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.

Overview

Proton pump inhibitors (PPIs) are common medications used to treat gastrointestinal acid-related disorders.¹ They work on the parietal cells in the stomach by selectively blocking the hydrogen-potassium ATPase channels through covalent binding with the cysteine residue of the proton pump. This action blocks the secretion of gastric acid, enabling the healing of peptic ulcers, gastroesophageal reflux disease (GERD), and other related disorders.

In Malaysia, there are currently 6 PPIs—pantoprazole (30 products), omeprazole (20), esomeprazole (19), rabeprazole (4), lansoprazole (3), and dexlansoprazole (2)—registered with the Drug Control Authority (DCA).² These registered PPIs are available in oral or injection dosage forms, either as single-ingredient products, fixed-dose combinations, or combination packs. 

Erectile dysfunction (ED) is characterised by a consistent or recurrent inability to attain and/or maintain a penile erection sufficient for sexual performances.³ It predominantly affects older men over 40 years old and is closely linked with underlying risk factors such as coronary artery disease, diabetes mellitus, hypertension, obesity, smoking, and use of certain medications.⁴

Background of the Safety Issue 

The National Pharmaceutical Regulatory Agency (NPRA) received safety notifications from local product registration holders about the new labelling requirements by the United States Food and Drug Administration (US FDA) regarding the risk of ED associated with PPIs. This safety issue was identified as a potential signal arising from the FDA Adverse Event Reporting System (FAERS).⁵ The US FDA determined that the product information for all PPI-containing products, including combination products and combination packs, should be updated to include information on the risk of ED.⁶ 

Several mechanisms behind PPIs-induced ED have been suggested in the literature.^4,7 Firstly, the induction of the CYP3A4 enzyme by PPIs may result in lower testosterone levels in some patients. Another hypothesis proposes that PPIs can impair the production of endothelial nitric oxide, which plays a role in erectile function, thereby leading to ED. Additionally, it has been suggested that altered function of calcium channels may inhibit the spontaneous contraction of the corpus cavernosum. 

Current medical literature associating ED as a potential adverse effect of PPIs is limited.⁴ A report by the Netherlands Pharmacovigilance Centre Lareb identified 17 cases of ED suspected to be linked to omeprazole use between 1992 and 2015.⁷  The reported time to onset of ED ranged from 1 day to 6 months, primarily manifesting within 1 month following the initiation of omeprazole treatment. Of these cases, 8 positive dechallenges and 2 positive rechallenges were reported. Three cases did not recover; however, the majority of the patients either recovered or showed signs of recovery from ED.

Adverse Drug Reaction Reports⁸ 

To date, the NPRA has received 1,372 reports with 2,517 adverse events suspected to be related to PPI-containing products. There have been no reported local cases of erectile dysfunction associated with PPI use.

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing ADR reports of erectile dysfunction associated with the use of PPIs.
• When a patient presents with ED, it is important to obtain medication history, in addition to gathering information about underlying illnesses that may predispose them to ED.
• If a patient experiences ED while receiving PPI therapy, consider a PPI as a potential cause of ED, especially in young and healthy patients.
• If an alternative aetiology cannot be established, consider discontinuing the PPI and opting for alternative medications.
• Report all adverse events suspected to be related to the use of PPIs-containing products to the NPRA.

References:

1. Ashfaq M, Haroon MZ, Alkahraman YM. Proton pump inhibitors therapy and risk of hyperprolactinemia with associated sexual disorders. Endocr Regul. 2022 Apr 30;56(2):134-147. Available from: https://doi.org/10.2478/enr-2022-0015
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Jan 31]. Available from: https://quest3plus.bpfk.gov.my/pmo2/index.php
3. Samajdar SS, Mukherjee S, Saha D, Jumani D, Tripathi SK. Drug-Induced erectile dysfunction: Two interesting cases. Journal of Pharmacology and Pharmacotherapeutics. 2021 Dec;12(4):177-9. Available from: https://doi.org/10.4103/jpp.jpp_129_21
4. Perry TW. Abrupt-onset, profound erectile dysfunction in a healthy young man after initiating over-the-counter omeprazole: a case report. J Med Case Rep. 2021 Jul 24;15(1):360. Available from: https://doi.org/10.1186/s13256-021-02981-5
5. United States Food and Drug Administration (FDA). October - December 2021 Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. 2022 Apr 6 [cited 2023 27 Oct]. Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/october-december-2021-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
6. United States Food and Drug Administration (FDA). Drug Safety-related Labeling Changes (SrLC): rabeprazole, omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole [Internet] 2023 [cited 2023 Nov 1]. Available from: https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/
7. Bijwerkingen Centrum Lareb. Omeprazole and erectile dysfunction- an update [Internet]. 2015 Nov 27 [cited 2024 Feb 2]. Available from: https://databankws.lareb.nl/Downloads/Signals_2015_Omeprazole_erect.pdf
8. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Feb 1]. 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