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Postdoctoral Research Fellow Pharmacology and Anaesthesiology Unit School of Medicine and Pharmacology University of Western Australia Crawley, Australia
Senior Pharmacist Pharmacy Department Women's and Children's Health Service Subiaco, Australia
Senior Research Scientist Clinical Pharmacology and Toxicology Laboratory PathWest Laboratory Medicine W.A. Nedlands, Australia
Consultant Neurologist Department of Neurology Liverpool Hospital Liverpool, Australia
Consultant Psychiatrist Department of Psychological Medicine Women's and Children's Health Service
Professor of Pediatrics Texas Tech University School of Medicine Amarillo, Texas
Consultant Neonatologist Department of Neonatal Services Women's and Children's Health Service
Emeritus Professor of Pharmacology Pharmacology and Anaesthesiology Unit M510 School of Medicine and Pharmacology University of Western Australia 35 Stirling Highway Crawley, 6009 Australia fax 618-0346-3469 Ken.Ilett{at}uwa.edu.au
Published Online, July 25, 2006. www.theannals.com, DOI 10.1345/aph.1G667
30% of maternal) without adverse effects in the
breast-fed infants. The aim of our study was to present additional data to
assist physicians and patients in making informed risk-benefit
assessments. Methods. Six breast-feeding women (age 30-38 y) treated with lamotrigine at a mean dose of 400 mg/day (range 175-800) for epilepsy (n = 5) or bipolar disorder (n = 1) were recruited. They provided written informed consent under a protocol approved by 2 ethics committees. Their infants (breast-fed 50% for infant of Patient 1, 100% for others) were 2 girls and 4 boys, with a median age of 4.1 months (0.4-5.1) and a median weight of 5.6 kg (3-8) on the study day. The women collected milk samples by hand expression at various times (up to 14 times per pt.) over 1 or 2 dose intervals.
Infant health and well-being were investigated by interview of the mother and/or the referring physician, and body weight was assessed by reference to standard growth charts. Three infants were given a full clinical examination. Venous blood samples were collected from 5 of the mothers (1-6 samples per pt.) and their infants (1 sample per infant; Table 1). Lamotrigine concentrations in milk or plasma were measured by a validated HPLC method. Inter- and intraday relative standard deviations for the assay were less than 3.6%, with a limit of quantitation of 0.1 mg/L.
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In 5 patients, AUCs were calculated for milk5 and average drug concentration in milk was calculated as Cavg = (AUC)/Ù, where Ù = dose interval. In one patient, milk Cavg was determined as the average of 4 measurements made on 2 days. Absolute infant dose (mg/kg/day) was calculated as the product of milk Cavg and an infant milk intake of 0.15 L/kg/day.5 Relative infant dose (%) was calculated as absolute infant dose x 100/maternal dose (mg/kg/day). Infant plasma concentration (% of maternal plasma concentration) was calculated using data collected at the same time after dose.
Results. Study-day weight was unavailable for one infant. Infant body weights were within 50-95th percentiles, except for one (age 2 wk) who was between the 25th and 50th percentiles. No adverse effects were reported by the mothers or attending physicians. The clinical pediatric assessment performed for 3 of the infants also did not reveal any adverse findings. Table 1 summarizes maternal and infant doses and infant plasma concentrations as a percent of those in maternal plasma. Mean absolute infant doses, relative infant doses, and infant/maternal plasma lamotrigine values were 0.45 mg/kg/day, 7.6%, and 18%, respectively.
Discussion. The 4 previous reports of lamotrigine transfer into milk summarize data from 12 patients. The first details a single case of a mother taking 500 mg/day.1 Absolute and relative infant doses and the infant's mean serum drug concentration (% maternal concentration) were 0.52 mg/kg/day,13%, and 36%, respectively. The second is also a single case report (mother's dosage 250 mg/day) in which the absolute infant dose, relative infant dose, and infant plasma lamotrigine were 0.5 mg/kg/day, 10%, and 25%, respectively.2 The third study, of 9 breast-feeding women (median dosage 300 mg/day), reported absolute infant dose, relative infant dose, and infant plasma lamotrigine values of 0.2-1 mg/kg/day, 9%, and 30%, respectively.3 The final study was a single case (maternal dosage 300 mg/day) in which the 4-month-old breast-fed infant's development was normal. No adverse effects were observed in these studies.
Our mean absolute infant dosage (0.45 mg/kg/day), relative infant dose (7.6%), and concentration of lamotrigine in the infant's plasma as percent of that in the mother's plasma (18%) were similar to those in previous reports. All infants in our study were observed at an age older than 12 days after birth and, given that lamotrigine's half-life is approximately 24 hours in neonates,6 drug exposure from pregnancy is unlikely to have influenced the infants' plasma concentrations. We also found no adverse effects in any of the infants. Hence, our study confirms and extends previously published data and brings the total of reported cases to 18. While this number is still small, the consistency of the data across studies, together with a lack of adverse events, are encouraging for the cautious use of lamotrigine when indicated. Use of lamotrigine during breast-feeding should always be subject to an individualized risk-benefit analysis. Regular observation of the infant's progress should be made, and occasional monitoring of plasma lamotrigine concentrations in infant and mother can be reassuring.
Footnotes
This work was supported by a grant from The Women's and Infant's Research Foundation.
We gratefully acknowledge the assistance of Deborah Oosterbaan with sample collection at the Subiaco site and Georgia D Montouris MD at the US site.
References
This article has been cited by other articles:
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  D. J. Newport, P. B. Pennell, M. R. Calamaras, J. C. Ritchie, M. Newman, B. Knight, A. C. Viguera, J. Liporace, and Z. N. Stowe Lamotrigine in Breast Milk and Nursing Infants: Determination of Exposure Pediatrics, July 1, 2008; 122(1): e223 - e231. [Abstract] [Full Text] [PDF]
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