LAMICTAL

Epilepsy

Adults and adolescents aged 13 years and older

· Monotherapy or combination treatment of partial and generalized epilepsies, including tonic-clonic seizures.

· Seizures associated with Lennox-Gastaut syndrome. LAMOTRIGINE VIATRIS is administered in association with another treatment but may be the first-line anti-epileptic (AE) in Lennox-Gastaut syndrome.

Children and adolescents from 2 to 12 years

· Combination treatment of partial and generalized epilepsies, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

· Monotherapy treatment of typical absences.

Bipolar disorders

Adults aged 18 years and older

· Prevention of depressive episodes in patients with bipolar I disorder who have a predominance of depressive episodes (see section 5.1).

LAMOTRIGINE VIATRIS is not indicated in the acute treatment of manic or depressive episodes.

Pregnancy

Risk related to antiepileptic drugs in general

Specialized advice should be given to women with epilepsy of childbearing potential. Antiepileptic treatment should be re-evaluated when a woman is planning a pregnancy. In women being treated for epilepsy, sudden discontinuation of antiepileptic treatment should be avoided as this may lead to breakthrough seizures that could have serious consequences for the mother and the fetus.

Monotherapy should be preferred whenever possible because polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy. The risk of congenital malformations associated with polytherapy varies depending on the co-administered antiepileptic drugs.

Risk related to lamotrigine

Analysis of a large number of data in women exposed to lamotrigine monotherapy during the first trimester of pregnancy (more than 8700) did not demonstrate a substantial increase in the risk of major congenital malformations including oral clefts. Animal studies have shown developmental toxicity (see section 5.3).

If treatment with LAMOTRIGINE VIATRIS is considered necessary during pregnancy, the lowest therapeutic dose is recommended.

Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase and could therefore theoretically lead to an increased risk of embryofetal harm by reducing folic acid levels. Folic acid intake should be considered when a pregnancy is planned and during early pregnancy.

Physiological changes during pregnancy may alter lamotrigine concentrations and/or its therapeutic effect. Cases of decreased lamotrigine plasma levels during pregnancy have been reported with a potential risk of loss of seizure control. After birth, lamotrigine levels may rise rapidly with a risk of dose-dependent adverse effects. Therefore, serum lamotrigine concentrations should be monitored before, during and after pregnancy, as well as rapidly after birth.

If necessary, the dose should be adapted to maintain the serum concentration of lamotrigine at the same level as before pregnancy, or adapted to the clinical response. Furthermore, dose-dependent adverse effects should be monitored after birth.

Breastfeeding

It has been reported that lamotrigine passes into breast milk in highly variable concentrations resulting in total lamotrigine levels in infants of up to approximately 50 % of those of the mother. Consequently, in breast-fed infants, serum lamotrigine concentrations may reach levels at which pharmacological effects may occur.

The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant. If a woman decides to breastfeed her child while she is being treated with lamotrigine, the infant should be monitored for adverse effects, such as somnolence, a skin rash or poor weight gain.

Fertility

Studies in animals have not revealed any impairment of fertility by lamotrigine (see section 5.3).

Due to the variability of individual response to all AE treatments, patients taking LAMOTRIGINE VIATRIS to treat their epilepsy must consult their doctor regarding specific questions related to driving and epilepsy.

The effects on the ability to drive vehicles and use machines have not been studied. Two studies in volunteers showed that the effect of lamotrigine on fine visual motor coordination, eye movements, body sway and subjective sedative effects are not different from placebo. In clinical trials with lamotrigine, neurological adverse events such as dizzy sensations and diplopia have been reported. Consequently, patients should see to what extent treatment with LAMOTRIGINE VIATRIS affects them before driving or using a machine.

Adverse effects for the indications of epilepsy and bipolar disorders are based on available data from controlled clinical trials and other clinical experiences and are listed in the table below. Frequency categories are derived from controlled clinical trials (in monotherapy for epilepsy (identified by a †) and for bipolar disorders (identified by the symbol §)). When frequency categories differ between epilepsy clinical trial data and those for bipolar disorders, the highest frequency is mentioned. However, when no controlled clinical trial data is available, frequency categories were obtained from other clinical trials.

The following convention has been used for the classification of adverse effects: very frequent (≥ 1/10), frequent (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), undetermined (cannot be estimated from the available data).

Description of selected adverse effects

1 Hematological abnormalities and lymphadenopathies may or may not be associated with drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS)/hypersensitivity syndrome (see «Special warnings and precautions for use and Immune system disorders»).

2 Skin rashes have also been reported in the context of this syndrome, also known as DRESS. This disease is associated with a variable presentation of systemic symptoms including fever, lymphadenopathies, facial oedema and hematological, hepatic and renal abnormalities. This syndrome of variable clinical expression can, rarely, lead to disseminated intravascular coagulation and multi-organ failure. It is important to note that early hypersensitivity reactions (for example fever, lymphadenopathies) may be observed while a skin rash is not evident. If these signs and symptoms occur, the patient must then be examined immediately and LAMOTRIGINE VIATRIS discontinued if another etiology cannot be established (see section 4.4).

3 These effects have been reported in other clinical trials.

Cases of worsening of parkinsonian symptoms related to lamotrigine have been reported in patients with pre-existing Parkinson's disease, extrapyramidal effects and choreoathetosis have also been reported in isolation in patients not having this underlying pathology.

4 Hepatic dysfunction generally occurs in association with hypersensitivity reactions but isolated cases have been reported without manifest sign of hypersensitivity.

5 In clinical trials in adults, skin rashes occurred in up to 8 to 12 % of patients taking lamotrigine and in 5 to 6 % of patients taking a placebo. Skin rashes led to discontinuation of lamotrigine treatment in 2 % of patients. The rash, generally maculopapular in appearance, generally appears within the first eight weeks of treatment and resolves upon discontinuation of LAMOTRIGINE VIATRIS treatment (see section 4.4).

Severe skin rashes that may be life-threatening, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) and a drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome) have been reported. Although the majority recover upon discontinuation of lamotrigine treatment, some patients have irreversible sequelae and there have been rare associated deaths (see section 4.4).

The overall risk of skin rashes seems to be strongly linked to:

· high initial doses of lamotrigine exceeding the recommended dose escalation schedule (see section 4.2);

· concomitant use of valproate (see section 4.2).

Cases of decreased bone mineral density, osteopenia, osteoporosis and fractures have been reported in patients treated long-term with lamotrigine. The mechanism by which lamotrigine affects bone metabolism has not been identified.

Reporting of suspected adverse effects

Reporting suspected adverse effects after medicinal product authorization is important. It allows for continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/ .