Limitations of Use

PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19 [see Clinical Studies (14.3)].

2.1 Important Dosage and Administration Information

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are three different dose packs available:

•

PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg [see Dosage and Administration (2.2)].

•

PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment [see Dosage and Administration (2.3)].

•

PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg (Day 1) and 150 mg;100 mg (Days 2-5) for patients with severe renal impairment [see Dosage and Administration (2.3)].

Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect.

Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID [see Dosage and Administration (2.2, 2.3)]. Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2.

The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider's discretion.

If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.

PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food [see Clinical Pharmacology (12.3)]. The tablets should be swallowed whole and not chewed, broken, or crushed.

2.2 Recommended Dosage

The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily in the morning and at bedtime for 5 days.

2.3 Dosage in Patients with Renal Impairment

Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)].

No dosage adjustment is recommended in patients with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥60 to <90 mL/min].

In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min) or with severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis, the dosage of PAXLOVID should be reduced as shown in Table 1. PAXLOVID should be administered at approximately the same time each day for 5 days. On days patients with severe renal impairment undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and How Supplied/Storage and Handling (16)].

Table 1: Recommended Dose and Regimen for Patients with Renal Impairment

2.4 Use in Patients with Hepatic Impairment

No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment; therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of PAXLOVID, which contains ritonavir, a strong CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:

•

Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.

•

Loss of therapeutic effect of PAXLOVID and possible development of viral resistance.

Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (e.g., tacrolimus, cyclosporine), followed by calcium channel blockers.

Prior to prescribing PAXLOVID, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors) [see Contraindications (4) and Drug Interactions (7)]. See Table 2 for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID.

Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed [see Drug Interactions (7) and Clinical Studies (14)].

5.2 Hypersensitivity Reactions

Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID [see Adverse Reactions (6.1)]. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.

5.3 Hepatotoxicity

Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

5.4 Risk of HIV-1 Resistance Development

Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection [see Contraindications (4) and Drug Interactions (7)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of PAXLOVID is based on two Phase 2/3 randomized, placebo-controlled trials in symptomatic adult subjects 18 years of age and older with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Subjects in both studies received PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo every 12 hours for 5 days for the treatment of mild-to-moderate COVID-19 within 5 days of symptom onset [see Clinical Studies (14)]:

•

Trial C4671005 (EPIC-HR) enrolled subjects who were at high risk for progression to severe disease.

•

Trial C4671002 (EPIC-SR) enrolled subjects who were at standard risk for progression to severe disease (previously unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease).

Adverse reactions were those reported while subjects were on study medication and through 28 days after the last dose of study treatment.

In Trial C4671005 (EPIC-HR), 1,038 subjects received PAXLOVID and 1,053 subjects received placebo. The most common adverse reactions (≥1% incidence in the PAXLOVID group and occurring at a greater frequency than in the placebo group) were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively).

Among vaccinated or unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease in Trial C4671002 (EPIC-SR), 540 subjects received PAXLOVID and 528 subjects received placebo. The adverse reactions observed were consistent with those observed in EPIC-HR.

Trial C4671028 (EPIC-SRI) was a Phase 1, open-label trial that evaluated the effects of severe renal impairment on the pharmacokinetics, safety, and tolerability of PAXLOVID in non-hospitalized adult participants with COVID-19 and severe renal impairment. A total of 15 subjects with severe renal impairment were enrolled in this trial, with 12 subjects receiving intermittent hemodialysis and 3 subjects not on hemodialysis. Subjects received nirmatrelvir/ritonavir 300 mg/100 mg once on Day 1 followed by nirmatrelvir/ritonavir 150 mg/100 mg once daily from Days 2-5. The safety profile of PAXLOVID in subjects with severe renal impairment, including those requiring hemodialysis, was consistent with the safety profile observed in the Phase 2/3 randomized, placebo-controlled trials.

Emergency Use Authorization Experience in Subjects with COVID-19

The following adverse reactions have been identified during use of PAXLOVID under Emergency Use Authorization.

Immune System Disorders: Anaphylaxis, hypersensitivity reactions [see Warnings and Precautions (5.2)]

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome [see Warnings and Precautions (5.2)]

Nervous System Disorders: Headache

Vascular Disorders: Hypertension

Gastrointestinal Disorders: Abdominal pain, nausea, vomiting

General Disorders and Administration Site Conditions: Malaise

7.1 Potential for PAXLOVID to Affect Other Drugs

PAXLOVID (nirmatrelvir co-packaged with ritonavir) is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse events. Co-administration of PAXLOVID with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated [see Contraindications (4) and Drug Interactions (7.3) Table 2]. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 2.

7.2 Potential for Other Drugs to Affect PAXLOVID

Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect [see Contraindications (4) and Drug Interactions (7.3) Table 2].

7.3 Established and Other Potentially Significant Drug Interactions

Table 2 provides a listing of clinically significant drug interactions, including contraindicated drugs [see Contraindications (4) and Warnings and Precautions (5.1)]. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The optimal dose of PAXLOVID has not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of PAXLOVID include subjects 65 years of age and older and their data contributes to the overall assessment of safety and efficacy [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Of the total number of subjects in the integrated dataset consisting of EPIC-HR and EPIC-SR who were randomized to and received PAXLOVID (N=1,578), 165 (10%) were 65 years of age and older and 39 (2%) were 75 years of age and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in safety between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Renal impairment increases nirmatrelvir exposure, which may increase the risk of PAXLOVID adverse reactions. No dosage adjustment is recommended in patients with mild renal impairment (eGFR ≥60 to <90 mL/min). Reduce the PAXLOVID dosage in patients with moderate renal impairment (eGFR ≥30 to <60 mL/min). Reduce the PAXLOVID dose and dose frequency in patients with severe renal impairment (eGFR <30 mL/min), including those requiring hemodialysis. On days when patients undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)].

8.7 Hepatic Impairment

No dosage adjustment of PAXLOVID is recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment, therefore, PAXLOVID is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Nirmatrelvir

The chemical name of active ingredient of nirmatrelvir is (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide]. It has a molecular formula of C23H32F3N5O4 and a molecular weight of 499.54. Nirmatrelvir has the following structural formula:

Nirmatrelvir is available as immediate-release, film-coated tablets. Each tablet contains 150 mg nirmatrelvir with the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The following are the ingredients in the film coating: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide.

Ritonavir

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1 methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Ritonavir is available as film-coated tablets. Each tablet contains 100 mg ritonavir with the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating may include the following ingredients: colloidal anhydrous silica, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide.

12.1 Mechanism of Action

Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4)].

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19.

Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir. Nirmatrelvir steady state was achieved on Day 2 following administration of the approved recommended dosage and the mean accumulation ratio was approximately 2-fold.

The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 3.

The predicted Day 5 nirmatrelvir exposure parameters in adult subjects with mild-to-moderate COVID-19 who were treated with PAXLOVID in EPIC-HR are presented in Table 4.

12.4 Microbiology

Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Efficacy in Subjects at High Risk of Progression to Severe COVID-19 (EPIC-HR)

EPIC-HR (NCT04960202) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Subjects with COVID-19 symptom onset of ≤5 days were included in the study. Subjects were randomized (1:1) to receive PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The trial excluded individuals with a history of prior COVID-19 infection or vaccination and excluded individuals taking any medications with clinically significant drug interactions with PAXLOVID. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set [all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days).

A total of 2,113 subjects were randomized to receive either PAXLOVID or placebo. At baseline, mean age was 45 years; 51% were male; 71% were White, 15% were Asian, 9% were American Indian or Alaska Native, 4% were Black or African American, and 1% was missing or unknown; 41% were Hispanic or Latino; 67% of subjects had onset of symptoms ≤3 days before initiation of study treatment; 49% of subjects were serological negative at baseline; the mean (SD) baseline viral RNA in nasopharyngeal samples was 4.71 log10 copies/mL (2.89); 27% of subjects had a baseline viral RNA of ≥10^7 (log10 copies/mL); 6% of subjects either received or were expected to receive COVID-19 therapeutic monoclonal antibody treatment at the time of randomization and were excluded from the mITT and mITT1 analyses.

The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups.

The proportions of subjects who discontinued treatment due to an adverse event were 2.0% in the PAXLOVID group and 4.2% in the placebo group.

Table 9 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for PAXLOVID compared to placebo was 86% (95% CI: 72%, 93%).

Consistent results were observed in the mITT and mITT2 analysis populations.

Similar trends have been observed across subgroups of subjects (see Figure 1).

Figure 1: Subgroup Analysis of Adults with COVID-19 Dosed within 5 Days of Symptom Onset with COVID-19 Related Hospitalization or Death from Any Cause Through Day 28: EPIC-HR

Abbreviations: BMI=body mass index; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT=modified intent-to-treat; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. N=number of subjects in the category of the analysis set. All categories are based on mITT1 population except for COVID-19 mAb treatment which is based on mITT2 population. Seropositivity was defined if results were positive in either Elecsys anti-SARS-CoV-2 S or Elecsys anti-SARS-CoV-2 (N) assay. The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on normal approximation of the data are presented.

Among subjects who were SARS-CoV-2 seropositive at baseline, 1/490 (0.2%) PAXLOVID recipients versus 8/479 (1.7%) placebo recipients met the primary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 [reduction relative to placebo -1.47% (-2.70%, -0.25%)].

14.2 Trial in Unvaccinated Subjects Without a Risk Factor for Progression to Severe COVID-19 or Subjects Fully Vaccinated Against COVID-19 With at Least One Factor for Progression to Severe COVID-19 (EPIC-SR)

PAXLOVID is not indicated for the treatment of COVID-19 in patients without a risk factor for progression to severe COVID-19.

EPIC-SR (NCT05011513) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e., completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR. Through the December 19, 2021, data cutoff, a total of 1,075 subjects were randomized (1:1) to receive PAXLOVID or placebo orally every 12 hours for 5 days; of these, 59% were fully vaccinated high-risk subjects.

The primary endpoint in this trial, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among PAXLOVID versus placebo recipients, was not met.

In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction relative to placebo for the secondary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 was observed.

14.3 Post-Exposure Prophylaxis Trial

PAXLOVID is not indicated for the post-exposure prophylaxis of COVID-19.

In a double-blind, double-dummy, placebo-controlled trial, the efficacy of PAXLOVID when administered for 5 or 10 days as post-exposure prophylaxis of COVID-19 was evaluated. Eligible subjects were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at baseline and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2,736 subjects were randomized (1:1:1) to receive PAXLOVID orally every 12 hours for 5 days, PAXLOVID orally every 12 hours for 10 days, or placebo.

The primary endpoint for this trial was not met. The primary endpoint was the risk reduction between the 5-day and 10-day PAXLOVID regimens versus placebo in the proportion of subjects who developed RT-PCR or RAT-confirmed symptomatic SARS-CoV-2 infection through Day 14 who had a negative SARS-CoV-2 RT-PCR result at baseline. The proportion of subjects who had events through Day 14 was 2.6% for the 5-day PAXLOVID regimen, 2.4% for the 10-day PAXLOVID regimen, and 3.9% for placebo. There was not a statistically significant risk reduction versus placebo for either the 5-day or 10-day PAXLOVID regimen.

How Supplied

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. It is supplied in three different Dose Packs.

Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.

Storage and Handling

Store at USP controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Inform patients that PAXLOVID may interact with certain drugs and is contraindicated for use with certain drugs; therefore, advise patients to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].

Hypersensitivity Reactions

Inform patients that anaphylaxis, serious skin reactions, and other hypersensitivity reactions have been reported, even following a single dose of PAXLOVID. Advise them to immediately discontinue the drug and to inform their healthcare provider at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction [see Warnings and Precautions (5.2)].

Dosage Modification in Patients with Renal Impairment

Moderate Renal Impairment

To ensure appropriate dosing in patients with moderate renal impairment, instruct such patients that they will be taking one 150 mg nirmatrelvir tablet with one 100 mg ritonavir tablet together twice daily for 5 days [see Dosage and Administration (2.3)].

Severe Renal Impairment (Including Those Requiring Hemodialysis)

To ensure appropriate dosing in patients with severe renal impairment, including those requiring hemodialysis, instruct patients that they will be taking two 150 mg nirmatrelvir tablets with one 100 mg ritonavir tablet together once on Day 1, followed by one 150 mg nirmatrelvir tablet with one 100 mg ritonavir together once daily on Days 2-5. Instruct patients to take their dose at approximately the same time each day. On days when patients undergo hemodialysis, instruct them to take the PAXLOVID dose after hemodialysis [see Dosage and Administration (2.3)].

Administration Instructions

Inform patients to take PAXLOVID with or without food at approximately the same time each day as instructed. Advise patients to swallow all tablets for PAXLOVID whole and not to chew, break, or crush the tablets. Alert the patient of the importance of completing the full 5-day treatment course and to continuing isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of SARS-CoV-2. If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose [see Dosage and Administration (2)].