DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Product Overview

Domperidone is a peripheral dopamine D2-receptor antagonist that exhibits both gastrokinetic and antiemetic properties, achieved by inhibiting dopamine receptors in the smooth muscle of the gastrointestinal tract and the chemoreceptor trigger zone.¹

In Malaysia, there are currently 14 domperidone-containing products available in the form of tablets or oral suspensions registered with the Drug Control Authority (DCA).² Domperidone is approved locally for the relief of nausea and vomiting of functional, organic, infectious, or dietary origin.³ It is also used to alleviate nausea and vomiting induced by radiotherapy, drug therapy, or dopamine agonist used in the treatment of Parkinson’s disease. Generally, the lowest effective dose is 30 mg/day, which can be increased to a maximum daily dose of 40 mg. For acute nausea and vomiting, the treatment duration should not extend beyond 1 week.

Additionally, domperidone has been used off-label to promote lactation in breastfeeding mothers by increasing prolactin release from the pituitary gland.¹ However, the available evidence regarding the effectiveness and safety of domperidone as a galactagogue remains inconclusive, leading to inconsistent prescribing practices and wide variations in utilisation patterns for breastfeeding.^4-5

Background of the Safety Issue

In September 2023, the National Pharmaceutical Regulatory Agency (NPRA) learned from Health Canada about the risk of psychiatric withdrawal events, including depression, anxiety, and insomnia, following the abrupt discontinuation or dose tapering of domperidone used off-label for lactation stimulation.⁶ Triggered by reports published in the scientific literature, Health Canada’s review found a link between such risk and the off-label use of domperidone for lactation stimulation. As a result, Health Canada instructed updates to the Canadian Product Monograph for products containing domperidone to reflect this risk.

The literature suggests several plausible mechanisms for how withdrawal from domperidone may lead to these psychiatric events.^1,9-10 One hypothesis proposes that these withdrawal events are mediated by a sudden drop in plasma prolactin levels, which follows prolonged hyperprolactinaemia induced by long-term use of domperidone.¹ Another explanation delves into the possibility of dopamine supersensitivity psychosis, triggered by sudden domperidone withdrawal,^9-10 which result from the upregulation of dopamine receptors as a compensatory response to prolonged dopamine blockade.^9,11-12

Adverse Drug Reaction Reports¹³

To date, the NPRA has received a total of 68 reports with 133 adverse events suspected to be related to domperidone-containing products. No psychiatric withdrawal events following the discontinuation of domperidone have been reported to the NPRA.

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing ADR reports of psychiatric withdrawal events associated with the off-label use of domperidone for lactation stimulation.
• Although this risk is commonly confused with postpartum depression, it is crucial to probe about domperidone usage in lactating mothers presenting psychiatric symptoms. Maternal hesitancy to disclose domperidone use can lead to suboptimal patient outcomes and delay the management of withdrawal manifestations. 
• Be aware that this risk also occurs in individuals using domperidone long-term for its registered indications. Use domperidone at the lowest possible dose for the shortest duration necessary.
• Inform patients about the potential risks upon abrupt withdrawal of long-term domperidone usage, including psychiatric manifestations. Advise patients on the necessity of a gradual taper and the potential impacts of using higher than recommended doses.
• Report all adverse events suspected to be related to the use of domperidone to the NPRA.

References:

1. Papastergiou J, Abdallah M, Tran A, Folkins C. Domperidone withdrawal in a breastfeeding woman. Can Pharm J (Ott). 2013 Jul;146(4):210-2. Available from: https://doi.org/10.1177/1715163513492928
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [cited 2023 Dec 13]. Available from: https://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency (NPRA). MOTILIUM (domperidone) [Package Insert]. QUEST3+ Product Search. 2022 Dec 1 [cited 2023 Oct 23]. Available from: http://www.npra.gov.my.
4. McBride GM, Stevenson R, Zizzo G, Rumbold AR, Amir LH, Keir A, Grzeskowiak LE. Women's experiences with using domperidone as a galactagogue to increase breast milk supply: an australian cross-sectional survey. Int Breastfeed J. 2023 Feb 7;18(1):11. Available from: https://doi.org/10.1186/s13006-023-00541-9
5. Doyle M, Grossman M. Case report: domperidone use as a galactagogue resulting in withdrawal symptoms upon discontinuation. Arch Womens Ment Health. 2018 Aug;21(4):461-463. Available from: https://doi.org/10.1007/s00737-017-0796-8
6. Health Canada. Summary safety review - Domperidone - assessing the potential risk of psychiatric withdrawal events when used for lactation stimulation. [Internet]. 2023 August [cited 2023 Sep 26]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1691692252806
7. Health Canada. Health Product InfoWatch: August 2023 – domperidone and psychiatric withdrawal events when used off-label for lactation stimulation [Internet]. 2023 Aug [cited 2023 Sep 26]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/august-2023.html#a3-1-1
8. Majdinasab E, Haque S, Stark A, Krutsch K, Hale TW. Psychiatric Manifestations of Withdrawal Following Domperidone Used as a Galactagogue. Breastfeed Med. 2022 Dec;17(12):1018-1024. Available from: doi: 10.1089/bfm.2022.0190. https://doi.org/10.1089/bfm.2022.0190
9. Seeman P. Yes, breast is best but taper domperidone when stopping [Internet]. British Journal of General Practice. 2014 Jan 15. [cited 2023 Oct 23]. Available from: https://bjgp.org/content/yes-breast-best-taper-domperidone-when-stopping
10. Seeman MV. Transient psychosis in women on clomiphene, bromocriptine, domperidone and related endocrine drugs. Gynecol Endocrinol. 2015 Oct;31(10):751-4. Available from: https://doi.org/10.3109/09513590.2015.1060957
11. Roy-Desruisseaux J, Landry J, Bocti C, Tessier D, Hottin P, Trudel JF. Domperidone-induced tardive dyskinesia and withdrawal psychosis in an elderly woman with dementia. Ann Pharmacother. 2011 Sep;45(9):e51. doi: 10.1345/aph.1Q214. Available from: https://doi.org/10.1345/aph.1q214
12. Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N, Takase M, Iyo M. Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. Psychother Psychosom. 2017;86(4):189-219. Available from: https://doi.org/10.1159/000477313
13. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Sep 29]. Available from: https://www.npra.gov.my (access restricted)

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali