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Mechanism of Action
US Drug Names
NOTE: Information on medical conditions and factors associated with an increased risk for progression to severe COVID-19 can be obtained on the Centers for Disease Control and Prevention (CDC) website at www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Health care providers are advised to consider the benefit-risk for each individual patient.
NOTE: Health care providers should choose an authorized therapeutic option with activity against the circulating variants in their state, territory, or US jurisdiction. Current variant frequency data are available at: www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html. Nirmatrelvir; ritonavir is expected to be active against the Omicron SARS-CoV-2 variant and its subvariants, although there is currently a lack of data on the clinical efficacy against these variants. 
NOTE: Due to the Omicron variant being the dominant variant in many parts of the United States, the National Institutes of Health (NIH) has issued a statement to provide guidance on treating nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics:
Before prescribing nirmatrelvir; ritonavir, the NIH recommends health care providers carefully review the patient's concomitant medications (including over-the-counter medications and herbal supplements) to evaluate for potential drug interactions. If a significant drug interaction is identified, consider the risks and benefits of treatment. Consider expert consultation, especially for patients receiving highly specialized therapies such as antineoplastics, neuropsychiatric drugs, and certain immunosuppressants.
NOTE: There may be logistical or supply constraints that make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Health care providers should prioritize their use for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies.
NOTE: Nirmatrelvir; ritonavir is NOT authorized for use in patients requiring hospitalization due to severe COVID-19; however, should a patient require hospitalization after starting treatment, the full 5-day treatment course should be completed unless there are drug interactions that preclude its use. Additionally, the drug may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19, are at high risk for progression, and are within 5 days of symptom onset.
NOTE: Nirmatrelvir; ritonavir is NOT authorized for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19.
300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together by mouth twice daily for 5 days. Initiate treatment as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset. Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations; treatment for longer than 5 days consecutive days is not authorized.
40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO.
less than 40 kg: Use not authorized.
12 years and weighing 40 kg or more: 600 mg nirmatrelvir and 200 mg ritonavir per day PO.
12 years and weighing less than 40 kg: Use not authorized.
1 to 11 years: Use not authorized.
Use not authorized.
No dosage adjustment is needed for mild to moderate hepatic impairment (Child-Pugh A and B). Not authorized for use in patients with severe hepatic impairment (Child-Pugh C), as pharmacokinetic and safety data are unavailable.
eGFR 60 mL/minute or more: No dosage adjustment is needed.
eGFR 30 to 59 mL/minute: Reduce dose to 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days.
eGFR less than 30 mL/minute: Use not authorized.
Nirmatrelvir; ritonavir is an investigational oral antiviral medication with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nirmatrelvir works as a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor and ritonavir (an HIV-1 protease inhibitor and CYP3A inhibitor) is used as a pharmacokinetic enhancer or booster. The combination product is not an FDA-approved medication; however, it has been authorized for emergency use to treat mild to moderate coronavirus disease (COVID-19) in patients (12 years of age and older weighing at least 40 kg) with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. Nirmatrelvir; ritonavir is NOT authorized for use in patients who are hospitalized due to severe COVID-19; however, should a patient require hospitalization after starting treatment, the full 5-day treatment course should be completed unless there are drug interactions that preclude its use. The drug is also NOT authorized for use as a pre-exposure or post-exposure prophylaxis to prevent COVID-19. Nirmatrelvir and ritonavir are co-packaged and supplied in 2 different Dose Packs (Paxlovid 300 mg; 100 mg Dose Pack and Paxlovid 150 mg; 100 mg Dose Pack). Each Dose Pack contains a carton holding 5 daily blister cards; DO NOT exceed the authorized treatment duration of 5 consecutive days.
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend nirmatrelvir; ritonavir as a treatment option for nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease; however, due to the potential for significant drug interactions with concomitant medications, this regimen may not be a safe choice for all patients. Nirmatrelvir; ritonavir should be started as soon as possible after positive test results for SARS-CoV-2 and within 5 days of symptom onset. Although the drug is not authorized for use in patients hospitalized due to severe COVID-19, it may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19, are at high risk for progression, and are within 5 days of symptom onset.
NOTE: Nirmatrelvir; ritonavir is expected to be active against the Omicron SARS-CoV-2 variant and its subvariants, although there is currently a lack of data on the clinical efficacy against these variants..
For storage information, see the specific product information within the How Supplied section.
NOTE: Nirmatrelvir; ritonavir is not an FDA-approved medication; however, it has been authorized for emergency use as a treatment for mild to moderate COVID-19 in patients with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death. Under the Emergency Use Authorization (EUA), health care providers are required to communicate to the patient or caregiver information consistent with the "Fact Sheet for Patients, Parents, and Caregivers" prior to the patient receiving treatment; such information includes the following:
NOTE: Nirmatrelvir; ritonavir may be prescribed for an individual patient by:
If any of the following apply, the state-licensed pharmacist should refer an individual patient for clinical evaluation with a physician, advanced practice registered nurse, or physician assistant licensed or authorized under state law to prescribe drugs:
To help identify appropriate candidates for treatment, the FDA has published a "Paxlovid Patient Eligibility Screening Checklist Tool for Prescribers", accessible at www.fda.gov/media/158165/download. This checklist is intended for use as an aid to support clinical decision-making, and is NOT required to prescribe nirmatrelvir; ritonavir under the EUA.
NOTE: Under the EUA, health care providers are required to report all medication errors and serious adverse events potentially related to nirmatrelvir; ritonavir therapy within 7 calendar days from the health care provider's awareness of the event.
The safety of nirmatrelvir; ritonavir was evaluated in a placebo-controlled trial of non-hospitalized adults with laboratory confirmed SARS-CoV-2 infection and symptomatic COVID-19. A total of 1,109 patients received at least 1 dose of nirmatrelvir; ritonavir and 1,115 received a placebo. Adverse events were reported during treatment and through Day 34 after treatment initiation. Adverse events that occurred in the treatment group at a higher frequency than the placebo group included dysgeusia (6% vs less than 1%, respectively), diarrhea (3% vs 2%), hypertension (1% vs less than 1%), and myalgia (1% vs less than 1%). Overall, 2% of patients in the nirmatrelvir; ritonavir group and 4% in the placebo group discontinued treatment due to an adverse event.
Anaphylaxis or anaphylactoid reactions and other hypersensitivity reactions have been reported with the use of nirmatrelvir; ritonavir. Additionally, cases of toxic epidermal necrolysis (TEN), and Stevens-Johnson Syndrome (SJS) have been reported with the ritonavir component. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue use of the drug and initiate appropriate medications and supportive care.
Abdominal pain, nausea, and malaise have been reported during post-authorization use of nirmatrelvir; ritonavir. Due to the voluntary nature of these reports, neither a frequency nor a definitive causal relationship can be established.
Consider the potential for drug interactions (including over-the-counter medications and herbal supplements) prior to and during nirmatrelvir; ritonavir therapy. Nirmatrelvir; ritonavir (a CYP3A inhibitor) is contraindicated for use with medications that are highly dependent on CYP3A for clearance and are associated with serious or life-threatening adverse events. Additionally, the drug is contraindicated for use with strong CYP3A inducers (i.e., apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort); concurrent use of strong CYP3A inducers can lead to a marked decrease in plasma concentrations of nirmatrelvir and ritonavir, which may result in loss of therapeutic effect and viral resistance. Due to the delayed offset, nirmatrelvir; ritonavir cannot be started immediately after discontinuing any of the above listed CYP3A inducers. If a significant drug interaction is identified, consider the risks and benefits of treatment. Consider expert consultation, especially for patients receiving highly specialized therapies such as antineoplastics, neuropsychiatric drugs, and certain immunosuppressants. Potential management strategies to facility the use of nirmatrelvir; ritonavir include (depending on the magnitude and significance of the interaction): dose adjustment of the concomitant medication; use of an alternative concomitant medication; increased monitoring for potential adverse reactions; temporarily withholding the concomitant medication. These strategies should be considered during the 5-day treatment and for at least 3 to 5 days after the end of therapy (potentially longer for concomitant medications with long half-lives). In settings where these strategies are not feasible, consider use of an alternative COVID-19 therapeutic. Health care providers are advised NOT to adjust the dose of nirmatrelvir; ritonavir to avoid or mitigate a drug interaction.
Nirmatrelvir; ritonavir is authorized for use as an oral therapy, given over 5 days, to treat mild to moderate COVID-19 in patients at high risk for progression to severe COVID-19, including hospitalization or death. The drug is NOT authorized for use in patients requiring hospitalization due to severe or critical COVID-19; nor is it authorized for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19. In order to minimize antimicrobial resistance and transmission of SARS-CoV-2, instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations. Should a patient require hospitalization after starting treatment, the full 5-day treatment course should be completed unless there are drug interactions that preclude its use. Use of nirmatrelvir; ritonavir for longer than 5 consecutive days is NOT authorized.
There is a potential risk that human immunodeficiency virus (HIV) infection resistance to HIV protease inhibitors may develop if nirmatrelvir; ritonavir therapy is administered to individuals with uncontrolled or undiagnosed HIV infection. However, patients with HIV or HCV infections who are on a ritonavir- or cobicistat-containing regimen should continue their treatment as indicated. No dosage adjustments are required when nirmatrelvir; ritonavir is administered concurrently with other products containing ritonavir or cobicistat.
A dose reduction is required when administering nirmatrelvir; ritonavir to patients with moderate renal impairment (eGFR 30 to 59 mL/minute). Use of the drug is NOT authorized in patients with severe renal disease (eGFR less than 30 mL/minute), as data in this population is limited and the appropriate dosage has not been determined.
Elevated hepatic enzymes, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir; therefore, caution is advised when administering nirmatrelvir; ritonavir to patients with pre-existing hepatic disease, hepatic enzyme abnormalities, or hepatitis. The drug is NOT authorized for use in patients with severe hepatic impairment (Child-Pugh C), as pharmacokinetic and safety data are unavailable in these patients.
There are no human data available regarding the use of nirmatrelvir during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. In animal embryo-fetal development studies, reduced fetal body weights (9% decrease) were observed in rabbits following maternal administration of nirmatrelvir doses resulting in systemic exposures 10-times higher than clinical exposures at the authorized human dose. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures greater than or equal to 3-times higher than clinical exposures at the authorized human dose. Published observational studies on ritonavir use in pregnant patients have not identified an increased risk for major birth defects [i.e., 2.3% (95% CI: 1.9 to 2.9) after first-trimester exposure vs. 2.7% background birth defect rate]; however, published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriages. When evaluating use of nirmatrelvir; ritonavir in pregnant patients, consider that untreated COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes (i.e., preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death). The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that nirmatrelvir; ritonavir be offered to pregnant and recently pregnant patients, especially since pregnancy is a risk factor for severe COVID-19. Obstetricians should be aware of potential drug-drug interactions when prescribing this medication.
There are no data available regarding the presence of nirmatrelvir in human milk, the effects on the breast-fed infant, or the effects on milk production. Limited published data show that ritonavir is present in human milk; however, no information is available for the effects of ritonavir on the breast-fed infant or milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, the potential for viral transmission to SARS-CoV-2-negative infants, and the risk of an untreated or inadequately treated condition. Lactating mothers are advised to follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
Nirmatrelvir; ritonavir is contraindicated for use in patients with a history of clinically significant hypersensitivity reactions, such as serious rash [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson Syndrome (SJS)], to its active ingredients or any other components of the product. Cases of TENs and SJS have been reported with the ritonavir component, and anaphylaxis and other hypersensitivity reactions have been reported during use of nirmatrelvir; ritonavir. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue use of the drug and initiate appropriate medications and supportive care.
Nirmatrelvir; ritonavir is an investigational oral antiviral medication with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ritonavir is an HIV-1 protease inhibitor and a CYP3A inhibitor. Ritonavir does not have antiviral activity against SARS-CoV-2, but instead is used as a pharmacokinetic enhancer to increase plasma concentrations of nirmatrelvir. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. By binding directly to the SARS-CoV-2 Mpro active site, nirmatrelvir renders the virus incapable of processing polyprotein precursors, thereby preventing viral replication.
In a biochemical assay, nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro with a half-maximal inhibitory concentration (IC50) value of 19.2 nanomolar. The 50% effective concentration (EC50) and 90% effective concentration (EC90) against SARS-CoV-2 in differentiated normal human bronchial epithelial cells after 3 days of drug exposure were 62 nanomolar and 181 nanomolar, respectively. Nirmatrelvir had similar cell culture antiviral activity (EC50 3-fold or less relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621), and Omicron (B.1.1.529/BA.1, BA.2, BA.2.12.1, and BA.4) variants. The Beta (B.1.351) variant was the least susceptible tested with an approximate 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods.
In the EPIC-HR clinical trial, treatment-emergent substitutions in SARS-CoV-2 Mpro or Mpro cleavage site that were more common in nirmatrelvir; ritonavir-treated subjects (n = 361) than in placebo (n = 402) included:
In 1 subject witha baseline Mpro L50F substitution, the Mpro E166V substitution co-occurred with L50F on Day 5 (included in the counts above). The Mpro E166V and L50F + E166V substitutions have been associated with nirmatrelvir resistance in cell cultures. None of these substitutions in Mpro gene or cleavage regions occurred in nirmatrelvir; ritonavir-treated subjects who also experienced hospitalization; thus, the clinical significance is unknown.
Cross-resistance is not expected between nirmatrelvir and remdesivir, molnupiravir, or anti-SARS-CoV-2 monoclonal antibodies.
Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e., viral RNA rebound) in nasopharyngeal samples have been observed on Day 10 and Day 14 in a subset of nirmatrelvir; ritonavir-treated patients and placebo recipients, irrespective of COVID-19 symptoms. Following a single 5-days course of nirmatrelvir; ritonavir, viral RNA rebound was not associated with COVID-19-related hospitalization or death from any cause through Day 28. Post-treatment viral RNA rebound also was not associated with drug resistance as measured by Mpro sequencing. The clinical relevance of post-treatment increases in viral RNA is unknown.
Nirmatrelvir; ritonavir is administered orally. Once in systemic circulation, 69% of nirmatrelvir and approximately 99% of ritonavir is bound to human plasma proteins. The mean apparent volume of distribution during the terminal phase for nirmatrelvir and ritonavir are 104.7 L and 112.4 L, respectively. Nirmatrelvir has a blood-to-plasma ratio of 0.6 and the ratio for ritonavir is 0.14. Nirmatrelvir is a CYP3A4 substrate, but the metabolic clearance is minimal when dosed with ritonavir. Ritonavir is primarily metabolized by CYP3A4, with minor contributions from CYP2D6 to form the isopropylthiazole oxidate metabolite M-2. Nirmatrelvir is primarily eliminated via the kidneys, with a mean half-life of 6.05 hours. Hepatic metabolism is the major route of elimination for ritonavir, which has a mean half-life of 6.15 hours. The percentage of nirmatrelvir drug-related material excreted in the urine and feces is 49.6% and 35.3%, respectively. The percentage of ritonavir drug-related material excreted in the feces and urine is 86.4% and 11.3%, respectively.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6 P-glycoprotein (P-gp)
In vitro data indicate that nirmatrelvir is a substrate for CYP3A4 and the drug transporter P-glycoprotein (P-gp). Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and P-gp. Ritonavir is a substrate for and inhibitor of CYP3A (major) and CYP2D6 (minor). Ritonavir is also a substrate and inhibitor of P-glycoprotein (P-gp). Additionally, ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.
Following administration of a single 300 mg/100 mg nirmatrelvir; ritonavir dose in health subjects, the maximum plasma concentration (Cmax) of nirmatrelvir was 2.21 mcg/mL and the time to reach peak concentration (Tmax) was 3 hours (range 1.02 to 6 hours). The systemic exposure (AUC) of nirmatrelvir after a single dose was 23.01 mcg x hour/mL. Upon administration of nirmatrelvir; ritonavir, the increase in nirmatrelvir exposure appears to be less than dose proportional up to 750 mg as a single dose and up to 500 mg twice daily as multiple doses. Twice daily dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Dosing with a high-fat meal modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean Cmax and 1.6% in mean AUC) relative to fasting conditions.
A single 100 mg/100 mg dose of nirmatrelvir; ritonavir in patients with moderate hepatic impairment resulted in nirmatrelvir exposures that were similar to those observed in subjects with normal hepatic function. The pharmacokinetics of nirmatrelvir; ritonavir have not been evaluated in patients with severe hepatic impairment.
The pharmacokinetics of nirmatrelvir were compared in healthy subjects and patients with mild (eGFR 60 to 89 mL/minute), moderate (eGFR 30 to 59 mL/minute), and severe (eGFR less than 30 mL/minute) renal impairment following administration of a single 100 mg/100 mg nirmatrelvir; ritonavir dose. Compared to the healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild impairment were 30% and 24% higher, in patients with moderate impairment they were 38% and 87% higher, and in patients with severe impairment they were 48% and 204% higher, respectively.
The pharmacokinetics of nirmatrelvir; ritonavir in patients less than 18 years of age have not been evaluated. Using a population PK model, the authorized dosing regimen is expected to result in comparable steady-state plasma exposure of nirmatrelvir in patients 12 years of age and older who weigh at least 40 kg to those observed in adults after adjusting for body weight.
Systemic exposure to nirmatrelvir in Japanese patients was numerically lower, but not clinically meaningfully different, than those in Western subjects.
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