What considerations should pharmacists prescribing nirmatrelvir-ritonavir for the treatment of COVID-19 in the outpatient population be aware of?
As of December 2021, Paxlovid (nirmatrelvir-ritonavir) was authorized by the Food and Drug Administration (FDA) as the first oral treatment option for COVID-19.1 On July 6, 2022, the FDA updated nirmatrelvir-ritonavir’s emergency use authorization (EUA) to allow state-licensed pharmacists to prescribe nirmatrelvir-ritonavir to patients that meet certain criteria.2 Nirmatrelvir-ritonavir is an anti-infective/antiviral agent that is used for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients ≥12 years of age weighing ≥40 kg with a positive COVID-19 test result who are at high-risk of hospitalization for severe disease.3 Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also known as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro prevents it from processing polyprotein precursor which results in blockade of the viral replication process. Ritonavir is an HIV-1 protease inhibitor that is not active against SARS-CoV-2 Mpro. Ritonavir works by inhibiting cytochrome P450 (CYP)3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir. The focus of this frequently asked question (FAQ) is to review the clinical evidence supporting the use of nirmatrelvir-ritonavir in its authorized patient population, and to provide valuable information to assist pharmacists in safely prescribing this medication in practice.
A search was conducted to find published literature supporting the use of nirmatrelvir-ritonavir for its authorized indication; this search yielded 1 published randomized controlled trial evaluating the efficacy of nirmatrelvir-ritonavir. The data supporting the EUA for nirmatrelvir-ritonavir are based on the results of the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial, an international, phase 2-3, double-blind, randomized, placebo-controlled trial conducted in non-hospitalized symptomatic adult participants with COVID-19 considered to be at high risk for progression to severe disease.4 Eligible participants were 18 years of age or older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (body mass index >25 kg/m2), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, chronic cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active malignancy, medically-related technological dependence, or age ≥60 years regardless of comorbidities. Patients with a prior confirmed case of COVID‑19 or previous COVID-19-related hospitalization, previous recipients of convalescent COVID-19 plasma, or previous recipients of a SARS-CoV-2 vaccine were excluded. A total of 2246 adults with confirmed SARS-CoV-2 infections were randomized within 5 days of symptom onset to receive oral nirmatrelvir (300 mg) plus ritonavir (100 mg) or matching placebo every 12 hours for a 5-day course; 1120 patients were treated with nirmatrelvir-ritonavir while 1126 patients received a placebo. The primary outcome compared rates of hospitalization for COVID-19 or death from any cause between the 2 groups through day 28; this outcome was specifically assessed in the modified intention-to-treat (mITT) population of patients who were randomized within 3 days of symptom onset and who had not received treatment with monoclonal antibodies. An interim analysis was planned to assess the primary outcome for efficacy, futility, and sample size re-estimation once assessments were completed for 45% of patients in the primary analysis population.
At baseline, the median age was 46 years; 51% of participants were male; 72% were White, and 45% were Hispanic or Latinx.4 Sixty-six percent of patients received treatment within 3 days of symptom onset and about 6% received or were expected to receive treatment with monoclonal antibodies. The planned interim analysis, which included 774 patients in the mITT population, showed that significantly fewer recipients of nirmatrelvir-ritonavir had COVID-19–related hospitalization or death by day 28 compared to placebo. In the final analysis of patients from the mITT population (n=1379), the estimated event rates of COVID-19–related hospitalization or death from any cause at 28 days were 0.72% and 6.53% in the nirmatrelvir-ritonavir and placebo groups, respectively, (risk difference, −5.81%; 95% CI, –7.78% to –3.84%; p<0.001). There were 9 deaths in the placebo group and 0 in the nirmatrelvir-ritonavir group. Results were similar for the key secondary outcome, which assessed COVID-19-related hospitalizations or deaths in the larger population of patients who received treatment within 5 days of symptom onset. Nirmatrelvir-ritonavir was also consistently associated with reduced rates of the primary outcome across various subgroups. The author concluded that the treatment of symptomatic COVID-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe COVID-19 that was 89% lower than the risk with placebo, without evident safety concerns.
Clinicaltrials.gov was searched for ongoing and planned trials of nirmatrelvir-ritonavir that may influence future prescribing of the drug. Although there are currently multiple trials of nirmatrelvir-ritonavir in various stages, 3 pertinent trials are briefly highlighted below:
- EPIC-SR (NCT05011513) is a phase 2/3, randomized, placebo-controlled trial assessing the efficacy of nirmatrelvir-ritonavir for symptom relief in nonhospitalized adults with symptomatic COVID-19 at low risk of progressing to severe illness.5
- EPIC-PEP (NCT05047601) is a phase 2/3, randomized, placebo-controlled trial aimed to investigate whether nirmatrelvir-ritonavir prevents development of COVID-19 in adults who have been exposed to household members with a confirmed symptomatic COVID‑19 infection within 96 hours of exposure.6
- EPIC-Peds (NCT05261139) is an ongoing phase 2/3, nonrandomized single arm trial aimed to study nirmatrelvir/ritonavir in patients less than 18 years of age with symptomatic COVID-19 who are not hospitalized but are at risk for severe disease.7 EPIC-Peds will be enrolling children from 0 years to 17 years of age in 5 different age cohorts.
Guideline recommendations and place in therapy
Practice guidelines provide additional recommendations regarding the place in therapy of nirmatrelvir-ritonavir in nonhospitalized adult patients with COVID-19 who are at risk for progression to severe disease.8,9 The Centers for Disease Control and Prevention describe conditions which place a patient at risk for severe COVID-19.10 These conditions generally mimic those previously described in the EPIC-HR study, and include a variety of chronic conditions (eg, chronic cardiovascular, renal, hepatic, and pulmonary disorders), and other patient-specific characteristics (eg, age, smoking history, weight).
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend nirmatrelvir-ritonavir as the preferred treatment for patients with COVID-19 who do not require hospitalization or supplemental oxygen and are at high risk of progression to severe disease.8 Remdesivir is also listed as a preferred therapy; however, nirmatrelvir-ritonavir is ranked higher in preference compared to remdesivir. While both agents have established efficacy in clinical trials, remdesivir is logistically more challenging to administer since it requires intravenous infusions over 3 consecutive days. When nirmatrelvir-ritonavir or remdesivir are clinically or logistically inappropriate to use, bebtelovimab or molnupiravir are recommended. Bebtelovimab is not preferred due to a lack of clinical efficacy data supporting its use in this patient population and molnupiravir is not preferred due to its lower efficacy compared to alternate treatment options.
Guidelines from the Infectious Diseases Society of America (IDSA) on management of COVID-19 suggest (weak or conditional recommendation based on low level evidence) use of nirmatrelvir-ritonavir (initiated within 5 days of symptom onset) over no treatment in ambulatory patients with mild to moderate COVID-19 at high-risk for progression to severe disease.9 The guideline also suggests alternative therapies for ambulatory patients, including remdesivir, molnupiravir, and neutralizing monoclonal antibodies, but does not provide suggestions for the specific place in therapy of each agent. Therefore, the IDSA suggests that selection of an agent should be determined based on patient-specific factors (eg, drug interactions, duration of symptoms, other clinical factors) and availability.
Important drug-related information and other clinical considerations
Dosing and Administration
In adults and pediatric patients ≥12 years of age weighing ≥40 kg, nirmatrelvir-ritonavir is typically dosed as 300 mg of nirmatrelvir (two 150 mg tablets) in combination with 100 mg of ritonavir (one 100 mg tablet) orally twice daily for 5 days.3 The product is available as a dose pack containing the total 5-day course (30 tablets) divided into 5 separate daily-dose blister cards.
- Mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 mL/min) or mild to moderate hepatic impairment (Child-Pugh Class A or B): No dosage adjustment necessary
- Moderate renal impairment (eGFR ≥30 to <60 mL/min):
- Reduce dosage to 150 mg nirmatrelvir and 100 mg ritonavir twice daily
- A separate dose pack is available for dosing of the drug in patients with moderate renal impairment
- Severe renal or hepatic impairment: not recommended due to a lack of data
Management of Drug-Drug Interactions
Nirmatrelvir-ritonavir is associated with a considerable number of drug-drug interactions, which can generally be attributed to the ritonavir component.8 Ritonavir is a potent CYP3A inhibitor; therefore, it is contraindicated with drugs that are highly dependent on CYP3A. Drug-drug interactions with nirmatrelvir-ritonavir occur at varying levels of severity, and may be managed by prescription of an alternate COVID-19 therapy, temporarily withholding the concomitant medication, dosage adjustment of the concomitant medication, or increased monitoring of the patient for adverse reactions to therapy; some interactions may also be clinically irrelevant and thus, will not require specific action.
Table 1 below describes some of the most severe drug-drug interactions for nirmatrelvir-ritonavir; an alternate COVID-19 treatment should be prescribed in patients taking the medications listed in the table.
| Table 1. Drug-drug interactions with nirmatrelvir-ritonavir that require prescription of an alternate COVID‑19 medication.8,11,12
| Drug and classification|| Clinical effect of interaction
| Carbamazepine|| The anticonvulsants listed are strong CYP3A4 inducers; coadministration with nirmatrelvir-ritonavir may lead to a loss of virologic response and possible resistance
| Anti-infective agents
| Glecaprevir/pibrentasvir|| Concomitant use of glecaprevir/pibrentasvir with OATP1B inhibitors, such as ritonavir, may substantially increase glecaprevir/pibrentasvir plasma concentration leading to risk of ALT elevation
| Rifampin/rifapentine|| Rifampin/rifapentine are strong CYP3A4 inducers. Coadministration with nirmatrelvir-ritonavir may lead to a loss of virologic response and possible resistance
| Cardiovascular drugs
| Amiodarone|| Amiodarone is metabolized by CYP3A4; coadministration may increase concentration of amiodarone, thus increasing the risk for arrhythmias
| Clopidogrel (patients with stent placement in the past 6 weeks)|| Clopidogrel is converted to its active metabolite by CYP3A4; coadministration is associated with reduced concentration of clopidogrel’s active metabolite, leading to insufficient platelet aggregation inhibition and an elevated risk of thrombosis
| Disopyramide|| Disopyramide is metabolized by CYP3A4 (25%); coadministration may increase disopyramide exposure, thus increasing the risk for arrhythmias
| Dofetilide|| Dofetilide is partially metabolized by CYP3A4; coadministration may increase dofetilide exposure, thus increasing the risk for arrhythmias
| Dronedarone|| Dronedarone is metabolized by CYP3A4; coadministration may increase concentration of dronedarone, thus increasing the risk for arrhythmias
| Eplerenone|| Eplerenone is metabolized by CYP3A4; coadministration may increase eplerenone exposure, thus increasing the risk for hyperkalemia
| Flecainide|| Coadministration is likely to increase flecainide concentrations and risk of serious and/or life-threatening reactions such as cardiac arrhythmias
| Ivabradine|| Coadministration of ivabradine with strong CYP3A4 inhibitors may increase the concentration of ivabradine, leading to excessive bradycardia
| Propafenone|| Propafenone is partially metabolized by CYP3A4; coadministration may increase propafenone concentrations, thus increasing the risk for arrhythmias
| Quinidine|| Quinidine is metabolized by CYP3A4; coadministration may increase concentration of quinidine, thus increasing the risk for arrhythmias
| Voclosporin|| Coadministration of voclosporin with strong CYP3A4 inhibitors (ie, nirmatrelvir-ritonavir) may significantly increase exposure to voclosporin and increase the risk of nephrotoxicity
| Neuropsychiatric drugs
| Clozapine|| Clozapine is partially metabolized by CYP3A4; coadministration may increase the potential for serious, life-threatening adverse effects (eg, serious hematologic abnormalities)
| Lumateperone|| Lumateperone is partially metabolized by CYP3A4; coadministration may increase the potential for adverse reactions
| Lurasidone|| Lurasidone is primarily metabolized by CYP3A4; coadministration may increase concentration of lurasidone, leading to serious, life-threatening reactions
| Midazolam (oral)|| Midazolam is extensively metabolized by CYP3A4; coadministration may increase plasma concentrations of midazolam, leading to excessive sedation and respiratory depression
| Pimozide|| Coadministration may increase concentration of pimozide, leading to serious, life-threatening reactions
| Pain medications
| Meperidine|| Meperidine is partially metabolized by CYP3A4; coadministration may lead to increased concentrations of meperidine or its active metabolite, leading to severe respiratory depression
| Pulmonary hypertension drugs
| Sildenafil|| Sildenafil, tadalafil, and vardenafil are metabolized by CYP3A4; coadministration may increase the concentration of the pulmonary hypertension drug, thus increasing adverse effects
| Bosentan|| Coadministration may significantly increase bosentan trough concentrations
| Certain chemotherapeutic agents|| Clinical effects are variable; nirmatrelvir-ritonavir may increase concentrations of some chemotherapeutic agents, leading to an increased risk of adverse effects. Some chemotherapeutic agents may also decrease the effectiveness of nirmatrelvir-ritonavir, leading to a loss of virologic response and possible resistance
| Ergot derivatives|| Coadministration may increase dihydroergotamine concentrations, leading to serious, life-threatening reactions such as ergot toxicity
| Lumacaftor/ivacaftor|| Lumacaftor is a strong CYP3A4 inducer; coadministration with nirmatrelvir-ritonavir may lead to a loss of virologic response and possible resistance
| Rivaroxaban|| Rivaroxaban is partially metabolized by CYP3A4; coadministration may increase the concentration of rivaroxaban, thus increasing the risk of bleeding
| Salmeterol|| Salmeterol is metabolized by CYP3A4; coadministration may increase concentrations of salmeterol, leading to an increased risk of cardiovascular adverse events (eg, QT prolongation, palpitations, sinus tachycardia)
| St. John’s wort|| Hyperforin, one of the constituents of St John’s Wort, induces CYP3A4 and P-gp and may cause a significant reduction in nirmatrelvir-ritonavir concentration, leading to a loss of virologic response and possible resistance
| Tolvaptan|| Tolvaptan is extensively metabolized by CYP3A; coadministration may lead to increased tolvaptan exposure, leading to dehydration, hypovolemia, and hyperkalemia
| Abbreviations: ALT=alanine aminotransferase; CYP=cytochrome P450; OATP=organic anion transporting polypeptide; P-gp=P-glycoprotein.
Interactions between nirmatrelvir-ritonavir and other drugs are numerous, and likely to change over time as additional research is conducted. Healthcare providers should consult other appropriate resources, such as the drug’s EUA and other drug interaction checkers, to ensure safe prescribing of the drug.
The University of Liverpool has created a COVID-19 drug interaction checker (see here), which may a useful tool for clinicians when determining how to appropriately manage drug-drug interactions with nirmatrelvir-ritonavir.11 Additionally, the IDSA provides recommendations related to management of drug-drug interactions with nirmatrelvir-ritonavir here.12
Pharmacist prescribing of nirmatrelvir-ritonavir via the emergency use authorization
In order to prescribe nirmatrelvir-ritonavir in an outpatient setting, pharmacists must ensure that the following stipulations from the EUA are met in appropriate patients:3
- Electronic health records less than 12-months-old are available and sufficient to allow for adequate assessment of the patient’s clinical status (eg, renal and hepatic function)
- Comprehensive list of both prescription and over-the-counter medications obtained to ensure appropriate management of drug-drug interactions
A pharmacist should refer a patient to their healthcare provider when the above-mentioned information is unavailable, if medication adjustment is required due to drug-drug interactions, or when nirmatrelvir-ritonavir is otherwise inappropriate to prescribe.3 Healthcare providers who prescribe nirmatrelvir-ritonavir must also report all serious adverse events and medication errors to FDA MedWatch within 7 calendar days from the healthcare provider’s awareness.
For a complete list of considerations when prescribing nirmatrelvir-ritonavir, pharmacists may refer to the patient eligibility screening checklist tool provided by the FDA (see here).13
Nirmatrelvir-ritonavir was approved by the FDA in December of 2021 as the first oral treatment option for COVID-19. An amendment to the drug’s EUA was made on July 06, 2022 allowing state-licensed pharmacists to prescribe nirmatrelvir-ritonavir to patients that meet specific criteria. This FAQ contains important clinical information that pharmacists can use as guide for prescribing nirmatrelvir-ritonavir to outpatients with COVID-19 who are at risk for progression to severe disease. Clinical use of nirmatrelvir-ritonavir will continue to evolve as additional studies are performed; clinicians should refer to the drug’s EUA and additional resources, such as clinical guidelines from the NIH and the IDSA, for the most updated information on appropriate use of the drug.
- Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. U.S. Food and Drug Administration. Published December 22, 2021. Accessed July 25, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
- Coronavirus (COVID-19) update: FDA authorized pharmacists to prescribe Paxlovid with certain limitations. U.S. Food and Drug Administration. Published July 6, 2022. Accessed July 25, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pharmacists-prescribe-paxlovid-certain-limitations
- Paxlovid. Fact sheet for health care providers. Pfizer, Inc.; 2022. Updated August 26, 2022. Accessed August 29, 2022. https://www.fda.gov/media/155050/download
- Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542
- Evaluation of protease inhibition for COVID-19 in standard-risk patients (EPIC-SR). ClinicalTrials.gov identifier: NCT05011513. Updated July 22, 2022. Accessed August 07,2022. https://clinicaltrials.gov/ct2/show/NCT05011513?term=epic-sr&draw=2&rank=1
- A study of a potential oral treatment to prevent COVID-19 in adults who are exposed to household member(s) with a confirmed symptomatic COVID-19 infection. ClinicalTrials.gov identifier: NCT05047601. Updated July 30, 2022. Accessed August 07, 2022. https://clinicaltrials.gov/ct2/show/NCT05047601?term=NCT05047601&draw=2&rank=1
- Epic-Peds: a study to learn about the study medicine called PF-07321332 (nirmatrelvir)/ritonavir in patients under 18 years of age with COVID-19 that are not hospitalized but are at risk for severe disease. ClinicalTrials.gov identifier: NCT05261139. Updated August 5, 2022. Accessed August 07, 2022. https://clinicaltrials.gov/ct2/show/NCT05261139?term=nirmatrelvir%2BAND%2Britonavir&cond=COVID-19&draw=2&rank=1
- Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Updated August 18, 2022. Accessed August 29, 2022. https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf
- Bhimraj A, Morgan RL, Shumaker AH, et al. IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America. Updated June 29, 2022. Accessed August 29, 2022. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-19
- Underlying medical conditions associated with higher risk for severe COVID-19: information for healthcare professionals. Centers for Disease Control and Prevention. Updated June 15, 2022. Accessed August 08, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html
- COVID-19 drug interactions. University of Liverpool. Accessed July 28, 2022. https://www.covid19-druginteractions.org/checker
- Management of drug interactions with nirmatrelvir/ritonavir (Paxlovid®): resource for clinicians. Infectious Diseases Society of America. Updated May 6, 2022. Accessed July 28, 2022. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/management-of-drug-interactions-with-nirmatrelvirritonavir-paxlovid/
- Paxlovid patient eligibility screening checklist tool for prescribers. U.S. Food and Drug Administration. Updated August 26, 2022. Assessed August 29, 2022. https://www.fda.gov/media/158165/download
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of August 2, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.