Drug Interactions With Nirmatrelvir-Ritonavir in Older Adults Using Multiple Medications

The antiviral nirmatrelvir-ritonavir reduces the risk of severe complications in high-risk, symptomatic, unvaccinated adults with COVID-19.¹ However, the ritonavir component has several important drug-drug interactions (DDIs), particularly through CYP3A4 inhibition. We used data from the MedSafer cluster randomized clinical trial² (ClinicalTrials.gov Identifier NCT03272607) to identify DDIs between nirmatrelvir-ritonavir and potentially inappropriate medications (PIMs) in older adults with polypharmacy and to craft deprescribing guidance.

Ethics board approval was obtained from the study sites of the MedSafer trial,² and participants provided consent to the secondary use of data. Additional details for the present quality improvement study are provided in the eMethods in the Supplement. We followed the SQUIRE reporting guideline.³

Briefly, the MedSafer trial enrolled hospitalized adults 65 years or older who were taking 5 or more medications. Data pertaining to medications and comorbidities were analyzed according to an expert rule set for identifying PIMs (eMethods in the Supplement). Deprescribing reports were provided to the treating teams and compared with usual care to prevent postdischarge adverse drug events.

Herein, we theoretically exposed the trial cohort to treatment with nirmatrelvir-ritonavir to identify DDIs with maintenance medications and, specifically, with PIMs (candidate drugs for deprescribing). We linked these interactions with potential harms, which were classified as other, moderate, or severe (eMethods in the Supplement). The DDIs were identified from the product monograph,⁴ drug interaction checker website,⁵ and exclusion criteria from the EPIC-HR trial.¹ We crafted mitigation strategies to diminish DDIs. Strategies included (1) anticipatory deprescribing for drugs that cannot simply be held or dose-reduced at the time of nirmatrelvir-ritonavir exposure, and/or (2) deprescribing at the approximate time of nirmatrelvir-ritonavir receipt. Recommendations were based on the literature and our expert opinion (E.G.M., T.C.L., M.G.W., S.B.R.).^2,6 Data were analyzed from January 20 to February 8, 2022.

The MedSafer trial² included 5698 patients (median [IQR] age, 78 [71-86] years; 2858 women [50.2%], 2840 men [49.8%]). The median (IQR) number of daily at-home medications was 10 (8-14) and PIMs was 2 (1-4).

Of 5698 patients, 3869 (67.9%) received at least 1 interacting medication prescription (Table 1). The most common DDIs were with antithrombotic medications (2131 [37.4%]) or statins (1901 [33.4%]). Among the 3869 patients with interacting medication prescriptions, 823 (21.3%) had at least 1 PIM, of whom 627 (76.2%) had a high-risk DDI with nirmatrelvir-ritonavir. Common deprescribing opportunities included dual anticoagulant therapy without a recent coronary event or intervention (200 of 489 [41.0%]), alfuzosin or tamsulosin for benign prostatic hypertrophy in a person with orthostatic hypotension or recurrent falls (174 of 779 [22.3%]), and antipsychotics for sleep or agitation (62 of 274 [22.6%]) (Table 2).

In a population of older adults with polypharmacy, DDIs with nirmatrelvir-ritonavir were common. Many DDIs involved PIMs, which were candidate drugs for deprescribing. Because of these DDIs, many older adults with polypharmacy could not safely receive nirmatrelvir-ritonavir. Not all DDIs could be mitigated by simply holding or dose-reducing a medication. Some medications required anticipatory deprescribing to prevent adverse drug withdrawal events attributed to sudden stopping (eg, benzodiazepines) or prolonged half-life (eg, amiodarone).

Intercurrent health conditions can be an opportune time to deprescribe PIMs.² Symptomatic COVID-19 and potential treatment with nirmatrelvir-ritonavir should prompt a thorough medication review for DDIs, at which point deprescribing could be considered for PIMs. A study limitation was the theoretical nature of exposure to nirmatrelvir-ritonavir; however, with tens of millions of treatment courses purchased worldwide and with older adults at risk for both severe COVID-19 and polypharmacy, nirmatrelvir-ritonavir will be relatively common.

Overall, anticipatory deprescribing could increase the proportion of older adults who benefit from nirmatrelvir-ritonavir. Furthermore, deprescribing PIMs, rather than simply represcribing after receipt of nirmatrelvir-ritonavir, could be beneficial for older adults with polypharmacy.

Accepted for Publication: May 17, 2022.

Published: July 6, 2022. doi:10.1001/jamanetworkopen.2022.20184

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

Corresponding Author: Emily G. McDonald, MD, MSc, 5252 De Maisonneuve Boulevard, Office 3E.03, Montreal, QC H4A 3S9, Canada (emily.mcdonald@mcgill.ca).

Author Contributions: Drs McDonald and Goodwin Wilson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. For the purpose of authorship, Drs McDonald and Goodwin Wilson contributed equally.

Concept and design: Ross, Bortolussi-Courval, Lee, Goodwin Wilson, McDonald.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ross, Bortolussi-Courval, Hanula, Goodwin Wilson, McDonald.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ross, Bortolussi-Courval, Lee, Goodwin Wilson.

Administrative, technical, or material support: Bortolussi-Courval, Lee, McDonald.

Supervision: Ross, Goodwin Wilson, McDonald.

Conflict of Interest Disclosures: Dr Lee reported receiving research salary support from Fonds de Recherche du Québec–Sante and grants from Canadian Institutes of Health Research during the conduct of the study; holding a patent for MedSafer, copyright issued; and being co-inventor of MedSafer and co-owner of MedSafer Corporation. Dr McDonald reported holding a patent for MedSafer, copyright issued, and being co-inventor of MedSafer and co-owner of MedSafer Corporation (with Dr Lee and McGill University). No other disclosures were reported.

Additional Contributions: We thank the patients who enrolled in the MedSafer study and agreed to participate in the polypharmacy research.