nirmatrelvir/ritonavir (Investigational)

Brand and Other Names:Paxlovid
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablets

  • Dose pack 300 mg nirmatrelvir and 100 mg ritonavir: Each daily blister card contains 4 nirmatrelvir tablets (150-mg) and 2 ritonavir tablets (100-mg)
  • Dose pack 150 mg nirmatrelvir and 100 mg ritonavir: Each daily blister card contains 2 nirmatrelvir tablets (150-mg) and 2 ritonavir tablets (100-mg)

COVID-19 Disease Treatment (EUA)

December 22, 2021: Emergency use authorization issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (aged ≥12 years and weight ≥40 kg) testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and who are at high risk for progression to severe COVID-19, including hospitalization or death

300 mg nirmatrelvir plus 100 mg ritonavir PO BID x 5 days

Initiate as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset

Completing the full 5-day treatment course and isolate in accordance with public health recommendations are important to maximize viral clearance and minimize viral transmission

If patient is hospitalized due to severe or critical COVID-19 after starting treatment with nirmatrelvir/ritonavir, completion of the full 5-day treatment is at the healthcare provider’s discretion

Dosage Modifications

Renal impairment

  • Mild (eGFR ≥60 to <90 mL/min): No dosage adjustment required
  • Moderate (eGFR ≥30 to <60 mL/min): Decrease to 150 mg nirmatrelvir plus 100 mg ritonavir BID x 5 days
  • Severe (eGFR <30 mL/min): Not recommended; data are unavailable

Hepatic impairment

  • Mild or moderate (Child-Pugh Class A or B): No dosage adjustment required
  • Severe (Child-Pugh Class C): Not recommended; data are unavailable

Dosing Considerations

Limitations of use

  • Not authorized for initiation of treatment in patients requiring hospitalization owing to severe or critical COVID-19
  • Not authorized for preexposure or postexposure prophylaxis for prevention of COVID-19
  • Not authorized for >5 consecutive days

Prescribing

  • May be prescribed for an individual patient by physicians (MD, DO), advanced practice registered nurses (eg, NP), and physician assistants (PA) that are licensed or authorized under state law to prescribe drugs
  • May also be prescribed for an individual patient by a state-licensed pharmacist
  • Pharmacist prescribing conditions
    • Sufficient information is available, such as, access to health records <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 to obtain a comprehensive list of medications (prescribed and OTC) to assess for potential drug interactions
  • Conditions requiring pharmacist referral for clinical evaluation by MD, DO, NP, or PA
    • Sufficient information is not available to assess renal and hepatic function
    • Sufficient information is not available to assess for potential drug interactions
    • Modification of other medications needed owing to potential drug interaction
    • Nirmatrelvir/ritonavir is not an appropriate therapeutic option based on Fact Sheet for Healthcare
    • Providers or due to potential drug interactions for which recommended monitoring would not be feasible

Dosage Forms & Strengths

tablets

  • Dose pack 300 mg nirmatrelvir and 100 mg ritonavir: Each daily blister card contains 4 nirmatrelvir tablets (150-mg) and 2 ritonavir tablets (100-mg)
  • Dose pack 150 mg nirmatrelvir and 100 mg ritonavir: Each daily blister card contains 2 nirmatrelvir tablets (150-mg) and 2 ritonavir tablets (100-mg)

COVID-19 Disease Treatment (EUA)

December 22, 2021: Emergency use authorization issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (aged ≥12 years and weight ≥40 kg) testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and who are at high risk for progression to severe COVID-19, including hospitalization or death

<12 years: Safety and efficacy not established

300 mg nirmatrelvir plus 100 mg ritonavir PO BID x 5 days

Initiate as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset

Completing the full 5-day treatment course and isolate in accordance with public health recommendations are important to maximize viral clearance and minimize viral transmission

If patient is hospitalized due to severe or critical COVID-19 after starting treatment with nirmatrelvir/ritonavir, completion of the full 5-day treatment is at the healthcare provider’s discretion

Dosage Modifications

Renal impairment

  • Mild (eGFR ≥60 to <90 mL/min): No dosage adjustment required
  • Moderate (eGFR ≥30 to <60 mL/min): Decrease to 150 mg nirmatrelvir plus 100 mg ritonavir BID x 5 days
  • Severe (eGFR <30 mL/min): Not recommended; data are unavailable

Hepatic impairment

  • Mild or moderate (Child-Pugh Class A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Not recommended; data are unavailable

Dosing Considerations

Limitations of use

  • Not authorized for initiation of treatment in patients requiring hospitalization owing to severe or critical COVID-19
  • Not authorized for preexposure or postexposure prophylaxis for prevention of COVID-19
  • Not authorized for >5 consecutive days

Prescribing

  • May be prescribed for an individual patient by physicians (MD, DO), advanced practice registered nurses (eg, NP), and physician assistants (PA) that are licensed or authorized under state law to prescribe drugs
  • May also be prescribed for an individual patient by a state-licensed pharmacist
  • Pharmacist prescribing conditions
    • Sufficient information is available, such as, access to health records <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 to obtain a comprehensive list of medications (prescribed and OTC) to assess for potential drug interactions
  • Conditions requiring pharmacist referral for clinical evaluation by MD, DO, NP, or PA
    • Sufficient information is not available to assess renal and hepatic function
    • Sufficient information is not available to assess for potential drug interactions
    • Modification of other medications needed owing to potential drug interaction
    • Nirmatrelvir/ritonavir is not an appropriate therapeutic option based on Fact Sheet for Healthcare
    • Providers or due to potential drug interactions for which recommended monitoring would not be feasible
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Interactions

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and nirmatrelvir/ritonavir

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            Contraindicated (44)

            • alfuzosin

              nirmatrelvir/ritonavir will increase the level or effect of alfuzosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • amiodarone

              nirmatrelvir/ritonavir will increase the level or effect of amiodarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • apalutamide

              apalutamide will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • carbamazepine

              carbamazepine will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • clozapine

              nirmatrelvir/ritonavir will increase the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • colchicine

              nirmatrelvir/ritonavir will increase the level or effect of colchicine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • dihydroergotamine

              nirmatrelvir/ritonavir will increase the level or effect of dihydroergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • dronedarone

              nirmatrelvir/ritonavir will increase the level or effect of dronedarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • eletriptan

              nirmatrelvir/ritonavir will increase the level or effect of eletriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of eletriptan within at least 72 hours of nirmatrelvir/ritonavir is contraindicated owing to potential for serious adverse reactions including cardiovascular and cerebrovascular events.

            • enzalutamide

              enzalutamide will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • eplerenone

              nirmatrelvir/ritonavir will increase the level or effect of eplerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of hyperkalemia associated with eplerenone.

            • ergotamine

              nirmatrelvir/ritonavir will increase the level or effect of ergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • finerenone

              nirmatrelvir/ritonavir will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of hyperkalemia, hypotension, and hyponatremia associated with finerenone.

            • flecainide

              nirmatrelvir/ritonavir will increase the level or effect of flecainide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • flibanserin

              nirmatrelvir/ritonavir will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of hypotension, syncope, and CNS depression associated with flibanserin.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • ivabradine

              nirmatrelvir/ritonavir will increase the level or effect of ivabradine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of bradycardia or conduction disturbances associated with ivabradine.

            • lomitapide

              nirmatrelvir/ritonavir will increase the level or effect of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of hepatotoxicity and GI effects associated with lomitapide.

            • lovastatin

              nirmatrelvir/ritonavir will increase the level or effect of lovastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Discontinue lovastatin at least 12 hr before initiating nirmatrelvir/ritonavir , during the 5 days of treatment, and for 5 days after completing.

            • lumacaftor/ivacaftor

              lumacaftor/ivacaftor will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • lurasidone

              nirmatrelvir/ritonavir will increase the level or effect of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • mavacamten

              nirmatrelvir/ritonavir will increase the level or effect of mavacamten by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inhibitors may increase mavacamten systemic exposure, resulting in heart failure due to systolic dysfunction.

            • meperidine

              nirmatrelvir/ritonavir will increase the level or effect of meperidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • methylergonovine

              nirmatrelvir/ritonavir will increase the level or effect of methylergonovine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • midazolam

              nirmatrelvir/ritonavir will increase the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with oral midazolam. If IV midazolam required, reduce midazolam dose and administer in setting that ensures close monitoring and appropriate medical management if respiratory depression occurs.

            • mitotane

              mitotane will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • naloxegol

              nirmatrelvir/ritonavir will increase the level or effect of naloxegol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Potential for opioid withdrawal symptoms.

            • phenobarbital

              phenobarbital will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • phenytoin

              phenytoin will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • pimozide

              nirmatrelvir/ritonavir will increase the level or effect of pimozide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • piroxicam

              nirmatrelvir/ritonavir will increase the level or effect of piroxicam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • primidone

              primidone will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • propafenone

              nirmatrelvir/ritonavir will increase the level or effect of propafenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • quinidine

              nirmatrelvir/ritonavir will increase the level or effect of quinidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • ranolazine

              nirmatrelvir/ritonavir will increase the level or effect of ranolazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • rifampin

              rifampin will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • sildenafil

              nirmatrelvir/ritonavir will increase the level or effect of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration contraindicated if sildenafil used for pulmonary arterical hypertension. Reduce sildenafil dose if used for erectile dysfunction.

            • silodosin

              nirmatrelvir/ritonavir will increase the level or effect of silodosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of postural hypotension associated with silodosin.

            • simvastatin

              nirmatrelvir/ritonavir will increase the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Discontinue simvastatin at least 12 hr before initiating nirmatrelvir/ritonavir, during the 5 days of treatment, and for 5 days after completing.

            • St John's Wort

              St John's Wort will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

            • tolvaptan

              nirmatrelvir/ritonavir will increase the level or effect of tolvaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of dehydration, hypovolemia, and hyperkalemia associated with tolvaptan.

            • triazolam

              nirmatrelvir/ritonavir will increase the level or effect of triazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • ubrogepant

              nirmatrelvir/ritonavir will increase the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.

            • voclosporin

              nirmatrelvir/ritonavir will increase the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. May increase risk of acute and/or chronic nephrotoxicity associated with voclosporin.

            Serious - Use Alternative (28)

            • aliskiren

              nirmatrelvir/ritonavir will increase the level or effect of aliskiren by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Aliskiren product labeling recommends avoiding concomitant use with CYP3A4 and P-gp inhibitors.

            • apixaban

              nirmatrelvir/ritonavir will increase the level or effect of apixaban by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Apixaban is also substrate of P-gp; if concomitant administration necessary, adjust and hold dose as clinically necessary; may adjust apixaban dosage according to risk, indication and current dose; for treatment of atrial fibrillation with standard apixaban dose (eg, 5 mg twice daily), reduce apixaban to 2.5 mg twice daily; for treatment of atrial fibrillation with low dose apixaban (eg, 2.5 mg twice daily), continue low dose on case-by-case basis

            • avanafil

              nirmatrelvir/ritonavir will increase the level or effect of avanafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Safe and effective avanafil dosage regimen has not been established for coadministration with strong CYP3A4 inhibitors.

            • bosentan

              nirmatrelvir/ritonavir will increase the level or effect of bosentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of nirmatrelvir/ritonavir for 5 days may result in significant increases bosentan trough concentrations. Discontinue bosentan at least 36 hr before initiating nirmatrelvir/ritonavir. May resume bosentan 10 days after initiating nirmatrelvir/ritonavir.

            • clopidogrel

              nirmatrelvir/ritonavir will decrease the level or effect of clopidogrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Coadministration of clopidogrel and ritonavir-boosted HIV protease inhibitors has been evaluated in clinical studies and showed that ritonavir decreased the AUC and Cmax of clopidogrel?s active metabolite.

            • cyclosporine

              nirmatrelvir/ritonavir will increase the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid, monitor cyclosporine serum concentration and temporarily decrease dose or alter dose frequency.

            • elbasvir/grazoprevir

              nirmatrelvir/ritonavir will increase the level or effect of elbasvir/grazoprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Increased grazoprevir concentrations can result in ALT elevations.

            • encorafenib

              nirmatrelvir/ritonavir will increase the level or effect of encorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration owing to potential risk of serious adverse events (eg, QT interval prolongation).

            • everolimus

              nirmatrelvir/ritonavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • glecaprevir/pibrentasvir

              nirmatrelvir/ritonavir will increase the level or effect of glecaprevir/pibrentasvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Glecaprevir/pibrentasvir serum concentrations may be increased owing to P-gp, BCRP and OATP1B inhibition by ritonavir.

            • ibrutinib

              nirmatrelvir/ritonavir will increase the level or effect of ibrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • isavuconazonium sulfate

              nirmatrelvir/ritonavir will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ivosidenib

              nirmatrelvir/ritonavir will increase the level or effect of ivosidenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration owing to potential risk of serious adverse events (eg, QT interval prolongation).

            • neratinib

              nirmatrelvir/ritonavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • nilotinib

              nirmatrelvir/ritonavir will increase the level or effect of nilotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid with strong CYP3A4 inhibitors. If unable to avoid, reduce nilotinib dose.

            • rifapentine

              rifapentine will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • rimegepant

              nirmatrelvir/ritonavir will increase the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • rivaroxaban

              nirmatrelvir/ritonavir will increase the level or effect of rivaroxaban by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid rivaroxaban with strong CYP3A4/P-gp inhibitors owing to increased bleeding risk.

            • salmeterol

              nirmatrelvir/ritonavir will increase the level or effect of salmeterol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration may increase risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

            • sirolimus

              nirmatrelvir/ritonavir will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • suvorexant

              nirmatrelvir/ritonavir will increase the level or effect of suvorexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tacrolimus

              nirmatrelvir/ritonavir will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid, decrease tacrolimus dose by one-third. Strong CYP3A inhibitors may increase tacrolimus whole blood trough concentrations and increase risk of serious adverse reactions (eg, neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose.

            • tadalafil

              nirmatrelvir/ritonavir will increase the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration if tadalafil used for pulmonary arterial hpertension. Reduce tadalafil dose if used for erectile dysfunction.

            • tamsulosin

              nirmatrelvir/ritonavir will increase the level or effect of tamsulosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Tamsulosin metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6. Pause tamsulosin and restart 3 days after completing nirmatrelvir/ritonavir given that CYP3A4 inhibition takes several days to resolve.

            • ticagrelor

              nirmatrelvir/ritonavir will increase the level or effect of ticagrelor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. As an alternant antiiplatelet agent, prasugrel can be used with nirmatrelvir/ritonavir unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered.

            • venetoclax

              nirmatrelvir/ritonavir will increase the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • vorapaxar

              nirmatrelvir/ritonavir will increase the level or effect of vorapaxar by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • voriconazole

              nirmatrelvir/ritonavir will decrease the level or effect of voriconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of voriconazole and low-dose ritonavir (ie, 100 mg q12hr) owing to induction of CYP3A4 and CYP2C19 isoenzymes by ritonavir.

            Monitor Closely (64)

            • abemaciclib

              nirmatrelvir/ritonavir will increase the level or effect of abemaciclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce abemaciclib dose if coadministered with strong or moderate CYP3A4 inhibitors.

            • alprazolam

              nirmatrelvir/ritonavir will increase the level or effect of alprazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider lowering alprazolam dosing when coadministered with nirmatrelvir/ritonavir

            • amlodipine

              nirmatrelvir/ritonavir will increase the level or effect of amlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce amlodipine dose by 50% during coadministration and for 3 more days after the last nirmatrelvir/ritonavir dose.

            • atazanavir

              nirmatrelvir/ritonavir will increase the level or effect of atazanavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • atorvastatin

              nirmatrelvir/ritonavir will increase the level or effect of atorvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider temporary discontinuation of atorvastatin during treatment with nirmatrelvir/ritonavir.

            • bedaquiline

              nirmatrelvir/ritonavir will increase the level or effect of bedaquiline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for bedaquiline adverse effects (eg, QT prolongation).

            • betamethasone

              nirmatrelvir/ritonavir will increase the level or effect of betamethasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • bictegravir

              nirmatrelvir/ritonavir will increase the level or effect of bictegravir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase bictegravir systemic exposures.

            • budesonide

              nirmatrelvir/ritonavir will increase the level or effect of budesonide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • bupropion

              nirmatrelvir/ritonavir will decrease the level or effect of bupropion by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Bupropion is extensively metabolized by CYP2B6 to active metabolite. Monitor for adequate clinical response to bupropion when coadministered with CYP2B6 inhibitors.

            • ceritinib

              nirmatrelvir/ritonavir will increase the level or effect of ceritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid with strong CYP3A4 inhibitors. If unable to avoid, reduce nilotinib dose.

            • ciclesonide inhaled

              nirmatrelvir/ritonavir will increase the level or effect of ciclesonide inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • clarithromycin

              nirmatrelvir/ritonavir will increase the level or effect of clarithromycin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Do not exceed clarithromycin doses >1,000 mg/day in patients taking protease inhibitors. Consider clarithromcycin dose reduction in patients with renal impairment.

            • dabigatran

              nirmatrelvir/ritonavir will increase the level or effect of dabigatran by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Clinical significance dependent on degree of renal impairment. Dabigatran is mainly cleared by glomerular filtration. The prodrug of dabigatran is a substrate of P-gp and concentrations may increase due to inhibition of P-gp by ritonavir. Dabigatran dose may need to be reduced in patients with mild/moderate renal impairment if coadministered with a P-gp inhibitor. Dabigatran is not recommended in patients with severe renal impairment.

            • darunavir

              nirmatrelvir/ritonavir will increase the level or effect of darunavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • dasatinib

              nirmatrelvir/ritonavir will increase the level or effect of dasatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Dose reduction of dasatinib may be necessary if coadministered with strong CYP3A4 inhibitors.

            • dexamethasone

              nirmatrelvir/ritonavir will increase the level or effect of dexamethasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • digoxin

              nirmatrelvir/ritonavir will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Measure serum digoxin concentrations before initiating nirmatrelvir/ritonavir. Decrease digoxin dose by ~30-50% or by modifying dosing frequency and continue monitoring during coadministration.

            • diltiazem

              nirmatrelvir/ritonavir will increase the level or effect of diltiazem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider reducing diltiazem dose by 50% during coadministration and for 3 more days after the last nirmatrelvir/ritonavir dose.

            • efavirenz

              nirmatrelvir/ritonavir will increase the level or effect of efavirenz by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • erythromycin base

              nirmatrelvir/ritonavir will increase the level or effect of erythromycin base by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased erythromycin adverse effects, including QTc interval prolongation.

            • erythromycin ethylsuccinate

              nirmatrelvir/ritonavir will increase the level or effect of erythromycin ethylsuccinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased erythromycin adverse effects, including QTc interval prolongation.

            • erythromycin lactobionate

              nirmatrelvir/ritonavir will increase the level or effect of erythromycin lactobionate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased erythromycin adverse effects, including QTc interval prolongation.

            • erythromycin stearate

              nirmatrelvir/ritonavir will increase the level or effect of erythromycin stearate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased erythromycin adverse effects, including QTc interval prolongation.

            • ethinylestradiol

              nirmatrelvir/ritonavir will decrease the level or effect of ethinylestradiol by increasing metabolism. Modify Therapy/Monitor Closely. Consider using additional nonhormonal contraceptive method for remainder of cycle. Mechanism unknown, but possibly by ritonavir CYP2C9 or CYP1A2 induction.

            • felodipine

              nirmatrelvir/ritonavir will increase the level or effect of felodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider reducing felodipine dose by 50% during coadministration and for 3 more days after the last nirmatrelvir/ritonavir dose.

            • fentanyl

              nirmatrelvir/ritonavir will increase the level or effect of fentanyl by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Careful monitoring of fentanyl therapeutic and adverse effects (including potentially fatal respiratory depression) recommended when coadministered. Reduce fentanyl dose if necessary.

            • fluticasone furoate

              nirmatrelvir/ritonavir will increase the level or effect of fluticasone furoate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • fluticasone inhaled

              nirmatrelvir/ritonavir will increase the level or effect of fluticasone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • fosamprenavir

              nirmatrelvir/ritonavir will increase the level or effect of fosamprenavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • hydrocodone

              nirmatrelvir/ritonavir will increase the level or effect of hydrocodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Careful monitoring of hydrocodone therapeutic and adverse effects (including potentially fatal respiratory depression) recommended when coadministered. Reduce hydrocodone dose if necessary.

            • indinavir

              nirmatrelvir/ritonavir will increase the level or effect of indinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • itraconazole

              nirmatrelvir/ritonavir will increase the level or effect of itraconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit itraconazole adult dose to 200 mg/day if coadministered with ritonavir.

            • ivacaftor

              nirmatrelvir/ritonavir will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dosage of ivacaftor, elexacaftor/tezacaftor/ivacaftor, or tezacaftor/ivacaftor if coadministered.

            • ketoconazole

              nirmatrelvir/ritonavir will increase the level or effect of ketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit ketoconazole adult dose to 200 mg/day if coadministered with ritonavir.

            • levoketoconazole

              nirmatrelvir/ritonavir will increase the level or effect of levoketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit ketoconazole adult dose to 200 mg/day if coadministered with ritonavir.

            • lidocaine

              nirmatrelvir/ritonavir will increase the level or effect of lidocaine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Caution warranted. Monitor lidocaine therapeutic concentrations if available.

            • lumateperone

              nirmatrelvir/ritonavir will increase the level or effect of lumateperone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce lumateperone dose to 10.5 mg/day if coadministered with strong CYP3A4 inhibitors.

            • maraviroc

              nirmatrelvir/ritonavir will increase the level or effect of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • methadone

              nirmatrelvir/ritonavir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.

            • methylprednisolone

              nirmatrelvir/ritonavir will increase the level or effect of methylprednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • mometasone inhaled

              nirmatrelvir/ritonavir will increase the level or effect of mometasone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • nelfinavir

              nirmatrelvir/ritonavir will increase the level or effect of nelfinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • nevirapine

              nirmatrelvir/ritonavir will increase the level or effect of nevirapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nicardipine

              nirmatrelvir/ritonavir will increase the level or effect of nicardipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for side effects (eg, hypotension, flushing, edema). May consider temporary nicardipine dose reduction.

            • nifedipine

              nirmatrelvir/ritonavir will increase the level or effect of nifedipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider reducing nifedipine dose by 50% during coadministration and for 3 more days after the last nirmatrelvir/ritonavir dose.

            • oxycodone

              nirmatrelvir/ritonavir will increase the level or effect of oxycodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Careful monitoring of oxycodone therapeutic and adverse effects (including potentially fatal respiratory depression) recommended when coadministered. Reduce oxycodone dose if necessary.

            • prednisone

              nirmatrelvir/ritonavir will increase the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • quetiapine

              nirmatrelvir/ritonavir will increase the level or effect of quetiapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce quetiapine dose to one-sixth when coadministered with strong CYP3A4 inhibitors.

            • raltegravir

              nirmatrelvir/ritonavir will decrease the level or effect of raltegravir by Other (see comment). Use Caution/Monitor. Raltegravir is an UGT1A1 substrate. Ritonavir induces UGT 1A1.

            • rifabutin

              nirmatrelvir/ritonavir will increase the level or effect of rifabutin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitored closely for rifabutin adverse effects, including neutropenia and uveitis. Ritonavir prescribing information recommends reducing rifabutin doses by at least 75% to 150 mg every other day, or 3 times weekly, when coadministered with ritonavir.

            • rosuvastatin

              nirmatrelvir/ritonavir will increase the level or effect of rosuvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider temporary discontinuation of rosuvastatin during treatment with nirmatrelvir/ritonavir.

            • saquinavir

              nirmatrelvir/ritonavir will increase the level or effect of saquinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • tenofovir AF

              nirmatrelvir/ritonavir will increase the level or effect of tenofovir AF by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase tenofovir systemic exposures.

            • tipranavir

              nirmatrelvir/ritonavir will increase the level or effect of tipranavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.

            • trazodone

              nirmatrelvir/ritonavir will increase the level or effect of trazodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adverse reactions of nausea, dizziness, hypotension, and syncope observed following coadministration of trazodone and strong CYP3A4 inhibitors. Consider lower trazodone dose.

            • triamcinolone acetonide injectable suspension

              nirmatrelvir/ritonavir will increase the level or effect of triamcinolone acetonide injectable suspension by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • triamcinolone inhaled

              nirmatrelvir/ritonavir will increase the level or effect of triamcinolone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).

            • vardenafil

              nirmatrelvir/ritonavir will increase the level or effect of vardenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce vardenafil dose if coadministered.

            • vinblastine

              nirmatrelvir/ritonavir will increase the level or effect of vinblastine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may lead to significant hematologic or gastrointestinal side effects.

            • vincristine

              nirmatrelvir/ritonavir will increase the level or effect of vincristine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may lead to significant hematologic or gastrointestinal side effects.

            • voxilaprevir

              nirmatrelvir/ritonavir will increase the level or effect of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • warfarin

              nirmatrelvir/ritonavir will increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. INR may increase or decrease. Closely monitor INR if nirmatrelvir/ritonavir is coadministered with warfarin.

            • zidovudine

              nirmatrelvir/ritonavir will decrease the level or effect of zidovudine by unknown mechanism. Use Caution/Monitor.

            Minor (2)

            • emtricitabine

              nirmatrelvir/ritonavir will increase the level or effect of emtricitabine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • sofosbuvir/velpatasvir

              nirmatrelvir/ritonavir will decrease the level or effect of sofosbuvir/velpatasvir by affecting hepatic enzyme CYP2B6 metabolism. Minor/Significance Unknown.

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            Adverse Effects

            1-10%

            Dysgeusia (6%)

            Diarrhea (3%)

            Hypertension (1%)

            Myalgia (1%)

            Require Reporting

            Prescribers and/or the provider’s designee are/is responsible for mandatory reporting of all serious adverse events and medication errors potentially drug-related within 7 calendar days from the onset of the event

            Serious adverse events are defined as

            • Death or life-threatening adverse event;
            • Medical or surgical intervention to prevent death, life-threatening event, hospitalization, disability, or congenital anomaly;
            • Inpatient hospitalization or prolongation of existing hospitalization;
            • Persistent or significant incapacity or substantial disruption of ability to conduct normal life functions; or
            • Congenital anomaly/birth defect
            • FDA recommends that such reports, use FDA Form 3500

            Post-authorization Experience

            Immune system disorders: Hypersensitivity reactions

            Gastrointestinal disorders: Abdominal pain, nausea

            General disorders and administration site conditions: Malaise

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            Warnings

            Contraindications

            History of clinically significant hypersensitivity reactions (eg, toxic epidermal necrolysis [TEN], Stevens-Johnson syndrome [SJS]) to nirmatrelvir or ritonavir

            Drug highly dependent on CYP3A for clearance

            • Alpha1-adrenoreceptor antagonist: Alfuzosin
            • Analgesics: Meperidine
            • Antianginal: Ranolazine
            • Antiarrhythmic: Amiodarone, dronedarone, flecainide, propafenone, quinidine
            • Antigout: Colchicine
            • Antipsychotics: Lurasidone, pimozide, clozapine
            • BPH agents: Silodosin
            • Cardiovascular agents: Eplerenone, ivabradine
            • Ergot derivatives: Dihydroergotamine, ergotamine, methylergonovine
            • HMG-CoA reductase inhibitors: Lovastatin, simvastatin
            • 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 (PAH)
            • Sedative/hypnotics: Triazolam, oral midazolam
            • Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: Flibanserin
            • Vasopressin receptor antagonists: Tolvaptan

            Drugs that are potent CYP3A inducers

            • Anticancer drugs: Apalutamide
            • Anticonvulsant: Carbamazepine, phenobarbital, primidone, phenytoin
            • Antimycobacterials: Rifampin
            • CFTR modulator: Lumacaftor/ivacaftor
            • Herbal products: St. John’s Wort (hypericum perforatum)

            Cautions

            Hypersensitivity reactions reported including urticaria, angioedema, dyspnea, mild skin eruptions, and pruritus; cases of anaphylaxis; TEN, and SJS reported with ritonavir; if significant hypersensitivity reaction or anaphylaxis occurs, immediately discontinue and initiate appropriate medications and/or supportive care

            Hepatic transaminase elevations, clinical hepatitis, and jaundice reported with ritonavir; caution when administering to patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis

            Because nirmatrelvir is coadministered with ritonavir, possible risk of developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection

            COVID-19 rebound

            • May 24, 2022: CDC has issued a health advisory regarding potential for recurrence of COVID-19 or “viral RNA rebound” after case reports documented persons treated with nirmatrelvir/ritonavir and having recovered can experience recurrent illness
            • COVID-19 rebound is characterized by reoccurrence of symptoms or a new positive viral test after having testing negative
            • Currently, there is no evidence that additional treatment is needed for COVID-19 rebound and patient monitoring continues to be the most appropriate management of symptom reoccurrence
            • Persons with COVID-19 rebound should
              • Re-isolate for at least 5 days
              • Per CDC guidance, they can end their re-isolation period after 5 full days if fever has resolved for 24 hr (without use of antipyretics) and symptoms are improving
              • The patient should wear a mask for a total of 10 days after rebound symptoms started
              • Consider clinical evaluation of patients who have COVID-19 rebound and symptoms that persist or worsen
              • Healthcare workers are encouraged to report cases of COVID-19 rebound to after Paxlovid treatment using Pfizer Safety Reporting or FDA MedWatch

            Drug interaction overview

            • Potential for nirmatrelvir and ritonavir to affect other drugs
              • Nirmatrelvir and ritonavir is an inhibitor of CYP3A and may increase drugs primarily metabolized by CYP3A
              • Coadministration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated
            • Potential for other drugs to affect nirmatrelvir and ritonavir
              • Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce therapeutic effect
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            Pregnancy & Lactation

            Pregnancy

            Nirmatrelvir

            • Human data are unavailable on use of nirmatrelvir during pregnancy to evaluate for drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Ritonavir

            • Observational studies on ritonavir use in pregnant females have not identified an increase in the risk of major birth defects
            • Studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage

            Clinical considerations

            • There are maternal and fetal risks (eg, preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death) associated with untreated COVID-19 in pregnancy

            Contraception

            • Use of ritonavir may reduce 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

            Animal data

            • Nirmatrelvir: Reduced fetal body weights following oral administration to pregnant rabbits were observed at systemic exposures (AUC) ~10x higher than clinical exposure at the authorized human dose
            • Ritonavir: No evidence of teratogenicity for rats and rabbits at systemic exposures of ~4x higher than authorized human dose exposure

            Lactation

            Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19

            Nirmatrelvir

            • There are no available data on presence of nirmatrelvir in human or animal milk, effects on breastfed infants, or effects on milk production
            • Transient decrease in body weight observed in nursing offspring of rats administered nirmatrelvir

            Ritonavir

            • Limited published data reports that ritonavir is present in human milk
            • There is no information on effects of ritonavir on breastfed infants or its effects on milk production

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease

            Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, preventing viral replication

            Nirmatrelvir is boosted with low-dose ritonavir that slows nirmatrelvir metabolism via inhibition of CYP3A4, and thereby provides higher systemic exposure

            Absorption

            Peak plasma time (ritonavir): 3.98 hr

            Nirmatrelvir (when given with ritonavir)

            • Peak plasma time: 3 hr
            • Peak plasma concentration: 2.21 mcg/mL
            • AUC: 23.01 mcg⋅hr/mL

            Distribution

            Nirmatrelvir (when given with ritonavir)

            • Protein bound: 69%
            • Vd: 112.4 L

            Ritonavir

            • Protein bound: 98-99%
            • Vd:112.4 L

            Metabolism

            Nirmatrelvir (when given with ritonavir): CYP3A4 substrate, but when given with ritonavir, metabolic clearance is minimal

            Ritonavir: CYP3A4 substrate (major), CYP2D6 (minor), CYP3A4 inhibitor (major)

            Elimination

            Nirmatrelvir (when given with ritonavir)

            • Half-life: 6.05 hr
            • Oral clearance (CL/F): 8.99
            • Excretion: Feces 49.6%; urine 35.3%

            Ritonavir

            • Half-life: 6.15 hr
            • Oral clearance (CL/F): 13.92
            • Excretion: Feces 86.4%; urine 11.3%
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            Administration

            Oral Administration

            Swallowed tablets whole; do not chew, break, or crush

            May take with or without food

            Nirmatrelvir must be coadministered with ritonavir; failure to correctly coadminister may result in plasma levels of nirmatrelvir that are insufficient to achieve desired therapeutic effect

            Missed dose

            • ≤8 hours: Take missed dose as soon as possible, and resume normal dosing schedule
            • >8 hours: Skip dose, and take the next dose at the regularly scheduled time
            • Do not double dose to make up for missed dose

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Images

            No images available for this drug.
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            Patient Handout

            A Patient Handout is not currently available for this monograph.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.