Reason for posting: Domperidone has been widely used as a motility and antiemetic agent.1 In oral form it is also used off label to improve lactation in breast-feeding women. Intravenous domperidone has been withdrawn from the market worldwide because of reports of cardiac arrhythmia and sudden death in patients with malignant disease who received relatively high intravenous doses of the drug for nausea and vomiting induced by cytotoxic therapy.2,3,4,5 In the United States, it is not approved for any indication and thus is not marketed in any form.6 However, some breast-feeding women in the United States have been purchasing the oral form of the drug from compounding pharmacies and from sources in other countries in order to enhance lactation. The US Food and Drug Administration (FDA) has warned breast-feeding women not to use domperidone because of its potentially adverse effects.6 It has also expressed concerns about the unknown but potential risks to the breast-feeding infant since the drug is excreted in breast milk.7
The drug: Dopamine is a physiologic inhibitor of prolactin release from the pituitary gland. Domperidone is a peripheral dopamine-receptor antagonist, which is why its administration increases prolactin concentration and milk production.1,7 Domperidone has been approved for oral use in Canada and worldwide as a motility agent with an excellent safety record.1 As an antiemetic, the drug is usually given at an oral dose of 60– 80 mg/d; as a galactagogue, the current evidence supports a dose of 30 mg/d.7 Because of extensive first-pass and gut-wall metabolism, oral bioavailability is only 13%– 17%.1 Heykants and associates8 reported peak blood levels of 23 ng/mL after an oral dose of 10 mg of domperidone, compared with levels about 30 times higher with the same dose given intravenously. In women receiving 10 mg of domperidone 3 times daily to enhance lactation, the mean serum level on day 5 of therapy was 6.6 ng/mL.7 With respect to risks to the nursing infants, the mean level of domperidone excreted in the breast milk of women taking 10 mg of domperidone orally 3 times daily was only 1.2 ng/mL.7 The total amount of the drug that would be ingested by the infant would be extremely small (about 180 ng/kg daily, assuming a daily milk intake of 150 mL/kg).
What to do: The data on the use of domperidone orally as a galactagogue are limited. However, FDA warnings against the use of domperidone by lactating women were based on the increased risk of cardiac arrhythmia and sudden death in patients with malignant disease receiving high-dose intravenous domperidone therapy concurrently with chemotherapy. All of the patients whose serum potassium level was measured had low levels (between 2.0 and 3.3 mmol/L).4,5
Breast-feeding is recommended as the optimal form of nutrition for term and preterm infants for the psychological benefits of maternal–infant bonding and the nutritional properties of breast milk. Lactating women with decreased milk supply who are unresponsive to nonpharmacologic measures to enhance lactation, including counselling, relaxation techniques and mechanical expression, should continue to consider domperidone at antiemetic doses. Patients should be warned of the risk of life-threatening cardiac arrhythmias associated with high doses of domperidone, and women with known cardiac disease should refrain from using the drug. Further research is needed to define the best dose of domperidone and length of treatment in lactating women with reduced milk production.
Orlando P. da Silva Department of Paediatrics David C. Knoppert Department of Pharmacy University of Western Ontario St. Joseph's Health Care London London, Ont.
References
- 1.Barone JA. Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother 1999;33: 429-40. [DOI] [PubMed]
- 2.Joss RA, Goldhirsch A, Brunner KW, Galeazzi RL. Sudden death in cancer patient on high-dose domperidone. Lancet 1982;1:1019. [DOI] [PubMed]
- 3.Giaccone G, Bertetto O, Calciati A. Two deaths during prophylactic antiemetic treatment with high doses of domperidone and methylprednisolone. Lancet 1984;2:1336-7. [DOI] [PubMed]
- 4.Osborne RJ, Slevin ML, Hunter RW, Hamer J. Cardiotoxicity of intravenous domperidone. Lancet 1985; 2: 385. [DOI] [PubMed]
- 5.Roussak JB, Carey P, Parry H. Cardiac arrest after treatment with intravenous domperidone. BMJ (Clin Res Ed) 1984;289:1579. [DOI] [PMC free article] [PubMed]
- 6.US Food and Drug Administration. FDA warns against women using unapproved drug, domperidone, to increase milk production [FDA Talk Paper]. Rockville (Md): FDA; 2004 June 7. Available: www.fda.gov/bbs/topics/ANSWERS/2004/ANS01292.html (accessed 2004 Aug 31).
- 7.Da Silva OP, Knoppert DC, Angelini MM, Forret PA. Effect of domperidone on milk production in mothers of premature newborns: a randomized, double-blind, placebo-controlled trial. CMAJ 2001; 164(1):17-21. [PMC free article] [PubMed]
- 8.Heykants J, Hendriks R, Meuldermans W, Michiels M, Scheygrond H, Reyntjens H. On the pharmacokinetics of domperidone in animals and man. IV. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration. Eur J Drug Metab Pharmacokinet 1981;6(1):61-70. [DOI] [PubMed]