Overview

Labetalol is a combined alpha and beta-adrenoreceptor antagonist indicated for the treatment of hypertension, including hypertension in pregnancy, as well as angina pectoris with co-existing hypertension. Labetalol crosses the placental barrier and is excreted in breast milk in small amounts (approximately 0.004-0.07% of the maternal dose).¹

In Malaysia, there are currently five (5) products containing labetalol registered with the Drug Control Authority as a single active ingredient in oral or parenteral formulations.²

Raynaud's phenomenon is a condition marked by brief episodes of vasospasm or narrowing of the blood vessels, causing an intermittent decrease in blood flow, often to the outer parts of the body, such as the fingers, toes, and even the nipples. It has been observed to occur most commonly in response to a cold, but can also be secondary to other triggers such as emotional stress, caffeine consumption, and smoking. Affected areas of the skin will usually turn white or pale due to a lack of blood flow, and later blue with cold and numb sensations. When the blood circulation improves, the skin will become red or swell and throb or tingle.^3-5

Background of the Safety Issue

Based on the evidence from databases, literature reports and safety data from product registration holders, the European Medicines Agency (EMA) concluded that an update to the package insert and leaflet is warranted for all labetalol-containing products to reflect the risk of nipple pain and Raynaud's phenomenon of the nipple (RPN).⁶

The exact mechanism of labetalol causing nipple pain and RPN is still not known.^4,7 Published literature and post-marketing spontaneous reports revealed that RPN is predominant in lactating and pregnant patients.^4-5,7-8 The high prevalence in this population could be related to an exaggerated vasomotor response associated with increased hormones and emotional stress as well as elevated breast blood circulation along with breast growth.^5,7-8 When RPN is unrecognised or mistaken for Candida albicans due to its similar clinical presentation, it can lead to early cessation of breastfeeding or mistreatment with antifungals.^4-5

Based on several reports associated with the use of labetalol administrated in lactating and pregnant women, nipple pain and RPN occur 20–60 minutes after labetalol administration.^4,7 Some reported spontaneous recovery after withdrawal of labetalol, while a literature case reported the symptoms completely resolved following treatment with nifedipine.^4,7-8

Adverse Drug Reaction Reports⁹

To date, the NPRA has received 109 reports with 203 adverse events suspected to be related to products containing labetalol. The most reported adverse events were pruritus (22), dizziness (20) and urticaria (10). The NPRA has received no local reports of nipple pain thus far. However, there was one (1) report of breast pain received.

Advice for Healthcare Professionals

• Be aware of the risk of nipple pain and RPN following the administration of labetalol, particularly in pregnant or lactating women.
• Educate patients about the risk of nipple pain and RPN while taking labetalol, and remind them to inform healthcare professionals if they experience numbness, pain or colour change in nipples.
• Early identification and management can provide timely symptomatic relief, prevent misdiagnosis leading to unnecessary treatment, and avoid early breastfeeding cessation.
• Report all suspected adverse events associated with products containing labetalol to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (15) Jld.1] has been issued for all registration holders of products containing labetalol to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). TRANDATE (labetalol) [Package Insert]. 2022 May 15 [cited 2022 Jul 21]. QUEST3+ Product Search [Internet]. Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2021 [cited 2022 Jul 21] Available from: https://www.npra.gov.my
3. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Raynaud’s Phenomenon [Internet]. 2021 May [cited 2022 Jul 21]. Available from: https://www.niams.nih.gov/health-topics/raynauds-phenomenon#:~:text=Raynaud's%20phenomenon%20is%20a%20condition,as%20the%20ears%20or%20nose.
4. Avila-Vega J, Urrea-Mendoza E, Lee C. Raynaud's phenomenon of the nipple as a side-effect of labetalol: Case report and literature review. Case Rep Womens Health. 2019 Jul 24;23:e00135. Available from: https://doi.org/10.1016%2Fj.crwh.2019.e00135
5. Di Como, J, Tan, S, Weaver, M, Edmonson, D, Gass, JS. Nipple pain: Raynaud's beyond fingers and toes. Breast J. 2020; 26: 2045–2047. Available from: https://doi.org/10.1111/tbj.13991
6. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 25-28 October 2021 PRAC meeting [Internet]. 2021 Nov 22 [cited 2022 Jul 21]. Available from: https://www.ema.europa.eu/documents/prac-recommendation/prac-recommendations-signals-adopted-25-28-october-2021-prac-meeting_en.pdf
7. The Netherlands Pharmacovigilance Centre Lareb. Labetalol during pregnancy and nipple pain [Internet]. 2014 Jul [cited 2022 Jul 21] Available from: https://databankws.lareb.nl/Downloads/KWB_2014_2_labet.pdf
8. Medicines and Healthcare Products Regulatory Agency (MHRA). Case Studies: Labetalol and nipple pain [Internet]. 2022 [cited 2022 Jul 21]. Available from: https://yellowcard.mhra.gov.uk/case-studies
9. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2021 [cited 2021 Dec 8]. Available from: https://www.npra.gov.my (access restricted)

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, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Nafiza Bt. Mohd. Ismail
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli