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.

Overview

Hydrochlorothiazide is a diuretic indicated for the treatment of oedema and hypertension.¹ It works by decreasing certain electrolyte reabsorption in renal tubules, thereby causing diuresis.^1,2 There are currently 50 products containing hydrochlorothiazide (HCTZ), including combination products, registered with the Drug Control Authority (DCA).³

Acute respiratory distress syndrome (ARDS) is a critical medical condition triggered by severe injury to the lungs, often due to aetiologies such as infection or trauma.⁴ In ARDS, fluid leaks from the pulmonary capillaries into the alveoli, impairing oxygen exchange. This leakage results in breathing difficulty and hypoxia, which can subsequently harm the brain and other tissues, potentially leading to organ failure.

Background of Safety Issue

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) have requested the product registration holders of HCTZ-containing medicinal products, including those as combinations, to update their package insert with ARDS-related information.^5-6 This decision is based on the available data on acute respiratory toxicity, including ARDS, as reported in the literature, spontaneous reports with instances showing a close temporal relationship, a positive re-challenge, and a plausible mechanism of action.

The precise mechanism of ARDS induced by HCTZ remains uncertain.^2,7 Although several possible explanations have been proposed, they lack supporting evidence in the literature, leading to the prevailing view that the reaction is idiosyncratic.² One hypothesis suggests that IgG antibodies targeting HCTZ may deposit the antigen-antibody complexes in the lungs, which subsequently activate the complement cascade and recruit granulocytes and neutrophils.⁷

The signs and symptoms of pulmonary oedema typically emerges within minutes to hours following the intake of HCTZ, with its onset characterised by dyspnoea, fever, pulmonary deterioration and hypotension.⁵ According to the literature, the management of this condition is largely supportive, involving fluid management, respiratory support, and cessation of the offending medication.^2,4 Approximately 90% of the published case reports describing similar reactions have occurred in women.^2,7

Adverse Drug Reaction Reports⁸

The NPRA has received 2,196 reports with 3,733 adverse events suspected to be related to HCTZ. The most frequently reported adverse events are dizziness (586), hyponatraemia (326), and headache (235). No local reports of acute respiratory distress syndrome related to HCTZ have been received till date.

Advice for Healthcare Professionals

• Be alert to the risk of very rare but potentially life-threatening ARDS in patient treated with HCTZ, including those taking combination products.
• Avoid prescribing HCTZ to patients who have previously experienced ARDS following HCTZ intake.
• Advise patients to seek medical attention immediately if they develop initial signs and symptoms of pulmonary oedema, such as severe shortness of breath, fever, weakness, and confusion, which may arise within minutes to hours after taking hydrochlorothiazide.   
• If ARDS is suspected, withdraw hydrochlorothiazide and initiate appropriate treatment.
• Report all suspected adverse events associated with HCTZ-containing products to the NPRA.

Regulatory Actions

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(43) Jld.1] had been issued for all registration holders of products containing hydrochlorothiazide (including combination products) to update the local package inserts and consumer medication information leaflets (RiMUP—Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

 References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Hydrochlorzide Tablets local package insert [Internet]. 2023 May [cited 2024 Feb 22]. Available from: http://www.npra.gov.my.
2. Jansson PS, Leisten DC, Sarkisian TM, Wilcox SR, Lee J. Recurrent Hydrochlorothiazide-Induced Acute Respiratory Distress Syndrome Treated With Extracorporeal Membrane Oxygenation. J Emerg Med. 2018 Dec;55(6):836-840. Available from: https://doi.org/10.1016/j.jemermed.2018.09.019
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Feb 22] Available from: https://www.npra.gov.my
4. American Lung Association Acute Respiratory Distress Syndrome (ARDS) [Internet]. 2022 Nov 17 [cited 2024 Feb 22]. Available from: https://www.lung.org/lung-health-diseases/lung-disease-lookup/ards
5. European Medicines Agency (EMA). Hydrochlorothiazide/Spironolactone: CMDh Scientific conclusions and grounds for variation, amendments to the Product Information and timetable for the implementation - PSUSA/00001662/202101 [Internet] 2021 Nov 03 [cited 2024 Feb 22]. Available from: https://www.ema.europa.eu/en/documents/psusa/hydrochlorothiazide-spironolactone-cmdh-scientific-conclusions-and-grounds-variation-amendments-product-information-and-timetable-implementation-psusa00001662202101_en.pdf
6. European Medicines Agency (EMA). Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). Minutes for the meeting on 14-15 September 2021 [Internet]. 2021 Oct 13 [cited 2024 Feb 22]. Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Agendas_and_Minutes/Minutes/2021_09_CMDh_Minutes.pdf
7. Kane SP, Cohen E. Life-threatening idiopathic reaction to hydrochlorothiazide treated with veno-venous extracorporeal membrane oxygenation. Perfusion. 2018 May;33(4):320-322. doi: 10.1177/0267659117745370. Epub 2017 Nov 27. PMID: 29173003. Available from: https://pubmed.ncbi.nlm.nih.gov/29173003/
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Jan 22]. Available from: https://www.npra.gov.my (access restricted).

Written by: Wang Khee Ing

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