Ingenol Mebutate Is Associated With Increased Reporting Odds for SCC in Patients With Actinic Keratosis

TAKE-HOME MESSAGE

• The association between topical medications used for the treatment of actinic keratosis and the development of squamous cell carcinoma (SCC) was queried in the FDA Adverse Event Reporting System. A statistically significant reporting odds ratio signal for SCC was found for ingenol mebutate, and a smaller signal was also found for imiquimod. No signal was found for 5-fluorouracil or diclofenac.
• There appears to be an association between the development of SCC and the use of ingenol mebutate for treating patients with actinic keratosis.

–  Kelly B. Scarberry, MD

Abstract

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.

Journal of Cutaneous Medicine and Surgery

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)

J Cutan Med Surg 2022 Dec 10;[EPub Ahead of Print], PM Jedlowski 

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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