Nirmatrelvir-Ritonavir Shows Safety, Efficacy in Real-world Study of High-risk COVID-19 Patients


The retrospective study evaluated outcomes in patients prescribed nirmatrelvir-ritonavir, as well as the management of drug interactions by clinical pharmacists prescribing the regimen.

Combination nirmatrelvir-ritonavir (Paxlovid) showed safety and efficacy in high-risk patients with COVID-19 in a real-world observational study. The findings were published in the Journal of the American College of Clinical Pharmacy.

COVID-19 is highly contagious, but individuals with certain underlying conditions, such as obesity, cardiovascular disease, or older age, are at a higher risk of COVID-19 infection developing into severe disease and requiring hospitalization. In December 2021, nirmatrelvir-ritonavir was issued an emergency use authorization (EUA) by the FDA for high-risk patients with mild to moderate COVID-19. When taken within 5 days of symptom onset, nirmatrelvir-ritonavir showed an 89% decrease in composite hospitalizations or deaths vs placebo in a randomized, double-blind, controlled trial.

One potential drawback of nirmatrelvir-ritonavir is the significant risk of drug interactions due to ritonavir’s inhibition of the cytochrome P450 3A4 enzyme—a process that increases the pharmacodynamic activity of nirmatrelvir. The risk of drug interactions warrants close monitoring, and the University of Wisconsin Health Center developed a process that designates clinical pharmacists to clinically assess and order 5-day courses of nirmatrelvir-ritonavir in an effort to streamline ordering and ensure safety.

The retrospective, single-center study evaluated outcomes in patients prescribed nirmatrelvir-ritonavir, as well as the management of drug interactions by clinical pharmacists prescribing the regimen within the University of Wisconsin Health protocol. Main outcomes included safety, based on drug interaction management and adverse events; and efficacy, based on hospitalization and death within 28 days of treatment with nirmatrelvir-ritonavir.

A total of 60 patients were eligible for inclusion based on EUA criteria and filled their prescriptions for nirmatrelvir-ritonavir. The majority of patients had 2 or more risk factors for severe COVID-19, with the most common being obesity (70%), cardiovascular disease (43.3%), older age (43.3%), lung disease (25%), and immunosuppression (25%). Hospitalization and death incidences were unknown in 2 patients who had no records after the initial ordering of nirmatrelvir-ritonavir.

None of the patients died or were hospitalized within 28 days of therapy initiation. The 58 patients with available records completed the course of therapy without significant issues. Two patients experienced rebound disease symptoms and tested positive for COVID-19 again within 28 days of treatment initiation, but neither required hospitalization. The most common adverse events were cough, chest discomfort, migraines, and nausea.

Overall, 101 drug interactions were identified by pharmacists in patients receiving nirmatrelvir-ritonavir. Only 49 interactions in 36 patients were considered clinically significant and required mitigation, however. The most common drug interaction was between ritonavir and β-hydroxy β-methylglutaryl-CoA reductase inhibitors, which occurred in 21 (42.9%) patients. The second most addressed interaction was between calcium channel blockers and ritonavir, which occurred in 9 (18.4%) of the study participants prescribed nirmatrelvir-ritonavir. The pharmacist suggested a 7-day hold or dose adjustment to any interacting drugs during nirmatrelvir-ritonavir treatment, and primary care providers accepted the management strategies 100% of the time with no reported issues.

“Our use of a pharmacist-led screening process rapidly expanded access to antivirals for a large patient population. An additional benefit of leveraging pharmacists in the ordering of nirmatrelvir-ritonavir was the careful assessment and management of drug interactions,” the authors wrote. “More than half of the patients required intervention for the management of drug interactions by a pharmacist in collaboration with the patient's provider.”

The report’s limitations included its retrospective nature and small cohort size, as well as its single-center nature and reliance on a single electronic medical record. While patients who experienced rebound symptoms outside of the center would not have been reported, the rate of rebound COVID-19 symptoms was similar to previously reported rates. Another limitation was the predominantly White study population, which may limit the generalizability of the findings.

The authors conclude that the pharmacist-led assessment and communications to the prescribing physician helped streamline access to nirmatrelvir-ritonavir, as well as identify and mitigate drug interactions. Additionally, nirmatrelvir-ritonavir was found safe and was not associated with hospitalizations in patients at a high risk of severe COVID-19.


Kane AM, Keenan EM, Lee K, et al. Nirmatrelvir-ritonavir treatment of COVID-19 in a high-risk patient population: a retrospective observational study. J Am Coll Clin Pharm. Published online November 2, 2022. doi:10.1002/jac5.1729

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