Through our surveillance, we monitored the safety of COVID-19 drugs and evaluated potential AEs of interest across the four data sources. From 4 February, 2020, through 31 January, 2022, we identified 22,944 unique cases for inclusion in this analysis reporting an AE with a drug to treat or prevent COVID-19. Of these, we identified 21,167 in the FAERS database, 1107 in the biomedical literature, 638 in the FACT Sub-registry, and 32 in the NPDS database. A majority of these cases were reported from US sources. Variation in reporting between other countries and the USA is likely multifactorial and may include reasons such as authorization/approval status of drugs in other countries, the standard of care for treating COVID-19, and the number of literature publications varying from each country. In addition, in the USA, there are different regulatory requirements for domestic and foreign case reports. Adverse events that are both serious and unexpected (i.e., not in the drug product label), whether domestic or foreign, from all sources must be submitted to the FDA within 15 days of initial receipt of the information by the applicant. For AEs that are serious and expected or non-serious, only domestic reports must be submitted to the FDA by the applicant. Additionally, the NPDS database and the FACT Sub-registry are US-based data sources; therefore, foreign cases from these sources are not anticipated. Table 1 summarizes the descriptive characteristics of the patients described in the 22,944 cases.

Figure 1 illustrates the trend in cases reporting an AE with a drug to treat or prevent COVID-19 from 4 February, 2020 through 31 January, 2022. There were several upward trends in AE reporting during this period that appeared to correlate with the COVID-19 pandemic trajectory [21]. Early in the pandemic, prior to the issuance of any EUAs, certain drugs were used off-label to combat COVID-19, including antivirals and antimicrobials, such as lopinavir/ritonavir, azithromycin, ceftriaxone, and interferon. In addition to the overall reporting trends during this period, there were several trends observed with EUA drugs. As illustrated in Fig. 1, peaks and valleys in AE reporting for EUA drugs related to the issuance of new EUAs, shifts in variants, or revocations of EUAs. For example, the FDA issued an EUA for bamlanivimab on 9 November, 2020, which was followed by an increase in AE reporting for this product shortly thereafter in December 2020 and January 2021, followed by a sharp decline in April 2021 after revocation of the EUA of bamlanivimab because of a lack of susceptibility [22]. In addition, there are mandatory reporting requirements of all serious AEs and MEs for EUA drug products, which could be one explanation for an increase in AE reporting trends seen in Fig. 1. The trends depicted in the graph are unlikely related to changes in search strategies or the addition of new data sources, as these changes occurred early in the surveillance process prior to granting EUAs for COVID-19 products. As the pandemic evolved, changes in therapy to treat or prevent COVID-19 are reflected in the AE reporting trends.

Cases from the FDA Adverse Event Reporting System, biomedical literature, FDA-American College of Medical Toxicology COVID-19 Toxicology Investigators Consortium Pharmacovigilance Sub-registry, and the National Poison Data System reporting an adverse event with a drug to treat or prevent COVID-19 from 4 February, 2020 through 31 January, 2022. *All products, EUA and non-EUA, identified during surveillance. Monthly COVID-19 cases were calculated from the CDC COVID Data Tracker: https://covid.cdc.gov/covid-data-tracker/#trends_dailycases. BAM bamlanivimab, BCT baricitinib, CASI casirivimab, CDC Centers for Disease Control and Prevention, CIL cilgavimab, COVID coronavirus disease, CQ chloroquine, ETE etesevimab, EUA Emergency Use Authorization, HCQ hydroxychloroquine, IMDE imdevimab, MOV molnupiravir, NDA New Drug Application, NIRM nirmatrelvir, RDV remdesivir, RTV ritonavir, SOT sotrovimab, TCZ tocilizumab, TIX tixagevimab, US United States

Here forward, we focus on data collected through our heightened surveillance efforts to support actions related to certain COVID-19 EUA drugs. These actions included FDA public communications and safety-related updates to EUA FSs. Reporting frequencies, summarized in Tables 2, 3 and 4, were used to identify potential AEs of interest, which the FDA further investigated and assessed the need for regulatory action. An overview of these actions and the evidence supporting them follows.

On 28 March, 2020, the FDA issued an EUA for the antimalarial drugs, hydroxychloroquine and chloroquine, for adults and adolescents weighing ≥ 50 kg hospitalized with COVID-19 for whom a clinical trial was not available, or participation was not feasible. The FDA revoked the EUA on 15 June, 2020, after emerging scientific data, including a randomized trial, failed to show evidence of a benefit [23], prompting the National Institutes of Health to recommend against using these drugs to treat or prevent COVID-19 [24].

Cardiotoxicity, particularly when associated with the cardiac conduction system, is a known risk of hydroxychloroquine and chloroquine. Notably, prolongation of the QT interval was the most common AE reported with hydroxychloroquine and chloroquine (Table 2). Related life-threatening arrhythmias, torsades de pointes (26 cases), and ventricular fibrillation (16 cases), were also reported. An FDA evaluation of cases, which included four cases of torsades de pointes, prompted the FDA to issue a Drug Safety Communication on 24 April, 2020 (during the EUA period), reminding the public of the risk of arrhythmia and cautioning against hydroxychloroquine and chloroquine use for COVID-19 outside of the hospital setting or a clinical trial [25]. The FDA further evaluated cardiotoxicity in patients receiving these drugs for COVID-19 in a safety assessment during the EUA period, and concluded that the current hydroxychloroquine and chloroquine labeling, which describes cardiotoxicity in the Warnings and Precautions section, adequately conveyed these risks for approved indications, and further recommended an update to the chloroquine labeling to better describe cardiac electrophysiology study findings. The non-cardiac AEs were more likely related to COVID-19 infection than the use of hydroxychloroquine and chloroquine. For example, a recent study described the use of the FDA’s Sentinel System to measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability versus patients hospitalized with influenza. The authors concluded that there was a higher risk of venous thromboembolism in hospitalized patients with COVID-19 compared with hospitalized patients with influenza [26].

Remdesivir, a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor, became the first novel antiviral product issued an EUA on 1 May, 2020, and on 22 October, 2020 became the first approved treatment for COVID-19 in the USA. Hypersensitivity reactions, including infusion-related reactions (IRRs), were recognized as an important safety issue for remdesivir at the time of EUA issuance and were included in the Warnings and Precautions section of the FS for HCPs. Post-authorization AE cases received through the FAERS for remdesivir identified signs and symptoms of hypersensitivity reactions that were not included in the initial FS, including tachycardia, bradycardia, dyspnea, wheezing, angioedema, rash, and anaphylaxis. On 15 June, 2020, shortly after identification of these additional events, the FDA updated the FS to inform the medical community and public of these emerging safety issues.

Hepatotoxicity was another important safety issue for remdesivir, with liver impairment being the most frequently reported AE (Table 3). Transaminase elevations were observed across the remdesivir development program. Upon EUA issuance, the FS for HCPs included the risk of transaminase elevations in the Warnings and Precautions section with advice to discontinue or not initiate remdesivir in patients whose alanine aminotransferase (ALT) was greater than five times the upper limit of normal or who had an ALT elevation with signs or symptoms of liver inflammation. Although additional cases of transaminase elevations were identified post-authorization, all cases reporting hepatic failure had information suggesting alternative explanations or did not have sufficient information to attribute this AE to remdesivir. Labeling upon FDA approval retained transaminase elevations in the Warnings and Precautions with risk mitigation strategies including discontinuing remdesivir if ALT levels exceeded ten times the upper limit of normal or if the ALT elevation was accompanied by signs or symptoms of liver inflammation.

Renal impairment was also a frequently reported AE for remdesivir. Review of the cases did not identify a causal relationship between remdesivir and renal impairment; therefore, no FS changes were warranted.

The FDA issued EUAs for six SARS-CoV-2 neutralizing IgG1 monoclonal antibody (mAb) therapies to treat or prevent COVID-19, including bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, tixagevimab/cilgavimab, and bebtelovimab, with the first, bamlanivimab, authorized on 9 November, 2020. Through heightened surveillance, the FDA identified AEs of interest, resulting in several updates to the mAb FS for HCPs.

Based on clinical trial data for mAbs administered via an infusion, the FSs for HCPs included a warning for hypersensitivity reactions including anaphylaxis and IRRs, which included bronchospasm, hypotension, angioedema, rash including urticaria, myalgia, and dizziness. Most IRRs and hypersensitivity reactions in the clinical trials were reported as mild to moderate in severity. To mitigate the potential risks of severe IRRs, the FDA requires the administration of bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab, in settings in which HCPs have immediate access to medications to treat a severe reaction, such as anaphylaxis, and the ability to activate the emergency medical system as necessary. Patients should be monitored during infusion/injection(s) and observed for at least 1 hour after the infusion is complete.

A review of the post-authorization data identified difficulty breathing, reduced oxygen saturation, fatigue, arrhythmia, altered mental status, hypertension, and diaphoresis as the most frequently reported AEs occurring within 2 hours of mAb administration (i.e., IRRs) that were not included in the FSs at the time of initial authorization. In February 2021, the FDA updated the FS for HCP for the authorized mAbs at the time based on post-authorization cases identified in the FAERS database and FACT Sub-registry. The updates included the addition of new signs and symptoms under hypersensitivity including IRRs in the Warnings and Precautions section of the FSs. Additionally, the FDA included a new warning communicating the potential for clinical worsening after mAb administration based on cases identified of rapid respiratory decompensation during or shortly after mAb administration, some of which required hospitalization. In June 2021, the FDA updated the Warnings and Precautions section of the mAb FS for HCPs to include hypersensitivity reactions occurring more than 24 hours after infusion and vasovagal reactions (i.e., pre-syncope and syncope) based on post-authorization cases identified in the FAERS database and FACT Sub-registry describing pre-syncopal and syncopal episodes occurring during or shortly after administration of mAbs that were identified in the context of IRRs and hypersensitivity reactions, many of which required treatment in the emergency department or hospital admission. Additionally, the FDA identified cases of non-immediate (>2 hours after infusion) hypersensitivity reactions, which included cutaneous reactions and angioedema. The most frequently reported AEs (Table 4) with a reporting frequency of ≥5% with mAbs, including IRRs, are all labeled AEs in the mAb FS for HCPs, except for cough.

From 4 February, 2020, through 31 January, 2022, we identified 1052 unique US ME cases submitted to the FAERS. Healthcare professionals reported 90% of the cases. Approximately 20% (227/1,052) of the cases reported a serious AE; however, based on individual case reviews, the serious AEs were more likely related to drug therapy or underlying medical conditions (including COVID-19) than a ME.

As shown in Table 5, the number of reported ME cases varied by product, from one case (molnupiravir) to 484 cases (casirivimab/imdevimab). The number of cases was influenced by the length of time the product was authorized for use, individual definitions of an ME, utilization patterns, and product characteristics (e.g., route of administration, packaging, and procedures for use).

The most frequently reported MEs across all products were improper dose, product prepared incorrectly, product dispensing error (e.g., wrong strength or formulation dispensed), transcription error (e.g., incorrect order entry), wrong drug product administered (e.g., casirivimab administered instead of the intended COVID-19 vaccine), and wrong route of administration. Depending on the product and type of ME, multiple contributing factors for the errors were reported, including inconsistent or unfamiliar formatting and content on container labels (e.g., use of investigational drug nomenclature [27], lack of barcodes for product verification), multiple packaging presentations for the same product, limitations of electronic health systems, miscommunication, and changes to dosage regimens. Fast-paced stressful work environments with staffing and supply shortages and deviations from usual workflow practices also contributed to the errors.

As part of the EUA process, the FDA reviewed proposed FS language and packaging to minimize potential MEs. Post-authorization, the FDA monitored ME cases and subsequently updated FSs and requested manufacturers revise container labels, carton labeling, and packaging to help mitigate reported errors.