Pharmacovigilance Analysis of Serious Adverse Events Reported for Biologic Response Modifiers Used as Prophylaxis against Transplant Rejection: a Real-World Postmarketing Experience from the US FDA Adverse Event Reporting System (FAERS)

AK Ali


Background: Immunosuppression by biologic response modifiers (BRM) is a crucial component for successful organ transplantation. In addition to their variable effectiveness in the prevention of organ rejection, these medications have safety concerns that complicate therapeutic outcomes in organ transplant patients.

Objective: This study aims at identifying and characterizing safety signals of serious adverse events associated with exposure to BRM among organ transplant patients in a real-world environment.

Methods: The FDA Adverse Event Reporting System was utilized to apply a pharmacovigilance disproportionality analysis to indentify serious adverse events. Associations between drugs and events were measured by empirical Bayes geometric mean (EBGM) and the corresponding 95% confidence intervals (EB05–EB95). Associations with EBGM≥2 were considered significant safety signals.

Results: From 1997 to 2012, a total of 12,151 serious adverse event reports for BRM were reported; 15.6% of them (n=1,711) met the safety signal threshold of EB05>1, and 11.6% of these signals (n=199) were significant (EBGM≥2). Sirolimus and mycophenolate accounted for the majority of all signals; antithymocyte immunoglobulin (ATI) and cyclosporine contributed to the majority of significant signals. The following significant signals were identified for ATI (reduced therapeutic response, pulmonary edema, hypotension, serum sickness, infusion-related reaction, and anaphylactic reaction); for azathioprine (alternaria infection, fungal skin infection, and lymphoproliferative disorder); for cyclosporine (neurotoxicity, graft vs. host disease, and thyroid cancer); for cyclophosphamide (disease progression); for daclizumab (cytomegalovirus infection); and for tacrolimus (coma and tremor). 33.6% of these events contributed to patient death (n=67); 6.5% were life-threatening (n=13); 32.1% lead to hospitalization (n=64); and 27.6% resulted in other serious outcomes (n=55).

Conclusion: Utilization of BRM for the prophylaxis against transplant rejection is associated with serious adverse events that could be fatal.


Immunosuppressive medications; Biologic response modifiers; Pharmacovigilance; Serious adverse events; FAERS

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 pISSN: 2008-6482
 eISSN: 2008-6490


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