Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.
General
There are limited clinical data available for PAXLOVID. Serious and unexpected adverse events may occur that have not been previously reported with PAXLOVID use.
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 and Table 4 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 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).
Hepatic/Biliary/Pancreatic
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.
Immune
Allergic Reactions/Hypersensitivity reactions have been reported with PAXLOVID including urticaria, angioedema, dyspnea, mild skin eruptions, and pruritus. Cases of anaphylaxis, TEN, and Stevens-Johnson syndrome have also been reported with components of PAXLOVID (refer to NORVIR labeling). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care (see 8.5 Post-Market Adverse Reactions)
Reproductive Health: Female and Male Potential
Women of childbearing potential should use effective contraception during treatment with PAXLOVID. Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with PAXLOVID (see 7.1.1 Pregnant Women and 9 DRUG INTERACTIONS).
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Fertility
There are no available human data to evaluate the effect of PAXLOVID on fertility. No effects on fertility were observed in a study performed in rats with nirmatrelvir at systemic exposures (AUC) approximately 8 times higher than clinical exposure at the authorized human dose of PAXLOVID. Ritonavir produced no effects on fertility in rats (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).
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Teratogenic risk
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. Animal data with ritonavir have shown reproductive toxicity (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).
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 4 DOSAGE AND ADMINISTRATION, 2 CONTRAINDICATIONS, and 9 DRUG INTERACTIONS).
7.1 Special Populations
7.1.1 Pregnant Women
PAXLOVID should not be used in pregnant women unless the potential benefits outweigh the potential risks to the fetus.
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.
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 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).
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. Based on prospective reports to the antiretroviral pregnancy registry of approximately 6,900 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.
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 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).
7.1.2 Breastfeeding
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 exposed to nirmatrelvir at maternal systemic exposure (AUC) approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity). 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.
7.1.3 Pediatrics
The safety and effectiveness of PAXLOVID have not been established in pediatric patients.
7.1.4 Geriatrics
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 14 CLINICAL TRIALS). 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.