Overview

Hydrochlorothiazide is a thiazide diuretic, which is used to treat hypertension and oedema.^1-2 Indapamide and chlorthalidone are thiazide-like diuretics indicated for the treatment of hypertension.^3-5 As for acetazolamide, which has diuretic properties, is a carbonic anhydrase inhibitor approved for the treatment of glaucoma, selected cases of epilepsy, salicylate overdosage and abnormal retention of fluids.^6-7

In Malaysia, there is a total of 55 products containing hydrochlorothiazide, 15 products containing indapamide, three (3) products containing chlorthalidone, and two (2) products containing acetazolamide currently registered with the Drug Control Authority (DCA), including fixed-dose combinations.⁸

 

Background of Safety Issue

Health Canada had conducted an assessment on the risk of choroidal effusion, acute myopia, and acute angle-closure glaucoma for diuretics. It was concluded that there is a link between certain sulfonamide diuretics, namely hydrochlorothiazide, chlorthalidone, indapamide, and acetazolamide, and the risks of those ocular disorders.^9-10*

Choroidal effusion is an abnormal fluid accumulation in the space between the sclera and the choroid. It commonly occurs as a complication of glaucoma surgery. However, it may also arise due to other conditions, including trauma, inflammatory and infectious diseases, neoplasms, venous congestion as well as drug reactions.¹¹

Myopia, or short-sightedness, refers to an eye condition which causes blurred distant vision, while near objects can be seen clearly.¹² On the other hand, acute angle-closure glaucoma is an ophthalmic emergency where intraocular pressure rise rapidly due to blockage of aqueous humour drainage.¹³

The exact pathophysiology of how these diuretics can cause choroidal effusion, acute myopia, or acute angle-closure glaucoma has not been fully elucidated. Therefore, they are described as idiosyncratic reactions. In most literature, the sulfonamide moiety of these drugs is postulated of causing these ocular disorders.^10,14-17 Although acetazolamide is commonly used in the treatment of glaucoma, it has also been reported to cause paradoxical adverse reactions by provoking bilateral cilio-choroidal effusion, transient myopia and secondary acute angle-closure glaucoma in non-glaucomatous patients.^15-17

* Health Canada's review also concluded that there might be a link between metolazone and the risk of these eye disorders. However, metolazone is not registered in Malaysia.

 

Adverse Drug Reaction Reports¹⁸

At the time of review, the NPRA has received 2,643 reports suspected to be related to diuretic products containing hydrochlorothiazide (2379), chlorthalidone (8), indapamide (219) and acetazolamide (37). Of these reports, there are 4,518 adverse events suspected to be associated with diuretic products containing hydrochlorothiazide (4,063), chlorthalidone (11), indapamide (370) and acetazolamide (74).

No local cases of choroidal effusion, acute myopia or acute angle-closure glaucoma following the use of these diuretics have been reported to NPRA thus far.  However, there was one (1) report of visual acuity reduced for products containing indapamide, as well as 21 reports of vision blurred/visual disturbance/visual impairment/abnormal vision and two (2) reports of eye pain for products containing hydrochlorothiazide.

 

Advice for Healthcare Professionals

• Be vigilant on the risk of choroidal effusion, acute myopia, and acute angle-closure glaucoma with sulfonamide diuretics use, especially in patients with risk factors including a history of sulfonamide or penicillin allergy.
• Advise patients to seek medical attention immediately if they experience eye symptoms such as blurred vision, decreased visual acuity or eye pain within hours to weeks of drug initiation. Prompt recognition of symptoms and immediate drug discontinuation frequently resolve these transient conditions.
• Acute angle-closure glaucoma can lead to permanent vision loss if left untreated. Consider prompt medical or surgical treatments if the intraocular pressure remains uncontrolled.
• Avoid using acetazolamide in cases of sulfonamide-induced angle closure glaucoma given potential cross-reactivity and exacerbation of the underlying process.
• Report all suspected adverse events associated with products containing hydrochlorothiazide, chlorthalidone, indapamide and acetazolamide to the NPRA.

 

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (5) Jld.1] has been issued for all registration holders of products containing above-mentioned diuretics 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). The Malaysian Product Registration Database (QUEST). HYDROCHLORZIDE [Package Insert]. 2019 Sep [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). APO-HYDROCHLOROTHIAZIDE [Package Insert]. 2021 Oct [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
3. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). NATRILIX SR [Package Insert]. 2021 Jun [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
4. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). PRETENOL-C [Package Insert]. 2022 Jan [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
5. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). APO-ATENIDONE [Package Insert]. 2016 Sep [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
6. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). APO-ACETAZOLAMIDE [Package Insert]. 2018 Jan [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
7. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Acetazolamide 500mg powder for solution for injection [Package Insert]. 2010 Nov [cited 2022 Mar 1]. Available from: http://www.npra.gov.my (access restricted)
8. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2021 [cited 2021 Oct 28]. Available from: https://www.npra.gov.my
9. Health Canada. Summary safety review - diuretics, including acetazolamide-containing products [Internet]. 2021 Mar [cited 2022 Mar 1]. Available from: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00261
10. Health Canada. Health Product Info Watch [Internet]. 2021 Mar [cited 2022 Mar 1]. Available from: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/medeffect-canada/health-product-infowatch/Mar-2021/hpiw-ivps_2021-03-eng.pdf
11. Reddy AC, Salim S. Diagnosis and management of choroidal effusions. Ophthalmic Pearls [Internet]. 2012 [cited 2022 Mar 1]. Available from: https://www.aao.org/eyenet/article/choroidal-effusions
12. National Health Service (NHS). Short-sightedness (myopia) [Internet]. 2018 Jul [cited 2022 Mar 1]. Available from: https://www.nhs.uk/conditions/short-sightedness/
13. Khazaeni B, Khazaeni L. Acute closed angle glaucoma. StatPearls Publishing [Internet]. 2022 Jan [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/28613607/
14. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 9-12 March 2020 PRAC meeting [Internet]. 2020 April 6 [cited 2022 Mar 1]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-9-12-march-2020-prac-meeting_en.pdf
15. Kang YK, Son BJ, Park DH, Shin JP. Angiographic features of drug-induced bilateral angle closure and transient myopia with ciliochoroidal effusion. BMC Ophthalmology. 2019;19(1):213. Available from: https://doi.org/10.1186/s12886-019-1230-y
16. Parthasarathi S, Myint K, Singh G, Mon S, Sadasivam P, Dhillon B. Bilateral acetazolamide-induced choroidal effusion following cataract surgery. Eye. 2007;21:870–872. Available from: https://doi.org/1038/sj.eye.6702741
17. Wu A, Khawaja AP, Pasquale LR, Stein JD. A review of systemic medications that may modulate the risk of glaucoma. Eye (Lond). 2020 Jan;34(1):12-28. Available from: https://dx.doi.org/10.1038%2Fs41433-019-0603-z
18. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Mar 1]. 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: Ng Chiew Seng
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli