key: cord-0884243-yw4yxgnd
authors: Dauner, Daniel G.; Dauner, Kim Nichols
title: Summary of Adverse Drug Events for Hydroxychloroquine, Azithromycin, and Chloroquine During the COVID-19 Pandemic
date: 2021-01-11
journal: J Am Pharm Assoc (2003)
DOI: 10.1016/j.japh.2021.01.007
sha: ea4991e84b920f6fd4df89de378683321dba7918
doc_id: 884243
cord_uid: yw4yxgnd

Objective Given the increased use of hydroxychloroquine (HCQ), chloroquine (CQ), and azithromycin (AZM) during the early months of the SARS-CoV-2 (COVID-19) pandemic, there is a need to evaluate associated safety concerns. The objective of the study was to summarize the adverse drug events (ADEs) associated with HCQ, CQ, and AZM use during the COVID-19 national emergency declaration and compare the results to known adverse reactions listed in the drugs’ package inserts. Methods A cross-sectional study design was used. The publicly available Food and Drug Administration Adverse Event Reporting System quarterly data extract files from January 1, 2020 through June 30, 2020 were downloaded. A disproportionality analysis was conducted using the proportional reporting ratio (PRR) to identify possible ADE signals. Poisson regression was used to assess if the number of ADE reports for the three drugs increased over time. Results There was a significant increasing trend in reported ADEs for both HCQ (p < 0.001) and AZM (p < 0.001). Before the national emergency declaration, there were 592 reported ADEs for the three drugs compared to 2,492 ADEs reported since March 13, 2020. Fifty-nine (51.8%) ADEs were listed in the prescribing information, and the remaining 55 (48.2%) were not listed representing possible signals. Conclusions Our results show the reported ADEs for HCQ and AZM have increased during the COVID-19 pandemic. Differences were observed in both the type of and frequency of the top reported ADEs for the three selected drugs before and after the national emergency declaration. Even though causation cannot be determined from ADE reports, further investigation of some reports may be warranted. Our results highlight the need for pharmacovigilance and education for health care professionals on the safety of these drugs when being used for COVID-19 prophylaxis or treatment.

hospitalized for the treatment of COVID-19. 6 On April 24, 2020 the FDA, aware of reports of 51 serious heart rhythm problems in patients with COVID-19 treated with HCQ or CQ, often in combination with AZM and other QT prolonging drugs, issued a Drug Safety Communication 53 cautioning against the use of HCQ and CQ for COVID-19 outside of the hospital or a clinical trial 54 due to a risk of heart rhythm problems. In this same communication, the FDA also stated they 55 were aware of increased outpatient prescriptions for the drugs. 7 Then, on June 15, 2020, the 56 FDA revoked the EUA 6 citing a randomized, double-blind trial that found no significant difference 57 between the drugs and placebo for post-exposure prophylaxis. 8 The revocation also cited 58 research that the drugs lacked a treatment effect. 9

Two recent studies support the FDA's initial concerns about increased outpatient 

A cross-sectional study was conducted. The FDA Adverse Event Reporting System describe ADEs that occur domestically and internationally. The publicly available FAERS 79 quarterly data extract files from January 1, 2020 through June 30, 2020 were downloaded and a the highest PRIMARYID for each report. Only the primary suspect drug from a report 83 (ROLE_COD = PS) was included in our analysis. Adverse drug event terms were standardized 84 using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. Since multiple 85 ADEs can be listed on a report and do not correspond to a specific drug, we included all listed 86 ADEs from a report in our analysis. Reports missing a primary suspect drug or that did not list 87 an ADE were excluded. To ensure we were capturing only new reports during the six-month 88 period, the date the FDA received the first version of a report (INIT_FDA_DT) had to be on or 89 after January 1, 2020. Both brand and generic names were used to identify the three drugs 

Descriptive statistics were calculated using R (v3.6.3) and Excel (Microsoft Excel for the number of ADE reports for the three drugs increased over time where time in months is the 96 independent variable and the count of ADE reports is the dependent variable. Disproportionality 97 quantifies whether ADE reports for a specific drug-ADE pair are higher than expected in 98 spontaneous ADE report data, and disproportionality analyses are commonly used in 99 pharmacovigilance. We conducted a disproportionality analysis using the proportional reporting 100 ratio (PRR). The PRR is calculated by comparing the proportion of a specified ADE for each of 101 the three drugs to the proportion of the specified ADE in all other drugs in the data set. The null 102 value for a PRR is 1, meaning that the ADE is reported just as frequently for the drug(s) of Figure 2 shows the difference in both the type of and frequency of the most frequently reported 124 ADEs for the three selected drugs before and after the national emergency declaration. Before 125 the national emergency declaration, the top three ADEs were maternal exposure during 126 pregnancy (n=30), drug ineffective (n=24), and premature baby (n=19). After, the top three Table 1 contains the results of the PRR analysis for the period after the national 130 emergency declaration (March 13 -June 30, 2020). Overall, there were 708 unique preferred 131 terms (PTs) from 2,492 reported drug-ADE pairs. One hundred fourteen (13.4%) ADEs were 132 potential signals. Fifty-nine (51.8%) were listed in the prescribing information, and the remaining 

Our results suggest that about half of the ADEs might have been prevented given they 

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