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How Safe Are Recently FDA ‐Approved Antimicrobials? A Review of the FDA Adverse Event Reporting System Database
Author(s) -
Khadem Tina M.,
Manen Robbert P.,
Brown Jack
Publication year - 2014
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1519
Subject(s) - medicine , adverse event reporting system , adverse effect , database , sofosbuvir , darunavir , pharmacology , virology , human immunodeficiency virus (hiv) , computer science , antiretroviral therapy , viral load , hepatitis c virus , virus , ribavirin
Study Objective To review quantitatively and qualitatively the U.S. Food and Drug Administration ( FDA ) Adverse Event Reporting System ( AERS ) database to provide clinicians with a general understanding of the comparative occurrence of clinically meaningful adverse events associated with 15 antimicrobial new molecular entities approved by the FDA since 2006: anidulafungin, darunavir, maraviroc, raltegravir, doripenem, telavancin, ceftaroline, boceprevir, telaprevir, fidaxomicin, bedaquiline, dolutegravir, simeprevir, sofosbuvir, and dalbavancin. Design Retrospective analysis. Data Source FDA AERS database. Measurements and Main Results Empirica Signal software was used to query the AERS database from November 1968 to December 2012. Using disproportionality analyses, we calculated a relative reporting ratio ( RRR ) estimate for reports of antimicrobial adverse events. The RRR estimate compares the occurrence of a specific adverse event with an index drug of interest to the occurrence of the same adverse event with similar agents or with all other FDA ‐approved prescription drugs. Common industry practice considers an RRR meaningful if the 5th percentile of the distribution is at least 2 ( RRR 05 of 2.0 or higher). Antimicrobials were compared with agents within their respective antimicrobial therapeutic class as well as with all agents in the AERS database. Seventeen adverse signals with an RRR 05 of 2.0 or higher were identified from the database for six agents. Ten of the 17 signals were not included in the most up‐to‐date manufacturers' package inserts for four of the six agents: doripenem‐associated hepatic dysfunction ( RRR 05 3.7) and hyperchloremia ( RRR 05 2.6); boceprevir‐associated weight loss ( RRR 05 2.2); darunavir‐associated premature labor ( RRR 05 3.1), sudden infant death syndrome ( RRR 05 2.9), ventricular hypertrophy ( RRR 05 2.7), acute coronary syndrome ( RRR 05 2.4), and congenital anomaly in offspring ( RRR 05 2.4); and raltegravir‐associated congenital heart valve disorders ( RRR 05 2.5) and SIDS ( RRR 05 2.3). Conclusion Clinically meaningful adverse event signals appeared to be associated with antimicrobial new molecular entities approved since 2006 including many not yet identified in package inserts. Although a disproportionality analysis suggests a quantitative signal for these associations, causality cannot be inferred from the data. Due to several key limitations in this type of analysis, investigative studies are needed to further explore these adverse event signals and the potential mechanisms by which they occur.