PAXLOVID Film-coated tablet Ref.[49623] Active ingredients: Nirmatrelvir Nirmatrelvir and Ritonavir Ritonavir

There are limited clinical data available for PAXLOVID. Serious and unexpected adverse events may occur that have not been previously reported with PAXLOVID use.

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of PAXLOVID, a 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.

Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PAXLOVID, respectively.

These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of PAXLOVID.
• Loss of therapeutic effect of PAXLOVID and possible development of viral resistance.

See Table 1 for clinically significant drug interactions, including contraindicated drugs. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

5.2 Hepatotoxicity

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

5.3 Risk of HIV-1 Resistance Development

Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7)].

6.1 Adverse Reactions from Clinical Studies

The following adverse reactions have been observed in the clinical studies of PAXLOVID that supported the EUA. The adverse reaction rates observed in these clinical studies cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Additional adverse events associated with PAXLOVID may become apparent with more widespread use.

The safety of PAXLOVID is based on data from Study C4671005 (EPIC-HR), a Phase ⅔ randomized, placebo-controlled trial in non-hospitalized adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection [see Clinical Studies (14.1)]. A total of 2,224 symptomatic adult subjects 18 years of age and older who are at high risk of developing severe COVID-19 illness received at least one dose of either PAXLOVID (n=1,109) or placebo (n=1,115). Adverse events were those reported while subjects were on study medication and through Day 34 after initiating study treatment. PAXLOVID [300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir] or matching placebo were to be taken twice daily for 5 days.

Adverse events (all grades regardless of causality) in the PAXLOVID group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), hypertension (1% and <1%), and myalgia (1% and <1%).

The proportions of subjects who discontinued treatment due to an adverse event were 2% in the PAXLOVID group and 4% in the placebo group.

6.4 Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider’s designee are/is responsible for mandatory reporting of all serious adverse events³ and medication errors potentially related to PAXLOVID within 7 calendar days from the onset of the event, using FDA Form 3500 (for information on how to access this form, see below). The FDA recommends that such reports, using FDA Form 3500, include the following:

• Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race).
• A statement “ PAXLOVID use for COVID-19 under Emergency Use Authorization (EUA)” under the "Describe Event, Problem, or Product Use/Medication Error" heading.
• Information about the serious adverse event or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes).
• Patient’s pre-existing medical conditions and use of concomitant products.
• Information about the product (e.g., dosage, route of administration, NDC #).

Submit adverse event and medication error reports, using Form 3500, to FDA MedWatch using one of the following methods:

• Complete and submit the report online: https://www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:
  • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
  • Fax to 1-800-FDA-0178, or
• Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to:

The prescribing healthcare provider and/or the provider’s designee is/are to provide mandatory responses to requests from FDA for information about adverse events and medication errors associated with PAXLOVID.

³ Serious adverse events are defined as:

• Death or a life-threatening adverse event;
• A medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly;
• Inpatient hospitalization or prolongation of existing hospitalization;
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or
• A congenital anomaly/birth defect.

7.1 Potential for PAXLOVID to Affect Other Drugs

PAXLOVID (nirmatrelvir co-packaged with ritonavir) is an inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Co-administration of PAXLOVID with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated [see Contraindications (4) and Table 1]. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 1.

7.2 Potential for Other Drugs to Affect PAXLOVID

Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect.

7.3 Established and Other Potentially Significant Drug Interactions

Table 1 provides listing of clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 1 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. The healthcare provider should consult appropriate references for comprehensive information [see Contraindications (4)].

Table 1. Established and Other Potentially Significant Drug Interactions:

Risk Summary

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.

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 3,400 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.

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 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:

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.

Risk Summary

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.

Data

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.

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)].

PAXLOVID is not authorized for use in pediatric patients younger than 12 years of age or weighing less than 40 kg. The safety and effectiveness of PAXLOVID have not been established in pediatric patients. The authorized adult dosing regimen is expected to result in comparable serum exposures of nirmatrelvir and ritonavir in patients 12 years of age and older and weighing at least 40 kg as observed in adults, and adults with similar body weight were included in the trial EPIC-HR [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

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 EPIC-HR randomized to receive PAXLOVID (N=1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.

Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment [see Clinical Pharmacology (12.3)].

No dosage adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), reduce the dose of PAXLOVID to 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days. 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)].

PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min based on CKD-EPI formula) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined.

No dosage adjustment of PAXLOVID is needed for patients with either 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 hepatic impairment (Child-Pugh Class C), therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].