GIROTEC Tablet Ref.[51195] Active ingredients: Lamotrigine

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 GIROTEC TABLETS.

Patients receiving GIROTEC TABLETS should be closely monitored for changes in hepatic, renal and clotting parameters. 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 GIROTEC TABLETS. Withdrawal of 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 GIROTEC TABLETS may provoke rebound seizures. The risk may be reduced by tapering off the withdrawal of GIROTEC TABLETS over a period of two weeks.

The weight of a child must be monitored and the dose reviewed as weight changes occur. If the dose 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.

Cardiac rhythm and conduction abnormalities

GIROTEC TABLETS can increase the risk of serious arrhythmias, which can be life-threatening, in patients with clinically important structural or functional heart disorders

Skin Reactions

Adverse skin reactions have been reported, which have generally occurred within the first 8 weeks of starting GIROTEC TABLETS. Although the majority of rashes usually resolve when GIROTEC TABLETS are discontinued, irreversible scarring and cases of associated death have been reported, close monitoring is essential. Less frequently, serious and potentially life-threatening skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported especially in children and in patients using valproate concomitantly (see “Side-Effects”). Cases have also been reported after prolonged treatment (6 months).

The estimated incidence of serious skin rashes in adults is 1 in 1000. 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; doctors should consider the possibility of a medicine 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 GIROTEC TABLETS and exceeding the recommended dose escalation of GIROTEC TABLETS (see “Dosage and Directions For Use”).
• Concomitant use of valproate, which increases the mean half-life of GIROTEC TABLETS 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 GIROTEC TABLETS withdrawn immediately unless the rash is clearly not medicine 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 to note 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 GIROTEC TABLETS therapy discontinued if an alternative aetiology cannot be immediately established.

Bipolar Disorder: The possibility of a suicide attempt is inherent in bipolar disorder, and close supervision of high-risk patients should accompany medicine therapy.

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

Haemophagocytic Lymphohistiocytosis (HLH)

There is a risk of HLH associated with the use of lamotrigine as contained in GIROTEC TABLETS. HLH activates the body’s infection-fighting immune system, excessively, and can cause severe inflammation throughout the body and may lead to hospitalization and death. HLH typically presents as a persistent fever, usually greater than 38°C.

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

Evidence to date has not shown that GIROTEC TABLETS affects the plasma concentration of other concomitant antiepileptic medicines. GIROTEC TABLETS does not displace other antiepileptic medicines from protein binding sites.

Use with rifampicin significantly increased the clearance of lamotrigine. The total urinary excretion of lamotrigine and the amount excreted as glucuronide were significantly higher compared with placebo.

A study in healthy subjects found that ritonavir boosted lopinavir decreased the steady-state minimum plasma concentration of lamotrigine by about 55%; doubling the dose of lamotrigine achieved concentrations similar to those with lamotrigine alone.

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

GIROTEC TABLETS does not seem to affect plasma concentrations of ethinyloestradiol and levonorgestrel following the administration of the oral contraceptive pill. However, any change in the menstrual bleeding pattern should be investigated.

The pharmacokinetics of lithium after 2 g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by co-administration of 100 mg/day lamotrigine. Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 subjects and only had a slight increase in the AUC of lamotrigine glucuronide. In vitro inhibition experiments indicated that the formation of lamotrigine’s primary metabolite, the 2-N-glucuronide, was minimally affected by co-incubation with amitryptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Bufuralol metabolism data from human liver microsome suggested that lamotrigine does not reduce the clearance of medicines eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone.

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

GIROTEC TABLETS may cause dizziness, drowsiness and blurred or double vision. Driving and operating machinery should be avoided until the effect of GIROTEC TABLETS on the individual patient is determined.

Blood and the lymphatic system disorders

Less frequent: Blood dyscrasias including anaemia, eosinophilia, leukopenia or thrombocytopenia

Immune system disorders

Less frequent: Hypersensitivity syndrome, angioedema

Symptoms such as fever, malaise, influenza-like symptoms, drowsiness, lymphadenopathy, facial oedema, and less frequently, hepatic dysfunction, leukopenia and thrombocytopenia, disseminated intravascular coagulation, multi-organ failure have been reported in conjunction with rashes as part of a hypersensitivity syndrome (see “WARNINGS AND SPECIAL PRECAUTIONS”).

Psychiatric disorders

Less frequent: Aggression, hallucinations

Nervous system disorders

Frequent: Headache, dizziness, drowsiness, coordination abnormalities, ataxia, vertigo, paraesthesia

Less frequent: Anxiety, confusion, depression, irritability, increased seizures, nystagmus and insomnia, tremor, unsteadiness, movement disorders, worsening of disease, extrapyramidal effects, choreosthetosis

Eye disorders

Frequent: Vision abnormalities, including blurred vision; and diplopia

Less Frequent: Conjunctivitis

Gastrointestinal disorders

Frequent: Nausea and vomiting

Hepatobiliary disorders

Less frequent: Increased liver function tests, hepatic dysfunction, hepatic failure

Skin and subcutaneous tissue disorders

Frequent: Skin rash

Less frequent: Stevens-Johnson Syndrome, or toxic epidermal necrolysis

The following side-effect has been reported and frequency is unknown: Photosensitivity

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

Musculoskeletal, connective tissue and bone disorders

Frequent: Arthralgia

Less frequent: Lupus-like reaction

General disorders and administrative site conditions

Frequent: Pain, back pain, tiredness