Clinical Studies | PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets)

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(nirmatrelvir tablets; ritonavir tablets) ? Click here

AUTHORIZED USE

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the emergency use of PAXLOVID^TM(nirmatrelvir tablets; ritonavir tablets) for the treatment of adults and pediatric patients (12 years of age and older weighing at least 40 kg) with mild-to-moderate coronavirus disease 2019 (COVID‑19) and who are at high risk for progression to severe COVID-19, including hospitalization or death.

LIMITATIONS OF AUTHORIZED USE

PAXLOVID is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19
PAXLOVID is not authorized for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19
PAXLOVID is not authorized for use for longer than 5 consecutive days

PAXLOVID may be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs.

PAXLOVID may also be prescribed for an individual patient by a state-licensed pharmacist under the following conditions:

Sufficient information is available, such as through access to health records less than 12 months old or consultation with a health care provider in an established provider‑patient relationship with the individual patient, to assess renal and hepatic function; and
Sufficient information is available, such as through access to health records, patient reporting of medical history, or consultation with a health care provider in an established provider‑patient relationship with the individual patient, to obtain a comprehensive list of medications (prescribed and non-prescribed) that the patient is taking to assess for potential drug interaction.

The state-licensed pharmacist should refer an individual patient for clinical evaluation (e.g., telehealth, in-person visit) with a physician, advanced practice registered nurse, or physician assistant licensed or authorized under state law to prescribe drugs, if any of the following apply:

Sufficient information is not available to assess renal and hepatic function.
Sufficient information is not available to assess for a potential drug interaction.
Modification of other medications is needed due to a potential drug interaction.
PAXLOVID is not an appropriate therapeutic option based on the authorized Fact Sheet for Healthcare Providers or due to potential drug interactions for which recommended monitoring would not be feasible.

PAXLOVID is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of PAXLOVID under 564(b)(1) of the Food Drug and Cosmetic Act unless the authorization is terminated or revoked sooner.

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 participants were 18 years of age and older with at least one 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
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 ≥10⁷ (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 8 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%).

Table 8: COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 in
Non-Hospitalized Adults with COVID-19 (mlTT1 Analysis Set): EPIC-HR

	PAXLOVID N=977	Placebo N=989
COVID-19 Related Hospitalization or Death from Any Cause Through Day 28
n (%)	9 (0.9%)	64 (6.5%)
Reduction Relative to Placebo^a [95% CI], %	-5.6 (-7.3, -4.0)
COVID-19 Related Hospitalization Through Day 28, %	9 (0.9%)	63 (6.4%)
All-cause Mortality Through Day 28^b, %	0	12 (1.2%)

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% Cl of (-9.3%, -3.7%) and 2-sided p-value <0.0001.
a. The estimated cumulative proportion of subjects hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subiects without hospitalization and death status through Day 28 were censored at the time of study discontinuation.
b. 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.

Tablet	Embossed Text
nirmatrelvir	Front: 3CL \| Back: PFE
ritonavir, manufactured by AbbVie	Front: NK \| Back: No text
ritonavir, manufactured by Hetero	Front: H \| Back: R9

AUTHORIZED USE

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the emergency use of PAXLOVID for the treatment of adults and pediatric patients (12 years of age and older weighing at least 40 kg) with mild-to-moderate coronavirus disease 2019 (COVID-19) and who are at high risk for progression to severe COVID-19, including hospitalization or death.

LIMITATIONS OF AUTHORIZED USE

PAXLOVID is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19
PAXLOVID is not authorized for use as pre-exposure or post-exposure prophylaxis for prevention of
COVID-19
PAXLOVID is not authorized for use for longer than 5 consecutive days

Sufficient information is available, such as through access to health records less than 12 months old or consultation with a health care provider in an established provider-patient relationship with the individual patient, to assess renal and hepatic function; and
Sufficient information is available, such as through access to health records, patient reporting of medical history, or consultation with a health care provider in an established provider-patient relationship with the individual patient, to obtain a comprehensive list of medications (prescribed and non-prescribed) that the patient is taking to assess for potential drug interaction.

Sufficient information is not available to assess renal and hepatic function.
Sufficient information is not available to assess for a potential drug interaction.
Modification of other medications is needed due to a potential drug interaction.
PAXLOVID is not an appropriate therapeutic option based on the authorized Fact Sheet for Healthcare Providers or due to potential drug interactions for which recommended monitoring would not be feasible.

IMPORTANT SAFETY
INFORMATION

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IMPORTANT SAFETY INFORMATION

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WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID

PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certainconcomitant medications, resulting in potentially severe, life-threatening, or fatal events
Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess for 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

PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions (eg, toxic epidermal necrolysis or Stevens-Johnson syndrome), to its active ingredients (nirmatrelvir or ritonavir), or any other components of the product. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.

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 here 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:

Alpha₁-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
Sedative/hypnotics: triazolam, oral midazolam
Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
Vasopressin receptor antagonists: tolvaptan

Drugs that are strong CYP3A inducers: 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
Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
Antimycobacterials: rifampin, rifapentine
Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
Herbal Products: St. John’s Wort (hypericum perforatum)

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 (eg, tacrolimus, cyclosporine), followed by calcium channel blockers.

Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Caution should be exercised when administering PAXLOVID to patients withpre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

Because nirmatrelvir is co-administered with ritonavir, there may be arisk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

The most common adverse reactions in the PAXLOVID group (≥1%) that occurred at a greater frequency than in the placebo group were dysgeusia (5% and <1% respectively) and diarrhea (3% and 2% respectively).

The following adverse reactions have been identified during post-authorization use of PAXLOVID.

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

Required Reporting for Serious Adverse Events and Medication Errors: The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events and medication errors potentially related to PAXLOVID within 7 calendar days from the healthcare provider's awareness of the event.

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

Online: https://www.fda.gov/medwatch/report.htm
Complete and submit a postage-paid FDA Form 3500 and returning by mail/fax
Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to: www.pfizersafetyreporting.com, or by fax ( 1‑866‑635‑8337) or phone ( 1‑800‑438‑1985).

PAXLOVID 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 with other CYP3A substrates may require a dose adjustment or additional monitoring.

Pregnancy: 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.

Lactation: 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. 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.

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.

Pediatrics: 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.

Renal impairment increases nirmatrelvir exposure, which may increase the risk of 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). PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min) or patients with end stage renal disease (eGFR <15 mL/min) receiving dialysis until more data are available. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions.

PAXLOVID is not recommended for use in patients with severe hepatic impairment.

Please see Fact Sheet for Healthcare Providers and Fact Sheet for Patients, Parents, and Caregivers.