Department of Urology, University of California San Francisco, San Francisco, California, USA.
Department of Urology, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.
Andrology. 2023 Oct;11(7):1408-1417. doi: 10.1111/andr.13430. Epub 2023 Mar 22.
Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors.
To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma.
In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction.
A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma.
Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.
尽管磷酸二酯酶 5 抑制剂具有疗效和总体安全性，但仍与罕见但严重的药物不良反应有关。
确定口服磷酸二酯酶 5 抑制剂的安全性概况，特别关注阴茎异常勃起和恶性黑色素瘤。
在本病例对照研究中，我们在世界卫生组织全球个体病例安全报告数据库（VigiBase）中查询了 1983 年至 2021 年间磷酸二酯酶 5 抑制剂的个体病例安全报告。我们纳入了所有男性使用西地那非、他达拉非、伐地那非和阿伐那非的个体病例安全报告。为了比较，我们还从这些药物的食品和药物管理局试验中提取了安全性数据。我们通过测量最常见药物不良反应的报告比值比，评估磷酸二酯酶 5 抑制剂的安全性概况，一次是所有磷酸二酯酶 5 抑制剂报告，另一次是口服磷酸二酯酶 5 抑制剂在有性功能障碍的成年男性（≥18 岁）中的使用报告。
共提取了 94713 份磷酸二酯酶 5 抑制剂的个体病例安全报告。共确定了 31827 份与成年男性使用口服西地那非、他达拉非、伐地那非或阿伐那非治疗性功能障碍有关的个体病例安全报告。最常见的药物不良反应包括药物疗效不佳（42.5%）、头痛（10.4%[食品和药物管理局]）、视力异常（8.4%[食品和药物管理局]）、潮红（5.2%[食品和药物管理局]）和消化不良（4.2%[食品和药物管理局]）。阴茎异常勃起与西地那非（报告比值比=13.81，95%置信区间：11.75-16.24）、他达拉非（报告比值比=14.54，95%置信区间：11.56-18.06）和伐地那非（报告比值比=14.12，95%置信区间：8.36-22.35）有显著信号。与 VigiBase 中的其他药物相比，西地那非（报告比值比=8.73，95%置信区间：7.63-9.99）和他达拉非（报告比值比=4.25，95%置信区间：3.19-5.55）的报告比值比显著更高恶性黑色素瘤。
磷酸二酯酶 5 抑制剂在大型国际队列中显示出与阴茎异常勃起相关的显著信号。需要进一步的临床研究来阐明这是由于正确或不正确使用还是其他混杂条件引起的，因为药物警戒数据分析不允许量化临床风险。此外，磷酸二酯酶 5 抑制剂的使用与恶性黑色素瘤之间似乎存在关联，这需要进一步研究以更好地了解其因果关系。
