Dosage & Administration
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets.
Nirmatrelvir must be co-administered with ritonavir.
| Abbreviation: eGFR=estimated glomerular filtration rate. | ||
Days of Treatment | ||
Paxlovid Prescribing Information
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- PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].
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- Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring [see Drug Interactions (7)].
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- 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 Warnings and Precautions (5.1), Drug Interactions (7), and Clinical Studies (14)].
PAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.
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)].
Important Dosage and Administration Information
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are three different dose packs available:
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- PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg [see Dosage and Administration (2.2)].
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- PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment [see Dosage and Administration (2.3)].
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- 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.
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.
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
| Abbreviation: eGFR=estimated glomerular filtration rate. | ||
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Renal Function | Days of Treatment | Dose and Dose Frequency * |
Moderate renal impairment (eGFR ≥30 to <60 mL/min) | Days 1-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily |
Severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis † | Day 1 | 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once |
Days 2-5 | 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily | |
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)].
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets [see How Supplied/Storage and Handling (16)].
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- Nirmatrelvir is supplied as oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Each tablet contains 150 mg of nirmatrelvir.
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- Ritonavir is supplied as white or white to off-white film-coated tablets uniquely identified by the color, shape, and debossing. Each tablet contains 100 mg of ritonavir.
Pregnancy
Risk Summary
Available data on the use of nirmatrelvir during pregnancy are insufficient 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 11 times higher than clinical exposure at the approved 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 approved human dose of PAXLOVID (see Data).
In embryo-fetal developmental studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at systemic exposures (AUC) 5 (rat) or 8 (rabbits) times higher than clinical exposure at the approved 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.
Clinical Considerations
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.
Data
Human Data
Ritonavir
Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,500 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 2.4% [95% confidence interval (CI): 1.9%, 2.9%] following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%, 3.5%) 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.
Animal Data
Nirmatrelvir
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 GD 7 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 9 times higher than clinical exposures at the approved 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 11 times higher than clinical exposures at the approved human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed 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 approved 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 showed no adverse findings. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir-treated versus control animals, a decrease in the body weight of offspring was observed on Postnatal Day (PND) 17 (8% decrease) and PND 21 (up to 7% decrease) in the absence of maternal toxicity. 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 9 times higher than clinical exposures at the approved human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, where maternal systemic exposure (AUC24) was approximately 6 times higher than clinical exposures at the approved human dose of PAXLOVID.
Ritonavir
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 in rats and GD 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5 (rats) or 8 (rabbits) times higher than exposure at the approved 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 (AUC) approximately 10 times higher than exposure at the approved human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8 times higher than exposure at the approved human dose of PAXLOVID. In a PPND study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through PND 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10 times the exposure at the approved human dose of PAXLOVID.
Lactation
Risk Summary
Nirmatrelvir and ritonavir are present in human breast milk in small amounts (less than 2%). In a clinical lactation study in 8 lactating women, nirmatrelvir and ritonavir were estimated to be present in human milk at a mean weight-normalized infant daily dose of 0.16 mg/kg/day (1.8% of maternal weight-adjusted daily dose) and 0.006 mg/kg/day (0.2% of maternal weight-adjusted daily dose), respectively (see Data).
There are no available data on the effects of nirmatrelvir or ritonavir on the breastfed infant or 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.
Data
In a clinical pharmacokinetics study, 8 healthy lactating women who were at least 12 weeks postpartum were administered 3 oral doses every 12 hours (steady state dosing) of 300 mg/100 mg nirmatrelvir/ritonavir. The mean daily amount of nirmatrelvir and ritonavir recovered in breast milk was 0.752 mg and 0.027 mg, respectively, representing 0.13% and 0.014% of the corresponding administered daily maternal doses (unadjusted for weight). The estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 0.16 mg/kg/day and 0.006 mg/kg/day, 1.8% and 0.2% of the maternal dose, respectively, for nirmatrelvir and ritonavir.
Females and Males of Reproductive Potential
Contraception
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)].
Pediatric Use
The optimal dose of PAXLOVID has not been established in pediatric patients.
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.
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)].
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)].
PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome] to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product.
PAXLOVID is contraindicated with drugs that are primarily metabolized by CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions and drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. There are certain other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, interruption, or therapeutic monitoring is recommended. Drugs listed in this section are a guide and not considered a comprehensive list of all drugs that may be contraindicated 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 like PAXLOVID [see Drug Interactions (7.3)]:
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- Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.3)]:
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- Alpha 1-adrenoreceptor antagonist: alfuzosin
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- Antianginal: ranolazine
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- Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
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- Anti-gout: colchicine (in patients with renal and/or hepatic impairment [see Table 2, Drug Interactions (7.3)])
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- Antipsychotics: lurasidone, pimozide
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- Benign prostatic hyperplasia agents: silodosin
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- Cardiovascular agents: eplerenone, ivabradine
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- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
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- HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use [see Table 2, Drug Interactions (7.3)])
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- Immunosuppressants: voclosporin
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- Microsomal triglyceride transfer protein inhibitor: lomitapide
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- Migraine medications: eletriptan, ubrogepant
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- Mineralocorticoid receptor antagonists: finerenone
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- Opioid antagonists: naloxegol
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- PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH)
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- Sedative/hypnotics: triazolam, oral midazolam
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- Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
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- Vasopressin receptor antagonists: tolvaptan
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- Drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer [see Drug Interactions (7.3)]:
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- Anticancer drugs: apalutamide, enzalutamide
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- Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
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- Antimycobacterials: rifampin, rifapentine
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- Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
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- Herbal products: St. John's Wort (hypericum perforatum)