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 of Product

Itraconazole is a broad-spectrum antifungal agent indicated for the treatment of a wide range of fungal infections.¹ In Malaysia, six products containing itraconazole are registered with the Drug Control Authority (DCA), available as oral formulations (capsules and solution).²

 

Overview of Safety Concern

Pseudoaldosteronism is a clinical syndrome that mimics hyperaldosteronism and is characterised by hypertension, hypokalaemia, metabolic alkalosis, and suppressed plasma renin activity in the absence of elevated aldosterone levels.^3,4 It can result from specific genetic mutations or exposure to certain medications or substances.^3-5

Itraconazole has been associated with pseudoaldosteronism.⁶ Health care professionals should be aware of this potential adverse effect, particularly in patients who develop new-onset or worsening hypertension and hypokalaemia during itraconazole treatment.

 

Source of Safety Concern

The National Pharmaceutical Regulatory Agency (NPRA) received information from the Pharmaceuticals and Medical Devices Agency (PMDA), Japan, regarding the risk of pseudoaldosteronism associated with the use of itraconazole.^7,8 PMDA’s comprehensive assessment was based on its pharmacovigilance database, which included adverse event reports from Japan and overseas. Based on cases where a causal relationship between itraconazole and pseudoaldosteronism was considered reasonably possible, PMDA determined that regulatory action was warranted to address this risk.

 

Background of the Safety Issue

Although the exact mechanism is not fully understood, itraconazole may inhibit the steroid-metabolising enzyme cytochrome P450 11β-hydroxylase (CYP11B1).^5,9 However, its potent inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is considered the predominant mechanism underlying itraconazole-induced pseudoaldosteronism. Inhibition of 11β-HSD2, exacerbated by its major active metabolite, hydroxyitraconazole, reduces the conversion of cortisol to cortisone, thereby increasing cortisol-mediated activation of the mineralocorticoid receptor (MR).^5,9,10 This results in excessive MR activation despite low or suppressed aldosterone levels, leading to sodium and fluid retention, hypertension, and hypokalaemia.^5,9

Evidence suggests that this adverse effect may be dose-related, with higher doses associated with a greater frequency of hypertension and hypokalaemia.^10-12 However, pseudoaldosteronism has also been reported at therapeutic doses as low as 100 mg/day, indicating that a threshold dose below which the risk can be excluded has not been established.¹¹ The condition typically occurs during prolonged treatment, but onset has been observed within weeks of initiating treatment.^10,11

 

Local Adverse Drug Reaction Reports¹³

To date, the NPRA has received 232 reports involving 396 adverse events suspected to be related to itraconazole-containing products. None of these cases involved reports of pseudoaldosteronism associated with the use of itraconazole.

 

Regulatory Action

The NPRA has completed a review of the risk of pseudoaldosteronism associated with itraconazole. On 16 June 2026, a directive [NPRA.600-1/9/13(11) Jld. 2] was issued requiring all registration holders of itraconazole-containing products to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to include this safety information.

 

Advice for Health Care Professionals

• Be aware that itraconazole may cause pseudoaldosteronism, characterised by new-onset or worsening hypertension, hypokalaemia and peripheral oedema.
• Monitor blood pressure and serum potassium levels regularly during itraconazole treatment.
• If pseudoaldosteronism is suspected, consider discontinuing itraconazole and initiate an appropriate alternative antifungal therapy if ongoing treatment is required.
• Correct electrolyte abnormalities and manage hypertension as clinically indicated.
• Report all suspected adverse events related to itraconazole use to the NPRA.

 

References

1. Kurn H, Wadhwa R. Itraconazole [Internet]. Treasure Island (FL): StatPearls Publishing. 2023 [cited 2026 May 2]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557874/
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2026 [cited 2026 Jan 29] Available from: https://www.npra.gov.my
3. Rizzolo K, Beck NM, Ambruso SL. Syndromes of pseudo-hyperaldosteronism. Clin J Am Soc Nephrol. 2022 Apr;17(4):581-584. Available from: https://doi.org/10.2215/cjn.14201021
4. Armanini D, Calò L, Semplicini A. Pseudohyperaldosteronism: pathogenetic mechanisms. Crit Rev Clin Lab Sci. 2003;40(3):295-335. Available from: https://doi.org/10.1080/713609355
5. Beck KR, Telisman L, Van Koppen CJ, Thompson GR, Odermatt A. Molecular mechanisms of posaconazole- and itraconazole-induced pseudohyperaldosteronism and assessment of other systemically used azole antifungals. J Steroid Biochem Mol Biol. 2020 May;199:105605. Available from: https://doi.org/10.1016/j.jsbmb.2020.105605
6. United States Food and Drug Administration (US FDA). Sporanox (itraconazole) [Package Insert]. Drugs@FDA. 2024 Dec [cited 2026 Apr 30]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/
7. Pharmaceuticals and Medical Devices Agency. Summary of investigation results: Itraconazole. [Internet]. 2024 Feb 15. [cited 2024 Apr 23]. Available from: https://www.pmda.go.jp/files/000266908.pdf
8. Pharmaceuticals and Medical Devices Agency. Revision of PRECAUTIONS: Itraconazole. [Internet]. 2024 Feb 15. [cited 2024 Apr 23]. Available from: https://www.pmda.go.jp/files/000266904.pdf
9. Jäger MC, Joos FL, Winter DV, Odermatt A. Characterization of the interferences of systemic azole antifungal drugs with adrenal steroid biosynthesis using H295R cells and enzyme activity assays. Curr Res Toxicol. 2023;5:100119. Available from: https://doi.org/10.1016/j.crtox.2023.100119
10. Hoffmann WJ, McHardy I, Thompson GR. Itraconazole induced hypertension and hypokalemia: mechanistic evaluation. Mycoses. 2018 May;61(5):337-339. Available from: https://doi.org/10.1111/myc.12749
11. Brandi SL, Feltoft CL, Serup J, Eldrup E. Pseudohyperaldosteroism during itraconazole treatment: a hitherto neglected clinically significant side effect. BMJ Case Rep. 2021 Jun 18;14(6):e243191. Available from: https://doi.org/10.1136/bcr-2021-243191
12. DiPippo AJ, Kontoyiannis DP. Azole-associated pseudohyperaldosteronism: a class effect or azole-specific? Clin Infect Dis. 2020 Jul 15;71(2):467-468. Available from: https://doi.org/10.1093/cid/ciz944
13. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2026 [cited 2026 Jan 29]. Available from https://www.npra.gov.my (access restricted)

 

Written by: Nafiza Mohd. Ismail

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali