Epileptol®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPILEPTAL® (EPILEPTAL)
Composition:
Active substance: lamotrigine;
1 tablet contains lamotrigine 25 mg, 50 mg, or 100 mg calculated as 100% substance;
Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, yellow iron oxide (E 172), magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical characteristics: 25 mg and 100 mg tablets are round, biconvex, pale yellow in color; 50 mg tablets are round, flat cylindrical, with a score line and beveled edges, pale yellow in color. Slight mottling and specks on the surface are permissible.
Pharmacotherapeutic group. Antiepileptic agents. Lamotrigine.
ATC code N03A X09.
Pharmacological Properties
Pharmacodynamics
Lamotrigine is an anticonvulsant agent whose mechanism of action is related to the 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 playing 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 within 2.5 hours.
Lamotrigine is actively metabolized, with N-glucuronide being the main metabolite. The average elimination half-life in adult patients is 29 hours. Epithal® has a linear pharmacokinetic profile. It is excreted mainly as metabolites and partially unchanged, predominantly in 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 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 an increase in the mean half-life to 45–50 hours when co-administered exclusively with valproate.
Elderly patients
Pharmacokinetic analysis in patient groups, including both elderly and younger patients with epilepsy participating in one study, revealed that lamotrigine clearance did not change to a clinically significant extent. After single doses, apparent clearance decreased by 12%, from 35 ml/min/kg at age 20 to 31 ml/min/kg at age 70. The reduction after 48 weeks of treatment was 10%, from 41 to 37 ml/min between younger and elderly groups. 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 (from 0.31 to 0.65 ml/min/kg) obtained in 9 studies conducted in younger adult patients receiving single doses of 30 to 450 mg.
Patients with impaired renal function
A single 100 mg dose of lamotrigine was administered to 12 volunteers with chronic renal impairment and to 6 patients undergoing hemodialysis. Mean CL/F values were 0.42 ml/min/kg (chronic renal impairment), 0.33 ml/min/kg (between hemodialysis sessions), and 1.57 ml/min/kg (during hemodialysis), compared to 0.58 ml/min/kg in healthy volunteers. The mean elimination half-life from plasma was 42.9 hours (chronic renal impairment), 57.4 hours (between hemodialysis sessions), and 13 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1%) of the body load of lamotrigine was removed during a four-hour hemodialysis session. For this patient group, initial dosing of lamotrigine should be based on the patient's concomitant antiepileptic drug regimen; reduction of the maintenance dose may be effective in patients with significant functional renal impairment.
Patients with impaired hepatic function
A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy volunteers in the control group. The 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 control volunteers. Initial, titration, 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). Titration and maintenance doses should be adjusted according to the patient's response to treatment.
Clinical characteristics.
Indications.
Epilepsy.
Adults and children aged 13 years and older: monotherapy and adjunctive therapy of epilepsy, including partial and generalized seizures, such as tonic-clonic seizures.
Seizures associated with Lennox-Gastaut syndrome. Epileptal® may be used as adjunctive therapy, but in Lennox-Gastaut syndrome it may also be initiated as the first antiepileptic drug (AED).
Children aged 2 to 12 years: adjunctive therapy of epilepsy, including partial and generalized seizures, such as tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome.
Monotherapy of typical absence seizures.
Bipolar disorders (adults aged 18 years and older).
For prevention of mood episodes in patients with bipolar I disorder, primarily preventing depressive episodes.
Epileptal® is not indicated for emergency treatment of manic or depressive episodes.
Contraindications.
Epileptal® is contraindicated in patients with known hypersensitivity to lamotrigine or to any other component of the product.
Interaction with other medicinal products and other forms of interaction.
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 potency, which are known to induce UGT, may also enhance lamotrigine metabolism. 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 modest and not of major clinical significance.
Medicinal products that have a definite clinical effect on lamotrigine concentration are listed in Table 1. Specific dosage recommendations for these products are provided in the section "Administration and dosage". In addition, this table includes medicinal products that have little or no effect on lamotrigine concentration. Generally, co-administration of such products is not expected to cause any clinical impact. However, patients with epilepsy whose condition is particularly sensitive to fluctuations in lamotrigine concentration should be cautioned.
Table 1.
Effect of medicinal products on lamotrigine concentration
| Medicinal products that increase lamotrigine concentration |
Medicinal products that decrease lamotrigine concentration |
Medicinal products that have little or no effect on lamotrigine concentration |
| Valproate |
Carbamazepine Phenytoin Primidone Phenobarbital Rifampicin Lopinavir/ritonavir Atazanavir/ritonavir |
Lithium Bupropion Olanzapine Oxcarbazepine Felbamate Gabapentin Levetiracetam Pregabalin Topiramate Zonisamide Aripiprazole Lacosamide Paracetamol Perampanel |
For detailed dosage information, see the subsection "General dosage recommendations for special patient groups" in section "Dosage and administration". Dosage instructions for women taking hormonal contraceptives are provided in the subsection "Hormonal contraceptives" in section "Special precautions".
Interaction with antiepileptic drugs (see section "Dosage and administration").
Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases its average elimination half-life approximately twofold.
Some antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce hepatic cytochrome P450 enzymes, also induce UGT enzymes and consequently accelerate lamotrigine metabolism.
Reports describe central nervous system adverse reactions, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These effects usually resolve upon reduction of the carbamazepine dose. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, although dose reduction was not studied.
In a study in healthy adult volunteers receiving 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter lamotrigine metabolism, and lamotrigine did not alter oxcarbazepine metabolism.
In a study in healthy volunteers, concomitant administration of felbamate at a dose of 1200 mg twice daily and lamotrigine at a dose of 100 mg twice daily for 10 days had no clinically significant effect on the pharmacokinetics of lamotrigine.
According to data from a retrospective analysis of plasma levels in patients taking lamotrigine with or without gabapentin, gabapentin does not alter the existing clearance rate of lamotrigine.
Potential drug interaction between levetiracetam and lamotrigine was studied by assessing serum concentrations of both drugs during placebo-controlled clinical trials. According to these data, the two substances 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 lamotrigine plasma concentration. Lamotrigine administration 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 epilepsy treatment had no significant effect on lamotrigine pharmacokinetics.
Concomitant administration of lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures did not affect lamotrigine plasma concentration. According to data from three placebo-controlled clinical trials investigating adjunctive perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied dose of perampanel (12 mg/day) increased lamotrigine clearance by less than 10%.
Although cases of altered plasma concentrations of other antiepileptic drugs have been described, controlled studies have shown that lamotrigine does not affect plasma concentrations of concomitant antiepileptic agents. In vitro study results indicate that lamotrigine does not displace other antiepileptic drugs from their protein-binding sites.
Interaction with other psychotropic agents (see section "Dosage and administration").
When 100 mg/day lamotrigine and 2 g lithium gluconate (administered twice daily for 6 days) were co-administered to 20 healthy volunteers, the pharmacokinetics of lithium were unchanged.
Multiple oral doses of bupropion had no statistically significant effect on lamotrigine pharmacokinetics in a study of 12 patients, only causing a slight increase in lamotrigine glucuronide levels.
In a study in healthy adult volunteers, 15 mg olanzapine reduced the area under the concentration-time curve (AUC) and Cmax of lamotrigine by an average of 24% and 20%, respectively. 200 mg lamotrigine did not affect the pharmacokinetics of olanzapine.
Multiple oral doses of 400 mg/day lamotrigine did not cause a clinically significant effect on risperidone pharmacokinetics after a single 2 mg dose in a study involving 14 healthy adult volunteers. When 2 mg risperidone was co-administered with lamotrigine, somnolence was reported in 12 out of 14 volunteers, compared to 1 out of 20 volunteers receiving risperidone alone. No cases of somnolence were reported 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 maintained for an additional 7 days. Overall, there was approximately a 10% decrease in Cmax and AUC of lamotrigine.
In vitro experiments showed that the formation of lamotrigine's primary metabolite, N-glucuronide, is minimally affected by amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Studies of 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 lamotrigine clearance is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline, or trazodone.
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 twofold, resulting in a mean reduction of 52% in AUC and 39% in Cmax of lamotrigine. Lamotrigine serum concentration gradually increased during the weekly contraceptive-free interval (so-called "pill-free week"), reaching levels on average approximately twice as high as during concomitant use (see sections "Dosage and administration" and "Special precautions").
Effect of lamotrigine on hormonal contraceptive pharmacokinetics.
Study data in 16 female volunteers showed that a fixed dose of 300 mg lamotrigine 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 mean reductions of 19% in AUC and 12% in Cmax of levonorgestrel. Measurements of serum follicle-stimulating hormone, luteinizing hormone, and estradiol during the study showed ovarian hormonal suppression in some women, although serum progesterone measurements indicated no hormonal signs of ovulation in any of the 16 women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the slight increase in levonorgestrel clearance on ovarian ovulatory activity is unknown (see subsection "General dosage recommendations for special patient groups" in section "Dosage and administration" for dosage recommendations in women taking hormonal contraceptives, and subsection "Hormonal contraceptives" in section "Special precautions"). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Other hormonal contraceptives have not been investigated.
Interaction with other medicinal products.
In a study involving 10 male volunteers receiving rifampicin, lamotrigine clearance increased and elimination half-life decreased due to induction of hepatic enzymes responsible for glucuronidation. In patients receiving concomitant rifampicin therapy, the treatment regimen recommended for lamotrigine and concomitant inducers of glucuronidation should be followed (see section "Dosage and administration").
According to studies in healthy volunteers, lopinavir/ritonavir reduce lamotrigine plasma concentration by approximately half via induction of glucuronidation. For patients already receiving lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and inducers of glucuronidation should be followed (see section "Dosage and administration").
According to studies in healthy volunteers, administration of atazanavir/ritonavir (300 mg / 100 mg) reduced AUC and Cmax of lamotrigine (100 mg dose) in plasma by an average of 32% and 6%, respectively (see subsection "General dosage recommendations for special patient groups" in section "Dosage and administration").
According to study data, administration of paracetamol at a dose of 1 g (four times daily) in healthy volunteers reduced AUC and Cmin of lamotrigine in plasma by an average of 20% and 25%, respectively.
In vitro studies on the effect of lamotrigine on organic cation transporter 2 (OCT2) indicate that lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT2 with IC50 values of 53.8 µM (see section "Special precautions").
Interaction involving laboratory tests.
Interference of lamotrigine with tests used for rapid detection of certain drugs in urine 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.
Special warnings.
Skin rashes.
Skin rashes may occur within the first 8 weeks of initiating lamotrigine therapy. In most cases, rashes are mild and resolve without treatment. However, severe skin reactions requiring hospitalization and discontinuation of Epileptal® 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 syndrome) (see section "Adverse reactions").
Patients who have experienced Stevens–Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) following lamotrigine use must not be rechallenged with lamotrigine.
In adult patients participating in clinical trials using current dosing recommendations, the incidence of severe skin rashes is approximately 1 in 500 patients with epilepsy. Approximately half of these cases were diagnosed as Stevens–Johnson syndrome (1 in 1000).
The incidence of severe skin rashes in patients with bipolar disorder is 1 in 1000.
Children have a higher risk of developing serious skin rashes compared to adults.
Clinical trial data on lamotrigine use 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 within the first 8 weeks of therapy.
The overall risk of skin rashes appears closely related to high initial doses of lamotrigine and exceeding the recommended dose escalation regimen for lamotrigine therapy (see section "Dosage and administration"), as well as concomitant use of valproate (see section "Dosage and administration").
Lamotrigine should be used with caution in patients with a history of allergy or rash to other antiepileptic drugs, as the incidence of mild rashes following 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 treatment with Epileptal® discontinued if there is no evidence that the rash is unrelated to the drug. Reinitiating lamotrigine therapy after discontinuation due to rash from prior lamotrigine treatment is not recommended. In such cases, the decision to re-prescribe the drug should carefully weigh the expected benefit against the potential risk.
Skin rashes have also been reported as part of DRESS syndrome, also known as hypersensitivity syndrome, which is associated with various systemic manifestations including fever, lymphadenopathy, facial swelling, hematological abnormalities, hepatic and renal dysfunction, and aseptic meningitis (see section "Adverse reactions"). The syndrome may vary in severity and rarely may lead to disseminated intravascular coagulation and multiorgan failure. 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, treatment with Epileptal® should be discontinued.
In most cases, aseptic meningitis resolves after discontinuation of the drug, but in some cases it may recur upon rechallenge with lamotrigine. Reintroduction of lamotrigine often leads to rapid recurrence of symptoms, which may be more severe. Patients in whom lamotrigine was previously discontinued due to aseptic meningitis should not be rechallenged with lamotrigine.
Photosensitivity reactions associated with lamotrigine use have also been reported (see section "Adverse reactions"). In several cases, the reaction occurred with high-dose use (400 mg or more), following dose increases, or rapid titration. If a patient exhibits signs of photosensitivity (e.g., severe sunburn), and lamotrigine-related photosensitivity is suspected, discontinuation of treatment should be considered. If continued lamotrigine therapy is clinically justified, patients should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g., wearing protective clothing and using sunscreen).
The HLA-B*1502 allele in individuals of Asian (particularly Chinese and Thai) descent is associated with an increased risk of Stevens–Johnson syndrome/toxic epidermal necrolysis when using lamotrigine. 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 symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenia, high serum ferritin levels, hypertriglyceridemia, liver function abnormalities, and coagulation disorders. Symptoms typically occur within 4 weeks of starting treatment. HLH may be life-threatening.
Patients should be informed about possible symptoms associated with HLH and advised to seek immediate medical attention if such symptoms occur during lamotrigine therapy.
Patients presenting with these symptoms should be evaluated immediately, and a diagnosis of HLH should be considered. If an alternative etiology for the above symptoms cannot be established, lamotrigine therapy should be discontinued.
Suicidal risk.
Depressive symptoms and/or bipolar disorder may occur in patients with epilepsy, and data indicate that patients with epilepsy and bipolar disorder have an increased risk of suicide.
Between 25% and 50% of patients with bipolar disorder have at least one suicide attempt and may experience worsening of depressive symptoms and/or emergence of suicidal thoughts and behaviors (suicidality), regardless of whether they have received treatment for bipolar disorder, including Epileptal®.
Suicidal thoughts and behaviors have been reported in patients treated with antiepileptic drugs for various indications, including epilepsy. Meta-analysis of randomized placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, demonstrated 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 use 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 medical help immediately.
Clinical worsening in bipolar disorder.
Patients treated with Epileptal® 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 monitor for any worsening of their 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 evaluated and appropriate changes to the therapeutic regimen considered, including possible discontinuation of treatment in patients showing clinical worsening (including new symptoms) and/or emergence of suicidal thoughts/behaviors, particularly 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 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), typically by two-fold. In women not already taking lamotrigine metabolism-inducing drugs who are using hormonal contraceptives with a weekly break between cycles (so-called "pill-free week"), a gradual temporary increase in lamotrigine levels may occur during the pill-free week. This increase may be greater if the lamotrigine dose is increased a few days before or during the pill-free week. For detailed dosing recommendations, see the subsection "General dosage recommendations for special patient groups" in section "Dosage and administration". Therefore, women initiating or discontinuing oral contraceptives should remain under continuous medical supervision, and in most cases will require lamotrigine dose adjustment.
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 mcg / levonorgestrel 150 mcg) (see section "Interaction with other medicinal products and other forms of interaction"). The impact of these changes on ovulation is unknown. However, it cannot be ruled out that in some patients concurrently using lamotrigine and hormonal contraceptives, these changes may lead to reduced contraceptive efficacy. Patients should promptly report changes in their menstrual cycle, such as unexpected bleeding.
Effect of lamotrigine on organic cation transporter 2 (OCT2) substrates.
Lamotrigine inhibits renal tubular secretion via organic cation transporter proteins (see section "Interaction with other medicinal products and other forms of interaction"). This may lead to increased plasma levels of certain drugs primarily excreted via this pathway. Therefore, co-administration of Epileptal® with OCT2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended.
Dihydrofolate reductase.
Epileptal® is a weak inhibitor of dihydrofolate reductase, and thus may affect folate metabolism with long-term use. However, no significant changes in hemoglobin levels, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentrations over 5 years were observed during long-term Epileptal® use.
Renal function 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 using other lamotrigine-containing medicinal products.
Epileptal® must not be used in patients already receiving any other lamotrigine-containing medicinal product without physician consultation.
Brugada syndrome.
In patients taking lamotrigine, arrhythmogenic ST–T abnormalities and typical Brugada syndrome ECG patterns have been observed. The use of lamotrigine in patients with Brugada syndrome should be carefully considered.
Child development.
There are no data on the effects of lamotrigine on growth, sexual maturation, cognitive, emotional, and behavioral changes in children.
Epilepsy.
Abrupt discontinuation of Epileptal®, as with other antiepileptic drugs, may provoke increased seizure frequency. Except in cases where the patient's condition requires abrupt discontinuation (e.g., in case of rash), the dose of Epileptal® should be gradually reduced over at least 2 weeks.
According to literature, severe epileptic seizures may lead to rhabdomyolysis, multiorgan failure, and disseminated intravascular coagulation, sometimes with fatal outcomes. Similar cases may occur during Epileptal® therapy.
A significant clinical worsening in seizure frequency rather than improvement may occur. In patients with more than one seizure type, improvement in control of one seizure type should be carefully weighed against worsening of control of another seizure type.
Lamotrigine therapy may exacerbate myoclonic seizures.
Evidence suggests that response to lamotrigine in combination with enzyme inducers is weaker than response to lamotrigine in combination with non-enzyme-inducing antiepileptic drugs. The reason for this is unknown.
Treatment with lamotrigine does not achieve therapeutic effect in all children with 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.
Lamotrigine use in reproductive animal studies did not impair fertility. There are no data on the effect of Epileptal® on fertility in humans.
Teratogenicity.
Epileptal® is a weak inhibitor of dihydrofolate reductase. Theoretically, there is a risk of human fetal congenital malformations if women are treated with folate inhibitors during pregnancy. Reproductive toxicology studies of lamotrigine in animals, administered at doses lower than the human dose of 400 mg/day (on a body surface area basis, mg/m²), showed developmental toxicity (increased mortality, reduced body weight, increased structural abnormalities, neurobehavioral disturbances), but no teratogenic effect was demonstrated.
Epileptal® contains lactose; therefore, the drug should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding.
Risk associated with use of antiepileptic drugs in general.
Women of reproductive age should seek medical advice. The need for antiepileptic drug therapy 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. Monotherapy should be preferred whenever possible, as combination antiepileptic drug (AED) therapy may increase the risk of congenital malformations compared to monotherapy, depending on the AEDs used.
Risk associated with lamotrigine use.
Pregnancy.
Post-marketing surveillance data from over 8700 women receiving lamotrigine monotherapy during the first trimester of pregnancy are available. Overall, these data do not indicate a significant increase in the risk of serious congenital malformations, including oral clefts.
Animal studies have shown embryofetal toxicity.
If Epileptal® therapy is required during pregnancy, the lowest possible effective doses should be used.
Lamotrigine has a weak inhibitory effect on dihydrofolate reductase and theoretically may increase the risk of embryofetal developmental abnormalities due to reduced folic acid levels (see section "Special precautions"). Therefore, the need for folic acid supplementation during pregnancy planning and early pregnancy should be considered.
Physiological changes during pregnancy may affect lamotrigine concentration and/or its therapeutic effect. Cases of decreased lamotrigine plasma concentrations during pregnancy have been reported, increasing the risk of loss of seizure control. After delivery, lamotrigine levels may rapidly increase, with a potential risk of dose-dependent adverse reactions. Therefore, serum lamotrigine levels should be monitored before, during, and after pregnancy. Lamotrigine dosage should be modified as necessary to maintain serum concentrations at pre-pregnancy levels or according to clinical status. Dose-dependent adverse reactions should be closely monitored after delivery.
Period of breastfeeding.
Lamotrigine has been reported to pass into breast milk at variable concentrations, resulting in infant lamotrigine levels reaching up to 50% of maternal levels. Therefore, in some breastfed infants, serum lamotrigine levels may reach levels at which a pharmacological effect is possible.
The benefit of breastfeeding must therefore be weighed against the potential risk of adverse effects in the infant. If a woman decides to breastfeed during Epileptal® therapy, the infant should be monitored for adverse effects such as sedation, rash, and poor weight gain.
Fertility
Animal studies did not reveal any effect of lamotrigine on fertility.
Ability to affect reaction speed when driving or operating machinery.
Data from two studies in volunteers showed that lamotrigine's effects on visual coordination, eye movement, body control, and subjective sedation were no different from placebo. However, neurological adverse reactions such as dizziness and diplopia have been reported in clinical trials with lamotrigine. Therefore, patients should first assess their individual response to lamotrigine treatment 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.
Epileptol® tablets should be swallowed whole, without chewing or breaking.
If the calculated dose of Epileptol®, for example for use in children (epilepsy only) or patients with impaired liver function, does not correspond to the amount of active substance in whole tablets, the dose should be prescribed that corresponds to the nearest lower amount in whole tablets.
Reinitiation of treatment.
When reinitiating treatment in a patient who has previously discontinued therapy, it is essential to carefully assess the need for increasing the maintenance dose, as there is a risk of developing rashes due to a high initial dose or exceeding the recommended lamotrigine dose escalation regimen (see section "Special precautions for use"). The longer the interval since the last dose, the greater the attention required in adjusting the dose escalation regimen to reach the maintenance dose. When the interval since discontinuation of lamotrigine exceeds five times the elimination half-life (see section "Pharmacokinetics"), the lamotrigine dose should be increased to the maintenance dose according to the established regimen.
Reinitiating lamotrigine treatment is not recommended if prior treatment was discontinued due to rash development during previous lamotrigine therapy. In such cases, the decision to re-prescribe the drug should carefully weigh the expected benefits of treatment against the potential risks.
Epilepsy.
Dosage escalation recommendations 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 development, the initial dose and the rate of subsequent dose escalation should not be exceeded (see section "Special precautions for use").
When concomitant antiepileptic drugs (AEDs) are discontinued or other AEDs / medicinal products are added to treatment regimens containing lamotrigine, the potential impact on lamotrigine pharmacokinetics should be taken into account (see section "Interaction with other medicinal products and other forms of interaction").
Table 2.
Recommended treatment regimen for epilepsy in adults and children aged 13 years and older.
| Treatment regimen |
Weeks 1 and 2 |
Weeks 3 and 4 |
Maintenance dose |
| Monotherapy |
25 mg/day (1 dose) |
50 mg/day (1 dose) |
100–200 mg/day (in 1–2 doses). To reach the maintenance dose, the dose should be increased by no more than 50–100 mg every 1 or 2 weeks until optimal response is achieved. Some patients required a dose of 500 mg/day to achieve the desired response. |
| Adjunctive therapy with sodium valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") |
|||
| This treatment regimen involves the use of valproate, regardless of the use of other concomitant medicinal products |
12.5 mg/day (25 mg every other day) |
25 mg/day (1 dose) |
100–200 mg/day (in 1–2 doses). To reach the maintenance dose, the dose should be increased by no more than 25–50 mg every 1–2 weeks until optimal response is achieved. |
| Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
|||
| This treatment regimen does not involve the use of valproate, but includes the use of:
|
50 mg/day (1 dose) |
100 mg/day (2 doses) |
200–400 mg/day (in 2 doses). To reach the maintenance dose, the dose should be increased by no more than 100 mg every 1–2 weeks until optimal response is achieved. Some patients required a dose of 700 mg/day to achieve the desired response. |
| Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
|||
| This treatment regimen involves the use of other medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation |
25 mg/day (1 dose) |
50 mg/day (1 dose) |
100–200 mg/day (in 1–2 doses). To reach the maintenance dose, the dose should be increased by no more than 50–100 mg every 1–2 weeks until optimal response is achieved. |
| For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the dosing regimen recommended for concomitant use of lamotrigine and valproate should be used. |
|||
Table 3.
Recommended treatment regimen for epilepsy in children aged 2 to 12 years
(total daily dose in mg/kg body weight/day)**.
| Treatment regimen |
Weeks 1 and 2 |
Weeks 3 and 4 |
Maintenance dose |
|
| Monotherapy for typical absence seizures |
0.3 mg/kg/day (1–2 divided doses) |
0.6 mg/kg/day (1–2 divided doses) |
1–15 mg/kg/day (in 1–2 divided doses). To reach maintenance dose, increase dosage by no more than 0.6 mg/kg/day every 1–2 weeks until optimal response is achieved, maximum dose — 200 mg/day |
|
| Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This treatment regimen assumes use of valproate regardless of other concomitant medications |
0.15 mg/kg/day* (once daily) |
0.3 mg/kg/day (once daily) |
1–5 mg/kg/day (in 1–2 divided doses). To reach maintenance dose, increase dosage by no more than 0.3 mg/kg/day every 1–2 weeks until optimal response is achieved, maximum dose — 200 mg/day |
|
| Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This treatment regimen excludes valproate but includes use of:
|
0.6 mg/kg/day (2 divided doses) |
1.2 mg/kg/day (2 divided doses) |
5–15 mg/kg/day (in 1–2 divided doses) To reach maintenance dose, increase dosage by no more than 1.2 mg/kg/day every 1–2 weeks until optimal response is achieved, maximum dose — 400 mg/day |
|
| Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This treatment regimen includes other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation |
0.3 mg/kg/day (1–2 divided doses) |
0.6 mg/kg/day (1–2 divided doses) |
1–10 mg/kg/day (in 1–2 divided doses). To reach maintenance dose, increase dosage by no more than 0.6 mg/kg/day every 1–2 weeks until optimal response is achieved, maximum dose — 200 mg/day |
|
| For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the dosing regimen recommended for concomitant use of lamotrigine and valproate should be used. |
||||
* If the calculated dose is less than 1 mg, Epileptol® is not recommended.
** If the calculated dose of lamotrigine cannot be achieved by taking whole tablets, the dose should be rounded to the nearest whole tablet dose.
To ensure maintenance of the therapeutic dose, the child's body weight should be monitored and the dose adjusted accordingly if body weight changes. Patients aged 2 to 6 years may likely require a maintenance dose approaching the upper end of the recommended range.
If seizure control is achieved with adjunctive therapy, concomitant AEDs may be discontinued and monotherapy with Epileptol® continued.
It should be noted that, due to the absence of Epileptol® tablets in a 2 mg strength, appropriate initiation of treatment is not possible for children weighing less than 17 kg.
Children under 2 years of age.
Data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section "Special precautions for use") are limited. Data on the use of lamotrigine in children under 1 month of age are lacking. Therefore, Epileptol® is not recommended for use in children under 2 years of age. If treatment with Epileptol® is considered necessary based on clinical need, see sections "Special precautions for use" and "Pharmacological properties".
Bipolar disorders.
Adults (aged 18 years and older).
The recommended dose escalation and maintenance doses for adults (aged 18 years and older) are provided in the tables below.
The following transition regimen should be followed. This regimen includes titration of lamotrigine up to the maintenance stabilizing dose over 6 weeks (see Table 4), after which other psychotropic and/or antiepileptic drugs may be discontinued if clinically appropriate (see Table 5).
Due to the risk of rash, the initial dose and the rate of subsequent dose escalation must not be exceeded (see section "Special precautions for use").
Table 4.
Recommended dosage escalation regimen for lamotrigine to achieve the maintenance stabilizing daily dose in the treatment of adults (aged 18 years and older) with bipolar disorders.
| Treatment regimen |
Weeks 1 and 2 |
Weeks 3 and 4 |
Week 5 |
Target maintenance dose∗ (Week 6) |
| Lamotrigine monotherapy or adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions") |
||||
| This treatment regimen assumes the use of other medicinal products that do not exert significant inhibitory or inductive effects on lamotrigine glucuronidation |
25 mg/day (once daily) |
50 mg/day (1–2 divided doses) |
100 mg/day (1–2 divided doses) |
200 mg/day usual target dose to achieve optimal response (1–2 divided doses) Doses ranging from 100–400 mg/day have been used in clinical studies |
| Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation — see section "Interaction with other medicinal products and other forms of interactions") |
||||
| This treatment regimen assumes the use of valproate, regardless of other concomitant medicinal products |
12.5 mg/day (25 mg every other day) |
25 mg/day (once daily) |
50 mg/day (1–2 divided doses) |
100 mg/day — usual target dose to achieve optimal response (1–2 divided doses). The maximum daily dose of 200 mg may be used depending on clinical response |
| Adjunctive therapy without valproate but with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions") |
||||
| This treatment regimen does not include valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
50 mg/day (once daily) |
100 mg/day (2 divided doses) |
200 mg/day (2 divided doses) |
300 mg/day by week 6, increasing to 400 mg/day if necessary by week 7 to achieve optimal response (in 2 divided doses) |
| For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interactions"), the dose escalation regimen recommended for concomitant valproate use should be applied. |
||||
* The target maintenance dose may be adjusted depending on the clinical response.
After achieving the required maintenance stabilizing dose, other psychotropic medications may be discontinued according to the scheme provided below (see Table 5).
Table 5.
Adults (aged 18 years and older): maintenance stabilizing dose in bipolar disorders after discontinuation of concomitant medications.
| Treatment regimen |
Current maintenance dose of lamotrigine (prior to discontinuation) |
Week 1 (starting with discontinuation) |
Week 2 |
Week 3 and onwards∗ |
|
| Discontinuation of valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interaction") depending on the initial dose of lamotrigine |
|||||
| When discontinuing valproate, double the maintenance dose without exceeding an increase of 100 mg/week |
100 mg/day |
200 mg/day |
Maintain dose at 200 mg/day (divided into two doses) |
||
| 200 mg/day |
300 mg/day |
400 mg/day |
Maintain dose at 400 mg/day |
||
| Discontinuation of inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") depending on the initial dose of lamotrigine |
|||||
| This dosing regimen applies when discontinuing:
|
400 mg/day |
400 mg/day |
300 mg/day |
200 mg/day |
|
| 300 mg/day |
300 mg/day |
225 mg/day |
150 mg/day |
||
| 200 mg/day |
200 mg/day |
150 mg/day |
100 mg/day |
||
| Discontinuation of medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
|||||
| This dosing regimen applies when discontinuing other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation |
Maintain the achieved dose (200 mg/day), divided into two doses (dose range 100–400 mg) |
||||
| For patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the existing dose of Epileptal® should be maintained and adjusted based on clinical response. |
|||||
* The dose may be increased if necessary up to 400 mg/day.
Adjustment of lamotrigine dosage in patients with bipolar disorders when other drugs are added concomitantly.
There is no clinical experience regarding dosage adjustment of lamotrigine when other drugs are added, but based on data concerning drug interactions, the following dosage recommendations may be advised (see Table 6).
Table 6.
Adults (aged 18 years and older): adjustment of daily lamotrigine dosage in patients with bipolar disorders when other drugs are added concomitantly.
| Treatment regimen |
Current maintenance dose (prior to add-on therapy) |
Week 1 (starting with add-on therapy) |
Week 2 |
Week 3 and onwards |
| Add-on therapy with valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") depending on the initial dose of lamotrigine |
||||
| This regimen should be used when adding valproate regardless of concomitant use of any other medicinal products |
200 mg/day |
100 mg/day |
Maintain dose at 100 mg/day |
|
| 300 mg/day |
150 mg/day |
Maintain dose at 150 mg/day |
||
| 400 mg/day |
200 mg/day |
Maintain this dose at 200 mg/day |
||
| Add-on therapy with inducers of lamotrigine glucuronidation in patients not taking valproate (see section "Interaction with other medicinal products and other forms of interaction"), depending on the initial dose of lamotrigine |
||||
| This regimen should be used when adding the following medicinal products without concomitant use of valproate:
|
200 mg/day |
200 mg/day |
300 mg/day |
400 mg/day |
| 150 mg/day |
150 mg/day |
225 mg/day |
300 mg/day |
|
| 100 mg/day |
100 mg/day |
150 mg/day |
200 mg/day |
|
| Add-on therapy with medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This regimen should be used when adding other medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation |
Maintain the dose achieved after the dose escalation regimen (200 mg/day) (dose range 100–400 mg/day) |
|||
| Patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction") should follow the dosing regimen recommended for concomitant use with valproate. |
||||
Discontinuation of lamotrigine in patients with bipolar disorder.
Clinical trial data showed no increase in the frequency, severity, or type of adverse reactions after abrupt discontinuation of the drug compared to placebo. Therefore, the drug may be discontinued immediately without tapering the dose.
Children (under 18 years of age).
Epiteal® is not indicated for the treatment of bipolar disorder in children (under 18 years of age), as randomized withdrawal studies did not demonstrate significant efficacy and showed an increased rate of suicidality (see sections "Special precautions" and "Pharmacodynamics").
General dosing recommendations for special patient groups.
Women using hormonal contraceptives.
The use of the combination ethinylestradiol/levonorgestrel (30 mcg / 150 mcg) increases lamotrigine clearance approximately twofold, leading to 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 ethinylestradi0l/levonorgestrel was not taken, a twofold increase in lamotrigine levels was observed. Dose-dependent adverse reactions are possible. Therefore, consideration should be given to using contraception without a pill-free interval as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
Initiation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.
The maintenance dose of lamotrigine will need to be doubled in most cases (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). It is recommended that the dose of lamotrigine be increased by 50 to 100 mg/day weekly, according to individual clinical response to treatment, starting from the initiation of hormonal contraceptives. The dose increase should not exceed this level unless clinically indicated.
Measuring lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women taking hormonal contraceptives with a one-week pill-free interval, 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 pill-free interval as first-line therapy (e.g., continuous use of hormonal contraceptives or non-hormonal methods; see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").
Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and not taking inducers of lamotrigine glucuronidation.
The maintenance dose of lamotrigine will need to be reduced to 50% in most cases (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). It is recommended to gradually reduce the daily dose of lamotrigine by 50 to 100 mg weekly (not exceeding 25% of the total daily dose per week) over 3 weeks, unless otherwise indicated by individual clinical response to treatment.
Measuring lamotrigine concentration in blood serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women wishing to discontinue hormonal contraceptives with a one-week pill-free interval, 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 contraceptives should not be collected during the first week after stopping.
Initiation of lamotrigine therapy in women already taking hormonal contraceptives.
Dose escalation should follow the standard dosage recommendations provided in the tables above.
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.
Dose adjustment of lamotrigine when added to ongoing atazanavir/ritonavir therapy is not required.
For patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation, additional prescription of atazanavir/ritonavir may require an increase in lamotrigine dose, and discontinuation of atazanavir/ritonavir may require a dose reduction.
To determine the need for lamotrigine dose adjustment, plasma lamotrigine levels should be monitored before and within 2 weeks after starting or stopping atazanavir/ritonavir (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with lopinavir/ritonavir.
Dose adjustment of lamotrigine when added to ongoing lopinavir/ritonavir therapy is not required.
For patients already receiving maintenance doses of lamotrigine and not taking inducers of glucuronidation, additional prescription of lopinavir/ritonavir may require an increase in lamotrigine dose, and discontinuation of lopinavir/ritonavir may require a dose reduction. To determine the need for lamotrigine dose adjustment, plasma lamotrigine levels should be monitored before and within 2 weeks after starting or stopping lopinavir/ritonavir (see section "Interaction with other medicinal products and other forms of interaction").
Elderly patients (aged 65 years and older).
Dose adjustment is not required. The pharmacokinetics of lamotrigine in this age group does not differ from that in patients under 65 years of age (see section "Pharmacokinetics").
Hepatic impairment.
The initial dose, titration dose, and maintenance dose should 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. Titration and maintenance doses should be adjusted according to clinical effect (see section "Pharmacokinetics").
Renal impairment.
Caution should be exercised when prescribing the drug to patients with renal impairment. In patients with end-stage renal disease, the initial dose of lamotrigine should be based on an individual antiepileptic treatment regimen. In patients with significant renal impairment, the maintenance dose of lamotrigine should be reduced (see sections "Special precautions" and "Pharmacokinetics").
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 of this age group.
Lamotrigine is not indicated for use in children (under 18 years of age) with bipolar disorder due to lack of established efficacy and increased risk of suicidal ideation (see section "Special precautions").
Overdose.
Symptoms and signs
Cases of acute overdose (with doses 10–20 times higher than the maximum therapeutic doses) have been reported, including fatal cases. Symptoms of overdose included ataxia, nystagmus, impaired consciousness, major epileptic seizures, and coma. Prolongation of the QRS interval on electrocardiogram (intraventricular conduction delay) has also been observed in patients with overdose. QRS widening to more than 100 ms may be associated with more severe toxicity.
Treatment
In case of overdose, the patient should be hospitalized for appropriate supportive therapy. Treatment should aim to reduce absorption (activated charcoal), if necessary. Additional treatment should be administered based on clinical indications, considering the potential effects on cardiac conduction (see section "Special precautions"). In cases of cardiotoxicity insufficiently responsive to sodium bicarbonate, intravenous lipid therapy may be considered. There is no experience with hemodialysis as a treatment for overdose. In 6 volunteers with renal impairment, 20% of lamotrigine was eliminated during a 4-hour hemodialysis session (see section "Pharmacological properties").
Adverse reactions
Adverse reactions associated with lamotrigine use in the treatment of epilepsy and bipolar disorder are based on data from controlled clinical trials and other clinical experience, and are listed in Table 7 below. Frequency categories were derived from controlled clinical trials (epilepsy monotherapy† and bipolar disorder§). Where frequency categories differ between clinical trial data in epilepsy and bipolar disorder, the lowest frequency is indicated. However, where there are no controlled clinical trial data, frequency categories were derived from other clinical experience.
The following classification was used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).
Table 7.
| Body systems |
Adverse reactions |
Frequency |
| Blood and lymphatic system disorders |
Hematologic abnormalities1 (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, and agranulocytosis), hemophagocytic lymphohistiocytosis (see section "Special precautions") Lymphadenopathy1, cutaneous pseudolymphoma |
Very rare Unknown |
| Immune system disorders |
Drug hypersensitivity syndrome2 Hypogammaglobulinemia |
Very rare Unknown |
| Psychiatric disorders |
Aggression, irritability Tics (motor and/or vocal), hallucinations, confusion Nightmares |
Common Very rare Unknown |
| Nervous system disorders |
Headache§ Somnolence†§, insomnia†, dizziness†§, tremor†, anxiety§ Ataxia† Nystagmus†, aseptic meningitis (see section "Special precautions") |
Very common Common Uncommon Rare Very rare |
| Eye disorders |
Diplopia†, blurred vision† Conjunctivitis |
Uncommon Rare |
| Gastrointestinal disorders |
Nausea†, vomiting†, diarrhea†, dry mouth§ |
Common |
| Hepatobiliary disorders |
Elevated liver function test parameters, liver function impairment4, liver failure |
Very rare |
| Skin and subcutaneous tissue disorders |
Skin rash5§† Alopecia, photosensitivity reaction Stevens-Johnson syndrome§ Toxic epidermal necrolysis, DRESS syndrome2 |
Very common Uncommon Rare Very rare |
| Renal and urinary system disorders |
Tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis syndrome |
Unknown |
| Musculoskeletal and connective tissue disorders |
Arthralgia§ Lupus-like reactions |
Common Very rare |
| General disorders and administration site conditions |
Fatigue†, pain§, back pain§ |
Common |
Description of individual adverse reactions.
1 Hematological abnormalities and lymphadenopathy may be associated or not associated with a drug reaction involving eosinophilia and systemic manifestations (DRESS syndrome) / hypersensitivity syndrome (see "Special precautions" and Immune system disorders).
2 Skin rash has also been reported as part of a syndrome known as DRESS, associated with systemic manifestations including fever, lymphadenopathy, facial swelling, hematological abnormalities, and hepatic and renal dysfunction. The syndrome may vary in severity and, rarely, may lead to the development of DIC (disseminated intravascular coagulation) and multiorgan failure. It is important to note that early signs of hypersensitivity (e.g., fever, lymphadenopathy) may be present even before the onset of rash. If such signs and symptoms are present, the patient should seek immediate medical attention, and Epileptal® should be discontinued unless an alternative etiology can be established.
3 These effects were recorded during other clinical experience.
There have been reports that lamotrigine may worsen symptoms of parkinsonism in patients with pre-existing Parkinson's disease, as well as isolated reports of extrapyramidal effects and choreoathetosis in patients without this condition.
4 Hepatic dysfunction is usually observed in association with hypersensitivity reactions, but isolated cases have been reported without apparent signs of hypersensitivity.
5 In clinical trials in adults, skin rash was observed in 8–12% of patients receiving lamotrigine and in 5–6% of patients receiving placebo. Skin rashes led to discontinuation of the drug in 2% of patients. The rash was typically maculopapular, appeared within eight weeks of starting treatment, and resolved upon discontinuation of the drug (see section "Special precautions").
Serious, 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 syndrome). Although most patients recover after discontinuation of the drug, some may be left with permanent scarring; in isolated cases, these symptoms have led to fatal outcomes (see section "Special precautions").
The overall risk of developing skin rash appears to be closely related to high initial doses of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy (see section "Dosage and administration"), as well as concomitant use of valproate (see section "Dosage and administration").
There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients on long-term lamotrigine therapy. The mechanism by which lamotrigine affects bone metabolism has not been identified.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions. Store in a light-protected place at a temperature not exceeding 25 ºC.
Keep out of reach of children.
Packaging. 10 tablets per blister. 3 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Farmak".
Manufacturer's location and address of its place of business.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.