Adverse reactions of PDE5 inhibitors: An analysis of the World Health Organization pharmacovigilance database.
Level 4 - case-series / case-control
Case-non-case disproportionality study of a spontaneous adverse event reporting database
PubMed 36905319 · doi:10.1111/andr.13430
What was done
Researchers performed a case-non-case disproportionality study using the World Health Organization global pharmacovigilance database (VigiBase) from 1983 to 2021. They extracted individual case safety reports for men taking sildenafil, tadalafil, vardenafil, or avanafil, and conducted a specific subset analysis on adult men (≥18 years old) using oral PDE5 inhibitors for sexual dysfunction. Reporting odds ratios (ROR) with 95% confidence intervals (CI) were calculated for reported adverse drug reactions, with a focus on priapism and malignant melanoma, and adverse reaction frequencies were compared against safety data from Food and Drug Administration (FDA) clinical trials.
What was found
A total of 94,713 reports for PDE5 inhibitors were identified, including 31,827 reports for adult men with sexual dysfunction. In this subset, the most common adverse reactions were poor drug efficacy (42.5%), headache (10.4% vs. 8.5%–27.6% FDA), abnormal vision (8.4% vs. ≤4.6% FDA), flushing (5.2% vs. 5.1%–16.5% FDA), and dyspepsia (4.2% vs. 3.4%–11.1% FDA). Disproportionality analysis revealed significant signals for priapism with sildenafil (ROR = 13.81, 95% CI: 11.75–16.24), tadalafil (ROR = 14.54, 95% CI: 11.56–18.06), and vardenafil (ROR = 14.12, 95% CI: 8.36–22.35). Significant disproportionality signals for malignant melanoma were also found for sildenafil (ROR = 8.73, 95% CI: 7.63–9.99) and tadalafil (ROR = 4.25, 95% CI: 3.19–5.55) compared to other medications in VigiBase.
Why it matters
This study provides large-scale international surveillance data confirming robust statistical signals for rare adverse outcomes, specifically priapism and malignant melanoma, across multiple PDE5 inhibitors.
Limits
Spontaneous reporting databases are prone to underreporting, duplicate entries, reporting bias, and lack of complete clinical history. Disproportionality analysis measures reporting association rather than true incidence or absolute clinical risk, and it cannot establish causation or control for confounding factors such as dosage, incorrect use, or underlying medical conditions.
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