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Drug Details

Lamictal

• Drug Class Description
  other antiepileptics - ATC code: N03AX09
• Generic Name
  Lamotrigine
• Presentation
  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.
• Description
  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.
• 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.

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

• Adult Dosage
  

  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. 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, 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.

  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.

  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) :
  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 :
  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 :
  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, 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) :
  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 :
  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 :
  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, 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. 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.

  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.

  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 :
  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):
  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 :
  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, 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), 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, 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:
  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, 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), 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, 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.

  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.

  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. 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.

  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%. 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.

  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.

  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.

  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.

  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.

• Child Dosage
  Add-on therapy with enzyme inducers (not with valproate), under 2 years, not recommended; 2 - 12 years, initially 0.6mg/kg daily in two divided doses for 2 weeks, then 1.2mg/kg daily in two divided doses for 2 weeks. Then increase by maximum 1.2mg/kg increments every 1 - 2 weeks until optimal response. Usually 5-15mg/kg daily (given in two divided doses). Add-on therapy (with valproate), under 2 years, not recommended; 2 - 12 years, initially 0.15mg/kg once daily for 2 weeks, then 0.3mg/kg once daily for 2 weeks. Then increase by maximum 0 .3mg/kg increments every 1 - 2 weeks until optimal response. Usually, 1- 5mg/kg daily (given as a single dose or in two divided doses).
• Contra Indications
  

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

• Special Precautions
  

  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.

  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

  - concomitant use of valproate.

  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. 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. A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events. Patients should be monitored with respect to this.

  In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment. Variations in lamotrigine levels of this order may be associated with adverse effects. 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).

  The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.

  Effects of lamotrigine on hormonal contraceptive efficacy

  An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH. The impact of these changes on ovarian ovulatory activity is unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

  Dihydrofolate reductase

  Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.

  Renal failure

  In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.

  Patients taking other preparations containing lamotrigine

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

  25 , 50, 100 and 200 mg tablets:

  Excipient of Lamictal tablets

  Lamictal tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

  Development in children

  There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.

  Precautions relating to epilepsy

  As with other AEDs, abrupt withdrawal of Lamictal may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of Lamictal should be gradually decreased over a period of two weeks.

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

  A clinically significant worsening of seizure frequency instead of an improvement may be observed. In patients with more than one seizure type, the observed benefit of control for one seizure type should be weighed against any observed worsening in another seizure type.

  Myoclonic seizures may be worsened by lamotrigine.

  There is a suggestion in the data that responses in combination with enzyme inducers is less than in combination with non-enzyme inducing antiepileptic agents. The reason is unclear.

  In children taking lamotrigine for the treament of typical absence seizures, efficacy may not be maintained in all patients.

  Precautions relating to bipolar disorder

  Children and adolescents below 18 years

  Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.

• Interactions
  

  Interaction studies have only been performed in adults.

  UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug-metabolising enzymes, and interactions between lamotrigine and medicinal products metabolised by cytochrome P450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.

  Table 6: Effects of other medicinal products on glucuronidation of lamotrigine

  Medicinal products that significantly inhibit glucuronidation of lamotrigine	Medicinal products that significantly induce glucuronidation of lamotrigine	Medicinal products that do not significantly inhibit or induce glucuronidation of lamotrigine
  Valproate	Phenytoin	Oxcarbazepine
  	Carbamazepine	Felbamate
  	Phenobarbitone	Gabapentin
  	Primidone	Levetiracetam
  	Rifampicin	Pregabalin
  	Lopinavir/ritonavir	Topiramate
  	Ethinyloestradiol/ levonorgestrel combination**	Zonisamide
  	Atazanavir/ritonavir*	Lithium
  		Buproprion
  		Olanzapine
  		Aripiprazole

  *For dosing guidance

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

  Interactions involving antiepileptic drugs

  Valproate, which inhibits the glucuronidation of lamotrigine, reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly two-fold. In patients receiving concomitant therapy with valproate, the appropriate treatment regimen should be used.

  Certain AEDs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug-metabolising enzymes induce the glucuronidation of lamotrigine and enhance the metabolism of lamotrigine. In patients receiving concomitant therapy with phenytoin, carbamazepine, pheonbarbitone or primidone, the appropriate treatment regimen should be used.

  There have been reports of central nervous system events including dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine following the introduction of lamotrigine. These events usually resolve when the dose of carbamazepine is reduced. A similar effect was seen during a study of lamotrigine and oxcarbazepine in healthy adult volunteers, but dose reduction was not investigated.

  There are reports in the literature of decreased lamotrigine levels when lamotrigine was given in combination with oxcarbazepine. However, in a prospective study in healthy adult volunteers using doses of 200 mg lamotrigine and 1200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine. Therefore in patients receiving concomitant therapy with oxcarbazepine, the treatment regimen for lamotrigine adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation should be used.

  In a study of healthy volunteers, coadministration of felbamate (1200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

  Based on a retrospective analysis of plasma levels in patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

  Potential interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.

  Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg, 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.

  Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

  In a study of patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.

  Although changes in the plasma concentrations of other AEDs have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant AEDs. Evidence from in vitro studies indicates that lamotrigine does not displace other AEDs from protein binding sites.

  Interactions involving other psychoactive agents

  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 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. An effect of this magnitude is not generally expected to be clinically relevant. Lamotrigine at 200 mg did not affect the pharmacokinetics of olanzapine.

  Multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with lamotrigine, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.

  In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (100-400 mg/day), doses of aripiprazole were increased from 10 mg/day to a target of 30 mg/day over a 7 day period and continued once daily for a further 7 days. An average reduction of approximately 10% in C_max and AUC of lamotrigine was observed. An effect of this magnitude is not expected to be of clinical consequence.

  In vitro experiments indicated that the formation of lamotrigine's primary metabolite, the 2-N-glucuronide, was minimally inhibited by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol or lorazepam. These experiments also suggested that metabolism of lamotrigine was unlikely to be inhibited by clozapine, fluoxetine, phenelzine, risperidone, sertraline or trazodone. In addition, a study of bufuralol metabolism using human liver microsome preparations suggested that lamotrigine would not reduce the clearance of medicinal products metabolised predominantly by CYP2D6.

  Interactions involving hormonal contraceptives

  Effect of hormonal contraceptives on lamotrigine pharmacokinetics

  In a study of 16 female volunteers, dosing with 30 μg ethinyloestradiol/150 μg levonorgestrel in a combined oral contraceptive pill caused an approximately two-fold increase in lamotrigine oral clearance, resulting in an average 52% and 39% reduction in lamotrigine AUC and Cmax, respectively. Serum lamotrigine concentrations increased during the course of the week of inactive treatment (including the "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. No adjustments to the recommended dose escalation guidelines for lamotrigine should be necessary solely based on the use of hormonal contraceptives, but the maintenance dose of lamotrigine will need to be increased or decreased in most cases when starting or stopping hormonal contraceptives.

  Effect of lamotrigine on hormonal contraceptive pharmacokinetics

  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. 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.

  Interactions involving other medicinal products

  In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine half-life due to induction of the hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the appropriate treatment regimen should be used.

  In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine, probably by induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the appropriate treatment regimen should be used.

  In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) administered for 9 days reduced the plasma AUC and Cmax of lamotrigine (single 100 mg dose) by an average of 32% and 6%, respectively. In patients receiving concomitant therapy with atazanavir/ritonavir, the appropriate treatment regimen should be used.

  Data from in vitro assessment demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT 2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is a more potent in vitro inhibitor of OCT 2 than cimetidine, with IC₅₀ values of 53.8 µM and 186 µM, respectively. Co-administration of lamotrigine with renally excreted medicinal products which are substrates of OCT2 (e.g. metformin, gabapentin and varenicline) may result in increased plasma levels of these drugs.

  The clinical significance of this has not been clearly defined, however care should be taken in patients co-administered with these medicinal products.

• Adverse Drug Reactions
  

  The undesirable effects have been divided into epilepsy and bipolar specific sections based on the data currently available. However, both sections should be consulted when considering the overall safety profile of lamotrigine.

  Adverse reactions identified from monotherapy clinical trials (identified by a dagger ^†) and during other clinical experience are listed in the table below by their incidence in clinical trials.

  The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).

  Epilepsy

  System Organ Class	Adverse Event	Frequency
  Blood and lymphatic system disorders	Haematological abnormalities1 including neutropenia, leucopenia, anaemia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis Lymphadenopathy1	Very rare Not known
  Immune System Disorders	Hypersensitivity syndrome2 (including such symptoms as, fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver, disseminated intravascular coagulation, multi organ failure).	Very Rare
  Psychiatric Disorders	Aggression, irritability Confusion, hallucinations, tics	Common Very rare
  Nervous System Disorders	Headache† Somnolence†, dizziness†, tremor†, insomnia† Ataxia† Nystagmus† Agitation, unsteadiness, movement disorders, worsening of Parkinson's disease 3, extrapyramidal effects, choreoathetosis†, increase in seizure frequency Aseptic meningitis	Very Common Common Uncommon Rare Very Rare Not known
  Eye disorders	Diplopia†, blurred vision† Conjunctivitis	Uncommon Rare
  Gastrointestinal disorders	Nausea†, vomiting†, diarrhoea†	Common
  Hepatobiliary disorders	Hepatic failure, hepatic dysfunction4, increased liver function tests	Very rare
  Skin and subcutaneous tissue disorders	Skin rash5 Stevens–Johnson Syndrome Toxic epidermal necrolysis	Very common Rare Very rare
  Musculoskeletal and connective tissue disorders	Lupus-like reactions	Very rare
  General disorders and administration site conditions	Tiredness	Common

  Description of selected adverse reactions

  ¹Haematological abnormalities and lymphadenopathy may or may not be associated with the hypersensitivity syndrome (see Immune system disorders²).

  ²Rash 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 liver. 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.

  ³These effects have been reported during other clinical experience.

  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.

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

  ⁵In double-blind, adjunctive clinical trials in adults, 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 eight weeks of starting treatment and resolves on withdrawal of Lamictal.

  Serious potentially life-threatening skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell's Syndrome) have been reported. Although the majority recover on withdrawal of lamotrigine treatment, some patients experience irreversible scarring and there have been rare cases of associated death.

  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

  - concomitant use of valproate.

  Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see Immune system disorders²).

  Bipolar Disorder

  The undesirable effects below should be considered alongside those seen in epilepsy for an overall safety profile of lamotrigine. Adverse events included in the table were identified during bipolar disorder clinical trials.

  System Organ Class	Adverse Event	Frequency
  Nervous system disorders	Headache Agitation, somnolence, dizziness	Very common Common
  Gastrointestinal disorders	Dry mouth	Common
  Skin and subcutaneous tissue disorders	Skin rash Stevens–Johnson Syndrome	Very common1 Rare
  Musculoskeletal and connective tissue disorders	Arthralgia	Common
  General disorders and administration site conditions	Pain, back pain.	Common

  ¹When all bipolar disorder studies (controlled and uncontrolled) conducted with lamotrigine are considered, skin rashes occurred in 12% of patients on lamotrigine. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking lamotrigine and in 6% of patients taking placebo.