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 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.
WARNING: SIGNIFICANT DRUG INTERACTIONS WITH PAXLOVID
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PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events
- 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 with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.
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.
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:
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.
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