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Australian Journal of Pharmacy : March 2005
APPGuide 2 0 0 5 U P D A T E The Australian Presciption Products Guide Update is published each month by the Australian Pharmaceutical Publishing Company Limited as a supplement in the Australian Journal of Pharmacy. Editor: Jack Thomas, OAM, PhD, MSc, FRPharmS, FPS Email: firstname.lastname@example.org Production: Stuart Pavy Email: email@example.com New Product Information March 2005 UPDATES TO THE THIRTY FOURTH EDITION ? Part 2 Product Nogel ELMENDOS Cumulative list of Product Information updates that have appeared since the APPGuide 2005 Company Novartis (GlaxoSmithKline) Severe, potentially life-threatening rashes have been reported in asso- ciation with the use of lamotrigine, particularly in children. Accord- ingly, lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug related. (see Dosage and Administration) Composition: The chemical name for lamotrigine is 3,5-diamino-6-(2,3- dichlorophenyl)-1,2,4-triazine (CAS No: 84057-84-1) Elmendos Dispersible/Chewable Tablets contain lamotrigine. Description: Lamotrigine is a substituted asymmetric triazine. It is a white to pale cream-coloured powder. It is slightly soluble in ethanol and chloroform, and very slightly soluble in water. The pKa of lamotrigine at 25°C is 5.7. Each Elmendos Dispersible/Chewable tablet also contains calcium carbonate, hydroxypropyl cellulose, aluminium magnesium sili- cate, sodium starch glycollate, povidone, saccharin sodium, magnesium stearate and blackcurrant flavour. Pharmacology: The precise mechanism of the anticonvulsant action of lamotrigine is not certain. The results of neurochemical and electrophys- iological studies with various in vitro and in vivo preparations indicate that lamotrigine can inhibit voltage gated sodium channels and reduce the release of glutamate, an excitatory amino acid implicated in the patho- physiology of epilepsy. It is possible that these effects underlie inhibition of the sustained repetitive firing of action potentials characteristic of neurones in epileptic foci, thereby limiting the spread of seizures. In tests designed to evaluate the central nervous system effects of drugs, the results obtained using doses of 240mg lamotrigine administered to healthy adult volunteers did not differ from placebo, whereas both 1000mg phenytoin and 10mg diazepam each significantly impaired fine visual motor coordination and eye movements, increased body sway and produced subjective sedative effects. AUSTRALIAN PRESCRIPTION PRODUCTS GUIDE SUPPLEMENT Month February In another study, single oral doses of 600mg carbamazepine signif- icantly impaired fine visual motor coordination and eye move- ments, while increasing both body sway and heart rate, whereas results with lamotrigine at doses of 150mg and 300mg did not differ from placebo. Pharmacokinetics: Absorption: In healthy volunteers, lamotrigine is rapidly and completely absorbed from the gut. The peak plasma concentration occurs 2.5 hours after oral drug administration. Distribution: Lamotrigine is 55% bound to plasma proteins; it is unlikely that displacement from plasma proteins would result in toxicity. The volume of distribution is 0.92 to 1.22L/kg. Metabolism: Following multiple administrations of lamotrigine (150mg twice daily) to normal volunteers there is a modest induction of its own metabolism. Based on the available data, however, there is no clinical evidence that lamotrigine induces mono-oxygenase enzymes to an extent that would cause important interactions with drugs metabolised by these enzymes. Ninety-four percent of a radiolabelled dose of lamotrigine given to human volunteers was recovered in the urine over a period of 168 hours. Only 2% was recovered in the faeces. Lamotrigine is extensively metabolised in man and the major metabolite is an N-glucuronide which accounts for 65% of the dose recovered in the urine. A further 8% of the dose is recovered in the urine as unchanged lamotrigine. High-perfor- mance liquid chromatography radiodetection revealed the presence of another N-glucuronide metabolite present at about one-tenth of the concentration of the major metabolite. Elimination: The mean elimination half life is 29 hours and the pharma- cokinetic profile is linear up to 450mg, the highest single dose tested. The half-life of lamotrigine is greatly affected by concomitant medication with a mean value of approximately 14 hours when given with enzyme THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 ? 215