Information för alternativet: Lamotrigin Bmm Pharma 50 Mg Tablett, Lamotrigin Bmm Pharma 25 Mg Tablett, Lamotrigin Bmm Pharma 100 Mg Tablett, Lamotrigin Bmm Pharma 200 Mg Tablett, visa andra alternativ

Välj alternativ:

1. Lamotrigin Bmm Pharma 50 Mg Tablett Lamotrigin Bmm Pharma 25 Mg Tablett Lamotrigin Bmm Pharma 100 Mg Tablett Lamotrigin Bmm Pharma 200 Mg Tablett
2. Lamotrigin Bmm Pharma 50 Mg Tablett Lamotrigin Bmm Pharma 200 Mg Tablett Lamotrigin Bmm Pharma 100 Mg Tablett

Document: Lamotrigin BMM Pharma tablet ENG SmPC change

• Lamotrigin BMM Pharma tablet SmPC
• Lamotrigin BMM Pharma tablet ENG SmPC

---

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Lamotrigin BMM Pharma 25 mg tablet

Lamotrigin BMM Pharma 50 mg tablet

Lamotrigin BMM Pharma 100 mg tablet

Lamotrigin BMM Pharma 200 mg tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet Lamotrigin BMM Pharma 25 mg contains 25 mg lamotrigine.

Each tablet Lamotrigin BMM Pharma 50 mg contains 50 mg lamotrigine.

Each tablet Lamotrigin BMM Pharma 100 mg contains 100 mg lamotrigine.

Each tablet Lamotrigin BMM Pharma 200 mg contains 200 mg lamotrigine.

Excipients with known effect: Lactose monohydrate

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Tablet.

Lamotrigin BMM Pharma 25 mg tablets are yellow, round tablets marked “25” on one side and with a score line on the other. Size: 6 mm.

Lamotrigin BMM Pharma 50 mg tablets are yellow, round tablets marked “50” on one side and with a score line on the other. Size: 8 mm.

Lamotrigin BMM Pharma 100 mg tablets are yellow, round tablets marked “100” on one side and with a score line on the other. Size: 10 mm.

Lamotrigin BMM Pharma 200 mg tablets are yellow, capsule shaped, biconvex tablets marked “200” on one side. Size: 8x18 mm.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars

4.1 Therapeutic indications

Adults and adolescents:

As monotherapy in epilepsy:

• partial seizures

• generalised seizures

  • primary seizures

  • secondary tonic-clonic seizures

Adults and adolescents:

As add-on therapy in epilepsy:

• partial seizures

• generalised seizures

• primary seizures

• secondary tonic-clonic seizures

  seizures associated with Lennox-Gastaut Syndrome

Bipolar disorder

From 18 years: Prevention of depressive episodes in bipolar disorder.

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

Epilepsy

If a calculated dose of lamotrigine (e.g. for patients with hepatic impairment) is not equal to whole tablets, the dose to be administered should be that of the lower number of whole 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 with 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 Lamotrigin BMM Pharma for treatment of epilepsy in adults and adolescents (total daily dose in mg/day)

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

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.

Dosage in bipolar disorder

To reduce the risk of skin reactions, the following recommended initial doses and subsequent escalations should not be exceeded (see section 4.4).

Table 2

Monotherapy or combination therapy with Lamotrigin BMM Pharma in bipolar disorder in adults from 18 years.

Recommended initial dose, dose escalation and maintenance dose of Lamotrigin BMM Pharma
Treatment	Week 1 – 2	Week 3 - 4	Week 5	Maintenance dose (from week 6)
Monotherapy or in combination with lithium (or other medicinal product without pharmacokinetic interaction with lamotrigine)	25 mg (once daily)	50 mg (once daily or in 2 divided doses)	100 mg (once daily or in 2 divided doses)	Usually 200 mg (once daily or in 2 divided doses). Dose interval: 100-400 mg/day
Combination with valproate	25 mg every other day	25 mg (once daily)	50 mg (once daily or in 2 divided doses)	100 mg (once daily or in 2 divided doses) Maximum daily dose: 200 mg
Combination with enzyme inducing drug, e.g. carbamazepine or phenobarbital, in patients not using valproate	50 mg (once daily)	100 mg daily in 2 divided doses	200 mg daily in 2 divided doses	300 mg/day during week 6. May be increased to 400 mg/day during week 7 (in 2 divided doses) when required
NB: Patients receiving concomitant treatment with antiepileptics/psychotropics whose pharmacokinetic interaction with lamotrigine is currently unknown should follow the dose escalations applying to the concomitant valproate treatment.

When the maintenance dose of Lamotrigin BMM Pharma has been reached, other treatment, if clinically indicated, may be successively withdrawn. The following table may subsequently be used for dose adjustment of lamotrigine.

Table 3

Dose adjustment of Lamotrigin BMM Pharma after withdrawal of other treatment for bipolar disorder in adults from 18 years.

Recommended dose of Lamotrigin BMM Pharma after withdrawal of other treatment
Treatment withdrawn	Week 1 after withdrawal	Week 2	Week 3 and following weeks
Lithium or other medicinal product with no pharmacokinetic interaction with lamotrigine	Remain on current maintenance dose (100-400 mg/day).
Valproate	Double daily dose to no more than 200 mg/day.	Remain on current maintenance dose or increase daily dose successively by no more than 100 mg each week. Dose interval: 100-400 mg/day.
Enzyme inducing drug, e.g. carbamazepine	Remain on 400 mg/day*	300 mg/ day	200 mg/ day
	Remain on 300 mg/day*	225 mg/ day	150 mg/ day
	Remain on 200 mg/ day*	150 mg/ day	100 mg/ day
NB: After withdrawal of antiepileptics/psychotropics whose pharmacokinetic interaction with lamotrigine is currently unknown, the dose should be adjusted according to the recommendations for withdrawal of valproate.
* Depending on current maintenance dose.

When it is necessary to supplement the maintenance of Lamotrigin BMM Pharma with another treatment in bipolar disorder, the Lamotrigin BMM Pharma dose should be adjusted according to the following table.

Table 4

Dose adjustment of Lamotrigin BMM Pharma on addition of another drug in bipolar disorder in adults from 18 years.

Recommended dose of Lamotrigin BMM Pharma
Supplementary treatment	Current maintenance dose of lamotrigine	Week 1	Week 2	Week 3 and following weeks
Lithium or other drug with no pharmacokinetic interaction with lamotrigine	Adhere to current maintenance dose (100-400 mg/day).
Valproate	100-200 mg/day	100 mg/ day	Remain on 100 mg/ day
	300 mg/ day	150 mg/ day	Remain on 150 mg/ day
	400 mg/ day	200 mg/ day	Remain on 200 mg/ day
Enzyme inducing drug, e.g. carbamazepine in patients not concomitantly using valproate.	100 mg/ day	100 mg/ day	150 mg/ day	200 mg/ day
	150 mg/ day	150 mg/ day	225 mg/ day	300 mg/ day
	200 mg/ day	200 mg/ day	300 mg/ day	400 mg/ day
NB: On addition of antiepileptics/psychotropics whose pharmacokinetic interaction with lamotrigine is currently unknown, the dose should be adjusted according to the recommendations applying to addition of valproate.

Withdrawal of Lamotrigin BMM Pharma in bipolar disorder

There was no increase in incidence, degree of severity or undesirable effects after abrupt withdrawal of lamotrigine in clinical studies. Patients with bipolar disorder may therefore discontinue treatment without gradual dose reduction.

Special patient groups

Children below 12 years of age

This medicinal product is not recommended for children in this age group, because the product is not available in the appropriate strengths.

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 sections 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

Lamotrigin BMM Pharma tablets should be swallowed with water.

For doses not realisable/practicable with this strength since the tablets can not be divided into equal doses, other strengths of Lamotrigine BMM Pharma are available.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported.

These have included potentially life-threatening rashes such as Stevens Johnson syndrome toxic epidermal necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section 4.8).

In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients. Approximately half of these cases have been reported as Stevens–Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.

The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is 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 reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight 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).

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. 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. If the patient has developed SJS, TEN or DRESS with the use of lamotrigine, treatment with lamotrigine must not be re-started in this patient at any time.

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.

Caution is also needed when treating patients with a history of allergy or skin rash to other antiepileptic drugs since the incidence of non-serious skin rash during treatment with lamotrigine was about three times higher among such patients as compared to patients without such history.

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 oral contraceptives

An ethinyloestradiol/levonorgestrel (30 mcg /150 mcg) combination has been shown to decrease lamotrigine levels by increasing the clearance significantly (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. Therefore 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).

Patients taking other preparations containing lamotrigine

Lamotrigin BMM Pharma should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.

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.

Bipolar disorder

Suicidal ideation is a part of the clinical picture of bipolar disorder and patients who are thought to be at increased risk of suicide should therefore be carefully supervised during treatment.

Lactose intolerance

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lamotrigine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

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 overall clearance of the levonorgestrel component was observed. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women. The impact of the modest increase in levonorgestrel clearance, and the change 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). Half-life of lamotrigine is shortened to approximately 14 hours, in children below 12 years: approximately 7 hours.

Valproate reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly 2 fold (see sections 4.2 and 4.4). Half-life of lamotrigine is extented to approx. 70 hours, in children below 12 years: 45-55 hours.

Active substances that significantly inhibit glucuronidation of lamotrigine	Active substances that significantly induce glucuronidation of lamotrigine	Active substances that do not significantly inhibit or induce glucuronidation of lamotrigine
Valproate	Carbamazepine	Lithium
	Phenytoin	Bupropion
	Primidone	Olanzapine****
	Phenobarbital	Oxcarbazepine**
	Rifampicin***
	Ethinyloestradiol/Levonorgestrel 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 C_max 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 C_max. 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.

**** In a study in healthy adult volunteers, 15 mg olanzapine reduced the AUC and C_max of lamotrigine by an average of 24% and 20%, respectively. The clinical relevance for the individual patient is not known. In general the dose recommendations applying to monotherapy should be followed.

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 C_max, 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 only caused 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, there were no 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 Fertility, pregnancy and lactation

Pregnancy

Risk related to antiepileptic drugs in general

Specialist advice should be given to women who are of childbearing potential. The need for antiepileptic treatment should be reviewed when a women is planning to become pregnant. Sudden discontinuation of antiepileptic therapy should be avoided as this may lead to breakthrough seizures which could have serious consequences for the woman and the unborn child.

The risk of congenital malformations is increased by a factor of 2 to 3 in the offspring of mothers treated with antiepileptics compared with the expected incidence in the general population of approximately 3%. The most frequently reported defects are cleft lip, cardiovascular malformations and neural tube defects.

Multiple antiepileptic drug therapy is associated with a higher risk of congenital malformations than monotherapy and therefore monotherapy should be used whenever possible.

Risk related to lamotrigine

Epidemiological studies involving in total approximately 2000 women exposed to lamotrigine monotherapy during pregnancy cannot exclude an increased risk for congenital malformations. One registry has reported an increase incidence of facial clefts. Other data sets have not confirmed this finding. Animal studies have shown developmental toxicity (see section 5.3).

If therapy with lamotrigine is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.

Lamotrigine has 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 plasma levels during pregnancy. Appropriate clinical management of pregnant women during lamotrigine therapy should be ensured.

Breast-feeding

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.

The undesirable effects are divided according to currently available data for epilepsy and bipolar disorder. For a complete overview of undesirable effects, however, both conditions should be taken into consideration.

The undesirable effects are listed by frequency using the following classification: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10 000, <1/1000), very rare (<1/10 000)and not known (cannot be estimated from the available data)

Epilepsy

Undesirable effects are mainly CNS related and have been observed in 4-18% of patients.

Blood and lymphatic system disorders:

Very rare:

Haematological abnormalities such as neutropenia, leukopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia and agranulocytosis.

Immune system disorders:

Very rare:

Hypersensitivity syndrome (including symptoms such as fever, lymphadenopathy, facial oedema, angio-oedema, blood and hepatic reactions, see also section 4.4).

Psychiatric disorders:

Common:	Irritability.
Uncommon:	Aggression.
Very rare:	Tics, hallucinations, confusion.

Nervous system disorders:

Very common:	Headache, dizziness.
Common:	Ataxia, tremor, nystagmus, insomnia, drowsiness.
Very rare:	Agitation, unsteadiness, motor disorders, worsening of Parkinson’s disease, extrapyramidal effects, choreoathetosis, increased seizure frequency.
Not known	Aseptic meningitis

Eye disorders:

Very common:	Double vision, blurred vision.
Rare:	Conjunctivitis.

Gastrointestinal disorders:

Common:

Nausea, vomiting, diarrhoea.

Hepatobiliary disorders:

Very rare:

Increased liver enzyme values, hepatic dysfunction including hepatic failure.

Skin and subcutaneous tissue disorders

Very common: Rare:	Skin rash. Stevens–Johnson Syndrome
Very rare: Not known:	Toxic epidermal necrolysis DRESS

(If robust frequency data are available for a particular drug, the frequency may be assigned based

on these data).

Musculoskeletal and connective tissue disorders:

Very rare:

Lupus-like reactions.

General disorders:

Common:

Asthenia.

Exanthema has been reported in 10% of patients using supplementary lamotrigine compared to 5% using placebo. In 2% of patients this has necessitated discontinuation of lamotrigine treatment. Skin rash, usually maculopapular, occurs most frequently within 8 weeks of treatment start and is usually reversible on withdrawal of lamotrigine (see section 4.4).

In rare cases potentially fatal skin rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported.

Skin reactions have 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 ).

Hepatic dysfunction usually occurs in association with hypersensitivity reactions but rare cases have been reported in which hepatic effects have occurred with no clear signs of hypersensitivity syndrome.

There have been reports of worsening of Parkinson symptoms during lamotrigine treatment in patients with Parkinson's disease, and rare reports of extrapyramidal reactions and choreoathetosis in patients with no underlying condition.

The haematological abnormalities in the table above occurred both in association with and independently of the hypersensitivity syndrome.

CNS effects in the form of dizziness, ataxia, double vision, blurred vision and nausea occur more frequently in carbamazepine treated patients who receive lamotrigine as supplementary medication. These reactions usually resolve after reduction of the carbamazepine dose.

Bipolar disorder

For a complete picture of the pattern of undesirable effects, those described in the epilepsy section should also be taken into consideration.

Nervous system disorders:

Very common:	Headache.
Common:	Agitation, drowsiness, dizziness.
Not known	Aseptic meningitis

Skin and subcutaneous tissue disorders:

Very common:	Rash, usually maculopapular.
Rare:	Stevens-Johnson syndrome.
Very rare: Not known:	Toxic epidermal necrolysis DRESS

Musculoskeletal and connective tissue disorders:

Common:

Arthralgia.

General disorders:

Common:

Pain, backache.

In a compilation of all studies of bipolar disorder (controlled and uncontrolled), rash was reported in 14% of patients treated with lamotrigine. In the controlled clinical studies of bipolar disorder, rash was reported in 9% of patients receiving lamotrigine compared to 8% of patients receiving placebo.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures

in patients on long-term therapy with lamotrigine. The mechanism by which lamotrigine affects

bone metabolism has not been identified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

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.

Effect in bipolar disorder

In clinical studies in which lamotrigine was evaluated as long-term prophylaxis, the time to a new episode requiring treatment was significantly longer in patients receiving lamotrigine than in patients receiving placebo. Analysis of the secondary efficacy parameters showed time to occurrence of a new depressive episode requiring treatment to be significantly longer in patients receiving lamotrigine compared to placebo. Statistically, however, time to new manic/hypomanic or mixed episodes (mania/depression) requiring treatment was not significantly longer in patients treated with lamotrigine compared to placebo. Treatment of depressive episodes with antidepressants in bipolar disorder is thought to carry an increased risk of provoking mania/hypomania. There is no evidence that treatment with lamotrigine, compared with placebo, carries any increased risk of induction of mania, hypomania or mixed episodes. In a study of "rapid cycling" patients with bipolar disorder types I and II, the time to a new depressive episode requiring treatment was significantly longer in patients treated with lamotrigine compared to placebo and the number of patients needing treatment for depressive episodes was significantly less in the lamotrigine group than in the placebo group. Approximately 30% of the patients in the pivotal prophylactic studies were "rapid cyclers" (4-6 episodes/year).

The incidence of suicide or suicidal attempts was very low in the studies. There is no evidence of any difference in incidence between lamotrigine and placebo even though the studies were not dimensioned to discern such differences (see section 4.4). The effect of lamotrigine in unipolar depression could not be demonstrated in three placebo-controlled studies.

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

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

In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but reduced foetal weight and retarded skeletal ossification were observed, at exposure levels below or similar to the expected clinical exposure. Since higher exposure levels could not be tested in animal due to maternal toxicity, the teratogenic potential of lamotrigine has not been characterised above clinical exposure.

In rats, enhanced foetal as well as postnatal mortality was observed when lamotrigine was administered later during gestation (day 15-20). These effects were observed at the expected clinical exposure.

Animal experiments did not reveal impairment of fertility by lamotrigine. Lamotrigine reduced foetal folic acid levels in rats. Folic acid deficiency is assumed to be associated with an enhanced risk of congenital malformations in animal as well as in humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycollate

Yellow iron oxide (E 172)

Magnesium stearate

Maize starch

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Blisters (Al/PVC)

Lamotrigin BMM Pharma 25 mg, 50 mg, 100 mg and 200 mg: 10, 21, 28, 30, 42, 50, 56, 60, 98, 100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

BMM Pharma AB

Blasieholmsgatan 2

SE-111 48 Stockholm

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2006-05-05

10. DATE OF REVISION OF THE TEXT

2015-10-15