Pharmacovigilance analysis of melanoma adverse events in men treated with sildenafil for erectile dysfunction
Muhieddine Labban, MD1, David-Dan Nguyen, MPH1, Elio Adib, MD1, Kevin R Melnick, MD1, Alexander P. Cole, MD1, Stuart R. Lipsitz, ScD1, Toni K. Choueiri, MD2, Quoc-Dien Trinh, MD1.
1Brigham and Women's Hospital, BOSTON, MA, USA, 2Dana-Farber Cancer Institute, BOSTON, MA, USA.
BACKGROUND: Phosphodiesterase type-5 inhibitors are the first line of treatment for erectile dysfunction. In 2016, the Food and Drug Administration issued a warning regarding a possible association between phosphodiesterase type-5 inhibitors and melanoma. It is postulated that melanoma is associated with BRAF gene mutations resulting in the downregulation of the phosphodiesterase-type 5 pathway. In their latest update, the Food and Drug Administration stated that no action is necessary based on the available information. Therefore, we sought to conduct a pharmacovigilance analysis to examine the association between phosphodiesterase type-5 inhibitors and melanoma and to identify potential confounders.
METHODS: We collected spontaneous adverse drug reactions for men who used sildenafil for erectile dysfunction captured in VigiBase (1968-2019), the World Health Organization's global database of individual case safety reports. Our primary endpoint was cutaneous or ocular melanoma. The disproportionality signal for melanoma with sildenafil use was reported using the reporting odds ratio (ROR), the odds of having the adverse event (melanoma) with the drug of interest (sildenafil) compared to the odds of the same event occurring with all other drugs in the database. The ROR was only reported if the empirical Bayes estimator, a more robust measure of association for rare events, met the threshold value for signal detection. We examined confounding by (1) indication, (2) dose, (3) age at report submission, (4) region, (5) stimulated reporting before and after 2014 when there was a sharp increase in awareness about the topic, (6) another phosphodiesterase type-5 inhibitor (tadalafil), (7) drugs prescribed for erectile dysfunction with different mechanisms of action (prostaglandin E1, testosterone, and papaverine), (8) drugs unrelated to erectile dysfunction but prescribed among the same age group (tamsulosin, metoprolol, and metformin), and (9) drugs associated with non-melanoma skin cancer (irbesartan and valsartan).
RESULTS: We identified 11,250 reports of cutaneous and/or ocular melanoma, of which 763 (6.9%) were reported with sildenafil use among men. Among men who used sildenafil, most reports were among men 45-64 years of age (21.8%), originated from the Americas (99.6%), and were reported after 2015 (99.5%). We found a significant disproportionality signal of melanoma reports with sildenafil use for erectile dysfunction (ROR 90.0, 95%CI 80.6-100.4). More reports were recorded among men ≥45 years (ROR 34.8, 95%CI 30.8-39.3) and after 2014 (ROR 98.8, 95%CI 91.0-107.2). We also found a dose-response relationship with higher doses of sildenafil (≥50 mg) being associated with melanoma (ROR 12.3, 95%CI 9.5-15.9), but not lower doses. Similar trends were found for tadalafil across confounding variables. Other drugs with different mechanisms of action used for erectile dysfunction, drugs unrelated to the condition but prescribed among the same age group, and drugs associated with non-melanoma skin cancer did not meet the threshold for significance.
CONCLUSIONS: Herein, we found that phosphodiesterase type-5 inhibitors prescribed for erectile dysfunction are associated with cutaneous and ocular melanoma. While there may be confounding by age, region, dose, and stimulated reporting, our results support the need to keep sildenafil on the Food and Drug Administration's list of drugs with potential signals of serious risks.
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