Nirmatrelvir

Brand names: Paxlovid
Drug class: Antineoplastic Agents , Antineoplastic Agents

Usage of Nirmatrelvir

Coronavirus Disease 2019 (COVID-19)

Nirmatrelvir with low-dose ritonavir (ritonavir-boosted nirmatrelvir) is available under an emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥12 years of age weighing ≥40 kg) with a current diagnosis of mild-to-moderate COVID-19 and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Consult nirmatrelvir EUA letter of authorization ([Web]), EUA fact sheet for healthcare providers ([Web]), and EUA fact sheet for patients, parents, and caregivers ([Web]) for additional information.

Ritonavir-boosted nirmatrelvir is not authorized under the EUA for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19, for preexposure or postexposure prophylaxis of COVID-19, or for use >5 consecutive days.

Ritonavir-boosted nirmatrelvir 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; the combination therapy also may be prescribed for an individual patient by a state-licensed pharmacist under certain conditions.

There are several therapeutic options available for treatment of nonhospitalized adults with mild to moderate COVID-19 who are at high risk of disease progression. When selecting an appropriate treatment, consider factors such as clinical efficacy and availability of the various options, feasibility of administering parenteral medications (i.e., remdesivir), potential for significant drug-drug interactions (e.g., those associated with the use of ritonavir-boosted nirmatrelvir), and regional prevalence of variants of concern.

The National Institutes of Health (NIH) COVID-19 treatment guidelines panel recommends use of ritonavir-boosted nirmatrelvir or remdesivir, in order of preference, for treatment of nonhospitalized adult patients with COVID-19 who do not require hospitalization or supplemental oxygen but are at high risk for progression to severe disease. If ritonavir-boosted nirmatrelvir and remdesivir are unavailable, not feasible, or clinically inappropriate, the panel recommends molnupiravir.

The Infectious Diseases Society of American (IDSA) suggests a 5-day treatment course of ritonavir-boosted nirmatrelvir, dosed based on renal function, starting within 5 days of symptom onset over no ritonavir-boosted nirmatrelvir treatment in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progression to severe disease. Patients with mild to moderate COVID-19 who are hospitalized for reasons other than COVID-19 and who are at high risk of progression to severe disease may also receive ritonavir-boosted nirmatrelvir.

Ritonavir-boosted nirmatrelvir has the potential for significant drug-drug interactions with other medications and may not be a safe choice for all patients. However, because the antiviral combination is the only highly effective oral antiviral available for treatment of COVID-19, the NIH guideline panel states that drug-drug interactions that can be safely managed should not preclude the use of this regimen.

Consult the most recent guidelines available from NIH ([Web]) and IDSA ([Web]) for additional information.

Use of ritonavir-boosted nirmatrelvir early in the disease process when viral loads are high confers maximum benefit; therefore, it is critical to make a rapid diagnosis and treat nonhospitalized patients with COVID-19 early in the disease course.

Ritonavir-boosted nirmatrelvir is expected to be active against all Omicron subvariants, although clinical efficacy data are lacking.

Recent case reports suggest that some patients who have completed a 5-day course of ritonavir-boosted nirmatrelvir and have recovered can experience viral rebound (i.e., a recurrence of symptoms or a new positive viral test after having tested negative). There is currently no evidence that additional treatment for COVID-19 is needed for COVID-19 rebound. Based on currently available data, CDC states that patient monitoring continues to be the most appropriate management for such patients.

Relate drugs

How to use Nirmatrelvir

General

Pretreatment Screening

  • Consider the potential for drug interactions prior to and during treatment.
  • Monitor baseline renal and liver function.

    • Dispensing and Administration Precautions

  • Ritonavir-boosted nirmatrelvir is available in 2 packaging configurations: a dose pack that contains 300 mg nirmatrelvir and 100 mg ritonavir and a dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. Healthcare providers should be aware of differences in the ritonavir tablet appearance, including shape, color, and debossing depending on the package provided to the patient. In patients with moderate renal impairment, only dispense the dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. If this lower strength dose pack is unavailable for dispensing to patients with moderate renal impairment, pharmacists should refer to instructions in the document entitled “Important Paxlovid EUA dispensing information for patients with moderate renal impairment.”
  • Prescriptions must specify the numeric dose of each active ingredient in the antiviral drug combination (e.g., 300 mg nirmatrelvir with 100 mg ritonavir). Wrong-dose medication errors have occurred with ritonavir-boosted nirmatrelvir during prescribing, dispensing, and administration of the drug. Many of these errors have occurred during patient self-administration and generally involved patients taking the wrong combination of nirmatrelvir tablets and ritonavir tablets from the blister card. The blister card indicates which tablets need to be taken in the morning and evening each day.
  • Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to ritonavir-boosted nirmatrelvir is mandatory. The FDA fact sheet for health care providers should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.

    • Other General Considerations

  • Patients should continue isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • Patients on ritonavir- or cobicistat-containing HIV or hepatitis C virus treatment regimens should continue their treatment as indicated. No dosage adjustment is required when ritonavir-boosted nirmatrelvir is coadministered with other products containing ritonavir or cobicistat.

    • Administration

    Oral Administration

    Administer orally without regard to food.

    Swallow tablets whole; do not chew, break, or crush.

    Must administer nirmatrelvir in conjunction with low-dose ritonavir at the same time twice daily. Ritonavir is a pharmacokinetic enhancer that improves the pharmacokinetic profile of nirmatrelvir.

    Paxlovid is available as a 5-day blister pack; each daily blister card contains a morning dose (one or two 150-mg nirmatrelvir tablets and one 100-mg ritonavir tablet) and evening dose (one or two 150-mg nirmatrelvir tablets and one 100-mg ritonavir tablet). (See Dispensing and Administration Precautions under Dosage and Administration.)

    If a dose of ritonavir-boosted nirmatrelvir is missed by ≤8 hours, take the prescribed dose as soon as possible. If a dose is missed by >8 hours, administer prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.

    Dosage

    Pediatric Patients

    Treatment of Mild to Moderate COVID-19 in Nonhospitalized Patients Oral

    ≥12 years of age weighing ≥40 kg: FDA EUA permits use of 300 mg of nirmatrelvir (two 150 mg tablets) orally twice daily in conjunction with 100 mg of ritonavir (one 100 mg tablet) orally twice daily for 5 days (ritonavir-boosted nirmatrelvir) for the treatment of mild to moderate COVID-19. Complete full 5-day treatment course.

    Administer ritonavir-boosted nirmatrelvir as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.

    If hospitalization occurs due to progression to severe or critical COVID-19 after initiation of ritonavir-boosted nirmatrelvir therapy, treatment course may be continued per the clinician's discretion.

    Adults

    Treatment of Mild to Moderate COVID-19 in Nonhospitalized Patients Oral

    EUA permits use of 300 mg of nirmatrelvir (two 150 mg tablets) orally twice daily in conjunction with 100 mg of ritonavir (one 100 mg tablet) orally twice daily for 5 days (ritonavir-boosted nirmatrelvir) for the treatment of mild to moderate COVID-19. Complete full 5-day treatment course.

    Administer ritonavir-boosted nirmatrelvir as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.

    If hospitalization occurs due to progression to severe or critical COVID-19 after initiation of ritonavir-boosted nirmatrelvir therapy, treatment course may be continued per the clinician's discretion.

    Special Populations

    Hepatic Impairment

    Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment of ritonavir-boosted nirmatrelvir necessary.

    Severe hepatic impairment (Child-Pugh class C): Pharmacokinetic profile and safety of ritonavir-boosted nirmatrelvir not established; ritonavir-boosted nirmatrelvir not recommended in such patients.

    Renal Impairment

    Moderate renal impairment (eGFR 30 to <60 mL/minute): Reduce nirmatrelvir dosage to 150 mg twice daily in conjunction with ritonavir 100 mg twice daily for 5 days. Prescribing clinicians must specify the numeric dose of nirmatrelvir and ritonavir (e.g., 150 mg nirmatrelvir with 100 mg ritonavir for patients with moderate renal impairment) on prescriptions and should counsel patients about renal dosing instructions. When dispensing ritonavir-boosted nirmatrelvir for patients with moderate renal impairment, only dispense the dose pack that contains 150 mg nirmatrelvir and 100 mg ritonavir. If this lower strength dose pack is unavailable for dispensing to patients with moderate renal impairment, the pharmacist should refer to the document entitled “Important Paxlovid EUA dispensing information for patients with moderate renal impairment”.

    Mild renal impairment (eGFR 60 to <90 mL/minute): No dosage adjustment necessary.

    Severe renal impairment (eGFR <30 mL/minute): Appropriate dosage not established; use not recommended in such patients.

    Geriatric Patients

    No specific dosage recommendations.

    Warnings

    Contraindications

  • History of clinically significant hypersensitivity reactions to nirmatrelvir, ritonavir, or any other ingredient in the preparation.
  • Concomitant use of drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; these drugs include, but are not limited to, alfuzosin, ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, colchicine, lurasidone, pimozide, silodosin, eplerenone, ivabradine, dihydroergotamine, ergotamine, methylergonovine, lovastatin, simvastatin, voclosporin, lomitapide, eletriptan, ubrogepant, finerenone, naloxegol, sildenafil [Revatio] for treatment of pulmonary arterial hypertension, triazolam, oral midazolam, flibanserin, and tolvaptan.
  • Concomitant use of potent CYP3A inducers that can significantly reduce nirmatrelvir or ritonavir plasma concentrations and result in potential loss of virologic response and possible resistance; these drugs include, but are not limited to, apalutamide, Carbamazepine, phenobarbital, primidone, phenytoin, lumacaftor/ivacaftor, rifampin, and St. John's wort [Hypericum perforatum]). Do not start ritonavir-boosted nirmatrelvir immediately after discontinuation of any of these drugs due to the delayed offset of the recently discontinued CYP3A inducer.

    • Warnings/Precautions

    Serious Adverse Reactions Due to Drug Interactions

    Must be used in conjunction with ritonavir. Failure to administer nirmatrelvir with the recommended dosage of ritonavir will result in subtherapeutic nirmatrelvir concentrations and inadequate virologic response. Consider the cautions, precautions, contraindications, and drug interactions associated nirmatrelvir and ritonavir.

    Concomitant use of ritonavir-boosted nirmatrelvir with certain drugs is contraindicated or requires particular caution. Concomitant use with some drugs may result in clinically important adverse effects, including severe, life-threatening, or fatal events, due to higher exposures of the concomitant drug or higher exposures of nirmatrelvir and/or ritonavir. Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted nirmatrelvir and possible development of viral resistance. Because nirmatrelvir and ritonavir are inhibitors of CYP3A, concomitant use with drugs metabolized by CYP3A may increase plasma concentrations of CYP3A substrate drugs.

    Hypersensitivity Reactions

    Hypersensitivity reactions, including anaphylaxis, reported. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome reported in patients receiving ritonavir.

    Immediately discontinue treatment if signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis develop and initiate appropriate treatment and/or supportive care.

    Hepatotoxicity

    Hepatotoxicity (i.e., elevations in serum aminotransferase concentrations, clinical hepatitis, jaundice) reported in patients receiving ritonavir.

    Use ritonavir with caution in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis.

    HIV-1 Resistance Development

    Because nirmatrelvir is coadministered with ritonavir, cross-resistance to HIV protease inhibitors (HIV PIs) may occur in individuals with uncontrolled or undiagnosed HIV-1 infection.

    EUA Requirements for Patient Monitoring and Mandatory FDA MedWatch Reporting

    Safety and efficacy of ritonavir-boosted nirmatrelvir not established. FDA EUA that permits use of ritonavir-boosted nirmatrelvir for the treatment of mild to moderate COVID-19 in certain adults and pediatric patients requires use of dosages recommended in the EUA.

    Only limited data available to date regarding adverse effects associated with ritonavir-boosted nirmatrelvir. Serious and unexpected adverse events may occur that have not been previously reported with use of the drugs together.

    Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to ritonavir-boosted nirmatrelvir is mandatory. Consult the FDA fact sheet for health care providers for requirements and instructions regarding reporting of adverse reactions and medication errors.

    Specific Populations

    Pregnancy

    Nirmatrelvir: Data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Reduced fetal body weight observed in animal studies

    Ritonavir: Published observational studies have not identified an increase in the risk of major birth defects when ritonavir was used in pregnant women. Published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage.

    Estimated background risk of major birth defects and miscarriage in the indicated population unknown. 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.

    Lactation

    Nirmatrelvir: Not known whether nirmatrelvir is distributed into human or animal milk or has effects on the breast-fed infant or milk production.

    Ritonavir: Limited published data indicate that ritonavir is present in human milk. Not known whether ritonavir has effects on the breast-fed infant or milk production.

    Consider developmental and health benefits of breast-feeding along with the mother’s clinical need for ritonavir-boosted nirmatrelvir and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

    Females with COVID-19 who are breast-feeding should follow clinical guidelines to avoid exposing the infant to the virus.

    Females and Males of Reproductive Potential

    Use of ritonavir may reduce efficacy of combined hormonal contraceptives; advise patients to use an effective alternative contraceptive method or an additional barrier method of contraception until completion of one additional menstrual cycle.

    Pediatric Use

    The FDA EUA permits use of ritonavir-boosted nirmatrelvir for the treatment of COVID-19 in certain pediatric patients ≥12 years of age weighing ≥40 kg. Use of ritonavir-boosted nirmatrelvir is not authorized for pediatric patients <12 years of age or those weighing <40 kg.

    Safety and efficacy of ritonavir-boosted nirmatrelvir not established in pediatric patients.

    Pharmacokinetics of ritonavir-boosted nirmatrelvir not evaluated in pediatric patients <18 years of age. EUA-recommended dosage of ritonavir-boosted nirmatrelvir is expected to result in plasma concentrations of the drugs in patients ≥12 years of age weighing ≥40 kg that are comparable to those observed in adults.

    Geriatric Use

    In the EPIC-HR clinical trial, 13% of individuals who received ritonavir-boosted nirmatrelvir were ≥65 years of age and 3% were ≥75 years of age.

    Hepatic Impairment

    Moderate hepatic impairment: Systemic exposure to nirmatrelvir not substantially altered following administration of ritonavir-boosted nirmatrelvir.

    Severe hepatic impairment: Ritonavir-boosted nirmatrelvir not studied.

    Renal Impairment

    Mild renal impairment (eGFR 60 to <90 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 30 or 24%, respectively, following administration of ritonavir-boosted nirmatrelvir.

    Moderate renal impairment (eGFR 30 to <60 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 38 or 87%, respectively, following administration of ritonavir-boosted nirmatrelvir.

    Severe renal impairment (eGFR <30 mL/minute): Peak plasma concentrations or systemic exposure of nirmatrelvir increase by 48 or 204%, respectively, following administration of ritonavir-boosted nirmatrelvir.

    Common Adverse Effects

    Dysgeusia, diarrhea, hypertension, myalgia.

    What other drugs will affect Nirmatrelvir

    Nirmatrelvir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir); consider drug interactions associated with both nirmatrelvir and ritonavir.

    Nirmatrelvir: In vitro, nirmatrelvir is a substrate of P-glycoprotein (P-gp) and CYP3A4, but not a substrate of BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, or OATPs 1B1, 1B3, 2B1, and 4C1. Does not reversibly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Nirmatrelvir has potential to reversibly and time-dependently inhibit CYP3A4 and P-gp. Does not induce CYP isoenzymes at clinically relevant concentrations.

    Ritonavir: In vitro, ritonavir is primarily a substrate of CYP3A, and appears to be a substrate of CYP2D6. Ritonavir is an inhibitor of CYP3A and to a lesser extent CYP2D6. Appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

    The following drug interactions are based on studies using ritonavir-boosted nirmatrelvir. Guidelines from the National Institutes of Health (NIH) state that because ritonavir-boosted nirmatrelvir is the only highly effective oral option for treatment of COVID-19, drug-drug interactions that can be safely managed should not preclude the use of this regimen; consult the most recent version of the NIH COVID-19 guideline ([Web]) for specific recommendations regarding safety of coadministration of specific drugs with ritonavir-boosted nirmatrelvir.

    Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

    CYP3A Inducers: Potential pharmacokinetic interaction with drugs that induce CYP3A (decreased plasma concentrations of nirmatrelvir and ritonavir which may lead to reduced virologic response).

    Substrates of CYP3A

    Substrates of CYP3A: Potential pharmacokinetic interaction with drugs principally metabolized by CYP3A (increased plasma concentrations of drug metabolized by CYP3A). Concomitant use of nirmatrelvir and ritonavir with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Concomitant use of nirmatrelvir and ritonavir with other CYP3A substrates may require dosage adjustment or additional monitoring.

    Specific Drugs

    Drug

    Interaction

    Comments

    Alfuzosin

    Possible increased alfuzosin concentrations and increased risk of serious and/or life-threatening reactions (e.g., hypotension)

    Concomitant use contraindicated

    Aliskiren

    Possible increased concentrations of aliskiren

    Avoid concomitant use

    Antiarrhythmic agents (amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine)

    Possible increased concentrations of the antiarrhythmic agent

    Amiodarone, dronedarone, flecainide, propafenone, quinidine: Concomitant use contraindicated

    Lidocaine (systemic), disopyramide: Caution advised; therapeutic concentration monitoring recommended for the antiarrhythmic agent, if available

    Anticoagulants, oral (apixaban, rivaroxaban, warfarin, dabigatran)

    Dabigatran: Possible increased dabigatran concentrations and increased risk of bleeding

    Rivaroxaban: Possible increased rivaroxaban concentrations and increased risk of bleeding

    Warfarin: Possible altered warfarin concentrations

    Apixaban: Possible increased apixaban concentrations and increased risk of bleeding

    Dabigatran: Depending on indication and renal function, reduce dosage of dabigatran or avoid concomitant use

    Rivaroxaban: Avoid concomitant use

    Warfarin: Closely monitor INR if concomitant use is necessary

    Apixaban: Dosing recommendations depend on apixaban dosage; refer to product labeling for apixaban

    Anticonvulsants (carbamazepine, phenobarbital, primidone, phenytoin)

    Decreased concentrations of nirmatrelvir/ritonavir and potential loss of virologic response and possible resistance

    Concomitant use contraindicated

    Antifungals, azoles (isavuconazonium, itraconazole, ketoconazole, voriconazole)

    Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and increased nirmatrelvir and ritonavir concentrations

    Itraconazole: Possible increased itraconazole concentrations and increased nirmatrelvir and ritonavir concentrations

    Ketoconazole: Possible increased ketoconazole concentrations and increased nirmatrelvir and ritonavir concentrations

    Voriconazole: Possible decreased voriconazole concentrations and increased nirmatrelvir and ritonavir concentrations

    Voriconazole: Avoid concomitant use

    Ketoconazole, isavuconazonium, itraconazole: Refer to the respective product labels for additional information

    Antimycobacterials (Bedaquiline, rifabutin, rifapentine, rifampin)

    Bedaquiline: Possible increased bedaquiline concentrations

    Rifabutin: Possible increased rifabutin concentrations

    Rifapentine: Possible decreased nirmatrelvir/ritonavir concentrations

    Rifampin: Substantially decreased nirmatrelvir/ritonavir concentrations and possible loss of virologic response and development of resistance

    Rifampin: Concomitant use contraindicated; consider alternative antimycobacterial (e.g., rifabutin); do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of rifampin due to delayed offset of rifampin

    Rifapentine: Avoid concomitant use

    Bedaquiline, rifabutin: Refer to respective product label for additional information

    Antineoplastic agents (apalutamide, abemaciclib, Ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine)

    Apalutamide: Possible decreased systemic exposure to nirmatrelvir and ritonavir, loss of virologic response, and development of nirmatrelvir resistance

    Ibrutinib, neratinib, venetoclax: Possible increased antineoplastic concentrations

    Encorafenib, ivosidenib: Possible increased antineoplastic concentrations and potential for serious and/or life-threatening adverse effects (e.g., QT interval prolongation)

    Vincristine, vinblastine: Possible increased antineoplastic concentrations and potential for clinically important hematologic or GI adverse effects

    Abemaciclib, ceritinib, dasatinib, nilotinib: Possible increased antineoplastic concentrations

    Apalutamide: Concomitant use contraindicated; do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of apalutamide due to delayed offset of apalutamide

    Encorafenib, ibrutinib, ivosidenib, neratinib, venetoclax: Avoid concomitant use

    Antipsychotics (clozapine, lurasidone, pimozide, quetiapine, aripiprazole, Brexpiprazole, Cariprazine, iloperidone, lumateperone, pimavanserin)

    Possible increased concentrations of the antipsychotic agent and potential for adverse effects

    Lurasidone, pimozide: Concomitant use contraindicated because of serious and/or life-threatening reactions such as arrhythmias

    Quetiapine: If concomitant use is necessary, reduce quetiapine dosage and monitor for quetiapine adverse effects

    Clozapine: If concomitant use is necessary, consider reducing clozapine dosage and monitor for adverse reactions

    Aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin: Dosage adjustment of the antipsychotic agent recommended

    Antiretroviral agents, HIV protease inhibitors (PIs) (atazanavir, darunavir, tipranavir)

    Possible increased systemic exposure to the HIV PI

    In patients currently receiving a ritonavir- or cobicistat-boosted HIV regimen, continue treatment as indicated and monitor for increased adverse events from ritonavir, nirmatrelvir, or the HIV PI

    Antiretroviral agents, other (efavirenz, maraviroc, nevirapine, zidovudine, bictegravir/emtricitabine/tenofovir)

    Possible increased concentrations of efavirenz, maraviroc, nevirapine, bictegravir, and tenofovir

    Possible decreased concentrations of zidovudine

    No change in emtricitabine concentrations

    Refer to the respective product labels for additional information

    Avanafil

    Possible increased concentrations of avanafil

    Do not use nirmatrelvir/ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established

    Benzodiazepines (midazolam, triazolam, clorazepate, clonazepam, Diazepam, estazolam, flurazepam)

    Possible increased concentrations of the benzodiazepine

    Oral midazolam or triazolam: Concomitant use contraindicated

    Parenteral midazolam: Use concomitantly with caution and in monitored setting where respiratory depression and/or prolonged sedation can be managed; consider reduced midazolam dosage, especially if multiple midazolam doses are given

    Clorazepate, clonazepam, diazepam, estazolam, flurazepam: Dosage decrease for these drugs may be needed; monitor for adverse effects

    Bosentan

    Possible increased bosentan concentrations

    Discontinue bosentan for ≥36 hours prior to initiating ritonavir-boosted nirmatrelvir

    Bupropion

    Possible decreased concentrations of bupropion and its active metabolite (hydroxybupropion)

    Monitor for adequate clinical response to bupropion

    Buspirone

    Possible increased concentrations of buspirone

    Dosage reduction may be necessary for buspirone; monitor for adverse effects

    Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

    Possible increased concentrations of the calcium-channel blocking agent

    Use concomitantly with caution; clinical monitoring recommended

    If concomitant use cannot be avoided, dosage reduction of calcium-channel blocking agent may be necessary

    Cilostazol

    Possible increased cilostazol concentrations

    Dosage adjustment of cilostazol recommended

    Clopidogrel

    Potential for decreased concentrations of clopidogrel active metabolite

    Avoid concomitant use

    Colchicine

    Possible increased colchicine concentrations and potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment

    Concomitant use contraindicated

    Corticosteroids primarily metabolized by CYP3A (betamethasone, Budesonide, ciclesonide, Dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone)

    Possible increased corticosteroid concentrations (via all routes of administration) and increased risk of adrenal insufficiency or Cushing's syndrome

    Consider alternative corticosteroid (e.g., beclomethasone, prednisone, prednisolone)

    Cystic fibrosis transmembrane conductance regulator potentiators (lumacaftor/ivacaftor, ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor)

    Lumacaftor/ivacaftor: Possible decreased concentrations of nirmatrelvir/ritonavir and potential loss of virologic response and resistance

    Ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor: Possible increased concentrations of the cystic fibrosis agent

    Lumacaftor/ivacaftor: Concomitant use contraindicated

    Ivacaftor, elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor: Reduce dosage of the cystic fibrosis agent

    Darifenacin

    Possible increased darifenacin concentrations

    Do not exceed a darifenacin daily dose of 7.5 mg

    Dasabuvir

    Possible increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir/dasabuvir

    Digoxin

    Possible increased digoxin concentrations

    Use concomitantly with caution; monitor digoxin concentrations and adjust dosage as clinically indicated

    Eletriptan

    Possible increased eletriptan concentrations and increased risk of serious and/or life-threatening adverse effects

    Coadministration of eletriptan within at least 72 hours of nirmatrelvir/ritonavir is contraindicated

    Elbasvir

    Possible increased elbasvir concentrations and substantially increased grazoprevir concentrations if ritonavir-boosted nirmatrelvir used with fixed combination elbasvir/grazoprevir; increased grazoprevir concentrations may increase risk of increased ALT concentrations

    Eplerenone

    Possible increased eplerenone concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated due to potential for hyperkalemia

    Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

    Potential for serious or life-threatening adverse effects (e.g., vasospasm, ischemia of extremities or other tissues)

    Concomitant use contraindicated

    Estrogens

    Oral hormonal contraceptives containing ethinyl estradiol: Possible decreased ethinyl estradiol concentrations

    Use additional nonhormonal contraception methods during the 5 days of treatment and until 1 menstrual cycle after discontinuance of ritonavir-boosted nirmatrelvir

    Fentanyl

    Possible increased fentanyl concentrations

    Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals

    Flibanserin

    Possible increased flibanserin concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated due to potential for hypotension, syncope, and CNS depression

    Finerenone

    Possible increased finerenone concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated

    Glecaprevir and pibrentasvir

    Increased HCV antiviral drug concentrations

    Avoid concomitant use

    Grazoprevir

    Increased grazoprevir concentrations which can result in increased ALT concentrations

    HMG-CoA reductase inhibitors (statins)

    Lovastatin, simvastatin: Possible increased antilipemic concentrations and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis

    Atorvastatin, rosuvastatin: Possible increased antilipemic concentrations and increased risk of statin-associated adverse effects

    Atorvastatin, rosuvastatin: Consider temporarily withholding atorvastatin and rosuvastatin during ritonavir-boosted nirmatrelvir therapy; atorvastatin and rosuvastatin do not need to be held prior to or after discontinuance of ritonavir-boosted nirmatrelvir

    Lovastatin, simvastatin: Concomitant use with ritonavir-boosted nirmatrelvir contraindicated; discontinue lovastatin and simvastatin at least 12 hours prior to initiation of ritonavir-boosted nirmatrelvir, during the 5 days of treatment, and for 5 days after completion of ritonavir-boosted nirmatrelvir therapy

    Hydrocodone

    Possible increased concentrations of hydrocodone

    Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals

    Immunosuppressive agents (cyclosporine, sirolimus, everolimus, tacrolimus)

    Possible increased immunosuppressive agent concentrations

    Cyclosporine, tacrolimus: Monitor plasma concentrations of immunosuppressive agent; avoid concomitant use if monitoring of immunosuppressive agent concentrations not feasible

    If co-administered, dosage adjustments of the immunosuppressant and monitoring for immunosuppressant concentrations and associated adverse effects is recommended

    Sirolimus, everolimus: Avoid concomitant use

    Ivabradine

    Possible increased ivabradine concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated due to potential for bradycardia or conduction disturbances

    Lomitapide

    Possible increased lomitapide concentrations and increased risk of hepatotoxicity and GI adverse effects

    Concomitant use contraindicated

    Macrolides (clarithromycin, erythromycin)

    Possible increased macrolide concentration

    Meperidine

    Possible increased meperidine concentrations

    Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals

    Methadone

    Possible decreased methadone concentrations

    Closely monitor for opiate withdrawal since some patients may need adjustment of methadone maintenance dosage

    Naloxegol

    Possible increased naloxegol concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated

    Ombitasvir

    Increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir and dasabuvir

    Oxycodone

    Possible increased concentrations of oxycodone

    Carefully monitor patient for therapeutic and adverse effects, including potentially fatal respiratory depression; if concomitant use necessary, consider dosage reduction of the opioid and monitor patients closely at frequent intervals

    Paritaprevir

    Possible increased HCV antiviral drug concentrations if used with fixed combination ombitasvir/paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir/dasabuvir

    Ranolazine

    Possible increased ranolazine concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated

    Rimegepant

    Possible increased rimegepant concentrations

    Avoid concomitant use

    Riociguat

    Possible increased riociguat concentrations

    Dosage adjustment of riociguat recommended

    Salmeterol

    Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, and sinus tachycardia

    Avoid concomitant use

    Saxagliptin

    Possible increased saxagliptin concentrations

    Dosage adjustment of saxagliptin is recommended

    Sildenafil

    Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope)

    Concomitant use with sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH) contraindicated

    Dosage adjustment recommended for sildenafil used for erectile dysfunction

    Silodosin

    Possible increased silodosin concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated

    Sofosbuvir

    Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations

    Refer to the product label for sofosbuvir/velpatasvir/voxilaprevir for additional information

    St. John’s wort (Hypericum perforatum)

    Possible decreased nirmatrelvir and ritonavir concentrations, and possible loss of virologic response and development of resistance

    Concomitant use contraindicated; do not initiate ritonavir-boosted nirmatrelvir immediately after discontinuation of St. John's wort due to delayed offset of St. John's wort

    Suvorexant

    Possible increased concentrations of suvorexant

    Avoid concomitant use

    Tadalafil

    Possible increased tadalafil concentrations

    Avoid concomitant use of tadalafil for pulmonary hypertension

    Dosage adjustment recommended for tadalafil used for erectile dysfunction

    Tamsulosin

    Possible increased tamsulosin concentrations

    Avoid concomitant use

    Tenofovir alafenamide

    Fixed combination of bictegravir, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF): Possible increased TAF concentrations if used with ritonavir-boosted nirmatrelvir

    Ticagrelor

    Possible increased concentrations of ticagrelor

    Avoid concomitant use

    Tofacitinib

    Possible increased concentrations of tofacitinib

    Dosage adjustment of tofacitinib is recommended

    Tolvaptan

    Possible increased tolvaptan concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated due to potential for dehydration, hypovolemia, and hyperkalemia

    Trazodone

    Possible increased trazodone concentrations and increased risk of nausea, dizziness, hypotension, syncope

    Consider reduced trazodone dosage; refer to trazodone product labeling

    Ubrogepant

    Possible increased ubrogepant concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated

    Upadacitinib

    Possible increased concentrations of upadacitinib

    Dosing recommendations for upadacitinib depend on the indication; refer to the product label for additional information

    Vardenafil

    Possible increased concentrations of vardenafil

    Dosage adjustment of vardenafil recommended

    Velpatasvir

    Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations if ritonavir-boosted nirmatrelvir is used with fixed combination of sofosbuvir, velpatasvir, and voxilaprevir

    Voclosporin

    Possible increased voclosporin concentrations and increased risk of serious and/or life-threatening adverse effects

    Concomitant use contraindicated due to potential for acute and/or chronic nephrotoxicity

    Vorapaxar

    Possible increased concentrations of vorapaxar

    Avoid concomitant use

    Voxilaprevir

    Possible increased sofosbuvir/velpatasvir/voxilaprevir concentrations if ritonavir-boosted nirmatrelvir is used with fixed combination of sofosbuvir, velpatasvir, and voxilaprevir

    Zolpidem

    Possible increased concentrations of zolpidem

    Dosage reduction may be necessary for zolpidem; monitor for adverse effects

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