Original Article

High Prevalence of Potential Drug-Drug Interactions Among Patients Treated with Off-label Therapies for COVID-19


Background: During the first wave of the COVID-19 pandemic, severe patients were treated with the off-label drugs hydroxychloroquine and lopinavir/ritonavir. The aim of the study was to determine the prevalence of potential drug-drug interactions (DDIs) between hydroxychloroquine, lopinavir/ritonavir and concomitant medications used by hospitalized patients treated for COVID-19 in Costa Rica.Methods: We included all patients that received lopinavir/ritonavir or hydroxychloroquine as treatment for COVID-19. Clinical pharmacists reviewed the prescription profile of each patient and determined the probability and severity of any DDI through two databases (The Lexi-Interact program) and the Micromedex online interaction checker. A logistic regression model was used to identify variables associated with the occurrence of potential DDIs.Results: We identified a total of 108 potential DDIs in 34 inpatients (n=34). At least one of these DDIs occurred in 27 patients (79.4%; 95% CI: 65.8-92.9%). A total of 70 DDIs (64.8%) were classified as clinically relevant (grade D or X) by the clinical pharmacists. Only the number of concomitant drugs was associated with the occurrence of a probable DDI. The most common drugs associated with any DDI were fentanyl (n=12, 11.1%), midazolam (n=11, 10.2%), and insulin (n=10, 10.2%).Conclusion: A large proportion of patients treated with hydroxychloroquine and lopinavir/ritonavir for severe COVID-19 were at risk for clinical meaningful DDIs.

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727–33.
2. Huang C, Wang Y, Xingwang L, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.
3. Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020; 323: 1824–36.
4. Choy KT, Wong AY, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antivir Res 2020; 178: 104786.
5. Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382: 1787–99.
6. Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020;101663.
7. Fajgenbaum DC, Khor JS, Gorzewski A, et al. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infect Dis Ther 2020;9: 435-449.
8. Buajordet I, Ebbesen J, Erikssen J, et al. Fatal adverse drug events: The paradox of drug treatment. J Intern Med 2001;250:327-341.
9. Scheife RT, Hines LE, Boyce RD, et al. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug Saf 2015;38:197-206.
10. Cantudo-Cuenta MD, Gutiérrez-Pizarraya AG, Pinilla-Fernández A, et al. Drug–drug interactions between treatment specific pharmacotherapy and concomitant medication in patients with COVID‑19 in the first wave in Spain. Sci Rep 2021;11:12414.
11. Martínez-López-de-Castro N, Samartín-Ucha M, Paradela-Carreiro A, et al. Real world prevalence and consequences of potential drug-drug interactions in the first-wave COVID-19 treatments. J Clin Pharm Ther 2021;46:724-730.
12. Hodge C, Marra F, Marzolini C, et al. Drug interactions: a review of the unseen danger of experimental COVID-19 therapies. J Antimicrob Chem 2020;75:3417-3424.
13. Lemaitre F, Solas C, Grégoire M, et al. Potential drug–drug interactions associated with drugs currently proposed for COVID‐19 treatment in patients receiving other treatments. Fund Clin Pharmacol 2020; In press https://doi.org/10.1111/fcp.12586.
14. Preskorn SH, Quadri S. Why are patients with COVID19 at risk for drug-drug interactions? J Psyc Pract 2020;26:485-492.
15. World Health Organization. WHO COVID-19 Case definition. In: https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.2 Accessed: 13 Dec 2021.
16. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020; 383:517-525
17. Singh B, Ryan H, Kredo T, et al. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Cochrane Database Syst Rev 2021;2:CD013587
18. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020;383:2030-2034.
19. Recovery Collaborative Group. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2020;396:1345-52.
20. Sciaccaluga C, Cameli M, Menci D, et al. COVID-19 and the burning issue of drug interaction: never forget the ECG. Postgrad Med J 2021;97:180-184.
21. Brandariz-Nuñez D, Correas-Sanahuja M, Guarc E, et al. Potential drug–drug interactions in COVID 19 patients in treatment with lopinavir/ritonavir. Med Clin 2020; PMID:32718719.
22. Cattaneo D, Pasino L, Maggioni AP, et al. Drug–Drug Interactions and Prescription Appropriateness in Patients with COVID-19: A Retrospective Analysis from a Reference Hospital in Northern Italy. Drugs Aging 2020;37:925-33.
23. Macías J, Pinilla A, Lao-Dominguez FA, Corma A, et al. High rate of major drug–drug interactions of lopinavir–ritonavir for COVID-19 treatment. Scientific Rep 2020;10: 20958.
IssueVol 10, No 2 (Spring 2022) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/jpc.v10i2.9972
COVID-19 Drug Interactions Hydroxychloroquine Lopinavir-ritonavir

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Ramos-Esquivel A, Fernández C, Garro-Zamora L, Chaves A, Víquez-Jaikel Álvaro. High Prevalence of Potential Drug-Drug Interactions Among Patients Treated with Off-label Therapies for COVID-19. J Pharm Care. 2022;10(2):44-47.