Hepatotoxicity with Vismodegib: An MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project

Abstract

BackgroundOn 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma.ObjectiveOur objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers.MethodsFAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched.ResultsTwo cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website.ConclusionWe identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0168-2) contains supplementary material, which is available to authorized users.

Autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors for cancer: 68 cases from the Food and Drug Administration database and review

“…The mechanism by which CPIs cause AIHA is likely by augmenting or redirecting immune surveillance. This mechanism of action is different from other drug‐induced AIHA where a drug (often a cephalosporin) is absorbed to the red blood cell membrane which then triggers the development of autoantibodies to the red cell membrane, or when a drug neoantigen cross reacts with a red cell antigen (for example methyl dopa) . It is speculated that CPIs cause a random activation of the immune system resulting in the formation of autoantibodies, activation of T‐cell clones, and diminishing the function of regulatory T cells .…”

“…The FDA database of adverse events is a voluntary reporting system and has been found useful for the detection of rare or uncommon side effects in chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors . Other unexpected adverse events discovered in the FDA database are cholestasis following temozolomide and liver toxicity following vismodegib . Underreporting may occur if a patient suffers from multiple comorbidities or if the physicians treating an adverse event are not involved in the previous treatment.…”

“…29 Other unexpected adverse events discovered in the FDA database are cholestasis following temozolomide 30 and liver toxicity following vismodegib. 31,32 Underreporting antigen (for example methyl dopa). 31,32 It is speculated that CPIs cause a random activation of the immune system resulting in the formation of autoantibodies, activation of T-cell clones, and diminishing the function of regulatory T cells.…”

Hepatotoxicity Associated With Vismodegib

“…Ash and Jolly reported a case of acute liver injury due to the interaction between vismodegib, aspirin and naproxen, so concomitant use of hepatotoxic drugs with vismodegib can easily increase the susceptibility 8. Three cases of vismodegib associated severe liver dysfunction were published by the Australian Therapeutic Goods Administration 7. Ninety four patients with vismodegib-induced liver dysfunction were reported on FDA Adverse Events Reporting System and 35 of them were found to have severe liver 7.…”

“…Three cases of vismodegib associated severe liver dysfunction were published by the Australian Therapeutic Goods Administration 7. Ninety four patients with vismodegib-induced liver dysfunction were reported on FDA Adverse Events Reporting System and 35 of them were found to have severe liver 7. LiverTox as also listed hepatotoxicity as its adverse effect 9.…”