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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), Toxic Epidermal Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome (HSS) (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 reaction to LAMICTAL 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 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 AEDs 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All patients (adults and children) who develop a rash should be promptly evaluated and LAMICTAL withdrawn immediately unless the rash is clearly not related to lamotrigine treatment.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 LAMICTAL unless the potential benefit clearly outweighs the risk. If the patient has developed SJS, TEN or DRESS with the use of LAMICTAL, treatment with LAMICTAL must not be restarted 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, 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.
Haemophagocytic lymphohistiocytosis (HLH): HLH has been reported in patients taking LAMICTAL (see Adverse Reactions). HLH is characterised by signs and symptoms, like fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, high serum ferritin, hypertriglyceridaemia and abnormalities of liver function and coagulation. Symptoms occur generally within 4 weeks of treatment initiation, HLH can be life threatening.
Patients should be informed of the symptoms associated with HLH and should be advised to seek medical attention immediately if they experience these symptoms while on lamotrigine therapy.
Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. LAMICTAL should be promptly discontinued unless an alternative aetiology can be established.
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 LAMICTAL efficacy: The use of an ethinylestradiol/levonorgestrel (30 μg / 150 μg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see Interactions). 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 medication (e.g. "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see Dosage & Administration). 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 hormone replacement therapy (HRT) treatments and lamotrigine 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 (ethinyloestradiol/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.
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 (see Use in Pregnancy & Lactation). 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 and dispersible/chewable tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.
Brugada-type ECG: Arrhythmogenic ST-T abnormality and typical Brugada ECG pattern has been reported in patients treated with LAMICTAL. The use of LAMICTAL should be carefully considered in patients with Brugada syndrome.
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.
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 LAMICTAL.
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 AEDs. The reason is unclear.
Ability to perform tasks that require judgement, motor or cognitive skills: As there is individual variation in response to all AED therapy, patients taking LAMICTAL to treat epilepsy should consult their physician on the specific issues of driving and epilepsy.
No studies on the effects on the ability to drive and use machines have been performed. 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.
Use in Children: 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: In children taking lamotrigine for the treatment 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.
