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. 2022 Apr 1;5(4):e227970.
doi: 10.1001/jamanetworkopen.2022.7970.

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

Valeria Conti  1   2 , Carmine Sellitto  1   3 , Martina Torsiello  1   2 , Valentina Manzo  1   2 , Emanuela De Bellis  2   4 , Berenice Stefanelli  2   4 , Nicola Bertini  2   4 , Maria Costantino  1 , Chiara Maci  1 , Emanuel Raschi  5 , Francesco Sabbatino  1   6 , Graziamaria Corbi  7 , Pasquale Pagliano  1   8 , Amelia Filippelli  1   2
Affiliations

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

Valeria Conti et al. JAMA Netw Open. .

Abstract

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 Drugs.com, 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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Conflict of interest statement

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

Figures

Figure.
Figure.. Timeline of the Drugs Used During the COVID-19 Pandemic
ABC-110 indicates Study of Opaganib in Coronavirus Disease 2019 Pneumonia (COVID-19); ACE-ID-201, A Phase 2, Open Label, Randomized Study of the Efficacy and Safety of Acalabrutinib with Best Supportive Care Vs Best Supportive Care in Subjects Hospitalized with COVID-19; AMMURAVID, Factorial Randomized Trial of Remdesivir and Baricitinib Plus Dexamethasone for COVID-19; ColCOVID, Colchicine Counteracting Inflammation in COVID-19 Pneumonia; COMBAT-19, Mavrilimumab in Severe COVID-19 Pneumonia and Hyper-inflammation; COV-BARRIER, Study of Baricitinib (LY3009104) in Children With COVID-19; COVER, COVID Ivermectin - Randomized, Double-blind, Multi Centre Phase II, Proof of Concept, Dose Finding Clinical Trial on Ivermectin for the Early Treatment of COVID-19; DEF-IVID19, Defibrotide in COVID-19 Pneumonia - Use of Defibrotide to Reduce Progression of Acute Respiratory Failure Rate in Patients With COVID-19 Pneumonia; FibroCov, Open-label, Randomized, Parallel-arm Study Investigating the Efficacy and Safety of Intravenous Administration of Pamrevlumab Vs Standard of Care in Patients With COVID-19; HS216C17, Clinical Study to Evaluate the Performance and Safety of Favipiravir in COVID-19; IVIG/H/COVID-19, High Dose Intravenous Polyvalent Immunoglobulin (IVIG) in Patients With Early Inflammatory COVID-19; RANCONA, A Randomized Clinical Trial of Nafamostat: A Potent Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor for the Treatment of Covid-19; REPAVID-19, Reparixin in COVID-19 Pneumonia - Efficacy and Safety; SOBI.IMMUNO-101, Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection; SOLIDARITY, Efficacy of Different Anti-viral Drugs in COVID 19 Infected Patients; STAUNCH, Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection; TOGETHER, Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19; XPORT-CoV-1001, Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection.
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