INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
LAMITOR –25 (tablets)
LAMITOR –50 (tablets)
LAMITOR –100 (tablets)

SCHEDULING STATUS:
S3                8007547-6513

PROPRIETARY NAME
(and dosage form):

LAMITOR –25 (tablets)
LAMITOR –50 (tablets)
LAMITOR –100 (tablets)

COMPOSITION
LAMITOR –25: Each tablet contains 25 mg lamotrigine.
LAMITOR –50: Each tablet contains 50 mg lamotrigine.
LAMITOR –100: Each tablet contains 100 mg lamotrigine.

PHARMACOLOGICAL CLASSIFICATION
A.2.5 Antiepileptics

PHARMACOLOGICAL ACTION
Lamotrigine blocks voltage-sensitive sodium channels, thereby stabilising neuronal membranes and inhibiting neurotransmitter release, principally that of glutamate, an excitatory amino acid which is thought to play a key role in the generation of epileptic seizures.
Pharmacokinetics
Lamotrigine is rapidly and completely absorbed from the gut. The absorption is unaffected by food. The time to peak concentration is 1,4 to 4,8 hours. The mean elimination half-life is 25 +10 hours and the pharmacokinetic profile is linear up to 450 mg, the highest single dose tested. The half-life of lamotrigine is affected by concomitant use of enzyme-inducing drugs such as phenytoin, carbamazepine, phenobarbital or primidone with a mean value of approximately 14 hours.
The half-life of lamotrigine increases to approximately 59 hours when co-administered with valproic acid alone (see DOSAGE AND DIRECTIONS FOR USE). Following multiple administration of lamotrigine (150 mg twice daily) there is modest induction of its own metabolism, resulting in a 25% decrease in the elimination half-life at steady state. Lamotrigine is moderately (55%) bound to plasma proteins.
Clearance adjusted for bodyweight is higher in children aged 12 years and under than in adults, with the highest values in children under 5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme-inducing drugs such as carbamazepine and phenytoin.

INDICATIONS
Adults and children over 12 years
LAMITOR is 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
LAMITOR is 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 until such time as adequate information is made available from controlled trials in this particular target population.
Lennox-Gastaut Syndrome
LAMITOR is indicated as add-on treatment for seizures associated with Lennox-Gastaut Syndrome.

CONTRA-INDICATIONS
LAMITOR is contra-indicated in the following circumstances:

•	Individuals with known hypersensitivity to lamotrigine.
•	The safety of LAMITOR in pregnancy and lactation has not been established.
•	Renal and hepatic function impairment. Hepatic metabolism followed by renal excretion is the principal route of elimination of lamotrigine and until more information is available, the use of LAMITOR in patients with impairment of hepatic or renal function is contra-indicated.
•	Patients over the age of 65 years.

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 off 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 life-threatening 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. Available data suggest the incidence in children requiring hospitalisation ranges from 1 in 300 to 1 in 100.

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.

INTERACTIONS
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 half-life 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.

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

DOSAGE AND DIRECTIONS FOR USE
It is important to adhere to the recommended dosages especially in combination therapy with valproate where one-tenth to one-fifth of the normal dose is used.
Do not exceed the maximum dosage (see WARNINGS). 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, and patients with hepatic impairment, do not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.
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 –100 mg every 1 to 2 weeks until the optimal response is achieved.
Maintenance dose in monotherapy: The usual dose to achieve optimal response is 100 –200 mg per day given in one dose or two divided doses. Some patients have required 500 mg/day of LAMITOR to achieve the desired response.
Adults and Children over 12 years (total daily dose)

Weeks 1 & 2	Weeks 3 & 4	Maintenance Dose
25 mg (once daily)	50 mg (once daily)	100 –200 mg (once a day or two divided doses). To achieve maintenance, doses may be increased by 50 –100 mg every 1 –2 weeks

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see WARNINGS).
Dosage in add-on therapy
Adults and children over 12 years of age
The initial LAMITOR dose in those patients not taking sodium valproate: 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 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 200 –400 mg/day given in two divided doses.
In those patients taking sodium valproate: 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 –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 –200 mg/day given once a day or in two divided doses. In patients taking antiepileptic drugs where the pharmacokinetic interaction with LAMITOR is currently not known, the dose escalation as recommended for LAMITOR with concurrent valproate should be used. Thereafter, the dose should be increased until the optimal response is achieved.
Adults and Children over 12 years (total daily dose)

	Weeks 1 & 2	Weeks 3 & 4	Maintenance Dose
Patients not taking sodium valproate	50 mg (once a day)	100 mg (two divided doses)	200 –400 mg (two divided doses). To achieve maintenance, doses may be increased by 100 mg every 1 –2 weeks
Patients taking sodium valproate	25 mg (on alternative days)	25 mg (once a day)	100 –200 mg (once a day or two divided doses). To achieve maintenance, doses may be increased by 25 - 50 mg every 1 –2 weeks

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see WARNINGS).
Children aged 2 to 12 years
The initial LAMITOR dose in those children not taking sodium valproate: The initial dose is 0,6 mg/kg body-weight daily given in two divided doses for two weeks, followed by 1,2 mg/kg daily in 2 divided doses for two weeks. Thereafter, the dose should be increased by a maximum of 1,2 mg/kg every 1 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 5 –15 mg/kg/day given in two divided doses. A maximum daily dose of 400 mg must not be exceeded.
In those children taking sodium valproate; The initial dose of 0,15 mg/kg once daily for two weeks, followed by 0,3 mg/kg once daily for two weeks. Thereafter the dose is increased by a maximum of 0,3 mg/kg every 1 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 1 –5 mg/kg, which may be given once a day or in two divided doses. A maximum daily dose of 200 mg must not be exceeded.
In patients taking antiepileptic drugs where the pharmacokinetic interaction with LAMITOR is currently not known, the dose escalation as recommended for LAMITOR with concurrent valproate should be used. Thereafter, the dose should be increased until the optimal response is achieved.
Children Aged 2 to 12 years (total daily dose)

	Weeks 1 & 2	Weeks 3 & 4	Maintenance Dose
Patients not taking sodium valproate	0,6 mg/kg (two divided doses)	1,2 mg/kg (two divided doses)	5 –15 mg/kg (two divided doses) or maximum of 400 mg daily. To achieve maintenance, doses may be increased by 1,2 mg/kg every 1 –2 weeks
Patients taking sodium valproate	0,15 mg/kg (once a day)	0,3 mg/kg (once a day)	1 –5 mg/kg (once a day or in two divided doses) or maximum of 200 mg daily. To achieve maintenance, doses may be increased by 0,3 mg every 1 –2 weeks

The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash (see WARNINGS).
Note: If the calculated daily dose is 2,5 –5 mg, then 5 mg LAMITOR may be taken on alternate days for the first two weeks. If the calculated daily dose is less than 2,5 mg, then LAMITOR should not be administered. Patients aged 2 –6 years may require a maintenance dose at the higher end of the recommended range.
Dosage in seizures associated with Lennox-Gastaut Syndrome
The dosing guidelines outlined above for both adults and children aged 2 –12 years apply for the treatment of seizures associated with Lennox-Gastaut Syndrome.
Children aged less than 2 years
There is insufficient information on the use of LAMITOR in children aged less than two years.
Elderly (over 65 years of age):
No dosage adjustments from recommended schedule are required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly adult population.
Hepatic impairment:
Initial escalating and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according clinical response.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
SIDE-EFFECTS
Blood and lymphatic system disorders
Rare: Blood dyscrasias including anaemia, eosinophilia, leucopenia or thrombocytopenia
Immune system disorder
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 withrashes as part of a hypersensitivity syndrome (see WARNINGS).
Skin and subcutaneous tissue disorders
More frequent: Skin rash
Rare: Stevens-Johnson Syndrome, or toxic epidermal necrolysis, photosensitivity, 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.
Nervous system disorders
More frequent: Headache, tiredness, dizziness, drowsiness, coordination abnormalities, ataxia
Less frequent: Anxiety, confusion, depression, irritability, increased seizures, nystagmus, insomnia and tremor
Eye disorders
More frequent: Vision abnormalities, including blurred vision; and diplopia
Respiratory, thoracic and mediastinal disorders
Rare: Angioedema (trouble in breathing, swelling of face, mouth, hands or feet)
Gastrointestinal disorders
More frequent: Nausea and vomiting,
PRECAUTIONS
LAMITOR inhibits dihydrofolate reductase and should be used with caution with other folate antagonists.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms and signs
Acute indigestion of doses in excess of 10 –20 times the maximum therapeutic doses has been reported. Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.
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.

IDENTIFICATION
LAMITOR –25: Light yellow coloured, round, flat uncoated tablets, with bisecting line on one side.
LAMITOR –50: Light yellow coloured, round, flat uncoated tablets, with bisecting line on one side.
LAMITOR –100: Light yellow coloured, round, flat uncoated tablets, with bisecting line on one side.

PRESENTATION
LAMITOR –25: PVC/Aluminium blister pack of 60 tablets
LAMITOR –50: PVC/Aluminium blister pack of 60 tablets
LAMITOR –100: PVC/Aluminium blister pack of 60 tablets

STORAGE INSTRUCTIONS
Store below 25°C in a dry place
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
LAMITOR –25: 37/2.5/0051
LAMITOR - 50: 37/2.5/0052
LAMITOR - 100: 37/2.5/0053

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr. Reddy’s Laboratories (Pty) Ltd.
3rd floor, TA Bank Building
160 Jan Smuts Avenue
Rosebank
2196 Johannesburg

DATE OF PUBLICATION OF THIS PACKAGE INSERT
02 September 2005

8007547-6513

New addition to this site: January 2008
Source: Pharmaceutical Industry
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