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COVID-19 Studios: Navigating Drug-Drug Interactions

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A panel of experts discuss potential drug-drug interactions that can occur between an FDA-approved treatment option for mild-to-moderate COVID-19 and concomitant medications.


    PAXLOVID™ is indicated 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.  
    Limitations of Use 
    PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19.


    • PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, and/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:

    • 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
    • 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. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

    Because nirmatrelvir is coadministered 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 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

    PAXLOVID is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp, and OATP1B1. Coadministration 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. Coadministration 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 report 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.

    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: The optimal dose of PAXLOVID has not been established in pediatric patients.

    Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment. No dosage adjustment is recommended in patients with mild renal impairment. Reduce the dose of PAXLOVID 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 in patients with end-stage renal disease (eGFR <15 mL/min). 

    PAXLOVID is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).

    Please see Full Prescribing Information, including BOXED WARNING and Patient Information

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  • Overview

    PAXLOVID, a combination of nirmatrelvir and ritonavir, is an FDA-approved oral prescription treatment option for adult patients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death.1 It’s important to know that drug-drug interactions can occur between PAXLOVID and concomitant medications a patient is taking, and certain interactions may lead to serious adverse reactions.1 That’s why a panel of experts, featuring infectious disease physician-scientist Dr. Daniel Griffin, virologist Dr. Vincent Racaniello, cardiologist Dr. Jayne Morgan, and clinical pharmacist Dr. Samir Balile have come together to discuss approaches to managing potential drug-drug interactions appropriately.


    1. PAXLOVID [prescribing information]. New York, NY: Pfizer Inc.; May 2023.

    © 2023 Pfizer Inc. All rights reserved. PP-PAX-USA-1043 October 2023

Schedule5 Dec 2023