Lamictal
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMICTAL (LAMICTAL)
Composition:
Active substance: lamotrigine;
1 tablet contains lamotrigine 5 mg, 50 mg, or 100 mg;
Excipients: calcium carbonate, low-substituted hydroxypropylcellulose, aluminum magnesium silicate, sodium starch glycolate (type A), povidone K30, sodium saccharin, blackcurrant flavor, magnesium stearate.
Pharmaceutical form. Dispersible tablets.
Main physicochemical properties: white or off-white tablets; (for 5 mg tablets – oval-shaped, biconvex), (for 50 mg and 100 mg tablets – polyhedral superelliptical with smooth surface), tablets with a blackcurrant odor. On one side of the tablets, embossed with GS CL2 (for 5 mg tablets), GSCX7 (for 50 mg tablets), or GSCL7 (for 100 mg tablets); on the other side – the dosage of the drug, namely: 5, 50, or 100. Marbling on the surface of the tablets is permissible.
Pharmacotherapeutic group. Antiepileptic drugs. Lamotrigine. ATC code N03A X09.
Pharmacological properties.
Mechanism of action
Pharmacological studies have shown that lamotrigine is a use-dependent and voltage-dependent blocker of voltage-gated sodium channels. It suppresses sustained neuronal re-firing and inhibits the release of glutamate (a neurotransmitter that plays a key role in the development of epileptic seizures). This effect is likely responsible for the anticonvulsant properties of lamotrigine.
In contrast, the mechanisms underlying the therapeutic effect of lamotrigine in bipolar disorder remain to be fully elucidated, although interaction with voltage-gated sodium channels is believed to play an important role.
Pharmacodynamic effects
Studies assessing the effects of drugs on the central nervous system revealed no difference between healthy volunteers receiving 240 mg of lamotrigine and those receiving placebo, whereas both 1000 mg of phenytoin and 10 mg of diazepam significantly impaired fine visuomotor coordination, eye movements, and body balance, as well as caused a subjective sedative effect.
In another study, single oral doses of 600 mg of carbamazepine significantly impaired fine visuomotor coordination, eye movements, and body balance, and increased heart rate. In contrast, lamotrigine administered at doses of 150 mg and 300 mg showed no difference from placebo.
Effect of lamotrigine on cardiac conduction
In a study involving healthy adult volunteers, the effect of repeated doses of lamotrigine (up to 400 mg/day) on cardiac conduction was assessed using 12-lead ECG. Compared to placebo, lamotrigine showed no clinically significant effect on the QT interval.
Clinical efficacy and safety
Prevention of mood episodes in patients with bipolar disorder
The efficacy of lamotrigine for the prevention of mood episodes in patients with bipolar disorder type I was evaluated in two studies.
Study SCAB2003 was a multicenter, double-blind, double-dummy, placebo- and lithium-controlled, randomized fixed-dose study assessing long-term prevention of recurrent and relapsing depressive and/or manic episodes in patients with bipolar disorder type I who had a current or recent major depressive episode. After stabilization with lamotrigine monotherapy or adjunctive therapy, patients were randomly assigned to one of five treatment groups for up to 76 weeks (18 months): lamotrigine (50, 200, or 400 mg/day), lithium (serum level 0.8–1.1 mmol/L), or placebo. The primary endpoint was "time to intervention for a mood episode (TIME)," where interventions were defined as additional pharmacotherapy or electroconvulsive therapy (ECT). Study SCAB2006 was conducted with a design similar to SCAB2003 but used a more flexible dosing regimen of lamotrigine (100–400 mg/day) and included patients with bipolar disorder type I who had a current or recent manic episode. Results are presented in Table 1.
Table 1
Summary of results from efficacy studies of lamotrigine in the prevention of mood episodes in patients with bipolar disorder type I
| Proportion of patients event-free at week 76 |
||||||
| Study SCAB2003 Type I Bipolar Disorder |
Study SCAB2006 Type I Bipolar Disorder |
|||||
| Inclusion criterion |
Major Depressive Episode |
Major Manic Episode |
||||
| Lamotrigine |
Lithium |
Placebo |
Lamotrigine |
Lithium |
Placebo |
|
| Intervention-free |
0.22 |
0.21 |
0.12 |
0.17 |
0.24 |
0.04 |
| log-rank test p-value |
0.004 |
0.006 |
- |
0.023 |
0.006 |
- |
| Depression-free |
0.51 |
0.46 |
0.41 |
0.82 |
0.71 |
0.40 |
| log-rank test p-value |
0.047 |
0.209 |
- |
0.015 |
0.167 |
- |
| Mania-free |
0.70 |
0.86 |
0.67 |
0.53 |
0.64 |
0.37 |
| log-rank test p-value |
0.339 |
0.026 |
- |
0.280 |
0.006 |
- |
Additional analysis of time to first depressive episode and time to first manic/hypomanic or mixed episode showed that the first depressive episode occurred statistically later in patients receiving lamotrigine than in patients in the placebo group. No statistically significant difference was observed in time to first manic/hypomanic or mixed episode.
The efficacy of lamotritrigine in combination with mood stabilizers has not been adequately studied.
Children
Children aged 1 to 24 months
Efficacy and safety of adjunctive therapy for partial seizures in children aged 1 to 24 months were evaluated in a small, double-blind, placebo-controlled withdrawal trial. Treatment was initiated in 177 patients using a dosing regimen recommended for children aged 2 to 12 years. The lowest available lamotrigine dose is contained in 2 mg tablets. Therefore, in some cases, the standard dosing regimen during the titration phase was appropriately modified (e.g., by administering a 2 mg tablet every other day when the calculated dose was less than 2 mg). Serum concentrations were measured at the end of the 2nd week of the titration phase and the subsequent dose phase, reduced or not increased due to concentrations exceeding 0.41 µg/mL – predicted concentrations in adult patients at this time point of therapy. By the end of the 2nd week, some patients required dose reduction by up to 90%. Thirty-eight patients who responded to therapy (reduction in seizure frequency > 40%) were randomized into two groups: placebo or continued lamotrigine. Treatment failure was observed in 84% of patients in the placebo group (16 out of 19) and in 54% of patients in the lamotrigine group (11 out of 19). The difference was not statistically significant: 26.3%, 95% CI –2.6% < > 50.2%, p = 0.07.
Overall, 256 patients aged 1 to 24 months received lamotrigine at doses ranging from 1 to 15 mg/kg/day for up to 72 weeks. The safety profile of lamotrigine in this age group was similar to that in older children, except for seizure worsening (≥ 50%), which occurred statistically more frequently in children under 2 years of age (26%) compared to older children (14%).
Lennox–Gastaut syndrome
Data on monotherapy for seizures associated with Lennox–Gastaut syndrome are lacking.
Prevention of mood episodes in children (10–12 years) and adolescents (13–17 years)
In a multicenter, parallel-group, placebo-controlled, double-blind, randomized withdrawal trial, the safety and efficacy of immediate-release (IR) lamotrigine tablets as adjunctive maintenance therapy for delaying mood episodes were evaluated in children and adolescents (10–17 years) of both sexes diagnosed with bipolar I disorder who had achieved remission or improvement with lamotrigine in combination with antipsychotics or other antidepressants. The primary efficacy analysis (time to occurrence of a bipolar event) did not show a statistically significant result (p = 0.0717), indicating lack of efficacy. Additionally, safety analysis revealed a higher incidence of suicidal behavior in the lamotrigine group: 5% (4 patients) compared to 0 in the placebo group.
Pharmacokinetics
Absorption
In the absence of significant presystemic metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration is reached approximately 2.5 hours post-dose. Time to maximum concentration is slightly prolonged when the drug is taken after food, but this does not affect the extent of absorption. There are substantial inter-individual variations in steady-state maximum concentrations, although intra-individual variability in a single patient is generally low.
Distribution
Approximately 55% of the drug dose is bound to plasma proteins. Toxic effects due to displacement from plasma proteins are unlikely.
Volume of distribution ranges from 0.92 to 1.22 L/kg.
Biotransformation
UDP-glucuronosyltransferase has been identified as the primary enzyme responsible for lamotrigine metabolism.
Lamotrigine may induce its own metabolism to a minor, dose-dependent extent. However, the effect of lamotrigine on the pharmacokinetics of other anticonvulsants has not been established, and available data suggest that interactions between lamotrigine and other drugs metabolized by cytochrome P450 are unlikely.
Elimination
Theoretical plasma clearance in healthy volunteers is approximately 30 mL/min. Lamotrigine clearance occurs predominantly via metabolite formation, followed by urinary excretion of glucuronide-conjugated material. Less than 10% of the dose is excreted unchanged in urine. Only 2% of metabolized lamotrigine is excreted via the intestine. Clearance and half-life are dose-dependent. The theoretical plasma half-life in healthy volunteers is approximately 33 hours (range 14 to 103 hours). In a study involving patients with Gilbert’s syndrome, mean theoretical clearance in these subjects was 32% lower than in the control group, but within the range defined for the general patient population.
The half-life of lamotrigine is significantly influenced by concomitantly administered drugs. The average half-life may be reduced by approximately 14 hours when co-administered with glucuronidation inducers such as carbamazepine and phenytoin, or increased by approximately 70 hours when taken concomitantly with valproate alone (see section "Interaction with other medicinal products and other forms of interaction").
Linearity
Up to the highest studied dose of 450 mg, the pharmacokinetics of lamotrigine showed linear behavior.
Special patient populations
Children
Clearance, normalized per body weight, is higher in children than in adults, and highest in children under 5 years of age. The half-life of lamotrigine in children is generally shorter than in adults. When co-administered with enzyme inducers such as carbamazepine and phenytoin, the half-life averages approximately 7 hours, increasing to 45–50 hours when co-administered exclusively with valproate (see section "Interaction with other medicinal products and other forms of interaction").
Children aged 2 to 26 months
In 143 patients aged 2 to 26 months with body weight ranging from 3 to 16 kg, oral administration of equivalent doses per kilogram of body weight resulted in lower clearance compared to children over 2 years of age with similar body weight. The average half-life in children under 26 months was 23 hours when enzyme-inducing therapy was used, 136 hours when co-administered with valproate, and 38 hours without concomitant use of enzyme inhibitors or inducers. Inter-individual variability in clearance following oral dosing in patients aged 2 to 26 months was high (47%). Predicted serum concentrations in this age group were within the range observed in older patients, although patients with body weight below 10 kg showed higher maximum concentration values in some cases.
Elderly patients
Pharmacokinetic analysis results from one study in patients with epilepsy showed no clinically significant differences in lamotrigine clearance between elderly and younger patients. After single doses, theoretical clearance decreased by 12%: from 35 mL/min/kg in 20-year-old patients to 31 mL/min/kg in 70-year-old patients. After 48 weeks of treatment, the reduction was 10%: from 41 mL/min in younger patients to 37 mL/min in elderly patients. The pharmacokinetics of lamotrigine were also studied in 12 healthy elderly volunteers who received a single 150 mg dose. The mean clearance value in elderly subjects (0.39 mL/min/kg) falls within the range of mean clearance values (0.31–0.65 mL/min/kg) obtained in 9 studies involving non-elderly adult patients after single doses of 30 to 450 mg.
Patients with renal impairment
Twelve volunteers with chronic renal impairment and six patients on hemodialysis received a single 100 mg dose of lamotrigine. Mean clearance was 0.42 mL/min/kg (in chronic renal impairment), 0.33 mL/min/kg (between hemodialysis sessions), and 1.57 mL/min/kg (during hemodialysis), compared to 0.58 mL/min/kg in healthy volunteers. Mean plasma half-life was 42.9 hours (in chronic renal impairment), 57.4 hours (between hemodialysis sessions), and 13.0 hours (during hemodialysis), compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1%) of the body load of lamotrigine was removed during a four-hour hemodialysis session. Initial doses of lamotrigine in these patients should be determined based on concomitant medications. Reduction of maintenance dose may be effective in patients with significant renal impairment.
Patients with hepatic impairment
A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy volunteers in the control group. In patients with Child-Pugh class A, B, and C hepatic impairment, mean theoretical clearance of lamotrigine was 0.31 mL/min/kg, 0.24 mL/min/kg, and 0.10 mL/min/kg, respectively, compared to 0.34 mL/min/kg in control group volunteers. Initial, titrated, and maintenance doses in patients with moderate to severe hepatic impairment should be reduced.
Preclinical safety data
In vitro studies showed that lamotrigine, at concentrations corresponding to therapeutic doses, exhibits class IB antiarrhythmic activity. It inhibits human cardiac sodium channels, demonstrating rapid onset and offset kinetics and strong voltage dependence, consistent with the action of other class IB antiarrhythmic agents. At therapeutic doses, lamotrigine did not slow ventricular conduction (QRS widening) in healthy volunteers in a thorough QT study. However, in patients with clinically significant structural or functional heart disease, lamotrigine may potentially slow ventricular conduction (QRS widening) and cause proarrhythmia (see section "Special warnings and precautions for use").
Clinical characteristics.
Indications.
Epilepsy. Adults and children aged 13 years and older.
Adjunctive therapy or monotherapy of partial and generalized seizures of epilepsy, including tonic-clonic seizures.
Seizures associated with Lennox-Gastaut syndrome. Lamictal is indicated as adjunctive therapy, but in Lennox-Gastaut syndrome it may be prescribed as the initial antiepileptic drug (AED).
Children aged 2 to 12 years.
Adjunctive therapy of partial and generalized seizures of epilepsy, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.
Monotherapy of typical absence seizures.
Bipolar disorder.
Adults (aged 18 years and older).
Prevention of depressive episodes in patients with bipolar I disorder who predominantly experience depressive episodes.
Lamictal is not indicated for emergency treatment of manic or depressive episodes.
Contraindications.
Lamictal is contraindicated in patients with known hypersensitivity to lamotrigine or any other component of the medicinal product.
Interaction with other medicinal products and other forms of interactions.
Interaction studies have been conducted only in adult patients.
It has been established that uridine 5’-diphosphate (UDP)-glucuronosyltransferase (UGT) is the enzyme responsible for lamotrigine metabolism. Therefore, medicinal products that induce or inhibit glucuronidation may affect the theoretical clearance of lamotrigine. Inducers of cytochrome P450 3A4 (CYP3A4) of strong or moderate activity, which are known to induce UGT, may also enhance lamotrigine metabolism. There is no evidence that lamotrigine may cause clinically significant stimulation or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but this effect is moderate and has no significant clinical consequences.
Medicinal products that have been shown to have a relevant clinical effect on lamotrigine concentration are listed in Table 2. Specific dosage recommendations for these medicinal products are provided in the section "Method of administration and dosage". In addition, this table lists medicinal products that have been shown to have little or no effect on lamotrigine concentration. Generally, concomitant use of such medicinal products is not expected to cause any clinical effect. However, patients with epilepsy whose condition is particularly sensitive to fluctuations in lamotrigine concentration should be cautioned.
Table 2
Effect of medicinal products on lamotrigine concentration
| Medicinal products that increase lamotrigine concentration |
Medicinal products that decrease lamotrigine concentration |
Medicinal products with little or no effect on lamotrigine concentration |
| Valproate |
Atazanavir/ritonavir Carbamazepine Ethinylestradiol/levonorgestrel combination* Lopinavir/ritonavir Phenobarbital Phenytoin Primidone Rifampicin |
Aripiprazole Bupropion Felbamate Gabapentin Lacosamide Levetiracetam Lithium Olanzapine Oxcarbazepine Paracetamol Perampanel Pregabalin Topiramate Zonisamide |
* For detailed dosage information, see the section "General dosage recommendations for special patient groups" in the "Dosage and administration" section. For dosage recommendations for women taking hormonal contraceptives, see the "Hormonal contraceptives" subsection in the "Special precautions" section.
Interaction with antiepileptic drugs (AEDs)
Valproate, which inhibits glucuronidation of lamotrigine, reduces lamotrigine metabolism and increases the average elimination half-life by approximately two-fold. Patients receiving valproate concomitantly should follow an appropriate dosing regimen (see the "Dosage and administration" section).
Some AEDs (such as phenytoin, carbamazepine, phenobarbital, and primidone), which induce cytochrome P450 enzymes, also induce UGT enzymes and thereby accelerate lamotrigine metabolism. Patients receiving phenytoin, carbamazepine, phenobarbital, or primidone concomitantly should follow an appropriate dosing regimen (see the "Dosage and administration" section).
There have been reports of central nervous system adverse reactions, including dizziness, ataxia, diplopia, blurred vision, and nausea, in patients receiving carbamazepine concomitantly with lamotrigine. These effects usually resolve with a reduction in carbamazepine dose. A similar effect was observed in a study of lamotrigine and oxcarbazepine in healthy adult volunteers, but 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. Patients receiving oxcarbazepine concomitantly should follow the dosing regimen for lamotrigine adjunctive therapy without valproate and without inducers of glucuronidation (see the "Dosage and administration" section).
In a study in 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 taking lamotrigine with or without gabapentin, gabapentin does not alter the theoretical clearance of lamotrigine.
Potential drug interaction between levetiracetam and lamotrigine was studied by assessing serum concentrations of both drugs during placebo-controlled clinical trials. According to these data, the two substances do not affect each other's pharmacokinetics.
Plasma steady-state 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. Lamotrigine increases topiramate concentration by 15%.
According to study data, administration of zonisamide (200–400 mg/day) together with lamotrigine (150–500 mg/day) for 35 days in the treatment of epilepsy had no significant effect on lamotrigine pharmacokinetics.
Concomitant administration of lacosamide (200, 400, or 600 mg/day) did not affect lamotrigine plasma concentration in placebo-controlled clinical trials in patients with partial seizures.
In a pooled analysis of data from three placebo-controlled clinical trials investigating additional concomitant perampanel in patients with partial and primary generalized tonic-clonic seizures, the highest studied dose of perampanel (12 mg/day) increased lamotrigine clearance by less than 10%.
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 drugs. In vitro studies demonstrated that lamotrigine does not displace other antiepileptic drugs from their protein binding sites.
Interaction with other psychotropic agents
When 100 mg/day lamotrigine was administered concomitantly with 2 g anhydrous lithium gluconate twice daily for 6 days in 20 healthy volunteers, the pharmacokinetics of lithium were not altered.
In a study involving 12 patients, multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and resulted only in a slight increase in the area under the concentration-time curve of lamotrigine glucuronide.
In a study in healthy adult volunteers, 15 mg olanzapine reduced the area under the concentration-time curve and Cmax of lamotrigine by an average of 24% and 20%, respectively. Lamotrigine 200 mg did not affect the pharmacokinetics of olanzapine.
Multiple oral doses of lamotrigine 400 mg/day did not cause a clinically significant effect on the pharmacokinetics of risperidone after a single 2 mg dose in studies involving 14 healthy adult volunteers. With concomitant administration of 2 mg risperidone and lamotrigine, 12 out of 14 volunteers reported somnolence, 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 (100–400 mg/day), aripiprazole doses were increased from 10 mg/day to 30 mg/day over 7 days and maintained for another 7 days. A decrease in Cmax and AUC of lamotrigine by approximately 10% was observed.
In vitro experiments showed that the presence of amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam may minimally slow the formation of the primary metabolite of lamotrigine, 2-N-glucuronide. These experiments also demonstrated that lamotrigine metabolism is not inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone. Data from bufuralol metabolism studies in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs metabolized primarily via CYP2D6.
Interaction with hormonal contraceptives.
Effect of hormonal contraceptives on lamotrigine pharmacokinetics.
In a study involving 16 female volunteers taking a tablet containing ethinylestradiol 30 µg/levonorgestrel 150 µg, lamotrigine clearance increased by approximately two-fold, resulting in a mean reduction in the area under the concentration-time curve and Cmax of lamotrigine by 52% and 39%, respectively. During the weekly contraceptive-free interval (the so-called "pill-free week"), lamotrigine serum concentrations gradually increased, reaching levels approximately two-fold higher than during concomitant use (see the "Special precautions" section). Dose adjustments of lamotrigine during the titration phase are not required when hormonal contraceptives are used concomitantly. However, maintenance doses of lamotrigine should be increased or decreased each time a patient starts or stops taking hormonal contraceptives (see the "Dosage and administration" section).
Effect of lamotrigine on the pharmacokinetics of hormonal contraceptives.
According to study data in 16 female volunteers, lamotrigine at steady-state concentrations achieved with a 300 mg dose did not affect the pharmacokinetics of ethinylestradiol, a component of combined oral contraceptive tablets. A consistent slight increase in levonorgestrel clearance was observed, resulting in a mean reduction in the area under the concentration-time curve and Cmax of levonorgestrel by 19% and 12%, respectively. Serum levels of follicle-stimulating hormone, luteinizing hormone, and estradiol recorded in this study indicated reduced suppression of ovarian hormonal activity in some women, although serum progesterone levels indicated absence of any hormonal signs of ovulation in all 16 women. The impact of changes in serum follicle-stimulating and luteinizing hormone levels and the slight increase in levonorgestrel clearance on ovarian ovulatory activity is unknown (see the "General dosage recommendations for special patient groups" subsection in the "Dosage and administration" section regarding dosage for women taking hormonal contraceptives, and the "Hormonal contraceptives" subsection in the "Special precautions" section). The effect of lamotrigine at daily doses exceeding 300 mg has not been studied. Studies with other hormonal contraceptives have also not been conducted.
Interaction with other medicinal products
In a study involving 10 male volunteers, rifampicin accelerated lamotrigine clearance and shortened its elimination half-life by inducing hepatic enzymes responsible for glucuronidation. In patients receiving concomitant rifampicin therapy, the dosing regimen recommended for lamotrigine with inducers of glucuronidation should be followed (see the "Dosage and administration" section).
According to studies in healthy volunteers, lopinavir/ritonavir reduce lamotrigine plasma concentrations by approximately two-fold via induction of glucuronidation. For patients already taking lopinavir/ritonavir, the dosing regimen recommended for lamotrigine with inducers of glucuronidation should be followed (see the "Dosage and administration" section).
According to studies in healthy volunteers, administration of atazanavir/ritonavir (300 mg/100 mg) for 9 days reduced AUC and Cmax of lamotrigine in plasma (after a single 100 mg dose) by an average of 32% and 6%, respectively. Patients already taking lopinavir/ritonavir should follow the appropriate lamotrigine dosing regimen (see the "Dosage and administration" section).
According to studies in healthy volunteers, administration of paracetamol 1 g four times daily reduced AUC and Cmin of lamotrigine in plasma by an average of 20% and 25%, respectively.
In vitro studies demonstrated that only lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT2) at potentially clinically relevant concentrations. These data indicate that lamotrigine is an inhibitor of OCT2 with an IC50 value of 53.8 µM. Concomitant administration of lamotrigine with medicinal products that are substrates of OCT2 and eliminated renally (e.g., metformin, gabapentin, varenicline) may lead to increased plasma concentrations of these drugs. The clinical significance of this effect remains unclear, but lamotrigine should be used with caution in patients taking such medicinal products concomitantly.
Special precautions
Skin rashes
Skin rash may occur within the first 8 weeks of initiating lamotrigine therapy. In most cases, rashes are mild and resolve without treatment. However, severe skin reactions requiring hospitalization and discontinuation of Lamictal have been reported. These include potentially life-threatening rashes such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), also known as hypersensitivity syndrome (HSS) (see section "Adverse reactions").
Lamotrigine must not be re-administered to patients who have previously experienced Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS following lamotrigine use. In adult patients participating in clinical trials conducted according to current dosing recommendations for Lamictal, 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 1,000).
The incidence of severe skin rashes in patients with bipolar disorder is 1 in 1,000.
Children have a higher risk of developing serious skin rashes compared to adults. Clinical trial data on Lamictal use indicate that the incidence of rashes leading to hospitalization in children ranges from 1 in 300 to 1 in 100 patients.
In children, early signs of skin rashes may be mistaken for infection. Therefore, physicians should consider the possibility of an adverse drug reaction in children who develop rash and fever during the first 8 weeks of therapy.
The overall risk of skin rash appears to be closely associated with high initial doses of lamotrigine and exceeding the recommended dose escalation regimen (see section "Dosage and administration"), as well as concomitant use of valproate (see section "Dosage and administration").
Lamotrigine should be used with caution in patients with a history of allergy or rash to other antiepileptic drugs, as the frequency of mild rashes following lamotrigine treatment in this patient group was three times higher than in those without such history.
The presence of the HLA-B*1502 allele in individuals of Asian (particularly Chinese and Thai) ancestry has been associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with lamotrigine use. If a patient is confirmed to carry the HLA-B*1502 allele, lamotrigine should be used with particular caution.
If a rash develops, the patient (adult or child) should be examined immediately and Lamictal discontinued unless there is clear evidence that the rash is unrelated to the drug. Re-initiation of lamotrigine therapy is not recommended after discontinuation due to rash from prior lamotrigine treatment. In such cases, the decision to re-prescribe lamotrigine should carefully weigh the expected benefits against potential risks.
Skin rash may also be part of DRESS, also known as hypersensitivity syndrome. This condition is associated with various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, liver and kidney dysfunction, and aseptic meningitis (see section "Adverse reactions"). The syndrome may vary in severity and rarely may lead to disseminated intravascular coagulation and multi-organ failure. Importantly, early signs of hypersensitivity (e.g., fever and lymphadenopathy) may occur even in the absence of skin rash. Patients presenting with such symptoms should be examined immediately, and Lamictal should be discontinued if no other cause is identified.
In most cases, aseptic meningitis resolves after discontinuation of the drug, but in some cases it may recur upon re-administration of lamotrigine. Re-challenge with lamotrigine often leads to rapid recurrence of symptoms, which may be more severe. Lamotrigine must not be re-administered to patients who previously discontinued it due to aseptic meningitis.
Photosensitivity reactions associated with Lamictal 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 presents with signs of photosensitivity (e.g., severe sunburn), and Lamictal-related photosensitivity is suspected, discontinuation of therapy should be considered. If continued Lamictal treatment 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 sunscreens).
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, elevated serum ferritin, hypertriglyceridemia, and abnormalities in liver function and coagulation. Symptoms typically develop 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 promptly, and HLH should be considered in the differential diagnosis. Lamotrigine therapy should be discontinued if no alternative etiology for the symptoms can be established.
Clinical worsening and suicide risk
Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various conditions, including epilepsy. A meta-analysis of randomized placebo-controlled clinical trials of antiepileptic drugs, including lamotrigine, demonstrated a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, but available data do not exclude the possibility that lamotrigine contributes to this risk. Therefore, patients should be closely monitored for signs of suicidal thoughts and behavior. If such signs emerge, patients and caregivers should seek immediate medical help.
In patients with bipolar disorders, worsening of depressive symptoms and/or suicidal behavior may occur regardless of whether they are receiving treatment for bipolar disorder, including Lamictal. Patients receiving Lamictal for bipolar disorder should be closely monitored for clinical worsening (including emergence of new symptoms) and suicidal behavior, particularly at the beginning of treatment or during dosage adjustments. Patients with a history of suicidal behavior or ideation, younger patients, and those who exhibited marked suicidal ideation prior to treatment initiation may be at higher risk of developing suicidal thoughts or attempts and require careful monitoring during treatment.
If clinical worsening (including emergence of new symptoms) and/or suicidal thoughts/behavior occur, particularly if symptoms are severe, emerge suddenly, or are not part of pre-existing symptoms, consideration should be given to modifying the therapeutic regimen, including discontinuation of the drug.
Hormonal contraceptives
Effect of hormonal contraceptives on lamotrigine efficacy
The combination of ethinylestradiol 30 µg/levonorgestrel 150 µg increases lamotrigine clearance approximately two-fold, thereby reducing lamotrigine levels (see section "Interaction with other medicinal products and other forms of interaction"). Reduced lamotrigine levels may lead to loss of seizure control. To achieve optimal therapeutic effect, in most cases the maintenance dose of lamotrigine needs to be increased (via titration), typically by two-fold. After discontinuation of hormonal contraceptives, lamotrigine clearance may double. Increased lamotrigine concentrations may provoke dose-dependent adverse reactions; therefore, patients should be closely monitored by a physician.
In women who are not taking other lamotrigine glucuronidation-inducing drugs and who are using hormonal contraceptives with a weekly break between cycles (so-called "pill-free week"), a gradual, temporary increase in lamotrigine levels may occur during the pill-free week. This increase may provoke dose-dependent adverse reactions; therefore, consideration should be given to using contraception without a weekly break (e.g., continuous hormonal contraception or non-hormonal methods).
The interaction of lamotrigine with other oral contraceptives or hormone replacement therapies has not been studied, but they may similarly affect lamotrigine pharmacokinetics.
Effect of lamotrigine on hormonal contraceptive efficacy
A clinical interaction study involving 16 healthy volunteers showed a slight increase in levonorgestrel clearance and changes in serum levels of follicle-stimulating hormone and luteinizing hormone when lamotrigine was co-administered with hormonal contraceptives (ethinylestradiol 30 µg/levonorgestrel 150 µg) (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 receiving both lamotrigine and hormonal contraceptives, these changes may reduce contraceptive efficacy. Therefore, patients should promptly report changes in their menstrual cycle, such as breakthrough bleeding.
Effect of lamotrigine on organic cation transporter 2 (OCT2) substrates
Lamotrigine is an inhibitor of renal tubular secretion via organic cation transporter proteins (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 Lamictal with OCT2 substrates that have a narrow therapeutic index, such as dofetilide, is not recommended.
Dihydrofolate reductase
Lamictal is a weak inhibitor of dihydrofolate reductase, and thus may affect folate metabolism during long-term use. However, no significant changes in hemoglobin concentration, mean corpuscular volume, serum and erythrocyte folate concentrations over 1 year, or erythrocyte folate concentrations over 5 years were observed during long-term Lamictal use.
Renal impairment
In single-dose studies in patients with end-stage renal disease, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite may occur. Therefore, caution is required when treating patients with renal impairment.
Patients taking other lamotrigine-containing medications
Lamictal should not be prescribed to patients already receiving any other medication containing lamotrigine without physician consultation.
Brugada-type ECG and other cardiac rhythm disorders and conduction abnormalities
Arrhythmogenic ST-T abnormalities and Brugada-type ECG patterns have been observed in patients taking lamotrigine.
In vitro studies have shown that lamotrigine at concentrations corresponding to therapeutic doses may slow ventricular conduction (with QRS complex widening) and induce proarrhythmia in patients with heart disease. Lamotrigine acts as a weak class IB antiarrhythmic agent, which may pose potential risks of severe or fatal cardiac events. Concomitant use of other sodium channel blockers may increase these risks. In a thorough QT interval study in healthy volunteers, lamotrigine at therapeutic doses up to 400 mg/day did not slow ventricular conduction (QRS widening) or prolong the QT interval. The use of lamotrigine in patients with clinically significant structural or functional heart disease, such as Brugada syndrome or other cardiac channelopathies, heart failure, ischemic heart disease, heart block, or ventricular arrhythmias, should be carefully considered. If lamotrigine use is clinically justified in such patients, consultation with a cardiologist is recommended before initiating treatment.
Excipients
One dispersible tablet contains less than 1 mmol (23 mg) of sodium and may therefore be considered essentially "sodium-free."
Development in children
There are no data on the effects of lamotrigine on growth, sexual maturation, or the development of cognitive, emotional, and behavioral functions in children.
Epilepsy
Abrupt discontinuation of Lamictal, 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 Lamictal should be tapered gradually over at least 2 weeks.
According to the literature, severe epileptic seizures, including status epilepticus, may lead to rhabdomyolysis, multi-organ failure, and disseminated intravascular coagulation, sometimes with fatal outcome. Similar events are possible during Lamictal treatment.
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 treatment may exacerbate myoclonic seizures.
Evidence suggests that response to lamotrigine in combination with enzyme inducers is weaker than with lamotrigine in combination with non-enzyme-inducing antiepileptic drugs. The reason for this is unknown.
In children with typical absence seizures, therapeutic effect is not achieved in all patients.
Bipolar disorders
Children and adolescents (up to 18 years of age)
Antidepressant treatment is associated with an increased risk of suicidal thoughts and behavior in children and adolescents with major depressive disorders and other psychiatric disorders.
Use during pregnancy or breastfeeding
General risk associated with antiepileptic drugs
Women of childbearing potential require specialist counseling. When a woman is planning pregnancy, antiepileptic therapy should be appropriately reviewed. Abrupt discontinuation of antiepileptic drugs in patients already receiving them should be avoided, as this may lead to seizure recurrence with serious consequences for both the woman and the fetus. Monotherapy is preferred, as combination antiepileptic therapy increases the risk of congenital malformations compared to monotherapy, depending on the antiepileptic drugs used.
Risk associated with lamotrigine use
Pregnancy
A large amount of data from pregnant women receiving lamotrigine monotherapy during the first trimester (over 8,700 cases) does not indicate a significant increase in the risk of serious congenital malformations, including cleft lip and palate. Animal studies have shown embryofetal toxicity.
If lamotrigine therapy is considered necessary during pregnancy, it is recommended to use the lowest possible therapeutic dose.
Lamotrigine has a mild inhibitory effect on dihydrofolate reductase and, theoretically, may increase the risk of embryofetal developmental abnormalities due to reduced folate levels (see section "Special precautions"). Folic acid supplementation should be considered during pregnancy planning and early pregnancy.
Physiological changes during pregnancy may affect lamotrigine concentrations and/or its therapeutic effect. Reports indicate decreased plasma lamotrigine concentrations during pregnancy, with a potential risk of loss of seizure control. After delivery, lamotrigine levels may rise rapidly, increasing the risk of dose-dependent adverse events. Therefore, serum lamotrigine concentrations should be monitored before, during, and after pregnancy, and shortly after delivery. Dose adjustments should be made as necessary to maintain serum lamotrigine concentrations at pre-pregnancy levels or according to clinical response. Additionally, monitoring for dose-dependent adverse events is required after delivery.
Breastfeeding period
Lamotrigine is reported to pass into breast milk at various concentrations, resulting in infant plasma concentrations reaching approximately 50% of maternal levels. Thus, in some breastfed infants, lamotrigine serum concentrations may reach levels at which pharmacological effects may occur.
The potential benefits of breastfeeding should be weighed against the possible risk of adverse reactions in the infant. If a woman receiving lamotrigine treatment decides to breastfeed, the infant should be closely monitored for adverse effects such as sedation, rash, and poor weight gain.
Fertility
Animal studies did not reveal any effect of lamotrigine on fertility.
Ability to affect reaction speed when driving or operating machinery
Data from two studies involving volunteers showed that the effects of lamotrigine on visual-motor coordination, eye movement control, body control, and subjective sedative effects were not different from placebo. However, in clinical trials, neurological adverse reactions such as dizziness and diplopia have been reported with lamotrigine use. Therefore, patients should first assess their individual response to lamotrigine before driving or operating machinery. Since individual responses to antiepileptic drugs vary, patients should consult their physician regarding specific recommendations for driving in these cases.
Method of administration and dosing.
Lamictal dispersible tablets can be chewed, dissolved in a small amount of water (at least sufficient to cover the entire tablet), or swallowed whole with a small amount of water. Do not attempt to split the chewable tablet for administration.
If the calculated dose of lamotrigine (e.g., for treating children with epilepsy or patients with impaired liver function) is not a multiple of whole tablets, the administered dose should correspond to the nearest lower number of whole tablets.
Reinitiation of treatment.
Physicians should evaluate the need for dose escalation to maintenance levels when resuming Lamictal in patients who have discontinued Lamictal for any reason, as the risk of developing serious rash is associated with high initial doses and exceeding the recommended lamotrigine dose escalation regimen (see section "Special precautions"). The longer the time interval since the last dose was taken, the greater the caution required in escalating the dose to maintenance levels. If the interval since discontinuation of lamotrigine exceeds five elimination half-lives (see section "Pharmacokinetics"), Lamictal should be reinitiated and titrated to maintenance dose according to the established regimen.
Reinitiation of Lamictal is not recommended in patients who discontinued treatment due to a rash related to prior lamotrigine therapy, except in cases where the potential benefit clearly outweighs the risk.
Epilepsy.
Recommended dose escalation regimens and maintenance doses for adults and children aged 13 years and older (Table 3), as well as for children aged 2 to 12 years (Table 4), are provided below. To minimize the risk of rash, the initial dose and rate of subsequent dose escalation should not be exceeded (see section "Special precautions").
When concomitant antiepileptic drugs (AEDs) are discontinued or other AEDs/medicinal products are added to regimens containing lamotrigine, the potential impact on the pharmacokinetics of lamotrigine should be considered (see section "Interaction with other medicinal products and other forms of interaction").
Table 3
Recommended treatment regimens for epilepsy in adults and children aged 13 years and older
| Treatment regimen |
Weeks 1 + 2 |
Weeks 3 + 4 |
Usual maintenance dose |
|
| Monotherapy: |
25 mg/day (single dose) |
50 mg/day (single dose) |
100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 50 – 100 mg every one or two weeks until optimal response is achieved. Some patients required a dose of 500 mg/day to achieve the desired response. |
|
| Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This dosing regimen applies when valproate is used, regardless of other concomitant medications |
12.5 mg/day (take 25 mg every other day) |
25 mg/day (single dose) |
100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 25 – 50 mg every one or two 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 dosing regimen does not include valproate but includes: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
50 mg/day (single dose) |
100 mg/day (two doses) |
200 – 400 mg/day (two doses). To reach the maintenance dose, increase by no more than 100 mg every one or two 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 dosing regimen includes other medicinal products that do not have a significant inhibitory or inductive effect on lamotrigine glucuronidation |
25 mg/day (single dose) |
50 mg/day (single dose) |
100 – 200 mg/day (one or two doses). To reach the maintenance dose, increase by no more than 50 – 100 mg every one or two weeks until optimal response is achieved. |
|
| 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 of lamotrigine and valproate. |
||||
Table 4
Children aged 2 to 12 years: recommended epilepsy treatment regimen (total daily dose in mg/kg body weight/day) **
| Treatment regimen |
Weeks 1 and 2 |
Weeks 3 and 4 |
Usual maintenance dose |
|
| Monotherapy for typical absence seizures |
0.3 mg/kg/day (once or twice daily) |
0.6 mg/kg/day (once or twice daily) |
1 – 15 mg/kg/day (once or twice daily). To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day. |
|
| Adjunctive therapy with valproate (an inhibitor of lamotrigine glucuronidation; see section "Interaction with other medicinal products and other forms of interactions") |
||||
| This treatment regimen involves the use of valproate regardless of other concomitant medicinal products |
0.15 mg/kg/day* (once daily) |
0.3 mg/kg/day (once daily) |
1 – 5 mg/kg/day (once or twice daily). To reach the maintenance dose, it should be increased by no more than 0.3 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose is 200 mg/day. |
|
| Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interactions") |
||||
| This treatment regimen does not involve valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
0.6 mg/kg/day (twice daily) |
1.2 mg/kg/day (twice daily) |
5 – 15 mg/kg/day (once or twice daily). To reach the maintenance dose, it should be increased by no more than 1.2 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose is 400 mg/day. |
|
| 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 involves the use of other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation |
0.3 mg/kg/day (once or twice daily) |
0.6 mg/kg/day (once or twice daily) |
1 – 10 mg/kg/day (once or twice daily) To reach the maintenance dose, it should be increased by no more than 0.6 mg/kg/day every one or two weeks until optimal response is achieved; maximum maintenance dose is 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 interactions"), the dosing regimen recommended for concomitant use of lamotrigine and valproate should be used. |
||||
| * If the calculated dose for patients taking valproate is less than 1 mg, Lamictal is not recommended. |
||||
**If the calculated dose of lamotrigine cannot be achieved with whole tablets, the dose should be rounded to the nearest whole tablet.
To maintain the therapeutic dose, the child's body weight should be monitored and the dose adjusted accordingly in case of changes in body weight. Patients aged between two and six years may likely require a maintenance dose approaching the upper end of the recommended range.
If seizure control is achieved with adjunctive therapy, concomitant ASMs may be discontinued, and monotherapy with Lamictal may be continued.
Children under 2 years of age.
Data on the efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years (see section "Dosage and administration") are limited. Data on the use of lamotrigine in children under 1 month of age are lacking. Therefore, Lamictal is not recommended for use in children under 2 years of age. If a decision to treat with Lamictal is made based on clinical need, see sections "Dosage and administration" and "Pharmacological properties".
Bipolar disorder.
The recommended dose escalation and maintenance doses for adults aged 18 years and older are shown in the tables below. The dosing regimen includes increasing the lamotrigine dose to the maintenance stabilizing dose over six weeks (Table 5), after which other psychotropic and/or antiepileptic drugs may be discontinued if clinically appropriate (Table 6). Dose adjustment regimens following the addition of other psychotropic medications and/or ASMs are shown in Table 7. Due to the risk of rash, the initial dose and rate of subsequent dose escalation must not be exceeded (see section "Dosage and administration").
Table 5
Adults (aged 18 years and older): recommended dose escalation regimen to achieve maintenance stabilizing daily dose in the treatment of bipolar disorder
| Treatment regimen |
Weeks 1 + 2 |
Weeks 3 + 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 interaction") |
||||
| This treatment regimen assumes the use of other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation. |
25 mg/day (once daily) |
50 mg/day (once or twice daily) |
100 mg/day (once or twice daily) |
200 mg/day – usual target dose to achieve optimal response (once or twice daily). Doses ranging from 100–400 mg/day have been used in clinical studies |
| Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation – see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This treatment regimen includes valproate, regardless of other concomitant medications |
12.5 mg/day (25 mg every other day) |
25 mg/day (once daily) |
50 mg/day (once or twice daily) |
100 mg/day – usual target dose to achieve optimal response (once or twice daily) The maximum dose of 200 mg/day may be used depending on clinical response. |
| Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
||||
| This treatment regimen does not include valproate, but includes phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
50 mg/day (once daily) |
100 mg/day (twice daily) |
200 mg/day (twice daily) |
300 mg/day in week 6; if necessary, the usual target dose is increased to 400 mg/day in week 7 to achieve optimal response (twice daily) |
| 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 escalation regimen recommended for concomitant use of lamotrigine with valproate should be used. |
||||
* Target maintenance dose varies depending on clinical response.
Table 6
Adults (aged 18 years and older): maintenance stabilization daily dose after discontinuation of concomitant medications for the treatment of bipolar disorders.
After achieving the required maintenance stabilization dose, other psychotropic drugs may be discontinued according to the tapering schedules outlined below.
| 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 lamotrigine dose |
|||||
| When discontinuing valproate, the maintenance dose is doubled, without exceeding an increase of more than 100 mg/week |
100 mg/day |
200 mg/day |
Maintain dose of 200 mg/day (two doses) |
||
| 200 mg/day |
300 mg/day |
400 mg/day |
Maintain dose of 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 lamotrigine dose |
|||||
| This treatment regimen applies when discontinuing phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
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 treatment regimen applies when discontinuing other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation |
Maintain the target dose achieved during titration (200 mg/day in two divided doses) (dose range 100–400 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 recommended lamotrigine treatment regimen involves initially maintaining the current dose, followed by dose adjustments based on clinical response. |
|||||
* If necessary, the dose can be increased to 400 mg/day.
Table 7
Adults (aged 18 years and older): adjustment of daily dose when co-administering other medications in patients with bipolar disorders.
There is no clinical experience regarding dose adjustment of lamotrigine when other medications are co-administered.
However, based on data concerning drug interactions, the following regimens may be recommended.
| 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 valproate (inhibitor of lamotrigine glucuronidation, see section "Interaction with other medicinal products and other forms of interaction") depending on the initial dose of lamotrigine |
|||||
| This treatment regimen should be applied when adding valproate regardless of the use of any concomitant medicinal products |
200 mg/day |
100 mg/day |
Maintain dose of 100 mg/day |
||
| 300 mg/day |
150 mg/day |
Maintain dose of 150 mg/day |
|||
| 400 mg/day |
200 mg/day |
Maintain this dose of 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 treatment regimen should be applied when adding the following medications without concomitant use of valproate: phenytoin, carbamazepine, phenobarbital, primidone, rifampicin, lopinavir/ritonavir |
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 exhibit significant inhibitory or inductive effects on lamotrigine glucuronidation (see section "Interaction with other medicinal products and other forms of interaction") |
|||||
| This treatment regimen should be applied when adding other medicinal products that do not exhibit significant inhibitory or inductive effects on lamotrigine glucuronidation |
Maintain the target dose achieved during titration (200 mg/day; dose range 100–400 mg/day) |
||||
| In patients taking medicinal products with unknown effects on lamotrigine pharmacokinetics (see section "Interaction with other medicinal products and other forms of interaction"), the treatment regimen recommended for concomitant use of lamotrigine and valproate should be applied. |
|||||
Discontinuation of lamotrigine in patients with bipolar disorders.
Clinical trial data showed no increase in the frequency, severity, or type of adverse reactions after rapid discontinuation of lamotrigine compared to placebo. Therefore, patients may discontinue Lamictal without tapering the dose.
Children (under 18 years of age).
Lamictal is not recommended for use in children with bipolar disorders (under 18 years of age), as randomized discontinuation trials did not demonstrate significant efficacy and showed an increased risk of suicidality (see sections "Special precautions for use" and "Pharmacodynamics").
General dosage recommendations for special patient groups.
Women taking hormonal contraceptives.
The use of the combination ethinylestradiol/levonorgestrel (30 mcg/150 mcg) increases lamotrigine clearance approximately twofold, resulting in reduced lamotrigine levels. After titration, higher maintenance doses of lamotrigine (almost twice as high) may be required to achieve optimal therapeutic response. During the week when the contraceptive is not taken, a twofold increase in lamotrigine levels has been observed. Dose-dependent adverse reactions cannot be excluded. Therefore, consideration should be given to using contraception that does not include a hormone-free week as first-line therapy (e.g., continuous hormonal contraceptives or non-hormonal methods; see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
Initiation of hormonal contraceptives in patients receiving maintenance doses of lamotrigine and NOT taking inducers of its glucuronidation.
The maintenance dose of lamotrigine will usually need to be doubled (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). It is recommended that the lamotrigine dose be increased by 50–100 mg/day each week from the start of hormonal contraceptive use, according to individual clinical response. Dose increases should not exceed this rate unless clinically indicated.
Measurement of lamotrigine concentration in serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women taking hormonal contraceptives that include a hormone-free week (tablet-free week), monitoring of lamotrigine serum levels 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 products that do not include a tablet-free week as first-line therapy (e.g., continuous hormonal contraceptives or non-hormonal methods; see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
Discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine and NOT taking drugs that induce lamotrigine glucuronidation.
The maintenance dose of lamotrigine will usually need to be reduced by 50% (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). It is recommended to gradually reduce the daily dose of lamotrigine by 50–100 mg per week (not more than 25% of the total daily dose per week) over 3 weeks, unless otherwise indicated based on individual clinical response.
Measurement of lamotrigine concentration in blood serum before and after starting hormonal contraceptives can confirm that baseline lamotrigine levels are maintained. In women who wish to discontinue hormonal contraceptives that include a hormone-free week (tablet-free week), monitoring of lamotrigine serum levels 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 assessing lamotrigine levels after permanent discontinuation of the contraceptive should not be collected during the first week after stopping.
Initiation of lamotrigine therapy in women already taking hormonal contraceptives.
Dose escalation should follow the recommendations for standard dosing provided in the tables.
Initiation and discontinuation of hormonal contraceptives in patients already receiving maintenance doses of lamotrigine, who are also taking inducers of lamotrigine glucuronidation.
Adjustment of the recommended maintenance dose of lamotrigine is not required.
Concomitant use with atazanavir/ritonavir.
Adjustment of the recommended dose of lamotrigine when adding it to existing atazanavir/ritonavir therapy is not required.
Patients already receiving a maintenance dose of lamotrigine and not taking glucuronidation inducers may require an increase in lamotrigine dose when atazanavir/ritonavir is added, and a dose reduction when atazanavir/ritonavir is discontinued.
Monitoring of lamotrigine levels in blood plasma should be performed before and within 2 weeks after starting or stopping atazanavir/ritonavir to determine the need for dose adjustment of lamotrigine (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use with lopinavir/ritonavir.
Adjustment of the recommended dose of lamotrigine when adding it to existing lopinavir/ritonavir therapy is not required.
Patients already receiving maintenance doses of lamotrigine and not taking glucuronidation inducers may require an increase in lamotrigine dose when lopinavir/ritonavir is added, and a dose reduction when lopinavir/ritonavir is discontinued. Monitoring of lamotrigine in plasma should be performed before and within 2 weeks after starting or stopping lopinavir/ritonavir to determine the need for dose adjustment of lamotrigine (see section "Interaction with other medicinal products and other forms of interaction").
Elderly patients (aged 65 years and older).
Dose adjustment according to the recommended regimen is not required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from those in adult patients under 65 years of age (see section "Pharmacokinetics").
Renal impairment.
Caution should be exercised when administering Lamictal to patients with renal impairment. In patients with end-stage renal disease, the initial dose of lamotrigine should be determined according to concomitant medications; dose reduction may be effective in patients with significant renal dysfunction (see sections "Special precautions for use" and "Pharmacokinetics").
Hepatic impairment.
Initial, escalating, and maintenance doses should be reduced by approximately 50% in patients with moderate (Child-Pugh class B) and by 75% in patients with severe (Child-Pugh class C) hepatic impairment. Escalating and maintenance doses should be adjusted according to clinical response (see section "Pharmacokinetics").
Children.
The use of lamotrigine as monotherapy for the treatment of children under 2 years of age or as adjunctive therapy for children under 1 month of age has not been studied. The efficacy and safety of lamotrigine as adjunctive therapy for partial seizures in children aged 1 month to 2 years have not been established. Therefore, the drug is not recommended for use in children in this age group.
Lamotrigine is not indicated for use in children (under 18 years) with bipolar disorder due to lack of demonstrated efficacy and increased risk of suicidal ideation (see section "Special precautions for use").
Overdose.
Symptoms and signs
There have been reports of acute overdose (with doses 10–20 times higher than the maximum therapeutic doses), including fatal cases. Symptoms of overdose included ataxia, nystagmus, impaired consciousness, generalized seizures, and coma. QRS complex widening (intraventricular conduction delay) and QT interval prolongation have also been reported in overdose. QRS widening exceeding 100 msec may be associated with more severe toxicity.
Treatment
In case of overdose, the patient should be hospitalized for appropriate supportive therapy. Measures to reduce absorption (activated charcoal) should be applied if necessary. Additional treatment should be administered based on clinical indications, considering the potential risks of effects on ventricular conduction. In cases of cardiotoxicity with inadequate response to sodium bicarbonate treatment, intravenous lipid emulsion therapy should be considered. There is no experience with hemodialysis for the treatment of overdose. In six volunteers with renal impairment, 20% of lamotrigine was eliminated during a 4-hour hemodialysis session.
Adverse reactions.
Adverse reactions for indications in the treatment of epilepsy and bipolar disorders, based on available data from controlled clinical trials and other clinical experience, are listed in Table 8. Frequency categories were derived from controlled clinical trials (epilepsy monotherapy studies [marked as †] and bipolar disorder studies [marked as §]). If frequency categories differ between clinical data from epilepsy and bipolar disorder studies, the lowest frequency is applied. In the absence of controlled clinical trial data, frequency categories were derived from other clinical experience.
Adverse reactions are categorized by frequency as follows:
very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).
Table 8
| Systems and organs |
Adverse reactions |
Frequency |
| Blood and lymphatic system disorders |
Hematologic disorders1, including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis |
Very rare |
| Hemophagocytic lymphohistiocytosis (see section "Special precautions") |
Very rare |
|
| Lymphadenopathy1, pseudolymphoma |
Unknown |
|
| Immune system disorders |
hypersensitivity syndrome2 |
Very rare |
| hypogammaglobulinemia |
Unknown |
|
| Psychiatric disorders |
Aggression, irritability |
Common |
| Confusion, hallucinations, tics (motor and/or vocal) |
Very rare |
|
| Nightmares |
Unknown |
|
| Nervous system disorders |
Headache§ |
Very common |
| Somnolence†§, dizziness†§, tremor†, insomnia†, anxiety§ |
Common |
|
| Ataxia† |
Uncommon |
|
| Nystagmus†, aseptic meningitis (see section "Special precautions") |
Rare |
|
| Instability, movement disorders, exacerbation of Parkinson's disease3, extrapyramidal effects, choreoathetosis†, increased seizure frequency |
Very rare |
|
| Eye disorders |
Diplopia†, blurred vision† |
Uncommon |
| Conjunctivitis |
Rare |
|
| Gastrointestinal disorders |
Nausea†, vomiting†, diarrhea†, dry mouth§ |
Common |
| Hepatobiliary disorders |
Liver failure, liver dysfunction4, increased liver function tests |
Very rare |
| Skin and subcutaneous tissue disorders |
Skin rash5†§ |
Very common |
| Alopecia, photosensitivity reactions |
Uncommon |
|
| Stevens-Johnson syndrome§, erythema multiforme |
Rare |
|
| Toxic epidermal necrolysis |
Very rare |
|
| Drug reaction with eosinophilia and systemic symptoms2 |
Very rare |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia§ |
Common |
| Lupus-like reactions |
Very rare |
|
| Renal and urinary system disorders |
Tubulointerstitial nephritis, tubulointerstitial nephritis with uveitis syndrome |
Unknown |
| General disorders and administration site reactions |
Fatigue†, pain§, back pain§ |
Common |
Description of individual adverse reactions
1 Hematological abnormalities and lymphadenopathy may occur either associated or not associated with drug reaction with eosinophilia and systemic symptoms (DRESS)/hypersensitivity syndrome (see "Special precautions" and "Immune system disorders").
2 Skin rash has also been reported as part of this syndrome, also known as DRESS. This condition was accompanied by various systemic symptoms, including fever, lymphadenopathy, facial swelling, hematological abnormalities, and liver and kidney dysfunction. The syndrome may vary in severity and, in rare cases, may lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early signs of hypersensitivity (e.g., fever and lymphadenopathy) may appear even in the absence of skin rash. If such symptoms occur, the patient should be examined immediately and, in the absence of other causes, Lamictal should be discontinued.
3 These reactions have been observed in clinical practice under other clinical conditions.
It has been noted that lamotrigine may worsen symptoms of parkinsonism in patients with Parkinson's disease, and there have been isolated reports of extrapyramidal effects and choreoathetosis in patients without this condition.
4 Hepatic dysfunction is usually associated with hypersensitivity reactions, but isolated cases without prominent signs of hypersensitivity have been described.
5 In clinical trials in adults, skin rash was observed in 8–12% of patients taking lamotrigine and in 5–6% of patients receiving placebo. Rash led to drug discontinuation in 2% of patients. The rash was maculopapular in nature, most commonly occurring within eight weeks of starting treatment and resolving after discontinuation of Lamictal (see "Special precautions"). Serious, potentially life-threatening skin reactions have been reported, including Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although most patients recover after discontinuation of lamotrigine, some patients are left with irreversible scarring; in rare cases, these syndromes have been fatal (see "Special precautions").
The overall risk of developing skin rash is clearly related to:
- high initial doses of lamotrigine and exceeding the recommended dose escalation regimen during lamotrigine therapy (see "Dosage and administration");
- concomitant use of valproate (see "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 established.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
All suspected adverse reactions and lack of efficacy can also be reported to GlaxoSmithKline Pharmaceuticals Ukraine LLC at the 24-hour hotline (044) 585-51-85 or by email at [email protected].
Shelf life. 3 years.
Storage conditions.
Store in a dry, protected from light place at a temperature below 30 °C.
Keep out of reach of children.
Packaging.
14 tablets of 5 mg, 50 mg, or 100 mg in a blister; 2 blisters in a cardboard box labeled in Ukrainian.
14 tablets of 50 mg or 100 mg in a child-resistant blister; 2 blisters in a cardboard box labeled in Ukrainian.
30 tablets of 5 mg in a high-density polyethylene bottle with child-resistant closure; 1 bottle in a cardboard box labeled in Ukrainian.
Prescription category. Prescription only.
Manufacturer. Delpharm Poznan S.A., Poland / Delpharm Poznan S.A., Poland.
Manufacturer's address and location of its operations.
189, Grunwaldzka Street, 60-322 Poznan, Poland / 189 Grunwaldzka Str., 60-322 Poznan, Poland.