Lamictal tablets 100 mg No. 30

Instructions for Lamictal tablets 100 mg No. 30

Composition

active ingredient: lamotrigine;

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

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K30, sodium starch glycolate (type A), iron oxide yellow (E 172), magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: pale yellowish-brown multifaceted superelliptical tablet with a smooth surface, marked GSEC7 on one side and 25 on the other (for 25 mg tablets), marked GSEE1 on one side and 50 on the other (for 50 mg tablets), marked GSEE5 on one side and 100 on the other (for 100 mg tablets).

Pharmacotherapeutic group

Antiepileptic drugs. Lamotrigine.

ATX code N03A X09.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Pharmacological studies have shown that lamotrigine is an action-dependent and voltage-dependent blocker of voltage-gated sodium channels. It inhibits persistent neuronal reactivation and inhibits the release of glutamate (a neurotransmitter that plays a key role in the onset of epileptic seizures). It is likely that this effect is responsible for the anticonvulsant properties of lamotrigine.

However, the mechanisms that provide the therapeutic effect of lamotrigine in bipolar disorder remain unknown, although interaction with voltage-gated sodium channels plays an important role.

Pharmacodynamic effects

Studies of the effects of drugs on the central nervous system found no difference in healthy volunteers between 240 mg of lamotrigine and placebo, while both 1000 mg of phenytoin and 10 mg of diazepam significantly impaired fine visual-motor coordination, eye motility, and body balance, and also caused a subjective sedation effect.

In another study, single oral doses of 600 mg carbamazepine significantly impaired fine motor coordination, eye movements, and balance, and increased heart rate, while lamotrigine 150 mg and 300 mg did not differ from placebo.

Effect of lamotrigine on cardiac conduction

In a study in healthy adult volunteers, the effects of repeated doses of lamotrigine (up to 400 mg/day) on cardiac conduction were assessed using 12-lead ECG. There was no clinically significant effect of lamotrigine on the QT interval compared with placebo.

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 I disorder was evaluated in two studies.

The SCAB2003 study, a multicenter, double-blind, double-dummy, placebo- and lithium-controlled, randomized, fixed-dose study for the long-term prevention of recurrent and recurrent episodes of depression and/or mania, was conducted in patients with bipolar I disorder with an existing 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, 400 mg/day), lithium (serum level 0.8 to 1.1 mmol/L), or placebo. The primary endpoint was “time to intervention due to mood episode (TIME),” where interventions were considered adjunctive pharmacotherapy or electroconvulsive therapy (ECT). SCAB2006 was a similar study design to SCAB2003, but used a more flexible lamotrigine dosing regimen (100 to 400 mg/day) and included patients with bipolar I disorder with a current or recent manic episode. The results are shown in Table 1.

Table 1

Summary of the results of studies on the effectiveness of lamotrigine for the prevention of mood episodes in patients with bipolar I disorder

Additional analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode showed that patients treated with lamotrigine had a statistically significant later onset of their first depressive episode than those treated with placebo. There was no statistical difference in time to first manic/hypomanic or mixed episode.

The effectiveness of lamotrigine in combination with mood stabilizers has not been adequately studied.

Children

Children aged 1 to 24 months

The efficacy and safety of adjunctive therapy for partial onset seizures in children aged 1 to 24 months was assessed in a small double-blind, placebo-controlled withdrawal study. Treatment was initiated in 177 patients with a dose titration regimen recommended for children aged 2 to 12 years. The lowest available dose of lamotrigine is 2 mg tablets. Therefore, in some cases, the standard dosing regimen during the titration phase was adjusted accordingly (e.g., by administering a 2 mg tablet every other day for a calculated dose of less than 2 mg). Serum concentrations were determined at the end of week 2 of the titration phase and of the subsequent dose phase, reduced or not increased due to the achievement of concentrations exceeding 0.41 μg/mL, the predicted concentrations in adults at this time point of therapy. At the end of week 2, some patients required a dose reduction of up to 90%. Thirty-eight patients with a therapeutic effect (>40% reduction in seizure frequency) were randomized to placebo or continued lamotrigine. Failure to continue treatment was reported in 84% of patients in the placebo group (16 of 19) and 54% of patients in the lamotrigine group (11 of 19). The difference was not statistically significant: 26.3%, 95% CI 2.6% < >50.2%, p = 0.07.

A total of 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 children in this age group was similar to that in older children, with the exception of seizure progression (≥ 50%), which was statistically more common in children <2 years of age (26%) than in older children (14%).

Lennox-Gastaut syndrome

There are no data on monotherapy for seizures associated with Lennox-Gastaut syndrome.

Prevention of mood episodes in children (10–12 years) and adolescents (13–17 years)

A multicenter, parallel-group, placebo-controlled, double-blind, randomized withdrawal study evaluated the safety and efficacy of lamotrigine IR immediate-release tablets as adjunctive maintenance therapy for the postponement of mood episodes in children and adolescents (10–17 years of age) of both sexes diagnosed with bipolar I disorder who had achieved remission or improvement on lamotrigine in combination with antipsychotic medications or other antidepressants. The primary efficacy analysis (time to onset of bipolar event) did not show a statistically significant result (p = 0.0717), indicating a lack of efficacy. In addition, the safety analysis showed an increased rate of suicidal behavior in the lamotrigine group: 5% (4 patients) compared with 0 in the placebo group.

Pharmacokinetics.

Absorption

In the absence of significant first-pass metabolism, the drug is rapidly and completely absorbed from the gastrointestinal tract. After oral administration, peak plasma concentrations are reached in approximately 2.5 hours. The time to peak plasma concentrations is slightly prolonged when the drug is administered after meals, but this does not affect the extent of absorption. There is considerable interindividual variation in peak steady-state concentrations, but individual values for one patient are generally consistent.

Distribution

Approximately 55% of the dose is bound to plasma proteins. Toxic effects due to displacement from plasma proteins are unlikely.

The volume of distribution is from 0.92 to 1.22 l/kg.

Biotransformation

It has been established that the main enzyme responsible for the metabolism of lamotrigine is UDP-glucuronyltransferase.

Lamotrigine may induce its own metabolism to a small extent, depending on the dose. However, its effect on the pharmacokinetics of other anticonvulsants has not been demonstrated, and available data suggest that interactions between lamotrigine and other drugs metabolized by cytochrome P450 are unlikely.

Breeding

The elimination half-life of lamotrigine is significantly dependent on the concomitant medicinal products. The mean elimination half-life may be shortened by approximately 14 hours when glucuronidation inducers such as carbamazepine and phenytoin are administered concomitantly, or may be prolonged by approximately 70 hours when valproate is administered alone (see section 4.5).

Linearity

Up to the highest dose tested – 450 mg – the pharmacokinetics of lamotrigine showed a linear relationship.

Certain patient groups

Children

Clearance, calculated on the basis of body weight, is higher in children than in adults and is 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 and increases to 45-50 hours when co-administered exclusively with valproate (see section 4.5).

Children aged 2 to 26 months

In 143 patients aged 2 to 26 months and weighing 3 to 16 kg, the same oral doses were given on a per kilogram basis, with lower clearance compared to children over 2 years of age and of similar body weight. The mean half-life in children under 26 months of age with enzyme-inducing therapy was 23 hours, with concomitant valproate 136 hours, and 38 hours without enzyme-inducing or inhibitory drugs. The interindividual variability in clearance with oral doses in patients aged 2 to 26 months was high (47%). The predicted serum concentrations in patients in this age group were within the range of those in the older group, although some patients weighing less than 10 kg had higher peak concentrations.

Elderly patients

A pharmacokinetic analysis of patients with epilepsy in one study did not reveal any clinically significant differences in lamotrigine clearance between elderly and young patients. After single doses, theoretical clearance decreased by 12% from 35 mL/min/kg in patients aged 20 years to 31 mL/min/kg in patients aged 70 years. After 48 weeks of treatment, the decrease was 10% from 41 mL/min in young patients to 37 mL/min in elderly patients. 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 patients (0.39 mL/min/kg) is within the range of mean clearance values (0.31 - 0.65 mL/min/kg) obtained in 9 studies in non-elderly adults after single doses of 30 to 450 mg.

Patients with renal impairment

Twelve volunteers with chronic renal failure and 6 patients on hemodialysis received a single dose of 100 mg of lamotrigine. The mean clearance was 0.42 mL/min/kg (in chronic renal failure), 0.33 mL/min/kg (between hemodialysis sessions), and 1.57 mL/min/kg (during hemodialysis) compared with 0.58 mL/min/kg in healthy volunteers. The mean plasma elimination half-lives were 42.9 hours (in chronic renal failure), 57.4 hours (between hemodialysis sessions), and 13.0 hours (during hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range 5.6 to 35.1%) of the lamotrigine present in the body was removed during a four-hour hemodialysis session. Initial doses of lamotrigine for this group of patients should be determined taking into account the concomitant medications the patient is taking. A reduction in the maintenance dose may be effective in patients with significant renal impairment.

Patients with impaired liver function

A single-dose pharmacokinetic study was conducted in 24 patients with varying degrees of hepatic impairment and 12 healthy control subjects. In subjects with Child-Pugh class A, B, and C hepatic impairment, the mean theoretical clearance of lamotrigine was 0.31 mL/min/kg, 0.24 mL/min/kg, and 0.10 mL/min/kg, respectively, compared with 0.34 mL/min/kg in control subjects. The initial, titrated, and maintenance doses should be reduced in patients with moderate to severe hepatic impairment.

Preclinical safety data

In vitro studies have shown that lamotrigine, at concentrations consistent with therapeutic doses, exhibits class IB antiarrhythmic activity. It inhibits human cardiac sodium channels, exhibiting rapid onset and end kinetics, and a strong voltage-dependent action consistent with other class IB antiarrhythmics. At therapeutic doses, lamotrigine did not slow ventricular conduction (with QRS widening) in healthy volunteers with careful QT testing. However, in patients with clinically significant structural or functional heart disease, lamotrigine has the potential to slow ventricular conduction (with QRS widening) and induce proarrhythmia (see section 4.4).

Indication

Epilepsy. Adults and children aged 13 years and over.

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

Children aged 2 to 12 years.

Adjunctive therapy for partial and generalized seizures in epilepsy, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

Monotherapy of typical absence seizures.

Bipolar disorder.

Adults (ages 18 and over).

Prevention of depressive states in patients with bipolar I disorder who predominantly suffer from depressive states.

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

Contraindication

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

Interaction with other medicinal products and other types of interactions

Interaction studies have been conducted in adult patients only.

Uridine 5'-diphospho (UDP)-glucuronyl transferase (UGT) has been identified as the enzyme responsible for the metabolism of lamotrigine. Therefore, drugs that induce or inhibit glucuronidation may affect the theoretical clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are known to induce UGT, may also increase the metabolism of lamotrigine. There is no evidence that lamotrigine can cause clinically significant stimulation or inhibition of cytochrome P450 enzymes. Lamotrigine can induce its own metabolism, but this effect is modest and has no significant clinical consequences.

Those drugs that have been shown to have a relevant clinical effect on lamotrigine concentrations are listed in Table 2. Specific dosing recommendations for these drugs are provided in the Dosage and Administration section. In addition, this table lists those drugs that have been shown to have little or no effect on lamotrigine concentrations. In general, concomitant use of such drugs is not expected to have any clinical effect. However, caution should be exercised in patients with epilepsy whose disease state is particularly sensitive to fluctuations in lamotrigine concentrations.

Table 2

Effect of drugs on lamotrigine concentrations

For detailed information on dosage, see the section “General dosage recommendations for special patient groups” in the section “Method of administration and dosage”. For dosage instructions for women taking hormonal contraceptives, see the section “Hormonal contraceptives” in the section “Special warnings and precautions for use”

Interaction with antiepileptic drugs (AEDs)

Valproate, which inhibits lamotrigine glucuronidation, reduces the metabolism of lamotrigine and increases the mean half-life by approximately 2-fold. Patients receiving concomitant valproate should be given an appropriate dosage regimen (see section 4.2).

Some AEDs (such as phenytoin, carbamazepine, phenobarbital and primidone) that induce cytochrome P450 enzymes also induce UGT and thereby accelerate the metabolism of lamotrigine. Patients receiving concomitant phenytoin, carbamazepine, phenobarbital or primidone should be given an appropriate dosage regimen (see section 4.2).

There have been reports of central nervous system adverse events including dizziness, ataxia, diplopia, blurred vision, and nausea in patients receiving carbamazepine concomitantly with lamotrigine. These events usually resolve when the carbamazepine dose is reduced. A similar effect has been observed in studies of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction has not been studied.

In a study in healthy adult volunteers using a dose of lamotrigine 200 mg and a dose of oxcarbazepine 1200 mg, it was found that oxcarbazepine did not alter the metabolism of lamotrigine, and lamotrigine did not alter the metabolism of oxcarbazepine. Patients receiving concomitant oxcarbazepine should use the lamotrigine adjunctive therapy regimen without valproate and without glucuronidation inducers (see section "Method of administration and dosage").

In a study in healthy volunteers, it was found that the concomitant use 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 the latter.

The potential drug interaction between levetiracetam and lamotrigine was studied by evaluating serum concentrations of both drugs in placebo-controlled clinical trials. According to these data, the substances do not alter the pharmacokinetics of each other.

Steady-state plasma concentrations of lamotrigine are not altered by co-administration with pregabalin (200 mg 3 times daily). There is no pharmacokinetic interaction between lamotrigine and pregabalin.

Topiramate does not affect the plasma concentration of lamotrigine. The use of lamotrigine increases the concentration of topiramate by 15%.

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

Plasma lamotrigine concentrations were not affected by concomitant administration of lacosamide (200, 400 or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.

In a pooled analysis of data from three placebo-controlled clinical trials investigating the adjunctive use of perampanel in patients with partial-onset and primary generalized tonic-clonic seizures, the highest dose of perampanel studied (12 mg/day) increased lamotrigine clearance by less than 10%.

Although there have been reports of changes in plasma concentrations of other antiepileptic drugs, controlled studies have shown that lamotrigine does not affect the plasma concentrations of concomitant antiepileptic drugs. In vitro studies have shown that lamotrigine does not displace other antiepileptic drugs from their protein binding.

Interaction with other psychotropic substances

Coadministration of 100 mg/day of lamotrigine and 2 g of anhydrous lithium gluconate administered twice daily for 6 days to 20 healthy volunteers did not alter the pharmacokinetics of lithium.

In a study of 12 patients, multiple oral doses of bupropion had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and resulted in only a slight increase in the area under the concentration-time curve of lamotrigine glucuronide.

In a study in healthy adult volunteers, 15 mg of olanzapine reduced the area under the concentration-time curve and Cmax of lamotrigine by an average of 24% and 20%, respectively. Lamotrigine 200 mg had no effect on the pharmacokinetics of olanzapine.

Multiple oral doses of lamotrigine 400 mg/day had no clinically significant effect on the pharmacokinetics of risperidone given as a single 2 mg dose in studies involving 14 healthy adult volunteers. When risperidone 2 mg was coadministered with lamotrigine, 12 of 14 volunteers reported somnolence compared to 1 in 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 for 7 days and administered for an additional 7 days. A decrease in lamotrigine Cmax and AUC of approximately 10% was observed.

In vitro experiments have shown that the presence of amitriptyline, bupropion, clonazepam, haloperidol or lorazepam may minimally inhibit the formation of the primary metabolite of lamotrigine, 2-N-glucuronide. These experiments also showed that the metabolism of lamotrigine is not inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone. Studies of the metabolism of bufuralol in human liver microsomes indicate that lamotrigine does not reduce the clearance of drugs that are primarily metabolized by CYP2D6.

Interaction with hormonal contraceptives.

Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine.

In a study involving 16 female volunteers using the combination tablet "ethinylestradiol 30 mcg/levonorgestrel 150 mcg", an increase in the excretion of lamotrigine was noted by approximately 2-fold, which in turn caused a decrease in the area under the "concentration-time" curve and Cmax of lamotrigine by an average of 52% and 39%, respectively. During the week-long break in taking the contraceptive (the so-called contraceptive-free week), the concentration of lamotrigine in the blood serum gradually increased, reaching a concentration that was approximately 2-fold higher than during concomitant use of the drugs (see section "Special features of use"). When combined with hormonal contraceptives, dose adjustment of lamotrigine during the titration phase is not required. However, the maintenance dose of lamotrigine should be increased or decreased each time the patient starts or stops taking hormonal contraceptives (see section "Method of administration and dosage").

In a study of 16 female volunteers, lamotrigine at steady-state concentrations at 300 mg did not affect the pharmacokinetics of ethinyl estradiol, a component of a combined oral contraceptive pill. There was a consistent, small increase in the clearance of levonorgestrel, which resulted in a mean decrease in the area under the concentration-time curve and Cmax of levonorgestrel of 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 the absence of any hormonal signs of ovulation in all 16 women. The effect of changes in serum follicle-stimulating hormone and luteinizing hormone levels and the slight increase in levonorgestrel excretion on ovarian ovulatory activity is unknown (see the section “General dosage recommendations for special patient groups” in the “Method of administration and dosage” section for dosage in women taking hormonal contraceptives and the section “Hormonal contraceptives” in the “Special warnings and precautions for use” section). The effect of lamotrigine at daily doses above 300 mg has not been studied. Studies of other hormonal contraceptives have also not been conducted.

Interaction with other drugs.

In a study in 10 male volunteers, rifampicin increased the clearance and shortened the half-life of lamotrigine by inducing hepatic enzymes responsible for glucuronidation. Patients receiving concomitant rifampicin therapy should be treated with the same regimen recommended for lamotrigine and appropriate inducers of glucuronidation (see section 4.2).

In healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine by inducing glucuronidation. For the treatment of patients already taking lopinavir/ritonavir, the treatment regimen recommended for lamotrigine and glucuronidation inducers should be followed (see section 4.2).

In a study in healthy volunteers, co-administration of atazanavir/ritonavir (300 mg/100 mg) for 9 days reduced the plasma AUC and Cmax of lamotrigine (single dose of 100 mg) by an average of 32% and 6%, respectively. Patients already taking lopinavir/ritonavir should follow the appropriate lamotrigine dosing regimen (see section 4.2).

In studies in healthy volunteers, administration of paracetamol 1 g four times daily reduced the AUC and Cmin of lamotrigine in plasma by an average of 20% and 25%, respectively.

In vitro studies have shown that only lamotrigine, but not its N(2)-glucuronide metabolite, is an inhibitor of organic cation transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data indicate that lamotrigine is an inhibitor of OCT 2 with an IC50 of 53.8 µM. Concomitant use of lamotrigine with medicinal products that are substrates of OCT 2 and are excreted by the kidneys (e.g. metformin, gabapentin, varenicline) may result in increased plasma concentrations of these medicinal products. The clinical significance of this effect remains unclear, but lamotrigine should be used with caution in patients taking such medicinal products concomitantly.

Application features

Special precautions

Skin rashes

A skin rash may occur within the first 8 weeks of starting lamotrigine. In most cases, the rash is mild and resolves without treatment, but severe skin reactions requiring hospitalization and discontinuation of Lamictal have been reported. These have included potentially life-threatening rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), also known as hypersensitivity syndrome (see section 4.8).

In adults who participated in studies following current dosing recommendations for Lamictal, the incidence of severe skin rashes was approximately 1 in 500 patients with epilepsy. Approximately half of these cases were diagnosed as Stevens-Johnson syndrome (1 in 1,000). In patients with bipolar disorder, the incidence of severe skin rashes was 1 in 1,000.

Children are at higher risk of developing serious skin rashes than adults. The reported incidence of rashes leading to hospitalization in children ranges from 1 in 300 to 1 in 100 patients.

In children, the first signs of skin rashes may be mistaken for infection, so physicians should be aware of the possibility of this adverse reaction in children who develop rashes and fever during the first 8 weeks of therapy.

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

If a skin rash develops, the patient (both adults and children) should be evaluated immediately and Lamictal should be discontinued unless there is evidence that the skin rash is not related to the drug. It is not recommended to restart lamotrigine treatment if it has been discontinued due to a rash on previous lamotrigine treatment. In such cases, the potential benefits of treatment should be weighed against the potential risks when deciding whether to restart the drug. Lamotrigine should not be restarted in patients who have developed Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS) after taking lamotrigine.

Skin rashes have also been reported as part of DRESS: also known as hypersensitivity syndrome. This condition is accompanied by a variety of systemic symptoms including fever, lymphadenopathy, facial swelling, abnormal blood counts, liver and kidney function, and aseptic meningitis (see section 4.8). The syndrome can vary in severity and can occasionally 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 evaluated immediately and, unless otherwise indicated, Lamictal should be discontinued.

In most cases, aseptic meningitis is reversible after discontinuation of the drug, but in some cases it may recur when lamotrigine is re-administered. Re-administration of lamotrigine causes a rapid return of symptoms, often of a more severe nature. Lamotrigine should not be re-administered to patients who have been discontinued due to aseptic meningitis during previous administration.

Photosensitivity reactions have also been reported with Lamictal (see section 4.8). In a few cases, the reaction occurred with high doses (400 mg or more), after dose increases, or during rapid titration. If a patient with signs of photosensitivity (e.g., severe sunburn) is suspected of having photosensitivity related to Lamictal, discontinuation of treatment should be considered. If continued treatment with Lamictal is considered clinically warranted, the patient should be advised to avoid exposure to sunlight and artificial ultraviolet light and to take protective measures (e.g., use of protective clothing and sunscreen).

Hemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported in patients taking lamotrigine (see section 4.8). HLH is characterized by clinical signs and symptoms such as fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, elevated serum ferritin, hypertriglyceridemia, and abnormalities of liver function and coagulation. Symptoms usually occur within 4 weeks of initiating treatment. HLH can be life-threatening.

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

Patients presenting with these symptoms should be evaluated promptly and a diagnosis of GLH should be considered. Lamotrigine therapy should be discontinued if an alternative etiology for the above symptoms cannot be established.

Clinical deterioration and suicidal risk

When treating patients with various indications, including epilepsy, with antiepileptic drugs, there have been reports of