Nirmatrelvir-ritonavir Demonstrates Safety and Efficacy in a Real-World Study in High-Risk COVID-19 Patients

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

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

COVID-19 is highly contagious, but people with certain underlying medical conditions, such as obesity, cardiovascular disease, or older age, are at greater risk of COVID-19 infection developing into serious illness and requiring hospitalization. In December 2021, nirmatrelvir-ritonavir received an Emergency Use Authorization (EUA) from the FDA for high-risk patients with mild-to-moderate COVID-19. When taken within 5 days of symptom onset, nirmatrelvir-ritonavir demonstrated an 89% reduction in combined hospitalizations or deaths compared to placebo in a randomized, double-blind, controlled trial.

A potential disadvantage of nirmatrelvir-ritonavir is the significant risk of drug-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 requires close monitoring, and the University of Wisconsin Health Center has developed a process that designates clinical pharmacists to clinically evaluate and order 5-day cycles of nirmatrelvir-ritonavir to streamline the ordering and the to ensure security.

The retrospective, single-center study evaluated outcomes in patients prescribed nirmatrelvir-ritonavir and management of drug-drug interactions by clinical pharmacists prescribing the regimen under the University of Wisconsin Health Protocol. Key outcomes included safety based on management of drug interactions 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 enrollment based on EUA criteria and fulfilled 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%), pulmonary disease (25%) and immunosuppression were (25%). Hospitalizations and deaths were unknown in 2 patients who had no records after initial nirmatrelvir-ritonavir order.

None of the patients died or were hospitalized within 28 days of starting therapy. The 58 patients with available records completed the course of therapy without significant problems. Two patients had rebound disease symptoms and tested positive for COVID-19 again within 28 days of starting treatment, but neither required hospitalization. The most common side effects were cough, chest discomfort, migraine and nausea.

A total of 101 drug-drug interactions were identified by pharmacists in patients receiving nirmatrelvir-ritonavir. However, only 49 interactions in 36 patients were considered clinically significant and needed mitigation. The most common interaction between ritonavir and β-hydroxy-β-methylglutaryl-CoA reductase inhibitors occurred in 21 (42.9%) patients. The second most frequently reported interaction was between calcium channel blockers and ritonavir, occurring in 9 (18.4%) subjects prescribed nirmatrelvir-ritonavir. The pharmacist suggested a 7-day pause or dose adjustment of all interacting drugs during nirmatrelvir-ritonavir treatment, and the GPs accepted the treatment strategies 100% of the time with no reported problems.

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

Limitations of the report included its retrospective nature and small cohort size, as well as its single center nature and reliance on a single electronic health record. While patients who experienced off-center rebound symptoms 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 results.

The authors conclude that pharmacist-led assessment and communication with the prescribing physician helped streamline access to nirmatrelvir-ritonavir and identified and mitigated drug-drug interactions. In addition, nirmatrelvir-ritonavir was found to be safe and not associated with hospitalizations in patients at 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. clinical pharmacy. Published online November 2, 2022. doi:10.1002/jac5.1729


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