Ingenol Mebutate Is Associated With Increased Reporting Odds for Squamous Cell Carcinoma in Actinic Keratosis Patients, a Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

Background: Recently the production and marketing of ingenol mebutate in the European Union (EU) and Canada was halted due to a possible increased risk of squamous cell carcinoma (SCC) in patients with actinic keratosis (AK).

Objective: To investigate the relationship between SCC and topical AK medications including ingenol mebutate in the FDA Adverse Event Reporting System (FAERS).

Methods: Case/non-case analyses were performed in FAERS using data from 2012 to 2020 to examine the reporting odds ratio (ROR) signal for SCC for ingenol mebutate and all classes of topical AK medications under multiple conditions: i. comparison to all other drugs in FAERs, ii. comparison to other topical AK medications, iii. comparison to all other topical AK medications where only a single agent was implicated, iv. comparison of ingenol mebutate vs. imiquimod.

Results: A statistically significant ROR for SCC was found for ingenol mebutate under all conditions (i. 31.57 (25.45, 39.16), ii. 50.35 (32.21, 78.82), iii 61.09 (35.36, 105.56), iv. 2.53 (1.27, 5.05). A significant but substantially smaller signal was observed for imiquimod (i. 12.38 (6.42, 32.84), ii. 5.18 (2.61, 10.26), iii 5.42 (2.49, 11.78), but not for fluorouracil or diclofenac. When compared to imiquimod directly, ingenol mebutate had a statistically significant ROR for SCC (2.53 (1.27, 5.05).

Conclusion: Our findings support an association between SCC and ingenol mebutate. This association is maintained under controls to limit bias and falsely elevated signal including controlling for disease state and cases with multiple drug exposures and when compared to imiquimod as in Phase IV studies of ingenol mebutate.