Dosing & Uses
Dosage Forms & Strengths
tablets
- Copackaged as nirmatrelvir 150mg and ritonavir 100mg tablets
COVID-19 Disease Treatment (EUA)
December 22, 2021: Emergency use authorization issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (aged ≥12 years and weight ≥40 kg) testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and who are at high risk for progression to severe COVID-19, including hospitalization or death
300 mg nirmatrelvir plus 100 mg ritonavir PO BID x 5 days
Initiate as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset
Completing the full 5-day treatment course and isolate in accordance with public health recommendations are important to maximize viral clearance and minimize viral transmission
If patient is hospitalized due to severe or critical COVID-19 after starting treatment with nirmatrelvir/ritonavir, completion of the full 5-day treatment is at the healthcare provider’s discretion
Dosage Modifications
Renal impairment
- Mild (eGFR ≥60 to <90 mL/min): No dosage adjustment required
- Moderate (eGFR ≥30 to <60 mL/min): Decrease to 150 mg nirmatrelvir plus 100 mg ritonavir BID x 5 days
- Severe (eGFR <30 mL/min): Not recommended; data are unavailable
Hepatic impairment
- Mild or moderate (Child-Pugh Class A or B): No dosage adjustment required
- Severe (Child-Pugh Class C): Not recommended; data are unavailable
Dosing Considerations
Limitations of use
- Not authorized for initiation of treatment in patients requiring hospitalization owing to severe or critical COVID-19
- Not authorized for preexposure or postexposure prophylaxis for prevention of COVID-19
- Not authorized for >5 consecutive days
Dosage Forms & Strengths
tablets
- Copackaged as nirmatrelvir 150mg and ritonavir 100mg tablets
COVID-19 Disease Treatment (EUA)
December 22, 2021: Emergency use authorization issued for treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (aged ≥12 years and weight ≥40 kg) testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, and who are at high risk for progression to severe COVID-19, including hospitalization or death
<12 years: Safety and efficacy not established
300 mg nirmatrelvir plus 100 mg ritonavir PO BID x 5 days
Initiate as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset
Completing the full 5-day treatment course and isolate in accordance with public health recommendations are important to maximize viral clearance and minimize viral transmission
If patient is hospitalized due to severe or critical COVID-19 after starting treatment with nirmatrelvir/ritonavir, completion of the full 5-day treatment is at the healthcare provider’s discretion
Dosage Modifications
Renal impairment
- Mild (eGFR ≥60 to <90 mL/min): No dosage adjustment required
- Moderate (eGFR ≥30 to <60 mL/min): Decrease to 150 mg nirmatrelvir plus 100 mg ritonavir BID x 5 days
- Severe (eGFR <30 mL/min): Not recommended; data are unavailable
Hepatic impairment
- Mild or moderate (Child-Pugh Class A or B): No dosage adjustment required
- Severe (Child-Pugh C): Not recommended; data are unavailable
Dosing Considerations
Limitations of use
- Not authorized for initiation of treatment in patients requiring hospitalization owing to severe or critical COVID-19
- Not authorized for preexposure or postexposure prophylaxis for prevention of COVID-19
- Not authorized for >5 consecutive days
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (33)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
- 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.
- 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. 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.
- 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.
- 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.
- 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.
Serious - Use Alternative (16)
- 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.
- cyclosporine
nirmatrelvir/ritonavir will increase the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid, monitor cyclosporine serum concentration and temporarily decrease dose or alter dose frequency.
- elbasvir/grazoprevir
nirmatrelvir/ritonavir will increase the level or effect of elbasvir/grazoprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Increased grazoprevir concentrations can result in ALT elevations.
- encorafenib
nirmatrelvir/ritonavir will increase the level or effect of encorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration owing to potential risk of serious adverse events (eg, QT interval prolongation).
- 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.
- 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.
- 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.
- venetoclax
nirmatrelvir/ritonavir will increase the level or effect of venetoclax 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 (58)
- 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.
- 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. Buproion 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.
- 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. Use Caution/Monitor. May consider temporary diltiazem dose reduction.
- 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. Use Caution/Monitor. May consider temporary felodipine dose reduction.
- 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.
- 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.
- ketoconazole
nirmatrelvir/ritonavir will increase the level or effect of ketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit ketoconazole adult dose to 200 mg/day if coadministered with ritonavir.
- levoketoconazole
nirmatrelvir/ritonavir will increase the level or effect of levoketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Limit ketoconazole adult dose to 200 mg/day if coadministered with ritonavir.
- lidocaine
nirmatrelvir/ritonavir will increase the level or effect of lidocaine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Caution warranted. Monitor lidocaine therapeutic concentrations if available.
- lumateperone
nirmatrelvir/ritonavir will increase the level or effect of lumateperone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce lumateperone dose to 10.5 mg/day if coadministered with strong CYP3A4 inhibitors.
- maraviroc
nirmatrelvir/ritonavir will increase the level or effect of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- methadone
nirmatrelvir/ritonavir will decrease the level or effect of methadone by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Methadone is metabolized by CYP2B6 and CYP3A4. Ritonavir may decrease AUC and peak plasma concentration by CYP2B6 induction. This may be partially offset by ritonavir inhibiting CYP3A4.
- methylprednisolone
nirmatrelvir/ritonavir will increase the level or effect of methylprednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).
- mometasone inhaled
nirmatrelvir/ritonavir will increase the level or effect of mometasone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).
- nelfinavir
nirmatrelvir/ritonavir will increase the level or effect of nelfinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.
- nicardipine
nirmatrelvir/ritonavir will increase the level or effect of nicardipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May consider temporary nicardipine dose reduction.
- nifedipine
nirmatrelvir/ritonavir will increase the level or effect of nifedipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May consider temporary nifedipine dose reduction.
- prednisone
nirmatrelvir/ritonavir will increase the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may increase certain systemic corticosteroid concentrations. Increased risk for Cushing syndrome and adrenal suppression. Consider alternant corticosteroids, including beclomethasone and prednisolone).
- quetiapine
nirmatrelvir/ritonavir will increase the level or effect of quetiapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce quetiapine dose to one-sixth when coadministered with strong CYP3A4 inhibitors.
- raltegravir
nirmatrelvir/ritonavir will decrease the level or effect of raltegravir by Other (see comment). Use Caution/Monitor. Raltegravir is an UGT1A1 substrate. Ritonavir induces UGT 1A1.
- rifabutin
nirmatrelvir/ritonavir will increase the level or effect of rifabutin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitored closely for rifabutin adverse effects, including neutropenia and uveitis. Ritonavir prescribing information recommends reducing rifabutin doses by at least 75% to 150 mg every other day, or 3 times weekly, when coadministered with ritonavir.
- rosuvastatin
nirmatrelvir/ritonavir will increase the level or effect of rosuvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider temporary discontinuation of rosuvastatin during treatment with nirmatrelvir/ritonavir.
- saquinavir
nirmatrelvir/ritonavir will increase the level or effect of saquinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased nirmatrelvir/ritonavir or protease inhibitor adverse events with concomitant use.
- sofosbuvir/velpatasvir
nirmatrelvir/ritonavir will increase the level or effect of sofosbuvir/velpatasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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).
- vinblastine
nirmatrelvir/ritonavir will increase the level or effect of vinblastine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may lead to significant hematologic or gastrointestinal side effects.
- vincristine
nirmatrelvir/ritonavir will increase the level or effect of vincristine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration may lead to significant hematologic or gastrointestinal side effects.
- voxilaprevir
nirmatrelvir/ritonavir will increase the level or effect of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- warfarin
nirmatrelvir/ritonavir will increase the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. INR may increase or decrease. Closely monitor INR if nirmatrelvir/ritonavir is coadministered with warfarin.
- zidovudine
nirmatrelvir/ritonavir will decrease the level or effect of zidovudine by unknown mechanism. Use Caution/Monitor.
Minor (0)
Adverse Effects
1-10%
Dysgeusia (6%)
Diarrhea (3%)
Hypertension (1%)
Myalgia (1%)
Require reporting for serious adverse events and medication errors
Prescribers and/or the provider’s designee are/is responsible for mandatory reporting of all serious adverse events and medication errors potentially drug-related within 7 calendar days from the onset of the event
Serious adverse events are defined as
- Death or life-threatening adverse event;
- Medical or surgical intervention to prevent death, life-threatening event, hospitalization, disability, or congenital anomaly;
- Inpatient hospitalization or prolongation of existing hospitalization;
- Persistent or significant incapacity or substantial disruption of ability to conduct normal life functions; or
- Congenital anomaly/birth defect
FDA recommends that such reports, use FDA Form 3500
Warnings
Contraindications
History of clinically significant hypersensitivity to nirmatrelvir or ritonavir
Drug highly dependent on CYP3A for clearance
- Alpha1-adrenoreceptor antagonist: Alfuzosin
- Analgesics: Pethidine, piroxicam, propoxyphene
- Antianginal: Ranolazine
- Antiarrhythmic: Amiodarone, dronedarone, flecainide, propafenone, quinidine
- Antigout: Colchicine
- Antipsychotics: Lurasidone, pimozide, clozapine
- Ergot derivatives: Dihydroergotamine, ergotamine, methylergonovine
- HMG-CoA reductase inhibitors: Lovastatin, simvastatin
- PDE5 inhibitor: Sildenafil (Revatio) when used for pulmonary arterial hypertension (PAH)
- Sedative/hypnotics: Triazolam, oral midazolam
Drugs that are potent CYP3A inducers
- Anticancer drugs: Apalutamide
- Anticonvulsant: Carbamazepine, phenobarbital, phenytoin
- Antimycobacterials: Rifampin
- Herbal products: St. John’s Wort (hypericum perforatum)
Cautions
Hepatic transaminase elevations, clinical hepatitis, and jaundice reported with ritonavir; caution when administering to patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis
Because nirmatrelvir is coadministered with ritonavir, possible risk of developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection
Drug interaction overview
-
Potential for nirmatrelvir and ritonavir to affect other drugs
- Nirmatrelvir and ritonavir is an inhibitor of CYP3A and may increase drugs primarily metabolized by CYP3A
- Coadministration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated
-
Potential for other drugs to affect nirmatrelvir and ritonavir
- Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce therapeutic effect
Pregnancy & Lactation
Pregnancy
Nirmatrelvir
- Human data are unavailable on use of nirmatrelvir during pregnancy to evaluate for drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Ritonavir
- Observational studies on ritonavir use in pregnant females have not identified an increase in the risk of major birth defects
- Studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage
Clinical considerations
- There are maternal and fetal risks (eg, preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death) associated with untreated COVID-19 in pregnancy
Contraception
- Use of ritonavir may reduce efficacy of combined hormonal contraceptives
- Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception
Animal data
- Nirmatrelvir: Reduced fetal body weights following oral administration to pregnant rabbits were observed at systemic exposures (AUC) ~10x higher than clinical exposure at the authorized human dose
- Ritonavir: No evidence of teratogenicity for rats and rabbits at systemic exposures of ~4x higher than authorized human dose exposure
Lactation
Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19
Nirmatrelvir
- There are no available data on presence of nirmatrelvir in human or animal milk, effects on breastfed infants, or effects on milk production
- Transient decrease in body weight observed in nursing offspring of rats administered nirmatrelvir
Ritonavir
- Limited published data reports that ritonavir is present in human milk
- There is no information on effects of ritonavir on breastfed infants or its effects on milk production
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease
Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, preventing viral replication
Nirmatrelvir is boosted with low-dose ritonavir that slows nirmatrelvir metabolism via inhibition of CYP3A4, and thereby provides higher systemic exposure
Absorption
Peak plasma time (ritonavir): 3.98 hr
Nirmatrelvir (when given with ritonavir)
- Peak plasma time: 3 hr
- Peak plasma concentration: 2.21 mcg/mL
- AUC: 23.01 mcg⋅hr/mL
Distribution
Nirmatrelvir (when given with ritonavir)
- Protein bound: 69%
- Vd: 112.4 L
Ritonavir
- Protein bound: 98-99%
- Vd:112.4 L
Metabolism
Nirmatrelvir (when given with ritonavir): CYP3A4 substrate, but when given with ritonavir, metabolic clearance is minimal
Ritonavir: CYP3A4 substrate (major), CYP2D6 (minor), CYP3A4 inhibitor (major)
Elimination
Nirmatrelvir (when given with ritonavir)
- Half-life: 6.05 hr
- Oral clearance (CL/F): 8.99
- Excretion: Feces 49.6%; urine 35.3%
Ritonavir
- Half-life: 6.15 hr
- Oral clearance (CL/F): 13.92
- Excretion: Feces 86.4%; urine 11.3%
Administration
Oral Administration
Swallowed tablets whole; do not chew, break, or crush
May take with or without food
Nirmatrelvir must be coadministered with ritonavir; failure to correctly coadminister may result in plasma levels of nirmatrelvir that are insufficient to achieve desired therapeutic effect
Missed dose
- ≤8 hours: Take missed dose as soon as possible, and resume normal dosing schedule
- >8 hours: Skip dose, and take the next dose at the regularly scheduled time
- Do not double dose to make up for missed dose
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
