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Identification of Drug Interaction Adverse Events in Patients With COVID-19A Systematic Review

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is it possible to assess adverse events associated with drug-drug interactions (DDIs) by drug interaction checkers in patients with COVID-19?

Findings  The DDIs identified in this systematic review involved 46 different drugs, with 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) reported. Drug interaction checkers could have identified such events, including severe and life-threatening ones.

Meaning  Notwithstanding the emergency context of the COVID-19 pandemic, DDI-related adverse events should never be overlooked to customize the most effective and safest therapy.


Importance  During the COVID-19 pandemic, urgent clinical management of patients has mainly included drugs currently administered for other diseases, referred to as repositioned drugs. As a result, some of these drugs have proved to be not only ineffective but also harmful because of adverse events associated with drug-drug interactions (DDIs).

Objective  To identify DDIs that led to adverse clinical outcomes and/or adverse drug reactions in patients with COVID-19 by systematically reviewing the literature and assessing the value of drug interaction checkers in identifying such events.

Evidence Review  After identification of the drugs used during the COVID-19 pandemic, the drug interaction checkers, COVID-19 Drug Interactions, LexiComp, Medscape, and WebMD were consulted to analyze theoretical DDI-associated adverse events in patients with COVID-19 from March 1, 2020, through February 28, 2022. A systematic literature review was performed by searching the databases PubMed, Scopus, and Cochrane for articles published from March 1, 2020, through February 28, 2022, to retrieve articles describing actual adverse events associated with DDIs. The drug interaction checkers were consulted again to evaluate their potential to assess such events.

Findings  The DDIs identified in the reviewed articles involved 46 different drugs. In total, 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) were reported. The drugs most involved in DDIs were lopinavir and ritonavir. Of the 6917 identified studies, 20 met the inclusion criteria. These studies, which enrolled 1297 patients overall, reported 115 DDI-related adverse events: 15 (26%) were identifiable by all tools analyzed, 29 (50%) were identifiable by at least 1 of them, and 14 (24%) remained nonidentifiable.

Conclusions and Relevance  The main finding of this systematic review is that the use of drug interaction checkers could have identified several DDI-associated adverse drug reactions, including severe and life-threatening events. Both the interactions between the drugs used to treat COVID-19 and between the COVID-19 drugs and those already used by the patients should be evaluated.

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Article Information

Accepted for Publication: March 2, 2022.

Published: April 19, 2022. doi:10.1001/jamanetworkopen.2022.7970

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Conti V et al. JAMA Network Open.

Corresponding Author: Valeria Conti, PhD, Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, Via S Allende, 84081 Baronissi, SA, Italy (

Author Contributions: Drs Conti and Filippelli had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Conti and Sellitto contributed equally to this work.

Concept and design: Conti, Sellitto, Pagliano, Filippelli.

Acquisition, analysis, or interpretation of data: Conti, Sellitto, Torsiello, Manzo, De Bellis, Stefanelli, Bertini, Costantino, Maci, Raschi, Sabbatino, Corbi.

Drafting of the manuscript: Conti, Sellitto, Torsiello, Bertini, Sabbatino.

Critical revision of the manuscript for important intellectual content: Conti, Sellitto, Torsiello, Manzo, De Bellis, Stefanelli, Costantino, Maci, Raschi, Sabbatino, Corbi, Pagliano, Filippelli.

Supervision: Conti, Sellitto, Manzo, Stefanelli, Sabbatino, Corbi, Pagliano, Filippelli.

Conflict of Interest Disclosures: Dr Raschi reported receiving personal fees from Novartis outside the submitted work. No other disclosures were reported.

Additional Contributions: Native English-speaker Jan Festa, Morgan School, Salerno, Italy, revised the manuscript. She was not compensated for her work.

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