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Australian Journal of Pharmacy : March 2005
Indications: Elmendos is an antiepileptic drug for the treatment of partial and generalised seizures in adults and children. There is extensive experience with lamotrigine used initially as “add- on” therapy. The use of lamotrigine has also been found to be effec- tive as monotherapy following withdrawal of concomitant antiepileptic drugs. Initial monotherapy treatment in newly diagnosed paediatric patients is not recommended. (See Clinical Trials.) Contra-indications: Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine, or to any other ingredient in Elmendos Tablets (see Composition). Precautions: Skin Rash: SEE BOXED WARNING REGARDING THE RISK OF SEVERE, POTENTIALLY LIFE-THREATENING RASH ASSOCI- ATED WITH THE USE OF Lamotrigine. There have been reports of adverse skin reactions, which have gener- ally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamot- rigine have been reported. These have included potentially life-threat- ening rashes such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). (See Adverse Reactions). Although benign rashes also occur with lamotrigine, it is not possible to predict reliably which rashes will prove to be life-threatening. In adults enrolled in studies utilising 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 SJS (1 in 1000). The risk of serious skin rashes is higher in children 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 reac- tion 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 Dosage and Administration). - Concomitant use of valproate, which increases the mean half life of lamotrigine nearly two fold (see Dosage and Administration). All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related. It is recommended that lamotrigine not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk. Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver. The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagula- tion (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (eg. fever, lymphadenopathy) may be present even though rash is not evident. If such signs and symptoms are present the patient should be evaluated immedi- ately and lamotrigine discontinued if an alternative aetiology cannot be established. As with other antiepileptic drugs for the treatment of epilepsy, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (for example serious skin reactions) require an abrupt with- drawal, the dose of lamotrigine should be gradually decreased over a period of two weeks. AUSTRALIAN PRESCRIPTION PRODUCTS GUIDE SUPPLEMENT When concomitant antiepileptic drugs are withdrawn to achieve lamot- rigine monotherapy or other antiepileptic drugs are added-on to lamot- rigine monotherapy, considerations should be given to the effect this may have on lamotrigine pharmacokinetics (see Drug Interactions). Hormonal contraceptives: Effects of hormonal contraceptives on lamot- rigine efficacy: An ethinyloestradiol/levonorgestrel (30mcg / 150mcg) combination has been demonstrated to increase the clearance of lamotrigine by approxi- mately two-fold resulting in decreased lamotrigine levels (see Interac- tions). Following titration, higher maintenance doses of lamotrigine (by as much as two fold) may be needed 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 Recommenda- tions for Lamotrigine in Special Patient Populations, Dosage and Administration. Clinicians should exercise appropriate clinical management of women starting or stopping hormonal contraceptives during lamotrigine therapy and lamotrigine dosing adjustments may be needed. Other oral contraceptive and HRT treatments have not been stud- ied, 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 (see Inter- actions). 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 prepa- rations with lamotrigine cannot be excluded. Therefore patients should be instructed to promptly report changes in their menstrual pattern, ie, breakthrough bleeding. Dihydrofolate reductase: Lamotrigine is a weak inhibitor of dihydrofo- late reductase, hence there is a possibility of interference with folate metabolism during long-term therapy. During prolonged human dosing, however, lamotrigine did not induce significant changes in the haemo- globin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year, or red blood cell folate concentra- tions 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. Hepatic Impairment: Lamotrigine is cleared primarily by metabolism in the liver. Lamotrigine should be administered with caution in patients with hepatic impairment as clearance is reduced. Refer to Dosage and Administration; Hepatic Impairment. There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiorgan failure and disseminated intravascular coagulation, sometimes with a fatal outcome. Similar cases have occurred in association with the use of lamotrigine. Patients taking other lamotrogine containing preparations: Lamotrigine should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor. Carcinogenicity, Mutagenicity, Impairment of Fertility: Lamotrigine was not genotoxic in assays for gene mutation or chromosomal damage. THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 ? 217