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Australian Journal of Pharmacy : March 2005
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. Approximately 96% of a given dose of lamotrigine is eliminated by conjugation metabolism mediated by glucuronyl-transferases. Cytochrome P450 is not involved in the elimination of lamotrigine to any significant extent. Therefore the likelihood that lamotrigine inhibits the elimination of drugs metabolised by cytochrome P450 is low. The pharmacokinetics of lithium after 2g of anhydrous lithium gluconate given twice daily for six days to 20 healthy subjects were not altered by co-administration of 100mg/day lamotrigine. In vitro experiments indicated that the formation of lamotrigine’s primary metabolite, the 2-N-glucuronide, was inhibited by co-incuba- tion with sodium valproate, bupropion, clonazepam, amitriptyline, haloperidol, and lorazepam. Sodium valproate is known to reduce the clearance of lamotrigine in vivo (see above). In these experiments, the largest effect (after that of sodium valproate) was observed with bupropion; however, multiple oral doses of bupropion had no statisti- cally significant effects on the single dose pharmacokinetics of a low dose (100mg) of lamotrigine in 12 subjects and caused only a slight increase in the AUC of lamotrigine glucuronide. This observation suggests that the risk of a clinically relevant interaction with amitripty- line, clonazepam, haloperidol or lorazepam is therefore unlikely. The in vitro experiments also suggested that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertra- line, trazodone or fluoxetine. Bufuralol metabolism data from human liver microsomes suggest that lamotrigine does not reduce the clear- ance of drugs eliminated predominantly by CYP2D6. Adverse Reactions: In double-blind, add-on placebo controlled, clin- ical trials, skin rashes occurred in 10% of patients taking lamotrigine and in 5% of patients taking placebo. The skin rashes led to the with- drawal of lamotrigine treatment in 2% of patients in all clinical trials. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of lamotrigine. Serious, potentially life threatening skin rashes, including Stevens John- son syndrome and toxic epidermal necrolysis (Lyell Syndrome) have been reported. Although the majority recover on drug withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see Precautions). 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) 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 (see below). The syndrome shows a wide spectrum of clini- cal severity and may rarely lead to disseminated intravascular coagu- lation (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 immediately and lamotrig- ine discontinued if an alternative aetiology cannot be established. The table below presents a comparison of adverse experiences reported during clinical trials with lamotrigine. Data are presented, in decreasing order of the incidence seen in lamotrigine patients, from the pooled placebo controlled add-on studies that have been conducted with lamotrigine. For comparison, data are also presented from pooled monotherapy studies that have been conducted with lamotrigine. These adverse experiences have been reported most commonly during the initial weeks of treatment with lamotrigine. AUSTRALIAN PRESCRIPTION PRODUCTS GUIDE SUPPLEMENT TABLE OF ADVERSE EXPERIENCES FROM CLINICAL TRIALS % Reporting from Pooled Add-on Studies1 Adverse Experience Diplopia Dizziness Ataxia Headache Asthenia Nausea Somnolence Vomiting Respiratory Disorder Rash Pain Pharyngitis Flu syndrome Insomnia Menstrual disorder Tremor Lung disorder Depression Amnesia Thinking abnormality Lamotrigine Placebo (n = 242) (n = 233) 21 19 19 17 16 16 10 9 7 6 6 3 <1 4 1 3 <1 4 3 2 8 12 5 14 18 7 9 3 7 5 4 <1 <1 <1 <1 2 <1 3 4 2 % Reporting from Pooled Monotherapy Studies2 Lamotrigine Carbamazepine Phenytoin (n = 443) (n = 246) (n = 95) <1 8 <1 20 16 10 8 4 <1 12 2 5 5 6 1 2 1 2 3 2 3 14 6 17 24 10 20 4 1 14 2 4 4 2 <1 2 5 3 4 2 12 12 19 29 4 28 1 1 9 5 2 3 3 5 — 8 6 3 5 5 1. AEs with incidence = 5% of lamotrigine patients (includes corresponding rates for monotherapy events). 2. AEs with incidence = 5% in any treatment group (includes corresponding rates for add-on events). — Not reported Irritability/aggression, tiredness, drowsiness, agitation, confusion and hallucinations have also been reported. In children hyperkinesia has been reported (5%). Very rarely, lupus-like reactions have been reported. Arthralgia was reported commonly during the clinical development program for lamotrigine in bipolar disorder. There have been reports of haematological abnormalities which may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leucopenia, anaemia, thrombo- cytopenia, pancytopenia, and very rarely aplastic anaemia and agranulocytosis. Movement disorders such as tics, unsteadiness, ataxia, nystagmus and tremor have also been reported. 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. Elevations of liver functions tests and rare reports of hepatic dysfunction, including hepatic failure, have been reported. Hepatic dysfunction usually occurs in association with hypersensitivity reac- tions but isolated cases have been reported without overt signs of hypersensitivity. The incidence of adverse reactions to marketed drugs, such as lamotrigine, is difficult to reliably assess due to the nature of spon- taneous, voluntary, reporting systems and the problems associated with estimating the total exposure to the drug. With these limita- tions in mind the table below has been generated from post-market- ing data collected for lamotrigine. The adverse experiences included are those believed to be probably causally related to lamotrigine (at least in some instances) and are grouped by body system with an estimate of the frequency with which the reaction may be seen in the lamotrigine treated patient population (whether or not due to the drug in individual cases). FREQUENCY ESTIMATES OF ADVERSE REACTIONS SEEN WITH LAMOTRIGINE FROM POST-MARKETING DATA: Digestive Disorders: † Uncommon: Gastro-intestinal disturbances, eg nausea, vomiting, diar- rhoea, anorexia Haematological Disorders: † Uncommon: Transient leucopenia or thrombocytopenia THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 ? 219