Spontaneous reporting of serious cutaneous reactions with protein kinase inhibitors

Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not. We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010. Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand-foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6 +/- 15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib. Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors.