Background and importance Ingenol mebutate was granted a marketing authorisation from European Medicines Agency (EMA) to treat actinic keratosis. On 30 April 2020, due to an increased risk in provoking skin cancer in treated patients compared with imiquimod, the EMA withdrawn it after a safety data review. The final results of the 3 year safety study (NCT01926496) in 484 patients showed that, among skin malignancies, squamous cell carcinoma (SCC) had a higher incidence with ingenol mebutate gel compared with imiquimod (3.3% versus 0.4% of patients).

Aim and objectives This study aimed to evaluate the safety issue (signal) of increased occurrence of skin malignancy (eg, SCC of the skin) during therapy with ingenol mebutate by mining of the FDA Adverse Event Reporting System (FAERS) database.

Material and methods By querying the FAERS database, we searched for cases of SCC associated with ingenol mebutate using the following MedDRA preferred terms (PTs) ‘squamous cell carcinoma of skin’, ‘skin squamous cell carcinoma metastatic’ and ‘skin squamous cell carcinoma recurrent’. With a contingency table, we computed the PRR to evaluate the strength of association between SCC and ingenol mebutate.

Results We found the following co-occurrence data: ingenol mebutate/SCC (DE)=90 reports, ingenol mebutate/other ADR (De)=5128, other drugs/SCC (dE)=2882 and other drugs/other ADR (de)=13 899 084 from 2012 to 2020. The two by two contingency table showed a value for PRR of 44.4105 (95% CI 33.332 to 59.1711, p<0.001). Assessment of SCC reports revealed that all ADR were serious and resulted in different outcomes: 80% other outcomes, 11.11% life threatening, 6.6% hospitalised and 2.2% disabled. Patients affected were aged 65–85 years (56.6%), 18–64 years (23.3%), >85 years (7.7%) and not specified (12.2%); 75.6% were men and 23.3% women.

Conclusion and relevance Disproportionality analysis showed that the ingenol mebutate–SCC pair was reported more often than expected. Based on this statistical association, our data confirmed the safety signal evaluated by the EMA that led to the withdrawal of ingenol mebutate from the EU market. In addition, it raises the question of why the FDA has not revoked the marketing authorisation of the drug in the USA.

References and/or acknowledgements

1. https://clinicaltrials.gov/ct2/show/NCT01926496

2. https://www.ema.europa.eu/en/documents/referral/picato-article-20-referral-risks-picato-actinic-keratosis-outweigh-benefits_en.pdf

Conflict of interest No conflict of interest