An EUA is a U.S. Food and Drug Administration authorization for the emergency use of an unapproved product or unapproved use of an approved product (i.e., drug, biological product, or device) in the United States under certain circumstances including, but not limited to, when the Secretary of HHS declares that there is a public health emergency that affects the national security or the health and security of United States citizens living abroad, and that involves biological agent(s) or a disease or condition that may be attributable to such agent(s). Criteria for issuing an EUA include:
- The biological agent(s) can cause a serious or life-threatening disease or condition;
- Based on the totality of the available scientific evidence (including data from adequate and well-controlled clinical trials, if available), it is reasonable to believe that
- the product may be effective in diagnosing, treating, or preventing the serious or life-threatening disease or condition; and
- the known and potential benefits of the product—when used to diagnose, prevent, or treat such disease or condition—outweigh the known and potential risks of the product, taking into consideration the material threat posed by the biological agent(s);
- There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating the serious or life-threatening disease or condition.
Information Regarding Available Alternatives for the EUA Authorized Use
There are no approved alternatives to PAXLOVID for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.
Other therapeutics are currently authorized for the same use as PAXLOVID. For additional information on all products authorized for treatment or prevention of COVID-19, please see https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.
For information on clinical studies that are testing the use of PAXLOVID in COVID-19, please see www.clinicaltrials.gov.
There are no available human data on the use of nirmatrelvir during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage (see Data). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations).
In an embryo-fetal development study with nirmatrelvir, reduced fetal body weights following oral administration of nirmatrelvir to pregnant rabbits were observed at systemic exposures (AUC) approximately 10 times higher than clinical exposure at the authorized human dose of PAXLOVID. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures (AUC) greater than or equal to 3 times higher than clinical exposure at the authorized human dose of PAXLOVID (see Data).
In animal reproduction studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at doses (based on body surface area conversions) or systemic exposures (AUC) greater than or equal to 3 times higher than clinical doses or exposure at the authorized human dose of PAXLOVID (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-associated Maternal and/or Embryo-fetal Risk
COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.
Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,400 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.3% (95% confidence interval [CI]: 1.9%–2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%–3.6%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.
Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and 6 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC24) in rats was approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC24) in rabbits was approximately 10 times higher than clinical exposures at the authorized human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed at up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC24) approximately 3 times higher than clinical exposures at the authorized human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 is ongoing and only interim data through postnatal day (PND) 56 are currently available. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir treated versus control animals, a decrease (8% in males and females) in the body weight of offspring was observed at PND 17. No significant differences in offspring body weight were observed from PND 28 to PND 56. The maternal systemic exposure (AUC24) at 1,000 mg/kg/day was approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, resulting in systemic exposure (AUC24) approximately 5 times higher than clinical exposures at the authorized human dose of PAXLOVID.
Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) approximately 4 times higher than exposure at the authorized human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures approximately 4 times higher than exposure at the authorized human dose of PAXLOVID. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 5 times the exposure at the authorized human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses approximately 11 times higher than the authorized human dose of PAXLOVID, based on a body surface area conversion factor. In a pre- and postnatal development study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through postnatal day 20 resulted in no developmental toxicity, at ritonavir doses 3 times higher than the authorized human dose of PAXLOVID, based on a body surface area conversion factor.
There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the breastfed infant, or the effects on milk production. A transient decrease in body weight was observed in the nursing offspring of rats administered nirmatrelvir (see Data). Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.
In the pre- and postnatal developmental study, body weight decreases (up to 8%) were observed in the offspring of pregnant rats administered nirmatrelvir at maternal systemic exposure (AUC24) approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. No body weight changes in the offspring were noted at maternal systemic exposure (AUC24) approximately 5 times higher than clinical exposures at the authorized human dose of PAXLOVID.
Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)].
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 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 following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, and titanium dioxide.
Effect of Food on Oral Absorption of Nirmatrelvir
Dosing with a high fat meal modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean Cmax and 1.6% increase in mean AUClast) relative to fasting conditions following administration of a suspension formulation of nirmatrelvir co-administered with ritonavir tablets.
The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.
The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been evaluated.
Using a population PK model, the dosing regimen is expected to result in comparable steady-state plasma exposure of nirmatrelvir in patients 12 years of age and older and weighing at least 40 kg to those observed in adults after adjusting for body weight.
Racial or Ethnic Groups
Systemic exposure in Japanese subjects was numerically lower but not clinically meaningfully different than those in Western subjects.
Patients with Renal Impairment
An open-label study compared nirmatrelvir/ritonavir pharmacokinetics in healthy adult subjects and subjects with mild (eGFR ≥60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), and severe (eGFR <30 mL/min) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively (Table 4).
Table 4: Impact of Renal Impairment on Nirmatrelvir/Ritonavir Pharmacokinetics
|Normal Renal Function |
|Mild Renal Impairment |
|Moderate Renal Impairment |
|Severe Renal Impairment |
|Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for t1/2.|
|Cmax (µg/mL)||1.60 (31)||2.08 (29)||2.21 (17)||2.37 (38)|
|AUCinf (µg*hr/mL)||14.46 (20)||17.91 (30)||27.11 (27)||44.04 (33)|
|Tmax (hr)||2.0 (1.0 – 4.0)||2.0 (1.0 – 3.0)||2.50 (1.0 – 6.0)||3.0 (1.0 – 6.1)|
|T1/2 (hr)||7.73 ± 1.82||6.60 ± 1.53||9.95 ± 3.42||13.37 ± 3.32|
Patients with Hepatic Impairment
A single oral dose of 100 mg nirmatrelvir enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours and 24 hours in subjects with moderate hepatic impairment resulted in similar exposures compared to subjects with normal hepatic function (Table 5).
Table 5: Impact of Hepatic Impairment on Nirmatrelvir/Ritonavir Pharmacokinetics
|Normal Hepatic Function|
|Moderate Hepatic Impairment |
|Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for t1/2.|
|Cmax (µg/mL)||1.89 (20)||1.92 (48)|
|AUCinf (µg*hr/mL)||15.24 (36)||15.06 (43)|
|Tmax (hr)||2.0 (0.6 – 2.1)||1.5 (1.0 – 2.0)|
|T1/2 (hr)||7.21 ± 2.10||5.45 ± 1.57|
Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.
Drug Interaction Studies Conducted with Nirmatrelvir
In vitro data indicates that nirmatrelvir is a substrate for human MDR1 (P-gp) and 3A4, but not a substrate for human BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATPs 1B1, 1B3, 2B1, or 4C1.
Nirmatrelvir does not reversibly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro at clinically relevant concentrations. Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and inhibit MDR1 (P-gp).
Nirmatrelvir does not induce any CYPs at clinically relevant concentrations.
Drug Interaction Studies Conducted with Ritonavir
In vitro studies indicate that ritonavir is mainly a substrate of CYP3A. Ritonavir also appears to be a substrate of CYP2D6 which contributes to the formation of isopropylthiazole oxidation metabolite M-2.
Ritonavir is an inhibitor of CYP3A and to a lesser extent CYP2D6. Ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.
The effects of co-administration of PAXLOVID with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and Cmax are summarized in Table 6 (effect of other drugs on nirmatrelvir).
Table 6: Drug Interactions: Pharmacokinetic Parameters for Nirmatrelvir in the Presence of the Co-administered Drugs
|Co-administered Drug||Dose (Schedule)||N||Ratio (in combination with Co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI); |
|Co-administered Drug ||Nirmatrelvir/Ritonavir||Cmax||AUC|
For carbamazepine, AUC=AUCinf, for itraconazole, AUC=AUCtau.
|Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; Cmax=maximum plasma concentrations.|
Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7).
|300 mg twice daily |
|300 mg/100 mg twice daily|
|Itraconazole||200 mg once daily |
|300 mg/100 mg twice daily |
Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC50 and EC90 values of 62 nM and 181 nM, respectively, after 3 days of drug exposure.
Nirmatrelvir had similar cell culture antiviral activity (EC50 values ≤3-fold relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Lambda (C.37) variants. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
No data are available regarding the activity of nirmatrelvir against the SARS-CoV-2 Omicron (B.1.1.529) variant in cell culture. However, in a biochemical assay, the Mpro P132H substitution found in the Omicron variant did not reduce nirmatrelvir activity (Ki fold change <1) compared to the USA-WA1/2020 enzyme.
Antiviral Activity Against SARS-CoV-2 in Animal Models
Nirmatrelvir showed antiviral activity in BALB/c and 129 mice infected with mouse-adapted SARS-CoV-2. Oral administration of nirmatrelvir at 300 mg/kg or 1,000 mg/kg twice daily initiated 4 hours post-inoculation or 1,000 mg/kg twice daily initiated 12 hours post-inoculation resulted in reduction of lung viral titers and ameliorated indicators of disease (weight loss and lung pathology) compared to placebo-treated animals.
Phenotypic assessments were conducted to characterize the impact of naturally occurring SARS-CoV-2 Mpro polymorphisms on the activity of nirmatrelvir in a biochemical assay using recombinant Mpro enzyme. The clinical significance of these polymorphisms is unknown, and it is also unknown if results from the biochemical assay are predictive of antiviral activity in cell culture. The following Mpro amino acid substitutions were associated with reduced nirmatrelvir activity (≥3-fold higher Ki values): G15S (4.4-fold), T135I (3.5-fold), S144A (91.9-fold), H164N (6.4-fold), H172Y (233-fold), Q189K (65.4-fold), and D248E (3.7-fold). G15S is present in the Lambda variant, which did not have reduced susceptibility to nirmatrelvir (relative to USA-WA1/2020) in cell culture.
In addition, three SARS-CoV-2 Mpro amino acid positions where polymorphisms have not been naturally observed were evaluated by substituting alanine at these positions and assessing their impact on activity in biochemical assays. These Mpro amino acid substitutions were associated with reduced nirmatrelvir activity (i.e., higher Ki values): Y54A (23.6-fold), F140A (39.0-fold), and E166A (33.4-fold). The clinical significance of substitutions at these Mpro positions is unknown.
Cell culture resistance selection studies with nirmatrelvir using mouse hepatitis virus (MHV, a betacoronavirus used as a surrogate) resulted in the emergence of Mpro amino acid substitutions P15A, T50K, P55L, T129M, and/or S144A. The clinical relevance of these changes is not known. The presence of the substitutions P55L and S144A was associated with reduced nirmatrelvir susceptibility (~4- to 5-fold higher EC50 values). These positions correspond to E55 and S144 in SARS-CoV-2 Mpro, respectively. E55L alone did not affect nirmatrelvir activity against SARS-CoV-2 Mpro in a biochemical assay, while S144A reduced nirmatrelvir activity by 91.9-fold (based on Ki value).
Limited SARS-CoV-2 sequencing data are available to characterize nirmatrelvir resistance in clinical trials. The SARS-CoV-2 Mpro substitutions A260V (n=3) or A260T (n=1) emerged in 4% (4/97) of nirmatrelvir/ritonavir treated subjects in clinical trial EPIC-HR with available sequence analysis data. A260T and A260V substitutions are infrequent natural polymorphisms in publicly available SARS-CoV-2 sequences (as of Dec 5, 2021). In a biochemical assay, the A260V Mpro substitution did not reduce nirmatrelvir activity (Ki fold-change <1).
Cross-resistance is not expected between nirmatrelvir and anti-SARS-CoV-2 monoclonal antibodies or remdesivir based on their different mechanisms of action.
Carcinogenicity studies have not been conducted with nirmatrelvir.
Nirmatrelvir was negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the in vitro micronucleus assay using human lymphoblastoid TK6 cells, and the in vivo rat micronucleus assays.
In a fertility and early embryonic development study, nirmatrelvir was administered orally to male and female rats at doses of 60, 200, or 1,000 mg/kg/day once daily beginning 14 days prior to mating, throughout the mating phase, and continued through GD 6 for females and for a total of 32 doses for males. There were no effects on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day, resulting in systemic exposure (AUC24) approximately 4 times higher than exposure at the authorized human dose of PAXLOVID.
Carcinogenicity studies in mice and rats have been conducted on ritonavir. In male mice, at levels of 50, 100, or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 2 times higher (in males) than the exposure in humans at the authorized human dose of PAXLOVID. There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 4 times higher (in females) than the exposure in humans at the authorized human dose of PAXLOVID. In rats dosed at levels of 7, 15, or 30 mg/kg/day, there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 36% that of the exposure in humans at the authorized human dose of PAXLOVID.
Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Ritonavir produced no effects on fertility in rats at drug exposures approximately 2 (male) and 4 (female) times higher than the exposure in humans at the authorized human dose of PAXLOVID.
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets.
- Nirmatrelvir tablets, 150 mg are oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side.
- Ritonavir tablets, 100 mg are white film-coated ovaloid tablets debossed with the "a" logo and the code NK.
Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.
Each carton contains 30 tablets divided in 5 daily-dose blister cards (NDC number: 0069-1085-30).
Each daily blister card (NDC number: 0069-1085-06) contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each) and indicates which tablets need to be taken in the morning and evening.
Use in Patients with Renal Impairment
No dose adjustment is needed in patients with mild 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. Instruct patients that the pharmacist will alter their daily blister cards to ensure they receive the correct dose.
Pharmacist should refer to the provided instructions entitled "IMPORTANT PAXLOVID™ EUA DISPENSING INFORMATION FOR PATIENTS WITH MODERATE RENAL IMPAIRMENT" for dispensing of PAXLOVID to patients with moderate renal impairment [see Dosage and Administration (2.2)].
Appropriate dosage for patients with severe renal impairment has not been determined [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Inform patients that PAXLOVID may interact with some drugs and is contraindicated for use with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].
Inform patients to take PAXLOVID with or without food 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 (2.1)].