Nirmatrelvir, ritonavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Overview
Nirmatrelvir, ritonavir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, and , an HIV-1 protease inhibitor, respectively that is FDA approved 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.. Common adverse reactions include dysgeusia and diarrhea..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets.
- Nirmatrelvir must be co-administered with ritonavir.
- Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.
- Administer orally with or without food.
- Administer at approximately the same time each day.
- Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days.
PAXLOVID is not recommend in patients with severe hepatic impairment (Child-Pugh Class).
DOSAGE FORMS AND STRENGTHS
- Tablets: nirmatrelvir 150 mg.
- Tablets: ritonavir 100 mg.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nirmatrelvir, ritonavir in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nirmatrelvir, ritonavir in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nirmatrelvir, ritonavir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nirmatrelvir, ritonavir in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nirmatrelvir, ritonavir in pediatric patients.
Contraindications
====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.
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)]:
- Alpha 1-adrenoreceptor antagonist: **alfuzosin
- Antianginal: ranolazine
- Antiarrhythmic: amiodarone, **dronedarone,
- flecainide,
- propafenone,
- quinidine
- Anti-gout: colchicine (in patients with renal and/or hepatic impairment.
- Antipsychotics: lurasidone,
- pimozide
- Benign prostatic hyperplasia agents: silodosin
- Cardiovascular agents: eplerenone, ivabradine
- Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use).
- Immunosuppressants: voclosporin
- Microsomal triglyceride transfer protein inhibitor: lomitapide
- Migraine medications: eletriptan, ubrogepant
- Mineralocorticoid receptor antagonists: finerenone
- Opioid antagonists: naloxegol
- PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH)
- Sedative/hypnotics: triazolam, oral midazolam
- Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
- Vasopressin receptor antagonists: tolvaptan.
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.
- Anticancer drugs: apalutamide, enzalutamide**Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
- Antimycobacterials: rifampin, rifapentine
- Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
- Herbal products: St. John's Wort (hypericum perforatum).
Warnings
- 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). 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.
- Hypersensitivity Reactions
Anaphylaxis, serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and other hypersensitivity reactions have been reported with PAXLOVID .If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.
- 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.
- 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.
Adverse Reactions
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.
- 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.
- Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome.
- Nervous System Disorders: Headache
- Vascular Disorders: Hypertension.
- Gastrointestinal Disorders: Abdominal pain, nausea, vomiting.
- General Disorders and Administration Site Conditions: Malaise.
Postmarketing Experience
There is limited information regarding Nirmatrelvir, ritonavir Postmarketing Experience in the drug label.
Drug Interactions
- 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.
- Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring .
- 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.
- Established and Other Potentially Significant Drug Interactions.
- listing of clinically significant drug interactions, including contraindicated drugs.Drugs. **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.
PAXLOVID
Has numerous significant drug interactions across a wide range of drug classes.
- Among alpha-1 adrenoreceptor antagonists, alfuzosin and tamsulosin concentrations are increased with PAXLOVID, and co-administration is contraindicated due to the risk of hypotension. *In the antianginal category, ranolazine levels rise significantly, making co-administration contraindicated. For antiarrhythmics, drugs such as amiodarone, dronedarone, flecainide, propafenone, and quinidine show increased concentrations and should not be used concomitantly due to arrhythmia risks. Lidocaine and disopyramide also show elevated levels; caution and therapeutic monitoring are advised.
- Anticancer drugs such as apalutamide and enzalutamide can decrease nirmatrelvir/ritonavir levels, risking virologic failure, making co-administration contraindicated. Others, including ibrutinib, vincristine, and dasatinib, may increase toxicity risks; use caution or avoid as specified. Anticoagulants like warfarin may show increased or decreased levels, requiring INR monitoring, while rivaroxaban and dabigatran have elevated levels and associated bleeding risks—adjustments or avoidance may be necessary. Apixaban exposure is increased, with specific dosing guidance advised.
- Among anticonvulsants, carbamazepine, phenytoin, phenobarbital, and primidone reduce nirmatrelvir/ritonavir levels, risking treatment failure. Clonazepam levels increase and may require dose adjustment. Antidepressants such as bupropion may have reduced efficacy, while trazodone levels increase, potentially leading to adverse effects like hypotension.
- For antifungals, voriconazole levels are reduced, requiring avoidance, while ketoconazole and others increase and should be used with caution. Colchicine levels rise significantly, contraindicating use with renal/hepatic impairment. In HIV treatments, multiple protease inhibitors and antiretrovirals interact variably, requiring careful monitoring or dosage adjustments.
- Interactions also occur with antimycobacterials (e.g., rifampin contraindicated; rifabutin needs monitoring), antipsychotics (e.g., pimozide and lurasidone levels rise significantly—contraindicated), cardiovascular agents (e.g., ivabradine, eplerenone contraindicated), and corticosteroids (increased risk of Cushing’s and adrenal suppression with many, alternative steroids recommended).
- Other notable interactions include immunosuppressants (e.g., tacrolimus, cyclosporine require close monitoring), statins (e.g., lovastatin and simvastatin contraindicated), migraine medications (e.g., eletriptan and ubrogepant contraindicated), erectile dysfunction drugs, sedatives, and vasopressin antagonists such as tolvaptan, where increased drug concentrations pose serious safety concerns.
- Each of these interactions is associated with either increased or decreased drug concentrations and the need for contraindication, dosage adjustment, close monitoring, or referral to the respective product labels for detailed management recommendations.
Use in Specific Populations
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.There are maternal and fetal risks associated with untreated COVID-19 in pregnancy.
- 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.
- 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.
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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nirmatrelvir, ritonavir in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nirmatrelvir, ritonavir during labor and delivery.
Nursing Mothers
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.
- 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 0.00 mg/kg/day, 1.8% and 0.2% of the maternal dose, respectively, for nirmatrelvir and ritonavir.
Pediatric Use
The optimal dose of PAXLOVID has not been established in pediatric patients.
Geriatic Use
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. • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment. • 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. 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. 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. 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. 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. Table 1:
PAXLOVID should be administered at approximately the same time each day for 5 days. On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis.
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 .
Gender
There is no FDA guidance on the use of Nirmatrelvir, ritonavir with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nirmatrelvir, ritonavir with respect to specific racial populations.
Renal Impairment
Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions.
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 . 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.
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.
Females of Reproductive Potential and Males
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 .
Immunocompromised Patients
There is no FDA guidance one the use of Nirmatrelvir, ritonavir in patients who are immunocompromised.
Administration and Monitoring
Administration
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. • PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment. • 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. 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. 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. 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. 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. Table 1:
PAXLOVID should be administered at approximately the same time each day for 5 days. On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis.
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.
Monitoring
• 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. • 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.
IV Compatibility
There is limited information regarding the compatibility of Nirmatrelvir, ritonavir and IV administrations.
Overdosage
Treatment of overdose with PAXLOVID should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with PAXLOVID.
Pharmacology
There is limited information regarding Nirmatrelvir, ritonavir Pharmacology in the drug label.
Mechanism of Action
- Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug.
- 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.
Structure
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a SARS-CoV-2 main protease ( Mpro ) inhibitor, and ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor. 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 methylethy l) -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.
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.
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.
Effect of Food
No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1,000 calories; 50% fat) to healthy subjects.
Specific Populations
There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity.
- Pediatric Patients
- The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.
- Patients with Renal Impairment
- The pharmacokinetics of nirmatrelvir in subjects with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg were determined. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in subjects with mild renal impairment was 30% and 24% higher, in subjects with moderate renal impairment was 38% and 87% higher, and in subjects with severe renal impairment was 48% and 204% higher, respectively.
The pharmacokinetics of nirmatrelvir in subjects with mild-to-moderate COVID-19 and severe renal impairment (eGFR<30 mL/min) either requiring intermittent hemodialysis (n=12) or not requiring hemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of 5 doses. The administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 in subjects with severe renal impairment, either requiring intermittent hemodialysis or not requiring hemodialysis resulted in comparable exposures on Day 1 and at steady-state (AUC0-24 and Cmax) compared to those observed in subjects with normal renal function receiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days. During a 4-hour hemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared through dialysis. Hemodialysis clearance was 1.83 L/h. Patients with Hepatic Impairment The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied. Clinical Drug Interaction Studies Table 5 describes the effect of other drugs on the Cmax and AUC of nirmatrelvir.
- In Vitro Studies
Cytochrome P450 (CYP) Enzymes: • Nirmatrelvir is a reversible and time-dependent inhibitor of CYP3A, but not an inhibitor CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Nirmatrelvir is an inducer of CYP2B6, 2C8, 2C9, and 3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these CYP enzymes at the proposed therapeutic dose. • Ritonavir is a substrate of CYP2D6 and CYP3A. Ritonavir is an inducer of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A. Transporter Systems: Nirmatrelvir is an inhibitor of P-gp and OATP1B1. Nirmatrelvir is a substrate for P-gp, but not BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATP1B1, OATP1B3, OATP2B1, or OATP4C1.
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. Antiviral Activity Cell Culture Antiviral Activity 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 (31 ng/mL) and 181 nM (90 ng/mL), respectively, after 3 days of drug exposure. The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, XBB.1.5, EG.5, and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold changes ≤1.8 relative to the USA-WA1/2020 isolate. In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold changes ≤1.1 relative to USA-WA1/2020. Clinical Antiviral Activity In clinical trial EPIC-HR, which enrolled subjects who were primarily infected with the SARS-CoV-2 Delta variant, PAXLOVID treatment was associated with a 0.83 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5 (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); similar results were observed in the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). In the EPIC-SR trial, which included subjects who were infected with SARS-CoV-2 Delta (79%) or Omicron (19%) variants, PAXLOVID treatment was associated with a 1.05 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5, with similar declines observed in subjects infected with Delta or Omicron variants. The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR. Antiviral Resistance In Cell Culture and Biochemical Assays SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 7 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in SARS-CoV-2 under nirmatrelvir selective pressure in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.
Table 8 indicates Mpro substitutions and combinations of Mpro substitutions that have been found to reduce nirmatrelvir activity ≥3-fold (based on IC50 or Ki values) in biochemical assays using recombinant SARS-CoV-2 Mpro. Note that these Mpro substitutions were laboratory engineered and most were not observed in PAXLOVID-treated subjects in clinical trials. In addition, according to public sequence databases, most of these substitutions have not been observed in clinical isolates or have been observed but with global cumulative frequencies ≤0.002%. Thus, the clinical relevance of these substitutions is unclear. The following Mpro substitutions and combinations of Mpro substitutions emerged in cell culture in the presence of nirmatrelvir but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I, S46F, L50F, P108S, T135I, C160F, T169I, V186A, A191V, A193P, P252L, S301P, T304I, T21I+T304I, and L50F+T304I. Table 8: SARS-CoV-2 Mpro Amino Acid Substitutions That Reduce Nirmatrelvir Activity ≥3-Fold in Biochemical Assays
In Clinical Trials Treatment-emergent substitutions were evaluated among subjects in clinical trials EPIC-HR/SR with sequence data available at both baseline and post-baseline visits (n=907 PAXLOVID-treated subjects, n=946 placebo-treated subjects). SARS-CoV-2 Mpro amino acid changes were classified as PAXLOVID treatment-emergent substitutions if they occurred at the same amino acid position in 3 or more PAXLOVID-treated subjects and were ≥2.5-fold more common in PAXLOVID-treated subjects than placebo-treated subjects. The following PAXLOVID treatment-emergent Mpro substitutions were observed: T98I/R/del(n=4), E166V (n=3), and W207L/R/del (n=4). In biochemical assays, the T98I and W207L/R substitutions did not affect nirmatrelvir activity (Ki value fold changes were 0.3 and 0.7/0.3, respectively), whereas the E166V substitution (which occurs at a Mpro-nirmatrelvir contact residue) reduced nirmatrelvir activity 187-7,700-fold. Within the Mpro cleavage sites, the following PAXLOVID treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific Mpro substitutions. In a cell culture replicon assay, the A5328S/V and S6799A substitutions did not affect nirmatrelvir activity (EC50 value fold changes were 0.3/0.2 and 0.7, respectively). None of the treatment-emergent substitutions listed above in Mpro or Mpro cleavage sites occurred in PAXLOVID-treated subjects who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown. Viral RNA Rebound and Treatment-Emergent Substitutions EPIC-HR and EPIC-SR were not designed to evaluate COVID-19 rebound; exploratory analyses were conducted to assess the relationship between PAXLOVID use and rebound in viral RNA shedding levels. Post-treatment increases in SARS-CoV-2 RNA shedding levels in nasopharyngeal samples were observed on Day 10 and/or Day 14 in a subset of PAXLOVID and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral RNA rebound varied according to analysis parameters, but was generally similar among PAXLOVID and placebo recipients. A similar or smaller percentage of placebo recipients compared to PAXLOVID recipients had nasopharyngeal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods. In EPIC-HR, of 59 PAXLOVID-treated subjects identified with post-treatment viral RNA rebound and with available viral sequence data, treatment-emergent substitutions in Mpro potentially reducing nirmatrelvir activity were detected in 2 (3%) subjects, including E166V in 1 subject and T304I in 1 subject. Both subjects had viral RNA shedding levels <LLOQ by Day 14. Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 following the single 5-day course of PAXLOVID treatment. The clinical relevance of post-treatment increases in viral RNA following PAXLOVID or placebo treatment is unknown. Cross-Resistance Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not Mpro inhibitors).
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility Nirmatrelvir
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 5 times higher than exposure at the approved human dose of PAXLOVID.
Ritonavir
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 25 times higher than the exposure in humans at the approved human dose of PAXLOVID. No carcinogenic effects were observed in females at up to the highest dose tested, resulting in systemic exposure (AUC24) approximately 25 times higher than the exposure in humans at the approved 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 5 times higher than the exposure in humans at the approved 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 18 (male) and 27 (female) times higher than the exposure in humans at the approved human dose of PAXLOVID.
Clinical Studies
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%).
Abbreviations: CI=confidence interval; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT1=modified intent-to-treat 1 (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). The determination of primary efficacy was based on a planned interim analysis of 754 subjects in mITT population. The estimated risk reduction was -6.5% with a 95% CI of (-9.3%, -3.7%) and 2-sided p-value <0.0001.
The estimated cumulative proportion of subjects hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalization and death status through Day 28 were censored at the time of study discontinuation. † For the secondary endpoint of all-cause mortality through Week 24, there were 0 and 15 (1%) events in the PAXLOVID arm and placebo arm, respectively. Consistent results were observed in the mITT and mITT2 analysis populations. Similar trends have been observed across subgroups of subjects. 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.
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.
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.
- The standard dose pack contains 300 mg of nirmatrelvir and 100 mg of ritonavir per dose. Each carton includes 30 tablets divided into 10 blister cards, and is available under NDC 0069-5045-30 or NDC 0069-5321-30. In both versions, the nirmatrelvir tablets are oval, pink, immediate-release, film-coated tablets debossed with “PFE” on one side and “3CL” on the other. The ritonavir tablets vary slightly: under NDC 0069-5045-30, they are white to off-white, capsule-shaped, film-coated tablets debossed with “H” on one side and “R9” on the other, while under NDC 0069-5321-30, they are white, film-coated ovaloid tablets debossed with “NK” on one side. Each blister card in this configuration contains two 150 mg nirmatrelvir tablets and one 100 mg ritonavir tablet.
- A separate configuration contains 150 mg of nirmatrelvir and 100 mg of ritonavir per dose. This carton includes 20 tablets across 10 blister cards, and is available under NDC 0069-5317-20. The nirmatrelvir tablets remain pink, oval, and debossed with “PFE” and “3CL”, while the ritonavir tablets are white, ovaloid, and debossed with “NK”. Each blister card in this pack includes one 150 mg nirmatrelvir tablet and one 100 mg ritonavir tablet, with a corresponding NDC of 0069-5317-02.
- There is also a combination dose pack that includes a 300 mg nirmatrelvir / 100 mg ritonavir dose for Day 1, followed by a 150 mg nirmatrelvir / 100 mg ritonavir dose for Days 2 through 5. This pack contains 11 tablets in a single blister card, identified by NDC 0069-0521-11. It includes six 150 mg nirmatrelvir tablets and five 100 mg ritonavir tablets. As in other packs, the nirmatrelvir tablets are oval, pink, debossed with “PFE” and “3CL”, and the ritonavir tablets are white ovaloid tablets debossed with “NK”.
Storage
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).
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
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.
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.
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.
- 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.
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.
Precautions with Alcohol
Alcohol-Nirmatrelvir, ritonavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
PAXLOVID
Look-Alike Drug Names
There is limited information regarding Nirmatrelvir, ritonavir Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.