Latrigil

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Lamotrigin Stada 5 mg dispersible tablet Lamotrigin Stada 25 mg dispersible tablet Lamotrigin Stada 50 mg dispersible tablet Lamotrigin Stada 100 mg dispersible tablet Lamotrigin Stada 200 mg dispersible tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Lamotrigin Stada 5 mg dispersible tablets One tablet contains 5 mg lamotrigine. Lamotrigin Stada 25 mg dispersible tablets One tablet contains 25 mg lamotrigine. Lamotrigin Stada 50 mg dispersible tablets One tablet contains 50 mg lamotrigine. Lamotrigin Stada 100 mg dispersible tablets One tablet contains 100 mg lamotrigine. Lamotrigin Stada 200 mg dispersible tablets One tablet contains 200 mg lamotrigine.

For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Dispersible tablet

Lamotrigin Stada 5 mg: white, round, biconvex tablet, scored on one side. Lamotrigin Stada 25 mg: white, round, flat tablet, marked "25" on one side. Lamotrigin Stada 50 mg: white, round, flat tablet, marked "50" on one side. Lamotrigin Stada 100 mg: white, round, flat tablet, marked "100" on one side. Lamotrigin Stada 200 mg: white, round, flat tablet, marked "200" on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults and adolescents: As monotherapy in epilepsy: - partial seizures - generalised seizures o primary seizures o secondary tonic-clonic seizures

Adults and adolescents: As add-on therapy in epilepsy: - partial seizures - generalised seizures o primary seizures o secondary tonic-clonic seizures - seizures associated with Lennox- Gastaut Syndrome when other available anti-epileptic drug combinations fail.

Children over 2 years of age: As add-on therapy in epilepsy: - partial seizures - seizures associated with Lennox- Gastaut Syndrome

This medicinal product is to be started only by a neurologist or paediatric neurologist with experience in the treatment of epilepsy or to be used in departments of neurology and similar departments.

4.2 Posology and method of administration

To achieve the maintenance dose, the weight of a paediatric patient must be monitored and the dose reviewed as weight changes occur. If a calculated dose of lamotrigine (e.g. for children or patients with hepatic impairment) is not equal to whole tablets of any strength and not achievable with half 5 mg tablets, the dose to be administered should be that of the lower number of whole/half tablets.

When concomitant antiepileptic drugs are withdrawn to achieve lamotrigine monotherapy or other antiepileptic drugs are added-on to treatment regimes containing lamotrigine consideration should be given to the effect this may have on the pharmacokinetics of different active substances, including lamotrigine (see section 4.5).

The initial dose and subsequent dose escalation should not be exceeded to minimise the risk of rash (see section 4.4).

Adults and adolescents

Monotherapy (see Table 1)

The initial dose of lamotrigine in monotherapy is 25 mg/day once daily for 2 weeks, followed by 50 mg/day once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 50-100 mg every 1 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 100-200 mg/day given once daily or as 2 divided doses. Some patients have required 500 mg/day to obtain the desired response.

Add-on therapy with other antiepileptic drugs (see Table 1)

Patients, who receive valproate with or without other antiepileptics (see section 4.5)

The initial dose is 25 mg every alternate day for 2 weeks, followed by 25 mg/day once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 25-50 mg every 1 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 100-200 mg/day given once daily or in 2 divided doses. Some patients have required 500 mg/day to obtain the desired response.

Patients, who receive other antiepileptics or other active substances that induce the metabolism of lamotrigine with or without other antiepileptics except valproate (see section 4.5)

The initial dose is 50 mg/day once daily for 2 weeks, then 100 mg/day given in 2 divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 100 mg every 1 to 2 weeks until optimum response is achieved. The usual maintenance dose is 200-400 mg/day given in 2 divided doses. Some patients have required 500-700 mg/day to achieve the desired response.

Patients, who receive oxcarbazepine without other active substances that interfere lamotrigine metabolism (see section 4.5)

The initial dose is 25 mg once daily for two weeks, then 50 mg once daily for two weeks. Thereafter, the dose should be increased by a maximum of 50- 100 mg every 1 to 2 weeks until the optimal response is achieved. The usual maintenance dose is 100-200 mg/day given once daily or in 2 divided doses.

Table 1 Recommended dose escalation of lamotrigine for treatment of epilepsy in adults and adolescents (total daily dose in mg/day)

Treatment regimen Week 1 + 2 Week 3 + 4 Maintenance dose 100-200 mg Monotherapy 25 mg (once 50 mg (once daily or in 2 divided daily) (once doses) daily) to achieve maintenance, the daily dose should be increased by a maximum of 50-100 mg every 1 to 2 weeks 100-200 mg Add-on treatment 25 mg (once daily or in 2 divided with valproate 12.5 mg (25 mg (once doses) with or without every other daily) to achieve maintenance, the other day) daily dose should be antiepileptic increased by a maximum of drugs 25-50 mg every 1 to 2 weeks Add-on treatment 200-400 mg with 50 mg 100 mg (in 2 divided doses) enzyme-inducing (once daily) (in 2 to achieve maintenance, the antiepileptic divided daily dose should be drugs* with or doses) increased by a maximum of without other 100 mg every 1 to 2 weeks antiepileptic drugs (no valproate) Add-on treatment 100-200 mg with 25 mg 50 mg (once daily or in 2 divided oxcarbazepine (once daily) (once doses) without other daily) to achieve maintenance, the enzyme-inducers daily dose should be or -inhibitors increased by a maximum of 50-100 mg every 1 to 2 weeks * e.g. phenytoin, carbamazepine, phenobarbital, primidone or other enzyme-inducers (see section 4.5)

Children aged 2 to 12 years

Add-on therapy with other antiepileptic drugs (see Table 2)

Children, who receive valproate with/without other antiepileptic drugs

The initial dose of lamotrigine is 0.15 mg/kg/day once daily for 2 weeks, followed by 0.3 mg/kg/day once daily for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.3 mg/kg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose is 1-5 mg/kg/day given once daily or in 2 divided doses, with a maximum dose of 200 mg/day.

Children, who receive enzyme-inducing antiepileptic drugs or other enzyme- inducing active substances with/without other antiepileptic drugs except valproate

The initial dose of lamotrigine is 0.6 mg/kg/day given in 2 divided doses for 2 weeks, followed by 1.2 mg/kg/day given in 2 divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 1.2 mg/kg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose is 5-15 mg/kg/day given in 2 divided doses, with a maximum dose of 400 mg/day.

Children, who receive oxcarbazepine without enzyme-inducing or-inhibiting active substances

The initial dose of lamotrigine is 0.3 mg/kg/day given once daily or in 2 divided doses for 2 weeks, followed by 0.6 mg/kg/day given once daily or in 2 divided doses for 2 weeks. Thereafter, the dose should be increased by a maximum of 0.6 mg/kg every 1 to 2 weeks until optimal response is achieved. The usual maintenance dose is 1-10 mg/kg/day given in 2 divided doses, with a maximum dose of 200 mg/day.

Table 2 Recommended dose escalation of lamotrigine for combination therapy in children from 2 to 12 years (total daily dose in mg/kg body weight/day)

Treatment Week 1 + 2 Week 3 + Maintenance dose regimen 4 1-5 mg/kg Add-on 0.15 mg/kg** 0.3 mg/kg (once daily or in 2 divided treatment with (once daily) (once doses) valproate with daily) to achieve maintenance, the or without daily dose should be increased other by a maximum of 0.3 mg/kg every antiepileptic 1 to 2 weeks, up to a maximum drugs dose of 200 mg/day Add-on 5-15 mg/kg treatment with 0.6 mg/kg 1.2 mg/kg (in 2 divided doses) enzyme-inducin (in 2 divided (in 2 to achieve maintenance, the g doses) divided daily dose should be increased antiepileptic doses) by a maximum of 1.2 mg/kg every drugs* with or 1 to 2 weeks, up to a maximum without other dose of 400 mg/day antiepileptic drugs ( no valproate) Add-on 1-10 mg/kg treatment with 0.3 mg/kg 0.6 mg/kg (once daily or in 2 divided oxcarbazepine (once daily or (once doses) without other in 2 divided daily or to achieve maintenance, the enzyme-inducer doses) in 2 daily dose should be increased s or divided by a maximum of 0.6 mg/kg every –inhibitors doses) 1 to 2 weeks, up to a maximum dose of 200 mg/day * e.g. phenytoin, carbamazepine, phenobarbital, primidone or other enzyme-inducers (see section 4.5) **NOTE: If the calculated daily dose is less than 2.5 mg, Lamotrigin STADA dispersible tablets should not be administered. Depending on the bodyweight of the child, the titration schedule may not be performable with the current strengths of this medicinal product.

It is likely that patients aged 2-6 years will require a maintenance dose at the higher end of the recommended range. In pediatric patients whose weight is less than 17 kg it is not possible to administer the exact initial treatment dose with the smallest strength of this medicinal product (concerning add-on treatment with valproate).

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

Special patient groups

Children below 2 years of age There is insufficient information available about the use of lamotrigine in children under 2 years.

Elderly patients (>65 years of age): No dose adjustment from recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly population.

Hepatic impairment Initial, escalation and maintenance doses should be generally reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and by 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response.

Depending on the dose, the recommended dose may not be performable in patients with hepatic impairment with the current strengths of this medicinal product (see section 5.2).

Renal impairment: Caution should be exercised when administering lamotrigine to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.4 and 5.2).

Women taking hormonal contraceptives (a) Starting lamotrigine in patients already taking hormonal contraceptives: Although an oral contraceptive has been shown to increase the clearance of lamotrigine (see section 4.4 and 4.5), no adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of hormonal contraceptives. Dose escalation should follow the recommended guidelines (see Table 1).

(b) Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers/inhibitors of lamotrigine glucuronidation: The maintenance dose of lamotrigine may need to be increased by as much as two-fold according to the individual clinical response (see sections 4.4 and 4.5).

(c) Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers/inhibitors of lamotrigine glucuronidation: The maintenance dose of lamotrigine may need to be decreased by as much as 50% according to the individual clinical response (see sections 4.4 and 4.5).

Restarting therapy

The need for escalation to maintenance dose should be carefully assessed when restarting lamotrigine in patients who have discontinued it, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing lamotrigine exceeds five half-lives (see section 5.2), lamotrigine should generally be escalated to the maintenance dose according to the appropriate schedule.

Method of administration

Before administration lamotrigine dispersible tablets should be dispersed in a sufficient amount of water until a homogeneous dispersion is received. Alternatively the tablets may be swallowed whole or may be chewed. It is recommended to take the tablets at the same time of day before or after meal.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available.

4.3 Contraindications

Hypersensitivity to lamotrigine or to any of the excipients.

4.4 Special warnings and special precautions for use

Skin reactions

There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of skin rashes are mild and self-limiting. Rarely serious skin rashes including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.8).

Reports from epilepsy studies in adults with current dosing recommendations have shown an approximate serious skin rashes incidence of 1 in 500, but studies suggest that the incidence of rashes associated with hospitalisation in children under the age of 12 is higher (1/300 to 1/100).The approximate incidence of serious skin rashes reported as SJS in adults and adolescents is 1 in 1000.

In children, the initial presentation of a rash can be mistaken for an infection. Physicians should consider the possibility of an active substance reaction in children that develop symptoms of rash and fever during the first 8 weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:

- high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2) - concomitant use of valproate (see sections 4.2 and 4.5).

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine should be withdrawn immediately and not be restarted unless the rash is clearly not active substance related.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and the liver. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) 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. Patients should be warned to seek immediate medical advice if signs or symptoms develop. If such signs or symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.

Withdrawal of lamotrigine

Abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (e.g. rash) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.

Potential pharmacokinetic interactions should be taken into consideration in case of any alteration in treatment (e. g. the introduction or withdrawal of other antiepileptic drugs, see sections 4.2 and 4.5). Lamotrigine can increase attacks in some patients.

Folic acid metabolism

Lamotrigine is a weak inhibitor of dihydrofolic acid reductase hence there is a possibility of interference with folic acid metabolism during long- term therapy (see section 4.5).

Other organs

There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan dysfunction and disseminated intravascular coagulation (DIC), sometimes with fatal outcome. Similar cases have occurred in association with the use of lamotrigine.

Use in combination with hormonal contraceptives: An ethinyloestradiol/levonorgestrel (30 mcg / 150 mcg) combination has been demonstrated to increase the clearance of lamotrigine by approximately two- fold resulting in decreased lamotrigine levels (see section 4.5). Thus, the lamotrigine dosage may need titration (see section 4.2).There is also a modest increase in levonorgestrel clearance and serum FSH and LH concentrations when used with lamotrigine (see section 4.5). The possibility of effects on contraceptive efficacy cannot be excluded. Therfore, patients should be instructed to promptly report changes in their menstrual pattern.

Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.

Renal impairment

Caution should be exercised in treating patients with renal failure, because the half-life of lamotrigine may be extended in case of severe impaired renal function. Accumulation of the glucuronide metabolite is to be expected too.

Hepatic impairment

The main pathway of elimination is hepatic metabolism. Based on pharmacokinetic data in subjects with hepatic failure dose adjustment is recommended according to severity (Child-Pugh classification).

Restarting therapy

It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk (see section 4.2).

Women of childbearing age

Women of childbearing age and during pregnancy should use anticonvulsants as monotherapy whenever possible, since the risk of malformations may be enhanced in combination therapy with other anticonvulsants.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of lamotrigine on the pharmacokinetics of other active substances

Antiepileptics There have been reports of central nervous system events including headache, nausea, blurred vision, dizziness, diplopia and ataxia in patients taking carbamazepine following the introduction of lamotrigine. These events usually resolve when the dose of carbamazepine is reduced. Although changes in the plasma concentrations of other antiepileptic drugs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentration of concomitant antiepileptic drugs. In-vitro studies indicate that lamotrigine does not displace other antiepileptic drugs from protein binding sites.

Hormonal contraceptives In a study of 16 female volunteers, a steady state dose of 300 mg lamotrigine had no effect on the pharmacokinetics of the ethinyloestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax, respectively. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see section 4.4). The effects of doses of lamotrigine other than 300 mg/day have not been studied and studies with other female hormonal preparations have not been conducted.

Effect of other active substances on the pharmacokinetics of lamotrigine

Antiepileptic agents which induce drug-metabolising enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of lamotrigine and may increase dose requirements (see section 4.2). Valproate reduces the metabolism of lamotrigine and increases the mean half- life of lamotrigine nearly 2 fold (see sections 4.2 and 4.4).

Active substances Active substances that Active substances that that significantly significantly induce do not significantly inhibit glucuronidation of inhibit or induce glucuronidation of lamotrigine glucuronidation of lamotrigine lamotrigine Valproate Carbamazepine Lithium Phenytoin Bupropion Primidone Olanzapine Phenobarbital Oxcarbazepine** Rifampicine*** Ethinyloestradiol/Levonor gestrel combination*

* Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters. ** In a study in healthy adult volunteers using doses of 200 mg/day lamotrigine and 1200 mg/day oxcarbazepine, results showed that compared with placebo, the mean values for steady state Cmax and AUC(0-24) of lamotrigine were reduced by 2% and 8%, respectively. The 90% confidence intervals indicated that the differences were between -22% and +8% for AUC(0-24) and -15% and +15% for Cmax. Adverse events were reported more frequently with oxcarbazepine and lamotrigine than with either monotherapy. The most common adverse events were headache, dizziness, nausea and somnolence. *** In a study in 10 healthy adult males, rifampicine increased the clearance and shortened the half-life of lamotrigine.

Hormonal contraceptives In a study of 16 female volunteers, 30 mcg ethinyloestradiol/150 mcg levonorgestrel in a combined oral contraceptive pill caused an approximately two-fold increase in lamotrigine overall clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentrations gradually increased during the course of the week of inactive treatment (e.g. "pill-free" week), with pre-dose concentrations at the end of the week of inactive treatment being, on average, approximately two-fold higher than during co-therapy. If the therapeutic effect of lamotrigine is uncertain although dose adjustments have been made a non-hormonal contraceptive method could be considered. Clinicians should exercise appropriate clinical management of women starting or stopping oral contraceptives during lamotrigine therapy.

Antipsychotic active substances 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 had only 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 amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. Bufuralol metabolism data from human liver microsome suggested that lamotrigine does not reduce the clearance of active substances eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of lamotrigine is unlikely to be affected by clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone. However it has been reported that sertraline may increase the toxicity of lamotrigine by increasing the plasma concentration of lamotrigine.

Folic acid Interaction with folic acid metabolism (see sections 4.4 and 4.6). During prolonged human lamotrigine dosing, it did not induce significant changes in haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folic acid concentrations up to 1 year or red blood cell folic acid concentration up to 5 years.

4.6 Pregnancy and lactation

Pregnancy

Risk related to epilepsy and antiepileptic drugs in general

It is known that newborn children from mothers who use antiepileptic drugs or suffer from epilepsy more frequently have development disorders, such as cardiac abnormalities and cranial facial disorders, than other babies. Multiple antiepileptic drug therapy during pregnancy may increase the risk of foetal malformations and should therefore be avoided, unless it appears justified after having assessed the risk-benefit ratio.

Risk linked to lamotrigine

There are limited data available on the use of lamotrigine during pregnancy. Lamotrigine passes through the placenta, since plasma concentrations in some newborns were at therapeutic levels. Lamotrigine should not be used in pregnancy, unless the potential benefits of treatment to the mother outweigh any possible risks to the developing foetus. Reduction or discontinuation of seizure prophylaxis may carry considerable risk for both mother and foetus that is probably greater than any risk of malformation. Animal experiments have shown no evidence of teratogenic effects (see section 5.3). Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase and could therefore theoretically lead to an increased risk of embryofoetal damage by reducing folic acid levels. Intake of folic acid when planning pregnancy and during early pregnancy may be considered. Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine levels during pregnancy. Appropriate clinical management of pregnant women during lamotrigine therapy should be ensured.

Lactation

There is limited information on the use of lamotrigine during breast feeding. Lamotrigine is excreted into breast milk and may reach serum concentrations in the breast-fed infant that are in the usual therapeutic range in the mother. Mothers should therefore breast-feed only after a careful risk- benefit assessment for the infant or stop breast feeding. If the infant is breast-fed, he/she should be monitored for possible effects.

4.7 Effects on ability to drive and use machines

When treating with lamotrigine, the ability to react may be decreased. This should be taken into account when sharpened attention is required, e.g. when driving vehicles or using machines

4.8 Undesirable effects

The following convention has been utilised for the classification of undesirable effects: Very common: >1/10 Common: >1/100 and <1/10 Uncommon: >1/1,000 and <1/100 Rare: >1/10,000 and <1/1,000 Very rare: <1/10,000 including isolated reports

Very Common Uncommon Rare Very rare common Skin and Skin Stevens Toxic subcutaneous rash1) Johnson epidermal tissue Syndrome necrolysis disorders Blood and Haematological lymphatic abnormalities2 system ) disorders Immune Hypersensitivi system ty syndrome disorders Psychiatric Irritability Aggressio Tics, disorders n hallucinations , confusion Nervous Headache Drowsiness, Agitation, system , insomnia, unsteadiness, disorders dizzines tremor, movement s nystagmus, disorders, ataxia worsening of Parkinson's disease, extrapyramidal effects, choreoathetosi s, increase in seizure frequency3) Eye Diplopia Conjunctiv disorders , itis blurred vision Gastrointest Gastrointest inal inal disorders disturbance, nausea, vomiting, diarrhoea Hepatobiliar Increased y disorders liver function tests, hepatic dysfunction, hepatic failure4) Musculoskele Lupus-like tal and reactions connective tissue disorders General Tiredness disorders

1) In double-blind, add-on clinical trials, skin rashes occurred in up to 10% of patients taking lamotrigine and in 5% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within 8 weeks of starting treatment and resolves on withdrawal of lamotrigine (see section 4.4). Serious skin rashes are common in children (1 %) and uncommon in adults (0,3 %). Skin rashes are more common, when lamotrigine is taken with other antiepileptic drugs. Rarely, serious potentially life-threatening skin rashes, including Stevens Johnson syndrome and toxic epidermal necrolysis (Lyell Syndrome) have been reported. Although the majority recover on active substance withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see section 4.4). The overall risk of rash appears to be strongly associated with:

- High initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2 ) - Concomitant use of valproate (see section 4.2 )

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver, disseminated intravascular coagulation (DIC), multi-organ failure, see section 4.4 ).

2) Haematological abnormalities (including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis) may or may not be associated with the hypersensitivity syndrome.

3) There have been reports that lamotrigine may worsen parkinsonian symptoms in patients with pre-existing Parkinson’s disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.

4) Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.

There are insufficient data available about the effect of lamotrigine on growth, development and cognitive functions of children.

4.9 Overdose

Symptoms Acute ingestion of doses in excess of 10-20 times the maximum therapeutic dose has been reported. Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma. ECG changes (small broadening of the QRS-complex and extension of the PR-interval) may occur.

Treatment In the event of overdose, the patient should be admitted to hospital and given appropriate supportive therapy. Gastric lavage and treatment with activated charcoal for suspected intoxication should be performed if indicated. There is no experience with haemodialysis as treatment for overdose. In 6 patients with renal failure who had been dialysed for 4 hours, 20% of the amount of lamotrigine in the body was removed.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other Antiepileptics ATC code: N03A X09

Mode of action: The results of pharmacodynamic studies suggest that lamotrigine is a blocker of voltage-sensitive sodium channels. It blocks voltage-dependent sustained, repetitive impulses in cultured neurons and inhibits pathological release of glutamate (amino acid which plays a key role in the generation of seizures), as well as glutamate-evoked bursts of action potentials.

5.2 Pharmacokinetic properties

Absorption Lamotrigine is rapidly and completely absorbed from the gut with no significant first pass metabolism. Peak plasma concentration occur approximately 2-3 hours after oral administration. High interindividual variability in peak plasma concentration at steady state prevails. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. The pharmacokinetics are linear up to 450 mg, the highest single dose tested.

Distribution 55% of lamotrigine is bound to plasma proteins. It is very unlikely that displacement from plasma protein would result in toxicity. The volume of distribution is approximately 0.9-1.2 L/kg.

Metabolism Lamotrigine induces its own metabolism to a modest extent depending on the dose. This leads to a 25 % decrease in half-life at steady state when 150 mg is administered twice daily. However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs and data suggest that interactions between lamotrigine and active substances metabolised by cytochrome P450 enzymes are unlikely. UDP- glucuronyltransferases are responsible for the metabolism of lamotrigine. The main metabolite found in the urine is 2-N glucuronide which corresponds to 65 % of the dose.

Elimination The clearance and half-life are independent of the dosage. The mean elimination half-life in healthy adults is 24 to 35 hours. Mean steady- state clearance in healthy volunteers is 39(14 mL/min. Clearance occurs predominantly by metabolism, followed by elimination of glucuronated metabolites in the urine. Less than 10% is eliminated unchanged in the urine, while approximately 2% is excreted in the faeces. In a study in subjects with Gilbert’s syndrome (glucuronyltransferase deficiency), the mean apparent clearance was reduced by 32% compared with the control group, but the values are within the normal range for the general population. The half-life of lamotrigine is considerably affected by concomitant treatment. Mean half-life is reduced to approximately 14 hours when given with enzyme-inducing active substances such as carbamazepine or phenytoin and is increased to a mean of approximately 70 hours when co-administered with valproate alone (see section 4.2).

Special patients groups

Children Clearance adjusted for body weight is higher in children than in adults with the highest values in children under five 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 active substances such as carbamazepine and phenytoin and increasing to mean values of 45-50 hours when co-administered with valproate alone (see section 4.2).

Elderly Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of lamotrigine did not change to a clinically relevant extent. After single doses apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, pharmacokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/min/kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/min/kg) obtained in 9 studies with non-elderly adults after single doses of 30 to 450  mg.

Impaired renal function There is no experience of treatment with lamotrigine of patients with renal failure. Pharmacokinetic studies using single doses in subjects with renal failure indicate that the pharmacokinetics of lamotrigine are little affected, but that the plasma concentrations of the major glucuronide metabolite increased almost 8-fold due to reduced renal clearance.

Impaired hepatic function A single dose pharmacokinetic study was performed in 24 patients with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamotrigine was 0.31, 0.24 and 0.10 mL/min in patients with grade A, B and C (Child Pugh classification) hepatic impairment, respectively, compared to 0.34 mL/min in the healthy controls. Half-life: 36, 60, or 110 hours versus 32 hours in controls. Reduced doses should generally be used in patients with grade B and C hepatic impairment (see section 4.2).

5.3 Preclinical safety data

Lamotrigine in dosages above the highest therapeutic maintenance dose does not induce teratogenicity in rats, mice and rabbits. Doses eliciting maternal toxicity reduced foetal weight and retarded skeletal ossification in rats and mice. In rats an enhanced foetal as well as postnatal mortality was observed when lamotrigine was administered later during gestation (day 15-20). Animal experiments did not reveal impairment of fertility by lamotrigine. There is no experiences regarding the effect of lamotrigine on human fertility. Lamotrigine reduced foetal folic acid levels in rats. Folic acid deficiency is assumed to be associated with an enhanced risk of congenital malformations in animals as well as in humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Crospovidone, acesulfame potassium (E 950), orange flavour, mannitol (E 421), anhydrous colloidal silica, sodium stearyl fumarate.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

10, 14, 21, 28, 30, 42, 50, 56, 90, 100 and 200 tablets in an AL/AL blister or AL/PVC/Aclar blister. Not all pack sizes may be marketed.

6.6 Instructions for use and handling No special requirements

7. MARKETING AUTHORISATION HOLDER

STADA Arzneimittel AG Stadastrasse 2-18 D-61118 Bad Vilbel Germany

8. MARKETING AUTHORISATION NUMBER

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT