discontinuation of lamotrigine 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, the drug may be discontinued immediately without gradual dose reduction.

General dosing recommendations for special patient groups

Women taking hormonal contraceptives

Initiation of lamotrigine treatment in patients already taking hormonal contraceptives.

Although oral contraceptives increase lamotrigine clearance, no adjustments to the lamotrigine dose escalation regimen are required solely due to hormonal contraceptive use. Dose escalation follows the recommended schedule when lamotrigine is added to valproate (an inhibitor of lamotrigine glucuronidation), to an inducer of lamotrigine glucuronidation, or when lamotrigine is added in the absence of valproate or an inducer of lamotrigine glucuronidation (see Tables 1 and 3).

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

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

Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.

The maintenance dose of lamotrigine should generally be reduced by 50%. It is recommended that the daily dose of lamotrigine be gradually reduced by 50–100 mg per week (not exceeding 25% of the total weekly dose) over a period of 3 weeks, unless otherwise indicated by individual clinical response.

Concomitant use with atazanavir/ritonavir

Although atazanavir/ritonavir reduces lamotrigine plasma concentrations, the recommended lamotrigine dose escalation regimens do not need to be modified. Dose adjustments should follow recommendations based on concomitant lamotrigine regimens: either when lamotrigine is added to valproate (an inhibitor of lamotrigine glucuronidation), to an inducer of lamotrigine glucuronidation, or when lamotrigine is added in the absence of valproate or an inducer of lamotrigine glucuronidation.

For patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation, the lamotrigine dose may be increased when atazanavir/ritonavir is initiated, or decreased when atazanavir/ritonavir treatment is discontinued.

Elderly patients (over 65 years of age)

Dose adjustment is not required. The pharmacokinetics of lamotrigine in this age group do not differ from those in younger patients.

Hepatic impairment

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

Renal impairment

Caution should be exercised when prescribing to patients with renal impairment. For patients with end-stage renal disease, the initial lamotrigine dose should be based on individual antiepileptic treatment regimens. In patients with significant renal impairment, the maintenance dose of lamotrigine should be reduced.

Re-initiation of treatment

When restarting treatment in a patient who has previously discontinued lamotrigine, careful consideration must be given to the need for dose escalation, as there is a risk of rash due to high initial doses or exceeding the recommended dose escalation regimen. The longer the interval since the last dose, the greater the attention required in the dose escalation regimen to reach the maintenance dose. When the interval since discontinuation of lamotrigine exceeds five times its elimination half-life, the dose may be increased to the maintenance dose according to the established regimen.

Re-initiation of lamotrigine treatment is not recommended if treatment was previously discontinued due to rash. In such cases, the potential benefits of treatment must be carefully weighed against the possible risks before deciding on re-prescribing.

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 this age group.

Lamotrigine is not indicated for use in children with bipolar disorder. The efficacy and safety of lamotrigine for the treatment of bipolar disorder in this age group have not been studied, and therefore, dosing recommendations cannot be provided.

Overdose

Cases of acute overdose have been reported (with doses 10–20 times higher than the maximum therapeutic doses), presenting symptoms such as ataxia, nystagmus, impaired consciousness, coma (including fatal outcomes). Generalized epileptic seizures have also been observed. Prolongation of the QRS complex (intraventricular conduction delay) has been reported.

Treatment. In case of overdose, the patient should be hospitalized for appropriate supportive care. Measures to reduce absorption (e.g., activated charcoal) should be applied if necessary. Further treatment should be based on clinical indications, with attention to potential effects on cardiac conduction (see section "Special precautions"). Intravenous lipid therapy may be considered for the treatment of cardiotoxicity unresponsive to sodium bicarbonate. There is no experience with hemodialysis in the treatment of lamotrigine 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 are divided into 2 groups: those occurring during treatment of epilepsy and those occurring during treatment of bipolar disorders. To assess the overall safety profile of the drug, both groups should be considered.

Epilepsy

Skin-related: skin rashes, Stevens–Johnson syndrome, toxic epidermal necrolysis.

During studies of adjunctive lamotrigine therapy in adults, skin rashes were observed in 10% of patients receiving lamotrigine and in 5% of patients receiving placebo. Rashes were a reason for discontinuation of the drug. The rashes were maculopapular in nature, occurred most frequently within 8 weeks of starting treatment, and resolved after discontinuation of lamotrigine (see section "Special instructions").

Rare cases of severe, life-threatening skin reactions have been reported, including Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). Although most patients recover after discontinuation of the drug, some are left with irreversible scarring; in isolated cases, these symptoms have led to fatal outcomes.

The overall risk of skin rash appears to be closely associated with high initial doses of lamotrigine, exceeding the recommended dose escalation regimen during lamotrigine therapy, and concomitant use of valproate.

Skin rashes have also been reported as part of a hypersensitivity syndrome accompanied by various systemic symptoms.

Blood system disorders: hematological abnormalities (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), lymphadenopathy, cutaneous pseudolymphoma.

Hematological abnormalities and lymphadenopathy may or may not be associated with hypersensitivity syndrome.

Immune system disorders: hypersensitivity syndrome, including symptoms such as fever, lymphadenopathy, facial swelling, blood count changes, liver function abnormalities, disseminated intravascular coagulation, and multiorgan failure.

Skin rashes have also been reported as part of a hypersensitivity syndrome accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, blood count changes, and liver function abnormalities. The syndrome may vary in severity and rarely 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 occur even in the absence of skin rashes. If such symptoms occur, the patient should be examined immediately and, in the absence of other causes, the drug should be discontinued.

Psychiatric disorders: aggression, irritability, tics (motor and/or vocal tics), hallucinations and confusion, night terrors.

Nervous system disorders: headache, somnolence, insomnia, dizziness, tremor, ataxia, nystagmus, aseptic meningitis, anxiety, loss of balance, movement disorders, exacerbation of Parkinson’s disease, extrapyramidal effects, choreoathetosis, increased seizure frequency.

It has been described that lamotrigine may worsen symptoms of parkinsonism in patients with this condition. There have been isolated reports of extrapyramidal effects and choreoathetosis in patients with this pathology.

Eye disorders: diplopia, blurred vision, conjunctivitis.

Gastrointestinal disorders: nausea, vomiting, and diarrhea.

Hepatobiliary disorders: elevated liver function test parameters, liver function abnormalities, liver failure.

Liver function abnormalities usually occur in connection with hypersensitivity reactions, but isolated cases without apparent signs of hypersensitivity have been reported.

Musculoskeletal system disorders: lupus-like reactions.

General disorders: increased fatigue.

Bipolar disorders

Gastrointestinal disorders: dry mouth.

Skin-related: skin rashes, Stevens–Johnson syndrome.

Nervous system disorders: headache, anxiety, somnolence, dizziness.

Musculoskeletal system disorders: arthralgia.

Psychiatric disorders: night terrors.

General disorders: pain, back pain.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

TORRENT PHARMACEUTICALS LTD.

Manufacturer's address and place of business.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana Gujarat 382721, India

or

Bhad and Makhu Majra, Tehsil: Baddi, – 173205, Dist-Solan (H.P.), India.