TRANSFORM HOW YOU USE DRUG INFORMATION

NOTE: The National Institutes of Health (NIH) has issued a statement to provide guidance on treating nonhospitalized patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics:

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 patients (12 years of age and older weighing at least 40 kg) with a current diagnosis of mild to moderate coronavirus disease (COVID-19) and who are at high risk for progression 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 may be completed per the healthcare provider's discretion. 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.[67203]

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.[65314]

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.[65314][67203]

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 to treat patients (12 years of age and older weighing at least 40 kg) with a current diagnosis of mild to moderate coronavirus disease (COVID-19) and who are at high risk for progression to severe COVID-19, including hospitalization or death. Under the Emergency Use Authorization (EUA), healthcare 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:

• The option to accept or refuse nirmatrelvir; ritonavir
• The significant known and potential risks and benefits of treatment, and the extent to which such potential risks and benefits are unknown
• Available alternative treatments and the risk and benefits of those alternatives
• The need to continue to self-isolate and use infection control measures (e.g., wear mask, isolate, social distance, avoid sharing personal items, clean and disinfect, frequent handwashing) according to CDC guidelines

NOTE: Nirmatrelvir; ritonavir may be prescribed for an individual patient by:

• Physicians, advanced practice registered nurses, and physician assistants who are licensed or authorized under state law to prescribe drugs.
• State-licensed pharmacists under the following conditions:
• Sufficient information is available to assess renal and hepatic function (through access to health records less than 12 months old or via consultation with a healthcare provider in an established provider-patient relationship with the individual patient); AND
• Sufficient information (i.e., a comprehensive list of prescription and non-prescription medications that the patient is taking) is available to assess for potential drug interactions (obtained though access to health records, patient reporting of medical history, or consultation with a healthcare provider in an established provider-patient relationship with the individual patient).

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:

• Sufficient information is not available to assess renal and hepatic function.
• Sufficient information is not available to assess for a potential drug interaction.
• Modification of other medications is needed due to a potential drug interaction.
• Nirmatrelvir; ritonavir is not an appropriate therapeutic option based on the EUA or due to potential drug interactions for which recommended monitoring would not be feasible.

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.[67584]

NOTE: Under the EUA, healthcare providers are required to report all medication errors and serious adverse events potentially related to nirmatrelvir; ritonavir therapy within 7 calendar days from the healthcare provider's awareness of the event.[67203]

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.[67203] 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.[65314]

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.

• SARS-CoV-2 Mpro single amino acid substitutions selected by nirmatrelvir in cell cultures include T21I (1.1- to 4.6-fold EC₅₀ change), L50F (1.4- to 4.2-fold), S144A (2.2- to 2.5-fold), E166A (3.3-fold), E166V (25- to 267-fold), A173V (0.9- to 2.3-fold), P252L (5.9-fold), and T304I (2.1- to 5.5-fold).
• SARS-CoV-2 Mpro multiple amino acid substitutions (i.e. 2 or more) selected by nirmatrelvir in cell cultures include T21I + S144A (9.4-fold EC₅₀ change), T21I + E166V (83-fold), T21I + A173V (3.1-fold), T21I + T304I (3- to 7.9-fold), L50F + E166V (34- to 163-fold), L50F + T304I (5.9-fold), T135I + T304I (3.8-fold), F140L + A173V (10.1-fold), A173V + T304I (20.2-fold), T21I + L50F + A193P + S301P (28.8-fold), T21I + S144A + T304I (27.8-fold), T21I + C160F + A173V + V186A + T304I (28.5-fold), T21I + A173V + T304I (15-fold), and L50F + F140L + L167F + T304I (54.7-fold).
• In a biochemical assay using recombinant SARS-CoV-2 Mpro containing amino acid substitutions, the following SARS-CoV-2 Mpro substitutions resulted in a 3-fold or greater reduction in activity of nirmatrelvir: G15S (4.4-fold), Y54A (24-fold), T135I (3.2-fold), F140A (39-fold), F140L (5.4-fold), S144A (92-fold), S144E (470-fold), S144T (160-fold), H164N (6.4-fold), E166A (33-fold), E166G (16-fold), H172Y (230-fold), A173V (26-fold), V186G (13-fold), Q189K (65-fold), Q192L (28-fold), Q192P (33-fold), and D248E (3.7-fold). The clinical significance of these substitutions is unknown.

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:

• Mpro substitutions: A7S/T/V (n = 3), L30F (n = 3), M82I/R (n = 3), G109E/R/V (n = 3), P132L/S (n = 4), C145F/R/Y (n = 3), D153H/Y (n = 3), E166V (n = 3), T196A/K/M/R (n = 4), W207L/S/del (n = 5), A260D/T/V (n = 8), D263E (n = 3), A266P/V (n = 3), and V297A/F/del (n = 3)
• Mpro ORF1ab cleavage site substitutions: Q5324H/R (n = 3), A5328P/S (n = 6), and T6449I/P (n = 3)

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.[67203]

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.[67203]

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).[28380][34557][65314] Additionally, ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.[67203]