Ethinylestradiol and norethindrone may be associated with more than a 200-fold increased risk of melasma, according to a study analyzing two decades of U.S. Food and Drug Administration pharmacovigilance data.

In the pharmacovigilance study, published in BMC Pharmacology and Toxicology, investigators analyzed drug-associated melasma using real-world data from the FDA Adverse Event Reporting System (FAERS). The study represented a comprehensive evaluation of melasma as a drug-related adverse event using a large-scale pos-marketing surveillance database.

Lead study author Yaxin Qu, of the Department of Dermatology at the Guang’anmen Hospital at the China Academy of Chinese Medical Sciences, and colleagues, retrospectively reviewed adverse event reports submitted to FAERS between the first quarter of 2004 and the second quarter of 2024. After excluding duplicate entries, a total of nearly 18.2 million unique reports were assessed. Among these, 408 reports were specifically linked to melasma. 

The majority of melasma cases occurred in female patients (84.8%), with the highest prevalence among those aged 18 to 35 years (23.5%). Reports originated predominantly from the United States (57.4%), followed by the United Kingdom (5.6%) and France (4.7%). 

Among the 126 unique drugs evaluated, 22 met criteria for significant association with melasma across all analytical models. Notably, hormonal agents constituted 12 of the 22 drugs.

The strongest signal was observed for the contraceptive combination ethinylestradiol and norethindrone. Other highly ranked combinations included ethinylestradiol with norelgestromin (n = 44) and with levonorgestrel (n = 66). Nonhormonal agents such as isotretinoin, imatinib, and paroxetine also showed significant associations.

The findings support a robust pharmacovigilance signal linking hormonal therapies—particularly combined oral contraceptives—to melasma. While the study was limited by the voluntary nature of reporting and missing clinical data, the investigators noted the need for clinicians to monitor for drug-induced pigmentation disorders and to counsel patients accordingly.

The researchers reported no competing interests.