Lamictal Combined Tablets

1. Name Of The Medicinal Product

Lamictal

Lamictal

Lamictal

Lamictal

Lamictal

Lamictal

Lamictal

Lamictal

2. Qualitative And Quantitative Composition

Each Lamictal 25 mg tablet contains 25 mg lamotrigine.

Excipient: Each tablet contains 23.5 mg lactose.

Each Lamictal 50 mg tablet contains 50 mg lamotrigine.

Excipient: Each tablet contains 46.9 mg lactose.

Each Lamictal 100 mg tablet contains 100 mg lamotrigine.

Excipient: Each tablet contains 93.9 mg lactose.

Each Lamictal 200 mg tablet contains 200 mg lamotrigine.

Excipient: Each tablet contains 109.0 mg lactose.

Each Lamictal 2 mg dispersible/chewable tablet contains 2 mg lamotrigine.

Each Lamictal 5 mg dispersible/chewable tablet contains 5 mg lamotrigine.

Each Lamictal 25 mg dispersible/chewable tablet contains 25 mg lamotrigine.

Each Lamictal 100 mg dispersible/chewable tablet contains 100 mg lamotrigine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

Dispersible/chewable tablet.

25 mg tablets:

Pale, yellowish brown, multifaceted, super elliptical tablet, marked “GSEC7” on one side and “25” on the other.

50 mg tablets:

Pale, yellowish brown, multifaceted, super elliptical tablet, marked “GSEE1” on one side and “50” on the other.

100 mg tablets:

Pale, yellowish brown, multifaceted, super elliptical tablet, marked “GSEE5” on one side and “100” on the other.

200 mg tablets:

Pale, yellowish brown, multifaceted, super elliptical tablet, marked “GSEE7” on one side and “200” on the other.

2 mg dispersible/chewable tablets:

White to off white round tablet with a blackcurrant odour. One side has a bevelled edge and is marked “LTG” above the number 2. The other side is marked with two overlapping super ellipses at right angles. The tablets may be slightly mottled.

5 mg dispersible/chewable tablets:

White to off white, elongated, biconvex tablet with a blackcurrant odour, marked “GS CL2” on one side and “5” on the other. The tablets may be slightly mottled.

25 mg dispersible/chewable tablets:

White to off white multi faceted, super elliptical, tablet with a blackcurrant odour, marked “GSCL5” on one side “25” on the other. The tablets may be slightly mottled.

100 mg dispersible/chewable tablets:

White to off white multi faceted, super elliptical, tablet with a blackcurrant odour, marked “GSCL7” on one side and “100” on the other. The tablets may be slightly mottled.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Adults and adolescents aged 13 years and above

- Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic-clonic seizures.

- Seizures associated with Lennox-Gastaut syndrome. Lamictal is given as adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome.

Children and adolescents aged 2 to 12 years

- Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.

- Monotherapy of typical absence seizures.

Bipolar disorder

Adults aged 18 years and above

- Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).

Lamictal is not indicated for the acute treatment of manic or depressive episodes.

4.2 Posology And Method Of Administration

Lamictal tablets should be swallowed whole, and should not be chewed or crushed.

Lamictal dispersible/chewable tablets may be chewed, dispersed in a small volume of water (at least enough to cover the whole tablet) or swallowed whole with a little water.

If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamictal in patients who have discontinued Lamictal for any reason, 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), Lamictal should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamictal 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.

Epilepsy

The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5).

Table 1: Adults and adolescents aged 13 years and above – recommended treatment regimen in epilepsy

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy:	25 mg/day (once a day)	50 mg/day (once a day)	100 − 200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100 mg every one to two weeks until optimal response is achieved 500 mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	100 − 200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 25 - 50 mg every one to two weeks until optimal response is achieved
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200 − 400 mg/day (two divided doses) To achieve maintenance, doses may be increased by maximum of 100 mg every one to two weeks until optimal response is achieved 700 mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25 mg/day (once a day)	50 mg/day (once a day)	100 − 200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100 mg every one to two weeks until optimal response is achieved
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy of typical absence seizures:	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1 – 10 mg/kg/day, although some patients have required higher doses (up to 15 mg/kg/day) to achieve desired response (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6 mg/kg/day every one to two weeks until optimal response is achieved
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any other concomitant medicinal products	0.15 mg/kg/day* (once a day)	0.3 mg/kg/day (once a day)	1 − 5 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.3 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200 mg/day
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	0.6 mg/kg/day (two divided doses)	1.2 mg/kg/day (two divided doses)	5 − 15 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400 mg/day
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1 − 10 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6 mg/kg every one to two weeks until optimal response is achieved, with a maximum of maintenance dose of 200 mg/day
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.
* If the calculated daily dose in patients taking valproate is 1 mg or more but less than 2 mg, then Lamictal 2 mg dispersible/chewable tablets may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 1 mg, then Lamictal should not be administered.

To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.

If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lamictal monotherapy.

Children below 2 years

There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Thus Lamictal is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken, see sections 4.4, 5.1 and 5.2.

Bipolar disorder

The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables below. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided below (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

Table 3: Adults aged 18 years and above - recommended dose escalation to the maintenance total daily stabilisation dose in treatment of bipolar disorder

Treatment Regimen	Weeks 1 + 2	Weeks 3 + 4	Week 5	Target Stabilisation Dose (Week 6)*
Monotherapy with lamotrigine OR adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day (once a day or two divided doses)	200 mg/day - usual target dose for optimal response (once a day or two divided doses) Doses in the range 100 - 400 mg/day used in clinical trials
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation – see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day - usual target dose for optimal response (once a day or two divided doses) Maximum dose of 200 mg/day can be used depending on clinical response
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200 mg/day (two divided doses)	300 mg/day in week 6, if necessary increasing to usual target dose of 400 mg/day in week 7, to achieve optimal response (two divided doses)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the dose escalation as recommended for lamotrigine with concurrent valproate, should be used.

* The Target stabilisation dose will alter depending on clinical response

Table 4: Adults aged 18 years and above - maintenance stabilisation total daily dose following withdrawal of concomitant medicinal products in treatment of bipolar disorder

Once the target daily maintenance stabilisation dose has been achieved, other medicinal products may be withdrawn as shown below.

Treatment Regimen	Current lamotrigine stabilisation dose (prior to withdrawal)	Week 1 (beginning with withdrawal)	Week 2	Week 3 onwards *
Withdrawal of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
When valproate is withdrawn, double the stabilisation dose, not exceeding an increase of more than 100 mg/week	100 mg/day	200 mg/day	Maintain this dose (200 mg/day) (two divided doses)
200 mg/day	300 mg/day	400 mg/day	Maintain this dose (400 mg/day)
Withdrawal of inducers of lamotrigine glucuronidation (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are withdrawn: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	400 mg/day	400 mg/day	300 mg/day	200 mg/day
300 mg/day	300 mg/day	225 mg/day	150 mg/day
200 mg/day	200 mg/day	150 mg/day	100 mg/day
Withdrawal of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn	Maintain target dose achieved in dose escalation (200 mg/day; two divided doses) (dose range 100 - 400 mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen recommended for lamotrigine is to initially maintain the current dose and adjust the lamotrigine treatment based on clinical response .

* Dose may be increased to 400 mg/day as needed

Table 5: Adults aged 18 years and above - adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder

There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:

Treatment Regimen	Current lamotrigine stabilisation dose (prior to addition)	Week 1 (beginning with addition)	Week 2	Week 3 onwards
Addition of valproate (inhibitor of lamotrigine glucuronidation – see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when valproate is added regardless of any concomitant medicinal products	200 mg/day	100 mg/day	Maintain this dose (100 mg/day)
300 mg/day	150 mg/day	Maintain this dose (150 mg/day)
400 mg/day	200 mg/day	Maintain this dose (200 mg/day)
Addition of inducers of lamotrigine glucuronidation in patients NOT taking valproate (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are added without valproate: phenytoin carbamazepine phenobarbitone primidone rifampicin lopinavir/ritonavir	200 mg/day	200 mg/day	300 mg/day	400 mg/day
150 mg/day	150 mg/day	225 mg/day	300 mg/day
100 mg/day	100 mg/day	150 mg/day	200 mg/day
Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are added	Maintain target dose achieved in dose escalation (200 mg/day; dose range 100-400 mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate, should be used.

Discontinuation of Lamictal in patients with bipolar disorder

In clinical trials, there was no increase in the incidence, severity or type of adverse reactions following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate Lamictal without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamictal is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).

General dosing recommendations for Lamictal in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold (see sections 4.4 and 4.5). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100 mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases. Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine by 50-100 mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.

Starting lamotrigine in patients already taking hormonal contraceptives

Dose escalation should follow the normal dose recommendation described in the tables.

Starting and stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation

Adjustment to the recommended maintenance dose of lamotrigine may not be required.

Use with atazanavir/ritonavir

No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing atazanavir/ritonavir therapy.

In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping atazanavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Use with lopinavir/ritonavir

No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing lopinavir/ritonavir therapy.

In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Elderly (above 65 years)

No dosage adjustment from the recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non-elderly adult population (see section 5.2).

Renal impairment

Caution should be exercised when administering Lamictal 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).

Hepatic impairment

Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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 and toxic epidermal necrolysis (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 section 4.2).

Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

All patients (adults and children) who develop a rash should be promptly evaluated and Lamictal withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. It is recommended that Lamictal 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.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis (see section 4.8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example 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 Lamictal discontinued if an alternative aetiology cannot be established.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

Clinical worsening and suicide risk

Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs 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.

In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including Lamictal. Therefore patients receiving Lamictal for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Hormonal contraceptives

Effects of hormonal contraceptives on lamotrigine efficacy

The use of an ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss