by clicking the arrows at the side of the page, or by using the toolbar.
by clicking anywhere on the page.
by dragging the page around when zoomed in.
by clicking anywhere on the page when zoomed in.
web sites or send emails by clicking on hyperlinks.
Email this page to a friend
Search this issue
Index - jump to page or section
Archive - view past issues
Australian Journal of Pharmacy : March 2005
APPGuide 2 0 0 5 U P D A T E There was no evidence of carcinogenicity following daily oral adminis- tration of lamotrigine to mice and rats for up to two years at doses of up to 30 and 10mg/kg respectively. Fertility was reduced following oral administration of lamotrigine to male and female rats at a dose eliciting signs of toxicity (20mg/kg/day). There is no experience of the effect of lamotrigine on human fertility. Use in Pregnancy: Category B3. It is recommended that women on antiepileptic drugs receive prepregnancy counselling with regard to the risk of foetal abnormalities. Lamotrigine should not be used in pregnancy unless, in the opinion of the physician, the potential benefits of treatment to the mother outweigh any possible risks to the developing foetus. The risk to the mother and foetus of uncontrolled epilepsy should be consid- ered when deciding on treatment options. Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrig- ine levels during pregnancy. Appropriate clinical management of preg- nant women during lamotrigine therapy should be ensured. Antiepileptic drugs should be continued during pregnancy and monother- apy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication. There are insufficient data available on the use of lamotrigine in human pregnancy to evaluate its safety. Lamotrigine is a weak inhibitor of dihydrofolate reductase and studies in rats have shown a decrease in folic acid during pregnancy. There is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy. Women who are planning to become pregnant, or who are pregnant, while being treated with lamotrigine should take a folate supplement before conception and for the first 12 weeks of pregnancy, for example 5mg of folate daily. Specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered to pregnant women. Reproductive toxicology studies with lamotrigine in mice, rats and rabbits at doses up to 100mg/kg/day, 25mg/kg/day and 30mg/kg/day, respectively, did not reveal a clear teratogenic effect. An increased inci- dence of poorly ossified skeletal elements and rib anomalies, foetal weight decreases, prolonged gestation, fewer pups, increased incidence of still births, and reduced pup viability during lactation were observed in rats following administration of up to 25mg/kg/day. These foetotoxic effects may have been due to maternal toxicity. Australian categorisation definition of: Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. Use in Lactation: There is limited information on the use of Lamotrig- ine in lactation. Preliminary data indicate that lamotrigine passes into breast milk in concentrations usually of the order of 40-60% of the plasma concentration. In a small number of infants known to have been breastfed, the plasma concentrations of lamotrigine reached levels at which pharmacological effects may occur. The potential benefits of breast-feeding should be weighed against the potential risk of adverse effects occurring in the infant. Lamotrigine and/or its metabolites pass into the milk of lactating rats (approximately 5% of the dose was transferred to the litter). Oral admin- istration of lamotrigine 20mg/kg/day to rats during late gestation and lactation was associated with reduced pup viability, concomitant with signs of maternal toxicity. Driving: Two volunteer studies have demonstrated that the effect of lamotrigine on fine visual motor co-ordination, eye movements, body sway and subjective sedative effects did not differ from placebo. In clinical trials with lamotrigine adverse effects of a neurological nature, such as dizziness and blurred vision, have been reported. 218 ? THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 Therefore, patients should see how lamotrigine therapy affects them before driving or operating machinery. As there is individual variation in response to all antiepileptic drug ther- apy patients should consult their physician on the specific issues of driving and epilepsy. Interactions with other drugs: There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug-metabolising enzymes. Lamotrigine may induce its own metabo- lism but the effect is modest and unlikely to have significant clinical consequences. Increases in the plasma concentrations of other antiepileptic drugs have been reported in a few patients, however controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant antiepileptic drugs. Evidence from in vitro studies indicates that lamotrigine does not displace other antiepileptic drugs from protein binding sites. Effect of hormonal contraceptives on lamotrigine pharmacokinetics: In a study of 16 female volunteers, 30mcg ethinyloestradiol/150mcg levonorgestrel in a combined oral contraceptive pill caused an approximately two-fold increase in lamotrigine oral clearance, result- ing in an average 52% and 39% reduction in lamotrigine AUC and Cmax , respectively. Serum lamotrigine concentrations gradually increased during the course of the week of inactive medication (e.g. “pill-free” week), with pre-dose concentrations at the end of the week of inactive medication being, on average, approximately two-fold higher than during co-therapy. FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see Precautions). The effects of doses of lamotrigine other than 300mg/day have not been studied and studies with other female hormonal preparations have not been conducted. Interactions involving other medications: In a study in 10 male volun- teers, rifampicin increased lamotrigine clearance and decreased lamotrig- ine half-life due to induction of the hepatic enzymes responsible for glucuronidation. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for lamotrigine and concurrent hepatic enzyme inducers should be used (see Dosage and Administration). Effect of lamotrigine on hormonal contraceptive pharmacokinetics: In a study of 16 female volunteers, a steady state dose of 300mg lamotrigine had no effect on the pharmacokinetics of the ethiny- loestradiol component of a combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax A study in healthy male volunteers found that there was a slightly enhanced elimination of lamotrigine in the presence of paracetamol but this was not considered to be clinically significant. Antiepileptic drugs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce hepatic drug-metabolising enzymes enhance the metabolism of lamotrigine (see Dosage and Administra- tion). Other drug-classes which induce hepatic drug-metabolising enzymes may also enhance the metabolism of lamotrigine. Sodium valproate, which competes with lamotrigine for hepatic drug metabolising enzymes, reduces the metabolism of lamotrigine and increases the mean half life of lamotrigine nearly two fold (see Precau- tions and Dosage and Administration). There have been reports of central nervous system events including dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine following the introduction of lamotrigine. AUSTRALIAN PRESCRIPTION PRODUCTS GUIDE SUPPLEMENT , respectively. Measurement of serum