LAMITOR Tablet Ref.[50455] Active ingredients: Lamotrigine

WARNINGS

Severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation, usually with fatal outcome. Similar cases have occurred in association with the use of LAMITOR.

Patients receiving LAMITOR should be closely monitored and changes in hepatic, renal and clotting parameters looked for. Patients should be warned to consult their doctors immediately if rashes or flu-like symptoms associated with hypersensitivity develop, especially within the first month of starting treatment with LAMITOR. Withdrawal of LAMITOR therapy should be considered if unexplained rashes, fever, flu-like symptoms, drowsiness or worsening of seizure control occur.

Dosage recommendations should not be exceeded to minimise the risk of developing rash requiring withdrawal of therapy. Abrupt withdrawal of LAMITOR may provoke rebound seizures. The risk may be reduced by tapering the withdrawal of LAMITOR over a period of two weeks.

The weight of a child must be monitored and the dose reviewed as weight changes occur. If the doses calculated for children, according to bodyweight, do not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

Skin Reactions

Adverse skin reactions have been reported, which have generally occurred within the first 8 weeks of starting LAMITOR. Although the majority of rashes usually resolve when LAMITOR is discontinued, irreversible scarring and cases of associated death have been reported. A mild rash may subside even with continuation of LAMITOR therapy; however, close monitoring is essential. Less frequently, serious and potentially lifethreatening skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported especially in children and in patients using valproate (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS). Isolated cases have been reported after prolonged treatment (6 months).

The estimated incidence of serious skin rashes in adults is 1 in 1 000. The risk is higher in children than in adults. Some children may require hospitalisation because of the seriousness of skin rashes.

In children, the initial presentation of a rash can be mistaken for an infection; physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy.

The overall risk of rash appears to be strongly associated with:

• High initial doses of LAMITOR and exceeding the recommended dose escalation of LAMITOR (see DOSAGE AND DIRECTIONS FOR USE).
• Concomitant use of valproate, which increases the mean half-life of LAMITOR nearly two-fold (see DOSAGE AND DIRECTIONS FOR USE).

As it cannot be predicted reliably which rashes will prove to be life-threatening, all patients (adults and children) who develop a rash should be promptly evaluated and LAMITOR withdrawn immediately unless the rash is clearly not drug related.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, pruritus, facial oedema, abnormalities of the blood and liver and thrombocytopenia. The syndrome shows a wide spectrum of clinical severity and may lead to disseminated intravascular coagulation and multiorgan failure. It is important that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present the patient should be evaluated immediately and LAMITOR therapy discontinued if an alternative aetiology cannot be immediately established.

PRECAUTIONS

LAMITOR inhibits dihydrofolate reductase and should be used with caution with other folate antagonists.

Enzyme-inducing agents (such as phenytoin, carbamazepine, phenobarbitone and primidone) enhance the metabolism of LAMITOR leading to an increased clearance and subsequent reduction of the elimination halflife of LAMITOR. Concomitant use of valproic acid increases the half-life and plasma concentrations of LAMITOR due to competition for hepatic glucuronidation. Plasma concentrations of valproic acid may decrease slightly when LAMITOR is added.

No evidence was shown that LAMITOR affects the plasma concentration of concomitant antiepileptic drugs. LAMITOR does not displace other antiepileptic drugs from protein binding sites.

There is no evidence that LAMITOR causes clinically significant induction or inhibition of hepatic oxidative drug-metabolising enzymes. LAMITOR may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.

LAMITOR does not seem to affect plasma concentrations of ethinyloestradiol and levonorgestrel following the administration of the oral contraceptive pill. However, as with the introduction of other chronic therapy in patients taking oral contraceptives, any change in the menstrual bleeding pattern should be reported to the patient’s physician.

The safety of LAMITOR in pregnancy and lactation has not been established.

Side-effects

Very common (>1/10), Common (>1/100 and ≤1/10), Uncommon (>1/1000 and ≤1/100), Rare (>1/10 000 and ≤1/1000), Very rare (≤1/10 000).

Blood and lymphatic system disorders

Very rare: Blood dyscrasias including anaemia, eosinophilia, leucopenia or thrombocytopenia

Immune system disorder

Very rare: Hypersensitivity syndrome. Symptoms such as fever, malaise, influenza-like symptoms, drowsiness, lymphadenopathy, facial oedema and rarely, hepatic dysfunction, leucopenia and thrombocytopenia have been reported in conjunction with rashes as part of a hypersensitivity syndrome (see WARNINGS).

Skin and subcutaneous tissue disorders

Very common: Skin rash

Rare: Stevens-Johnson Syndrome, photosensitivity

Very rare: Toxic epidermal necrolysis

Severe skin rashes, including Stevens-Johnson Syndrome have been reported, especially in children. The skin rash usually occurs within 8 weeks of starting LAMITOR and resolves on withdrawal of LAMITOR (see WARNINGS).

Nervous system disorders

Very common: Headache

Common: Tiredness, insomnia, drowsiness, dizziness, anxiety, confusion, depression, irritability, nystagmus, tremor and ataxia

Uncommon: Increased seizures, coordination abnormalities

Eye disorders

Very common: Vision abnormalities, including blurred vision, diplopia

Respiratory, thoracic and mediastinal disorders

Rare: Angio-oedema (trouble in breathing, swelling of face, mouth, hands or feet)

Gastrointestinal disorders

Common: Nausea and vomiting