nirmatrelvir/ritonavir (Investigational)

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) 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

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) 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

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 (34)

• adagrasib

  nirmatrelvir/ritonavir will increase the level or effect of adagrasib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of adagrasib, a CYP3A4 substrate, with strong CYP3A4 inhibitors until adagrasib concentrations have reached steady-state (after ~8 days). If steady state is not reached, concomitant use of strong CYP3A4 inhibitors will increase adagrasib concentrations and risk of its toxicities

• 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.

• dofetilide

  nirmatrelvir/ritonavir will increase the level or effect of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration not studied. Dofetilide metabolized to a small degree by CYP3A4. Nirmatrelvir/ritonavir could potentially increase dofetilide exposure.

• elacestrant

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

• 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.

• futibatinib

  nirmatrelvir/ritonavir will increase the level or effect of futibatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of futibatinib with drugs that are dual P-gp and strong CYP3A inhibitors may increase incidence/severity of futibatinib toxicities.

• 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.

• omaveloxolone

  nirmatrelvir/ritonavir will increase the level or effect of omaveloxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unavoidable, reduce omaveloxolone dose to 50 mg/day. Closely monitor and discontinue if adverse effects emerge.

• 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.

• sparsentan

  nirmatrelvir/ritonavir, sparsentan. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. If unavoidable, interrupt treatment with sparsentan. When resuming sparsentan, consider dose titration. .

• 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 (73)

• 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.

• doxazosin

  nirmatrelvir/ritonavir will increase the level or effect of doxazosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased bradycardia, hypotension, or dizziness. If needed, temporarily pause the antihypertensive drug.

• edoxaban

  nirmatrelvir/ritonavir will increase the level or effect of edoxaban by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Coadministration is expected to increase edoxaban concentrations due to P-gp inhibition by ritonavir. Consider temporary edoxaban dose reduction or switching to LWMH. Resume usual edoxaban dose days after 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.

• labetalol

  nirmatrelvir/ritonavir will decrease the level or effect of labetalol by Other (see comment). Use Caution/Monitor. Labetalol undergoes glucuronidation by UGT1A1 and 2B7. Coadministration may decrease labetalol exposure owing to induction of UGT2B7 by ritonavir. Since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment, no dosage modification is needed.

• lenacapavir

  lenacapavir will increase the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.

• 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).

• mirvetuximab soravtansine

  nirmatrelvir/ritonavir will increase the level or effect of mirvetuximab soravtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with strong CYP3A4 inhibitors may increase unconjugated DM4 (a CYP3A4 substrate and the cytotoxic component of the antibody drug conjugate for mirvetuximab soravtansine) exposure, which may increase the risk of adverse reactions.

• 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.

• riociguat

  nirmatrelvir/ritonavir will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Riociguat is metabolized by CYP3A4 and eliminated unchanged in the bile and renally. Consider temporary dose reduction of riociguat and monitor for signs and symptoms of hypotension.

• 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. Limit vardenafil dose to 2.5 mg/72 hr

• venlafaxine

  nirmatrelvir/ritonavir increases levels of venlafaxine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• verapamil

  nirmatrelvir/ritonavir will increase the level or effect of verapamil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased bradycardia, hypotension, or dizziness. If needed, temporarily pause the antihypertensive drug.

• 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.

• zanubrutinib

  nirmatrelvir/ritonavir will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib (a CYP3A4 substrate) to 80 mg PO BID when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous zanubrutinib dose.

• zidovudine

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

Minor (8)

• emtricitabine

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

• irbesartan

  nirmatrelvir/ritonavir will decrease the level or effect of irbesartan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown. Irbesartan metabolized by glucuronidation and oxidation (mainly CYP2C9). Ritonavir is a weak CYP2C9 inducer and could potentially decrease irbesartan exposure. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• losartan

  nirmatrelvir/ritonavir will increase the level or effect of losartan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. Nirmatrelvir/ritonavir could potentially increase the conversion to the more pharmacologically active metabolite.

• macitentan

  nirmatrelvir/ritonavir will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Macitentan is metabolized mainly by CYP3A4, but is not a substrate of OATPs. The magnitude of interaction is expected to be low. No dosage adjustment required.

• mycophenolate

  nirmatrelvir/ritonavir, mycophenolate. Other (see comment). Minor/Significance Unknown. Comment: Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA). MPA undergoes glucuronidation; coadministration of inducers or inhibitors of glucuronidation (eg, ritonavir) could alter mycophenolate levels. .

• sacubitril/valsartan

  nirmatrelvir/ritonavir will increase the level or effect of sacubitril/valsartan by Other (see comment). Minor/Significance Unknown. Valsartan is a substrate of the hepatic uptake transporters OATP1B1 and MRP2. Ritonavir inhibits these transporters. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• sofosbuvir/velpatasvir

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

• valsartan

  nirmatrelvir/ritonavir will increase the level or effect of valsartan by Other (see comment). Minor/Significance Unknown. Valsartan is a substrate of the hepatic uptake transporters OATP1B1 and MRP2. Ritonavir inhibits these transporters. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• abemaciclib

  Monitor Closely (1)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.

• adagrasib

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of adagrasib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of adagrasib, a CYP3A4 substrate, with strong CYP3A4 inhibitors until adagrasib concentrations have reached steady-state (after ~8 days). If steady state is not reached, concomitant use of strong CYP3A4 inhibitors will increase adagrasib concentrations and risk of its toxicities

• alfuzosin

  Contraindicated (1)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.

• aliskiren

  Serious - Use Alternative (1)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.

• alprazolam

  Monitor Closely (1)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

• amiodarone

  Contraindicated (1)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.

• amlodipine

  Monitor Closely (1)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.

• apalutamide

  Contraindicated (1)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.

• apixaban

  Serious - Use Alternative (1)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

• atazanavir

  Monitor Closely (1)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

  Monitor Closely (1)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.

• avanafil

  Serious - Use Alternative (1)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.

• bedaquiline

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• bosentan

  Serious - Use Alternative (1)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.

• budesonide

  Monitor Closely (1)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

  Monitor Closely (1)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.

• carbamazepine

  Contraindicated (1)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.

• ceritinib

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• clopidogrel

  Serious - Use Alternative (1)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.

• clozapine

  Contraindicated (1)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

  Contraindicated (1)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.

• cyclosporine

  Serious - Use Alternative (1)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.

• dabigatran

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• dihydroergotamine

  Contraindicated (1)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.

• diltiazem

  Monitor Closely (1)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.

• dofetilide

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of dofetilide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration not studied. Dofetilide metabolized to a small degree by CYP3A4. Nirmatrelvir/ritonavir could potentially increase dofetilide exposure.

• doxazosin

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of doxazosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased bradycardia, hypotension, or dizziness. If needed, temporarily pause the antihypertensive drug.

• dronedarone

  Contraindicated (1)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.

• edoxaban

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of edoxaban by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Coadministration is expected to increase edoxaban concentrations due to P-gp inhibition by ritonavir. Consider temporary edoxaban dose reduction or switching to LWMH. Resume usual edoxaban dose days after last nirmatrelvir/ritonavir dose.

• efavirenz

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of efavirenz by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• elacestrant

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of elacestrant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• elbasvir/grazoprevir

  Serious - Use Alternative (1)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.

• eletriptan

  Contraindicated (1)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.

• emtricitabine

  Minor (1)nirmatrelvir/ritonavir will increase the level or effect of emtricitabine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• encorafenib

  Serious - Use Alternative (1)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).

• enzalutamide

  Contraindicated (1)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

  Contraindicated (1)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

  Contraindicated (1)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.

• erythromycin base

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• everolimus

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• felodipine

  Monitor Closely (1)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

  Monitor Closely (1)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.

• finerenone

  Contraindicated (1)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

  Contraindicated (1)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

  Contraindicated (1)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.

• fluticasone furoate

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• fosphenytoin

  Contraindicated (1)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.

• futibatinib

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of futibatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of futibatinib with drugs that are dual P-gp and strong CYP3A inhibitors may increase incidence/severity of futibatinib toxicities.

• glecaprevir/pibrentasvir

  Serious - Use Alternative (1)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.

• hydrocodone

  Monitor Closely (1)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.

• ibrutinib

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of ibrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• indinavir

  Monitor Closely (1)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.

• irbesartan

  Minor (1)nirmatrelvir/ritonavir will decrease the level or effect of irbesartan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown. Irbesartan metabolized by glucuronidation and oxidation (mainly CYP2C9). Ritonavir is a weak CYP2C9 inducer and could potentially decrease irbesartan exposure. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• isavuconazonium sulfate

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• itraconazole

  Monitor Closely (1)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.

• ivabradine

  Contraindicated (1)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.

• ivacaftor

  Monitor Closely (1)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.

• ivosidenib

  Serious - Use Alternative (1)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).

• ketoconazole

  Monitor Closely (1)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.

• labetalol

  Monitor Closely (1)nirmatrelvir/ritonavir will decrease the level or effect of labetalol by Other (see comment). Use Caution/Monitor. Labetalol undergoes glucuronidation by UGT1A1 and 2B7. Coadministration may decrease labetalol exposure owing to induction of UGT2B7 by ritonavir. Since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment, no dosage modification is needed.

• lenacapavir

  Monitor Closely (1)lenacapavir will increase the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.

• levoketoconazole

  Monitor Closely (1)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

  Monitor Closely (1)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.

• lomitapide

  Contraindicated (1)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.

• losartan

  Minor (1)nirmatrelvir/ritonavir will increase the level or effect of losartan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. Nirmatrelvir/ritonavir could potentially increase the conversion to the more pharmacologically active metabolite.

• lovastatin

  Contraindicated (1)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

  Contraindicated (1)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.

• lumateperone

  Monitor Closely (1)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.

• lurasidone

  Contraindicated (1)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.

• macitentan

  Minor (1)nirmatrelvir/ritonavir will increase the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Macitentan is metabolized mainly by CYP3A4, but is not a substrate of OATPs. The magnitude of interaction is expected to be low. No dosage adjustment required.

• maraviroc

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• mavacamten

  Contraindicated (1)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

  Contraindicated (1)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.

• methadone

  Monitor Closely (1)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.

• methylergonovine

  Contraindicated (1)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.

• methylprednisolone

  Monitor Closely (1)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).

• midazolam

  Contraindicated (1)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.

• mirvetuximab soravtansine

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of mirvetuximab soravtansine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with strong CYP3A4 inhibitors may increase unconjugated DM4 (a CYP3A4 substrate and the cytotoxic component of the antibody drug conjugate for mirvetuximab soravtansine) exposure, which may increase the risk of adverse reactions.

• mitotane

  Contraindicated (1)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.

• mometasone inhaled

  Monitor Closely (1)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).

• mycophenolate

  Minor (1)nirmatrelvir/ritonavir, mycophenolate. Other (see comment). Minor/Significance Unknown. Comment: Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA). MPA undergoes glucuronidation; coadministration of inducers or inhibitors of glucuronidation (eg, ritonavir) could alter mycophenolate levels. .

• naloxegol

  Contraindicated (1)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.

• nelfinavir

  Monitor Closely (1)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.

• neratinib

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• nevirapine

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of nevirapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nicardipine

  Monitor Closely (1)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

  Monitor Closely (1)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.

• nilotinib

  Serious - Use Alternative (1)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.

• omaveloxolone

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of omaveloxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unavoidable, reduce omaveloxolone dose to 50 mg/day. Closely monitor and discontinue if adverse effects emerge.

• oxycodone

  Monitor Closely (1)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.

• phenobarbital

  Contraindicated (1)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

  Contraindicated (1)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

  Contraindicated (1)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

  Contraindicated (1)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.

• prednisone

  Monitor Closely (1)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).

• primidone

  Contraindicated (1)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

  Contraindicated (1)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.

• quetiapine

  Monitor Closely (1)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.

• quinidine

  Contraindicated (1)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.

• raltegravir

  Monitor Closely (1)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.

• ranolazine

  Contraindicated (1)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.

• rifabutin

  Monitor Closely (1)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.

• rifampin

  Contraindicated (1)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.

• rifapentine

  Serious - Use Alternative (1)rifapentine will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• rimegepant

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• riociguat

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Riociguat is metabolized by CYP3A4 and eliminated unchanged in the bile and renally. Consider temporary dose reduction of riociguat and monitor for signs and symptoms of hypotension.

• rivaroxaban

  Serious - Use Alternative (1)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.

• rosuvastatin

  Monitor Closely (1)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.

• sacubitril/valsartan

  Minor (1)nirmatrelvir/ritonavir will increase the level or effect of sacubitril/valsartan by Other (see comment). Minor/Significance Unknown. Valsartan is a substrate of the hepatic uptake transporters OATP1B1 and MRP2. Ritonavir inhibits these transporters. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• salmeterol

  Serious - Use Alternative (1)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.

• saquinavir

  Monitor Closely (1)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.

• sildenafil

  Contraindicated (1)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

  Contraindicated (1)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

  Contraindicated (1)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.

• sirolimus

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• sofosbuvir/velpatasvir

  Minor (1)nirmatrelvir/ritonavir will decrease the level or effect of sofosbuvir/velpatasvir by affecting hepatic enzyme CYP2B6 metabolism. Minor/Significance Unknown.

• sparsentan

  Serious - Use Alternative (1)nirmatrelvir/ritonavir, sparsentan. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. If unavoidable, interrupt treatment with sparsentan. When resuming sparsentan, consider dose titration. .

• St John's Wort

  Contraindicated (1)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.

• suvorexant

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of suvorexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tacrolimus

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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.

• tenofovir AF

  Monitor Closely (1)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.

• ticagrelor

  Serious - Use Alternative (1)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.

• tipranavir

  Monitor Closely (1)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.

• tolvaptan

  Contraindicated (1)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.

• trazodone

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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).

• triazolam

  Contraindicated (1)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

  Contraindicated (1)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.

• valsartan

  Minor (1)nirmatrelvir/ritonavir will increase the level or effect of valsartan by Other (see comment). Minor/Significance Unknown. Valsartan is a substrate of the hepatic uptake transporters OATP1B1 and MRP2. Ritonavir inhibits these transporters. No dosage modification needed since induction reaches maximal effect after several days and the short duration of nirmatrelvir/ritonavir treatment.

• vardenafil

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of vardenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit vardenafil dose to 2.5 mg/72 hr

• venetoclax

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• venlafaxine

  Monitor Closely (1)nirmatrelvir/ritonavir increases levels of venlafaxine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

• verapamil

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of verapamil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for increased bradycardia, hypotension, or dizziness. If needed, temporarily pause the antihypertensive drug.

• vinblastine

  Monitor Closely (1)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

  Monitor Closely (1)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.

• voclosporin

  Contraindicated (1)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.

• vorapaxar

  Serious - Use Alternative (1)nirmatrelvir/ritonavir will increase the level or effect of vorapaxar by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• voriconazole

  Serious - Use Alternative (1)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.

• voxilaprevir

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• warfarin

  Monitor Closely (1)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.

• zanubrutinib

  Monitor Closely (1)nirmatrelvir/ritonavir will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib (a CYP3A4 substrate) to 80 mg PO BID when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous zanubrutinib dose.

• zidovudine

  Monitor Closely (1)nirmatrelvir/ritonavir will decrease the level or effect of zidovudine by unknown mechanism. Use Caution/Monitor.