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Skin rash: There have been reports of adverse skin reactions, which have generally occurred within the first eight weeks after initiation of LAMICTAL treatment. The majority of rashes are mild and self limiting, however serious rashes requiring hospitalisation and discontinuation of LAMICTAL have also been reported. These have included potentially life-threatening rashes such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see Adverse Reactions).
In adults enrolled in studies utilising the current LAMICTAL 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 SJS (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 drug reaction 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 LAMICTAL and exceeding the recommended dose escalation of LAMICTAL therapy (see Dosage & Administration); concomitant use of valproate (see Dosage & Administration).
Caution is also required when treating patients with a history of allergy or rash to other anti-epileptic drugs as the frequency of non-serious rash after treatment with LAMICTAL 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All patients (adults and children) who develop a rash should be promptly evaluated and LAMICTAL withdrawn immediately unless the rash is clearly not drug related. It is recommended that LAMICTAL not be restarted in patients who have discontinued due to rash associated with prior treatment with LAMICTAL 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 Adverse Reactions). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multi-organ failure. It is important to note that early manifestations of hypersensitivity (e.g. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present, the patient should be evaluated immediately and 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.
Suicide risk: Symptoms of depression and/or bipolar disorder may occur in patients with epilepsy, and there is evidence that patients with epilepsy and bipolar disorder have an elevated risk for suicidality.
Twenty-five to 50% of patients with bipolar disorder attempt suicide at least once, and may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder, including LAMICTAL.
Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications, including epilepsy and bipolar disorder. A meta-analysis of randomised placebo-controlled trials of AEDs (including lamotrigine) 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. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Clinical worsening in bipolar disorder: 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.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
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 LAMICTAL Efficacy: An ethinylestradiol/levonorgestrel (30 micrograms/150 micrograms) combination has been demonstrated to increase the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see Interactions). 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. In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive medication (e.g. "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive medication. These increases will be greater when lamotrigine dose increases are made in the days before or during the week of inactive medication. For dosing instructions see "General Dosing Recommendations for LAMICTAL in Special Patient Populations under Dosage & Administration".
Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during LAMICTAL therapy and lamotrigine dosing adjustments will be needed in most cases.
Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.
Effects of LAMICTAL on hormonal contraceptive efficacy: An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinylestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see Interactions). 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 LAMICTAL cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.
Effect of lamotrigine on organic cationic transporter 2 (OCT 2) substrates: Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins (see Interactions). This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Co-administration of LAMICTAL with OCT 2 substrates with a narrow therapeutic index e.g. dofetilide is not recommended.
Dihydrofolate reductase: Lamotrigine is a weak inhibitor of dihydrofolate reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. However, during prolonged human dosing, LAMICTAL 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 tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
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, multi-organ dysfunction and disseminated intravascular coagulation, sometimes with fatal outcome. Similar cases have occurred in association with the use of LAMICTAL.
BIPOLAR DISORDER: Children and adolescents (less than 18 years of age): 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.
Effects on Ability to Drive and Use Machines: Two volunteer studies have demonstrated that the effect of LAMICTAL on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with LAMICTAL, adverse events of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how LAMICTAL therapy affects them before driving or operating machinery.
Epilepsy: As there is individual variation in response to all anti-epileptic drug therapy, patients should consult their physician on the specific issues of driving and epilepsy.
