Girotec 25 Mg/50 Mg/100 Mg/200 Mg Tablets

EPILEPSY:

Adults and children over 12 years

GIROTEC TABLETS are indicated as monotherapy or add-on treatment of partial epilepsy with or without secondary generalised tonic-clonic seizures and in primary generalised tonic-clonic seizures.

Children 2 to 12 years

GIROTEC TABLETS are indicated as add-on treatment of partial epilepsy with or without secondary generalised tonic-clonic seizures not satisfactorily controlled with other antiepileptic medicines. Monotherapy in children under 12 years of age is not recommended.

Lennox-Gastaut Syndrome

GIROTEC TABLETS are indicated as add-on treatment for seizures associated with Lennox-Gastaut Syndrome.

BIPOLAR DISORDER:

Adults 18 years of age and over

GIROTEC TABLETS are indicated for the prevention of mood episodes in patients with bipolar disorder, predominantly by preventing depressive episodes.

It is important to adhere to the recommended dosages especially in combination therapy with valproate where one-tenth of the normal GIROTEC TABLETS dose is used. Do not exceed the maximum dosage (see u201cWARNINGS AND SPECIAL PRECAUTIONSu201d). To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed if necessary. 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.

Epilepsy:

DOSAGE IN MONOTHERAPY:

Adults and children over 12 years of age:

Initial dose in monotherapy: 25 mg once daily for two weeks, followed by 50 mg once daily for two weeks. The dosage may be increased by a maximum of 50 mg u2013 100 mg every 1 u2013 2 weeks until the optimal response is achieved.

Maintenance dose in monotherapy: The usual dose to achieve optimal response is 100 u2013 200 mg per day given in one dose or two divided doses. Some patients have required 500 mg/day of GIROTEC TABLETS to achieve the desired response.

Adults and Children over 12 years (total daily dose):

• Weeks 1 & 2: 25 mg (once daily)
• Weeks 3 & 4: 50 mg (once daily)
• Maintenance Dose: 100 u2013 200 mg (once a day or two divided doses).

To achieve maintenance, doses may be increased by 50 u2013 100 mg every 1 u2013 2 weeks.

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see u201cWARNINGS AND SPECIAL PRECAUTIONSu201d).

DOSAGE IN ADD-ON THERAPY:

Adults and children over 12 years of age:

With enzyme-inducing anticonvulsants only: The initial dose is 50 mg once a day for two weeks, then 100 mg a day, divided into two doses, for two weeks. The dosage may be increased by a maximum of 100 mg every 1 u2013 2 weeks until the optimal response is achieved. The usual maintenance dose is 200 u2013 400 mg/day given in two divided doses.

With enzyme-inducing anticonvulsants and valproic acid: The initial dose is 25 mg once every other day for two weeks, then 25 mg once a day for two weeks. The dosage may be increased by a maximum of 25 u2013 50 mg a day every 1 or 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 100 u2013 200 mg/day given once a day or in two divided doses.

In patients taking antiepileptic medicines where the pharmacokinetic interaction with GIROTEC TABLETS is currently not known, the dose escalation as recommended for GIROTEC TABLETS with concurrent valproate should be used. Thereafter, the dose should be increased until the optimal response is achieved.

Children aged 2 to 12 years:

The initial GIROTEC TABLETS dose in those not taking sodium valproate is 0.6 mg/kg body mass/day given in two divided doses for two weeks, followed by 1.2 mg/kg/day for two weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1 u2013 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 5 u2013 15 mg/kg/day given in two divided doses. A maximum daily dose of 400 mg must not be exceeded.

In those patients taking sodium valproate, the initial GIROTEC TABLETS dose is 0.15 mg/kg body mass/day given once a day for two weeks, followed by 0.3 mg/kg/day given once a day for two weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1- 2 weeks until the optimal response is achieved. The usual maintenance dose to achieve optimal response is 1- 5 mg/kg/day given once a day or in two divided doses. A maximum daily dose of 200 mg must not be exceeded.

GIROTEC TABLETS are contra-indicated in the following circumstances:

• Individuals with known hypersensitivity to lamotrigine or any of the ingredients of GIROTEC TABLETS.
• The safety of GIROTEC TABLETS in pregnancy and lactation has not been established.
• Renal and hepatic function impairment. The use of GIROTEC TABLETS in patients with impairment of hepatic or renal function is contra-indicated.
• Patients over the age of 65 years.

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 u201cSide - Effectsu201d). 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 u201cDosage and Directions For Useu201d).
• Concomitant use of valproate, which increases the mean half-life of GIROTEC TABLETS nearly two-fold (see u201cDosage and Directions For Useu201d).

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 bodyu2019s 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 u221eC.

Effects on the ability to drive and use machines:

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.

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 u201cPharmacokinetic propertiesu201d). 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 lamotrigineu2019s 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 u201cWARNINGS AND SPECIAL PRECAUTIONSu201d).

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

Symptoms and signs

Sedation, ataxia, diplopia, nausea and vomiting have been reported.

Treatment

In the event of overdosage, the patient should be admitted to hospital and given appropriate supportive therapy. Gastric lavage should be performed if indicated.