INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ASPEN LAMOTRIGINE 25 mg TABLETS
ASPEN LAMOTRIGINE 50 mg TABLETS
ASPEN LAMOTRIGINE 100 mg TABLETS
ASPEN LAMOTRIGINE 200 mg TABLETS

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

ASPEN LAMOTRIGINE 25 mg TABLETS
ASPEN LAMOTRIGINE 50 mg TABLETS
ASPEN LAMOTRIGINE 100 mg TABLETS
ASPEN LAMOTRIGINE 200 mg TABLETS

COMPOSITION
Each tablet contains:
ASPEN LAMOTRIGINE 25 mg TABLETS –Lamotrigine 25 mg
ASPEN LAMOTRIGINE 50 mg TABLETS –Lamotrigine 50 mg
ASPEN LAMOTRIGINE 100 mg TABLETS –Lamotrigine 100 mg
ASPEN LAMOTRIGINE 200 mg TABLETS –Lamotrigine 200 mg

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 major role in the generation of epileptic seizures.
Pharmacokinetics
Lamotrigine is well 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
ASPEN LAMOTRIGINE 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
ASPEN LAMOTRIGINE is indicated as add-on treatment of partial epilepsy with or without secondary generalised tonic-clonic seizures not satisfactorily controlled with other antiepileptic medicines.
Lennox-Gastaut Syndrome
ASPEN LAMOTRIGINE is indicated as add-on treatment for seizures associated with Lennox-Gastaut Syndrome.

CONTRA-INDICATIONS
ASPEN LAMOTRIGINE is contra-indicated in the following circumstances:

•	Individuals with known hypersensitivity to lamotrigine.
•	The safety of ASPEN LAMOTRIGINE 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 ASPEN LAMOTRIGINE in patients with impairment of hepatic or renal function is contra-indicated.
•	Patients over the age of 65 years.

WARNINGS
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.
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 ASPEN LAMOTRIGINE.
Patients receiving ASPEN LAMOTRIGINE 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 ASPEN LAMOTRIGINE.
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 ASPEN LAMOTRIGINE may provoke rebound seizures. The risk may be reduced by tapering off the withdrawal of ASPEN LAMOTRIGINE 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, does 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 ASPEN LAMOTRIGINE. Although the majority of rashes usually resolve when treatment is discontinued, irreversible scarring and cases of associated death have been reported. A mild rash may subside even with continuation of ASPEN LAMOTRIGINE 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 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; 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 ASPEN LAMOTRIGINE and exceeding the recommended dose escalation of ASPEN LAMOTRIGINE (see DOSAGE AND DIRECTIONS FOR USE). -        Concomitant use of valproate, which increases the mean half-life of ASPEN LAMOTRIGINE 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 ASPEN LAMOTRIGINE 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 has shown 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 ASPEN LAMOTRIGINE 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 ASPEN LAMOTRIGINE leading to an increased clearance and subsequent reduction of the elimination half-life of ASPEN LAMOTRIGINE. Concomitant use of valproic acid increases the half-life and plasma concentrations of ASPEN LAMOTRIGINE due to competition for hepatic glucuronidation. Plasma concentrations of valproic acid may decrease slightly when ASPEN LAMOTRIGINE is added (see pharmacokinetics)
There is no evidence that ASPEN LAMOTRIGINE affects the plasma concentration of other concomitant antiepileptic drugs.
ASPEN LAMOTRIGINE does not displace other antiepileptic drugs from protein binding sites.
There is no evidence that ASPEN LAMOTRIGINE causes clinically significant induction or inhibition of hepatic oxidative drug metabolising enzymes. ASPEN LAMOTRIGINE may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.
ASPEN LAMOTRIGINE 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.

PREGNANCY AND LACTATION
The safety of ASPEN LAMOTRIGINE 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 of the normal ASPEN LAMOTRIGINE dose is used. Do not exceed the maximum dosage (see WARNINGS).
To ensure that 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.

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 –100 mg every 1 - 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 ASPEN LAMOTRIGINE 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 the maintenance dose, 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:
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 –2 weeks until the optimal response is achieved. The usual maintenance dose is 200 –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 –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 ASPEN LAMOTRIGINE is currently not known, the dose escalation as recommended for ASPEN LAMOTRIGINE 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 the maintenance dose, 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 the maintenance dose, 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:
With enzyme-inducing anticonvulsants only: 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 in two divided doses must not be exceeded.
In children taking valproic acid: 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, given once a day or in two divided doses, must not be exceeded.
In patients taking antiepileptic drugs where the pharmacokinetic interaction with ASPEN LAMOTRIGINE is currently not known, the dose escalation as recommended for ASPEN LAMOTRIGINE 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)	1,2 mg/kg increments every 1 - 2 weeks to achieve a maintenance dose of 5 - 15 mg/kg (two divided doses) to a maximum of 400 mg/day
Patients taking sodium valproate	0,15 mg/kg (once a day)	0,3 mg/kg (once a day)	0,3 mg/kg increments every 1 - 2 weeks to achieve a maintenance dose of 1 - 5 mg/kg (once a day or two divided doses) to a maximum of 200 mg/day

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 1 - 2 mg, then 2 mg ASPEN LAMOTRIGINE may be taken on alternate days for the first two weeks. If the calculated daily dose is less than 1 mg, then ASPEN LAMOTRIGINE 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 ASPEN LAMOTRIGINE in children aged less than two years.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Adverse experiences reported during ASPEN LAMOTRIGINE monotherapy trials include headache, tiredness, rash, nausea, dizziness, drowsiness and insomnia. In double-blind, add-on clinical trials, transient skin rashes occurred in up to 10 % of patients taking lamotrigine. Skin rashes led to the withdrawal of lamotrigine treatment in 2 % of patients. The rash, usually maculopapular in appearance, generally appears within four weeks of starting treatment and resolves on withdrawal of lamotrigine. Severe skin rashes, including angioedema and Stevens-Johnson syndrome, have been reported. Rash has also been reported as part of a hypersensitivity syndrome (See WARNINGS)
Other frequent adverse experiences reported during trials with ASPEN LAMOTRIGINE added on to standard antiepileptic drug regimens have included diplopia, blurred vision, conjunctivitis, nystagmus, dizziness, drowsiness, headache, unsteadiness, tiredness, gastrointestinal disturbance (nausea and vomiting), irritability/aggression, depression, tremor, vertigo, parasthesia and haematological abnormalities (including neutropenia, leucopenia and thrombocytopenia)
Special precautions
ASPEN LAMOTRIGINE 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
Sedation, ataxia, diplopia, nausea and vomiting have been reported with very high serum lamotrigine concentrations of more than 15 micrograms/mL.
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
ASPEN LAMOTRIGINE 25 mg TABLETS - Off-white to cream, round, flat faced, beveled edge tablets marked “LM on the one side and “25”on the other side.
ASPEN LAMOTRIGINE 50 mg TABLETS - Off-white to cream, round, flat faced, beveled edge tablets marked “LM on the one side and “50”on the other side.
ASPEN LAMOTRIGINE 100 mg TABLETS Off-white to cream, round, flat faced, beveled edge tablets marked “LM on the one side and “100”on the other side.
ASPEN LAMOTRIGINE 200 mg TABLETS Off-white to cream, round, flat faced, beveled edge tablets marked “LM on the one side and “200”on the other side.

PRESENTATION
Packs of 56 or 60 tablets packed in either white, high density polypropylene containers with white, polyethylene caps or clear, PVC Aluminium foil blister strips (6x blister strips of 10 tablets each) packed into cardboard cartons. Keep blisters in carton until required for use.

STORAGE INSTRUCTIONS
Store below 25°C in a dry place. Keep well-closed.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
ASPEN LAMOTRIGINE 25 mg TABLETS –A38/2.5/0585
ASPEN LAMOTRIGINE 50 mg TABLETS –A38/2.5/0586
ASPEN LAMOTRIGINE 100 mg TABLETS –A38/2.5/0587
ASPEN LAMOTRIGINE 200 mg TABLETS –A38/2.5/0588

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
2052

DATE OF PUBLICATION OF THIS PACKAGE INSERT
19 August 2005

575028/051007
UNIPRINT-POS

New addition to this site: January 2006
Source: Pharmaceutical Industry
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