PAXLOVID 9 Drug Interactions | Pfizer Medical Information

9.1 Serious Drug Interactions

Serious Drug Interactions

Initiation of PAXLOVID, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A.

Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PAXLOVID, respectively. These interactions may lead to:

Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of PAXLOVID.
Loss of therapeutic effect of PAXLOVID and possible development of viral resistance.

See Table 4 for clinically significant drug interactions, including contraindicated drugs. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

9.2 Drug Interactions Overview

Potential for PAXLOVID to Affect Other Drugs

PAXLOVID is a strong inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Co-administration of PAXLOVID 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 (see 2 CONTRAINDICATIONS). Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 4.

Potential for Ritonavir to Affect Other Drugs

Ritonavir is an inhibitor of cytochrome CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Drugs that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir 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. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 4.

Ritonavir inhibits CYP2D6 and co-administration of CYP2D6 substrates with ritonavir could result in increases (up to 2-fold) in the AUC of the former, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as glucuronosyl transferase. Therefore, decreased plasma concentrations of the co-administered drugs and potential loss of therapeutic effects may signify the need for dosage alteration of these agents.

When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted (see Table 4).

Potential for Other Drugs to Affect PAXLOVID

Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce the therapeutic effect of PAXLOVID.

9.4 Drug-Drug Interactions

Established or Potentially Significant Drug Interactions

Table 4 provides listing of clinically significant drug interactions, including contraindicated drugs. The drugs listed in Table 4 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. Table 5 summarizes the effects of co-administration of PAXLOVID with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and C_max.

Table 4 - Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of PAXLOVID or Concomitant Drug		Clinical Comment
a. Product not marketed in Canada. ↑ Indicates increase; ↓ indicates decrease; ↔ indicates no change.
Alpha1-adrenoreceptor Antagonist:
alfuzosin	↑ alfuzosin		Based on results of a drug interaction study with ketoconazole, another potent inhibitor of CYP3A4, a significant increase in alfuzosin exposure is expected in the presence of ritonavir (600 mg twice daily). Therefore, alfuzosin is contraindicated with PAXLOVID (see 2 CONTRAINDICATIONS).
tamsulosin	↑tamsulosin		Avoid concomitant use with PAXLOVID.
Analgesics, Narcotic:
fentanyl, hydrocodone, oxycodone, meperidine,	↑fentanyl ↑hydrocodone ↑oxycodone ↑meperidine		Ritonavir inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of fentanyl, tramadol, and propoxyphene. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl, hydrocodone, oxycodone, or meperidine is concomitantly administered with PAXLOVID. If concomitant use with PAXLOVID is necessary, consider a dosage reduction of the narcotic analgesic and monitor patients closely at frequent intervals. Refer to the individual product label for more information.
tramadol propoxyphene^a	↑tramadol ↑propoxyphene		Use tramadol and propoxyphene with caution, dose reduction of these drugs may be needed.
methadone	↓methadone		Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Dosage increase of methadone may be considered.
Anesthetic:
meperidine	↓ meperidine ↑ normeperidine (metabolite)		Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antianginal:
ranolazine		↑ ranolazine	Co-administration contraindicated due to potential for serious and/or life threatening reactions (see 2 CONTRAINDICATIONS).
Antiarrhythmics:
disopyramide, lidocaine (systemic), mexiletine	↑ antiarrhythmics		Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
amiodarone, bepridil^a, dronedarone, flecainide, propafenone, quinidine^a	↑ antiarrhythmics		Co-administration may lead to serious and/or life-threatening reactions, such as cardiac arrhythmias. Therefore, use of these antiarrhythmics with PAXLOVID is contraindicated (see 2 CONTRAINDICATIONS).
Antibacterial:
fusidic acid	↑ fusidic acid ↑ ritonavir		Coadministration of protease inhibitors, including ritonavir with fusidic acid is expected to increase fusidic acid, as well as the protease inhibitor concentration in plasma (see 2 CONTRAINDICATIONS).
Anticancer agents:
apalutamide	↓nirmatrelvir/ritonavir		Co-administration is contraindicated (see 2 CONTRAINDICATIONS).
abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, vincristine, vinblastine	↑ anticancer agents		Serum concentrations increase when co-administered with ritonavir resulting in the potential for increased incidence of adverse events, some of which may be serious. Coadministration of ritonavir with ibrutinib is not recommended due to expected increase in ibrutinib exposure that could potentially result in a risk of tumor lysis syndrome. Coadministration of ritonavir with dasatinib should be avoided due to expected increase in dasatinib exposure. If the co-administration is unavoidable, close monitoring for toxicity and a dasatinib dose reduction should be considered (see SPRYCEL Product Monograph). Coadministration of encorafenib or ivosidenib with ritonavir should be avoided due to potential risk of serious adverse events such as QT interval prolongation. If coadministration cannot be avoided, modify encorafenib dose as recommended in the encorafenib Product Monograph. Coadministration of ritonavir with nilotinib should be avoided due to expected increase in nilotinib exposure. If the co-administration is unavoidable, close monitoring for the QT interval prolongation is recommended (see TASIGNA Product Monograph). Coadministration of ritonavir with abemaciclib should be avoided due to expected increase in abemaciclib exposure. If the co-administration is unavoidable, close monitoring for toxicity and abemaciclib dose reduction should be considered (see VERZENIO Product Monograph). Coadministration of ritonavir with neratinib is contraindicated due to expected increase in neratinib exposure (see 2 CONTRAINDICATIONS). Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects.
venetoclax	↑ venetoclax		Concomitant use of strong CYP3A inhibitors, such as ritonavir, and venetoclax may increase the risk of tumor lysis syndrome at the dose initiation and during the ramp-up phase (see 2 CONTRAINDICATIONS). For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (see VENCLEXTA Product Monograph).
Anticoagulants:
apixaban	↑apixaban		Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban and increase the risk of bleeding. Dosing recommendations for co-administration of apixaban with PAXLOVID depend on the apixaban dose. Refer to the apixaban product label for more information.
dabigatran	↑ dabigatran		Co-administration with PAXLOVID results in increased dabigatran exposure and an increased risk of bleeding. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran product label for further information.
rivaroxaban	↑ rivaroxaban		A study has shown that co-administration of ritonavir and rivaroxaban resulted in increased exposure of rivaroxaban which may lead to risk of increased bleeding. Co-administration of PAXLOVID and rivaroxaban is contraindicated (see 2 CONTRAINDICATIONS).
warfarin	↓ R-warfarin ↓ ↑ S-warfarin		Initial frequent monitoring of the INR (International Normalized Ratio) during ritonavir and warfarin co-administration is indicated.
Anticonvulsants:
clonazepam ethosuximide divalproex lamotrigine	↑ clonazepam ↑ ethosuximide ↓ divalproex ↓ lamotrigine		Plasma concentrations of clonazepam and ethosuximide are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed and clinical monitoring is recommended. Plasma concentrations of divalproex and lamotrigine are expected to decrease by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose increase of these drugs may be needed.
carbamazepine, phenobarbital, phenytoin, primidone,	↑ carbamazepine ↓ phenytoin ↓nirmatrelvir/ ritonavir		Co-administration of PAXLOVID with carbamazepine, phenobarbital, phenytoin or primidone is contraindicated (see 2 CONTRAINDICATIONS)
Antidepressants:
amitriptyline, clomipramine, fluoxetine, imipramine, maprotiline^a, nefazodone^a, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine,	↑ antidepressants		Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
bupropion	↓ bupropion and active metabolite hydroxy bupropion		Bupropion is primarily metabolized by CYP2B6. Concurrent administration of bupropion with repeated doses of ritonavir decreases bupropion levels. Monitor for an adequate clinical response to bupropion.
desipramine	↑ desipramine		A study has shown that co-administration of ritonavir and desipramine resulted in increased exposure of desipramine. Dosage reduction and concentration monitoring of desipramine is recommended.
trazodone	↑ trazodone		Concomitant use of ritonavir and trazodone increases concentrations of trazodone. Adverse events of nausea, dizziness, hypertension, and syncope have been observed. If trazodone is used with a CYP3A4 inhibitor, such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetics:
dronabinol^a	↑ dronabinol		Plasma concentrations of dronabinol are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of dronabinol may be needed.
Antifungal:
ketoconazole, isavuconazonium sulfate, itraconazole	↑ ketoconazole ↑isavuconazonium sulfate ↑ itraconazole ↑nirmatrelvir/ ritonavir		High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended. Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information.
voriconazole	↓voriconazole		Avoid concomitant use of voriconazole.
Antigout:
colchicine	↑ colchicine		For patients with renal and/or hepatic impairment: Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and ritonavir. For patients with renal and/or hepatic impairment co-administration of colchicine with PAXLOVID is contraindicated (see 2 CONTRAINDICATION). For patients with normal renal and/or hepatic function: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original colchicine regimen was 0.6 mg twice daily, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.3 mg twice daily, the regimen should be adjusted to 0.3 mg once every other day. Treatment of Familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin erythromycin	↑ clarithromycin ↑erythromycin		For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR < 30 mL/min the dose of clarithromycin should be reduced by 75%. No dose adjustment for patients with normal renal function is necessary. Refer to the respective prescribing information for anti-infective dose adjustment.
Antimycobacterial:
rifabutin	↑ rifabutin and rifabutin metabolite ↓ ritonavir		Dosage reduction of rifabutin by at least three- quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or 3 times a week). Further dosage reduction may be necessary.
rifampin	↓ ritonavir ↓nirmatrelvir		Co-administration of PAXLOVID with rifampin is contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered (see 2 CONTRAINDICATIONS).
Antiparasitics:
atovaquone	↓ atovaquone		Plasma concentrations of atovaquone are expected to decrease by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose increase of atovaquone may be needed.
quinine	↑ quinine		Plasma concentrations of quinine are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of quinine may be needed.
Anxiolytics/Sedative/Hypnotics:
triazolam midazolam oral^a	↑triazolam ↑ midazolam		Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Co-administration contraindicated due to potential for extreme sedation and respiratory depression (see 2 CONTRAINDICATIONS).
midazolam parenteral	↑ midazolam		Concomitant use of parenteral midazolam with ritonavir may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
buspirone, clorazepate, diazepam, estazolam^a, flurazepam, zolpidem	↑Anxiolytics/Sedatives/ Hypnotics		Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
Benign prostatic hyperplasia agents
silodosin	↑silodosin		Co-administration contraindicated due to potential for postural hypotension (see 2 CONTRAINDICATIONS).
Beta-blockers:
metoprolol, timolol	↑ beta-blockers		Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
Bronchodilator:
theophylline	↓ theophylline		Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil	↑ calcium channel blockers		Plasma concentrations of these drugs are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
Cardiovascular agents
eplerenone	↑ eplerenone		Co-administration with eplerenone is contraindicated due to potential for hyperkalemia (see 2 CONTRAINDICATIONS).
ivabradine	↑ ivabradine		Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances (see 2 CONTRAINDICATIONS).
aliskiren^a, ticagrelor, vorapaxar, clopidogrel	↑ aliskiren ↑ ticagrelor ↑ vorapaxar ↓ clopidogrel active metabolite		Avoid concomitant use with PAXLOVID.
Corticosteroids:
budesonide, fluticasone propionate, triamcinolone	↑ fluticasone ↑ budesonide ↑ triamcinolone		Concomitant use of ritonavir and inhaled, injectable, or intranasal fluticasone propionate, budesonide, triamcinolone, or other glucocorticoids that are metabolized by CYP3A4 are not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects, including Cushing’s syndrome and adrenal suppression. Concomitant use of ritonavir and fluticasone propionate, budesonide or triamcinolone can significantly increase fluticasone propionate, budesonide or triamcinolone plasma concentrations and reduce serum cortisol concentrations. Consider alternatives to fluticasone propionate, budesonide, or triamcinolone particularly for long-term use.
dexamethasone prednisone	↑dexamethasone ↓ ritonavir ↑ prednisone		Dexamethasone, which increases CYP3A activity, would be expected to increase the clearance of ritonavir resulting in decreased ritonavir plasma concentrations. Plasma concentrations of dexamethasone and prednisone are expected to increase by co-administration with ritonavir. Therefore, PAXLOVID should be used with caution, dose adjustment of these drugs may be needed.
digoxin	↑ digoxin		A literature report has shown that co-administration of ritonavir (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administrating ritonavir and digoxin, with appropriate monitoring of serum levels.
Cystic fibrosis transmembrane conductance regulator potentiators:
lumacaftor/ivacaftor	↓nirmatrelvir/ritonavir		Co-administration contraindicated due to potential loss of virologic response and possible resistance (see 2 CONTRAINDICATIONS).
ivacaftor	↑ivacaftor		Reduce dosage when co-administered with PAXLOVID. Refer to individual product labels for more information.
elexacaftor/ tezacaftor/ivacaftor	↑elexacaftor/ tezacaftor/ivacaftor
tezacaftor/ivacaftor	↑tezacaftor/ivacaftor
Dipeptidyl peptidase 4 (DPP4) inhibitors:
saxagliptin	↑saxagliptin		Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin product label for more information.
Endothelin receptor antagonist:
bosentan	↑ bosentan		Discontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID. Refer to the bosentan product label for further information.
Ergot derivatives:
dihydroergotamine, ergotamine, methylergonovine^a	↑dihydroergotamine ↑ergotamine ↑methylergonovine		Co-administration contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system (see 2 CONTRAINDICATIONS).
Gonadotropin releasing hormone (GnRH) receptor antagonist
elagolix	↑ elagolix		Coadministration of elagolix with ritonavir could increase elagolix exposure due to inhibition of CYP3A and P-gp. Known serious adverse events for elagolix include suicidal ideation and hepatic transaminase elevations. In addition, elagolix is a weak/moderate inducer of CYP3A, which may decrease exposure of ritonavir. Refer to the elagolix label for dosing information with strong CYP3A4 inhibitors.
*HCV-Antiviral Agents*
HCV Combination Drug:
elbasvir/grazoprevir, glecaprevir/pibrentasvir ombitasvir/paritaprevir/ ritonavir with or without dasabuvir^a sofosbuvir/velpatasvir/voxilaprevir	↑antiviral		Increased grazoprevir concentrations can result in ALT elevations. Coadministration with ritonavir is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure. Avoid concomitant use of glecaprevir/pibrentasvir with PAXLOVID. Refer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information. Refer to the sofosbuvir/velpatasvir/voxilaprevir product label for further information. Patients on ritonavir-containing HCV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or HCV drug adverse events with concomitant use.
HCV Protease Inhibitors:
simeprevir^a	↑ simeprevir		A pharmacokinetic study demonstrated that concomitant administration of simeprevir 200 mg once daily with ritonavir 100 mg twice daily resulted in an increase in simeprevir concentrations. It is not recommended to co-administer PAXLOVID with simeprevir.
Herbal products
St. John’s Wort (hypericum perforatum)	↓nirmatrelvir/ ritonavir		Co-administration contraindicated due to potential loss of virologic response and possible resistance use (see 2 CONTRAINDICATIONS).
*HIV-Antiretroviral* *Agents*
HIV Protease Inhibitors:
fosamprenavir	↑ amprenavir (↑ AUC, ↑ C_max, ↑ C_min)		Refer to the fosamprenavir Product Monograph for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily or fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily.
atazanavir	↑ atazanavir (↑ AUC, ↑ C_max, ↑ C_min)		Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. Refer to the atazanavir Product Monograph for details on co-administration of atazanavir 300 mg once daily, with ritonavir 100 mg once daily.
darunavir	↑ darunavir (↑ AUC, ↑ C_max, ↑ C_min)		Refer to the darunavir Product Monograph for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily.
indinavir^a	↑ indinavir (↑ AUC, ↑ C_max, ↑ C_min)		Alterations in concentrations are noted when reduced doses of indinavir are co-administered with reduced dose of ritonavir. The safety and efficacy of this combination have not yet been established. The risk of nephrolithiasis may be increased when doses of indinavir equal to or greater than 800 mg twice daily are given with ritonavir. Adequate hydration and monitoring of the patients is warranted.
nelfinavir	↑ M8 (major active metabolite of nelfinavir)		Ritonavir increases the concentrations of nelfinavir major active metabolite, M8. This interaction is likely to involve cytochrome P450 inhibition and induction.
saquinavir	↑ saquinavir (↑ AUC, ↑ C_max, ↑ C_min)		The recommended dosage regimen is saquinavir 1000 mg with ritonavir 100 mg twice daily taken within 2 hours after a meal. Dose adjustment may be needed if other HIV-protease inhibitors are used in combination with saquinavir and ritonavir. Saquinavir and ritonavir should not be given together with rifampin due to risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the 3 drugs are given together. In some cases, co-administration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis, and liver disorders, especially in patients with pre- existing liver disease. Refer to the saquinavir Product Monograph for prescribing information.
tipranavir	↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin)		Refer to the tipranavir Product Monograph for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily.
Nucleoside Reverse Transcriptase Inhibitors:
didanosine^a	↓ didanosine		Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility.
tenofovir	↑ tenofovir		Lopinavir/ritonavir has been shown to increase tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir- associated adverse events, including renal disorders. Patients receiving ritonavir and tenofovir disoproxil fumarate should be monitored for tenofovir-associated adverse events. Refer to the tenofovir Product Monograph for more information.
zidovudine, emtricitabine	↓zidovudine ↔emtricitabine		For further information, refer to the respective anti-HIV drugs prescribing information.
Non-Nucleoside Reverse Transcriptase Inhibitors:
delavirdine^a	↑ ritonavir ↔ delavirdine		When used in combination with delavirdine, a dose reduction of ritonavir should be considered. Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be affected by ritonavir. The safety and efficacy of this combination (delavirdine/ ritonavir) have not been established.
efavirenz	↑ efavirenz		In healthy volunteers receiving 500 mg ritonavir twice daily with efavirenz 600 mg once daily, the steady state AUC was increased by 21%. An associated increase in the AUC of ritonavir of 17% was observed.
nevirapine	↑nevirapine		For further information, refer to the respective anti-HIV drugs prescribing information.
Integrase Inhibitor:
raltegravir	↓ raltegravir		A pharmacokinetic study showed that co-administration of ritonavir 100 mg twice daily and raltegravir 400 mg single dose resulted in a reduction in raltegravir plasma concentration.
bictegravir	↑ bictegravir		For further information, refer to the respective anti-HIV drugs prescribing information.
CCR5 Antagonist:
maraviroc	↑ maraviroc (↑ AUC, ↑ C_max, ↑ C_min)		When co-administered with reduced doses of ritonavir plasma levels of maraviroc increases. The dose of maraviroc should be decreased during co-administration with ritonavir. Refer to the maraviroc Product Monograph for details on co-administration of maraviroc 150 mg twice daily with ritonavir.
Hypolipidemics, HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin	↑lovastatin, simvastatin		The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis (see 2 CONTRAINDICATIONS). Discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID, during the 5 days of PAXLOVID treatment and for 5 days after completing PAXLOVID.
lomitapide	↑ lomitapide		Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated (see 2 CONTRAINDICATIONS).
atorvastatin, rosuvastatin	↑atorvastatin, rosuvastatin		Caution must also be exercised, and reduced doses should be considered if ritonavir is used concurrently with atorvastatin, which is metabolized to a lesser extent by CYP3A4. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration. Atorvastatin and rosuvastatin do not need to be discontinued prior to or after completing PAXLOVID. Use the lowest doses of atorvastatin or rosuvastatin with careful monitoring for signs and symptoms of myopathy or rhabdomyolysis. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Immunosuppressants:
cyclosporine, tacrolimus, everolimus, sirolimus, rapamycina	↑ immunosuppressants		Avoid use of PAXLOVID when close monitoring of immunosuppressant concentrations is not feasible. If co-administered, dose adjustment of the immunosuppressant and monitoring for immunosuppressant concentrations and immunosuppressant-associated adverse reactions is recommended. Refer to the individual immunosuppressant product label for further information and obtain expert consultation from the patient’s immunosuppressive therapy specialist. Avoid concomitant use of everolimus and sirolimus and PAXLOVID.
Janus kinase (JAK) inhibitors
tofacitinib	↑tofacitinib		Dosage adjustment of tofacitinib is recommended. Refer to the tofacitinib product label for more information.
upadacitinib	↑upadacitinib		Dosing recommendations for co‑PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib product label for more information.
Kinase inhibitors (also see Anticancer agents above):
fostamatinib	↑ fostamatinib		Coadministration of fostamatinib with ritonavir could increase fostamatinib metabolite R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Monitor for toxicities of fostamatinib that may require fostamatinib dose modification (see fostamatinib Product Monograph).
Long-acting beta adrenoceptor agonist
salmeterol	↑salmeterol		Co-administration is not recommended. Avoid concomitant use with PAXLOVID. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Migraine medications :
eletriptan	↑eletriptan		Co-administration of eletriptan within at least 72 hours of PAXLOVID is contraindicated due to potential for serious adverse reactions including cardiovascular and cerebrovascular events (see 2 CONTRAINDICATIONS.
ubrogepant	↑ubrogepant		Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions (see 2 CONTRAINDICATIONS).
Mineralocorticoid receptor antagonists:
finerenone	↑ finerenone		Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia (see 2 CONTRAINDICATIONS).
Muscarinic receptor antagonists:
darifenacin	↑ darifenacin		The darifenacin daily dose should not exceed 7.5 mg when co-administered with PAXLOVID. Refer to the darifenacin product label for more information.
Neuroleptics/Antipsychotics:
clozapine	↑clozapine		If co-administration is necessary, consider reducing the clozapine dose and monitor for adverse reactions.
lurasidone	↑ lurasidone		Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected to increase. Co-administration of lurasidone with PAXLOVID is contraindicated (see 2 CONTRAINDICATIONS).
perphenazine, risperidone, thioridazine^a	↑ neuroleptics		Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
pimozide	↑ pimozide		Co-administration of PAXLOVID with pimozide is contraindicated as it may lead to serious and/or life-threatening reactions, such as cardiac arrhythmias (see 2 CONTRAINDICATIONS).
quetiapine	↑ quetiapine		Due to inhibition of CYP3A by PAXLOVID (ritonavir), co-administration of PAXLOVID with quetiapine may result in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions have been reported with CYP3A inhibitors. PAXLOVID should not be used in combination with quetiapine. Monitoring and dose reduction may be required if necessary.
Neuropsychiatric agents:
suvorexant^a	↑suvorexant		Avoid concomitant use of suvorexant with PAXLOVID.
aripiprazole, brexpiprazole, cariprazine, iloperidone^a, lumateperone^a, pimavanserin^a	↑aripiprazole ↑brexpiprazole ↑cariprazine ↑iloperidone ↑lumateperone ↑pimavanserin		Dosage adjustment of aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, and pimavanserin is recommended. Refer to individual product label for more information.
Opioid antagonists:
naloxegol	↑naloxegol		Co-administration contraindicated due to the potential for opioid withdrawal symptoms (see 2 CONTRAINDICATIONS).
Oral Contraceptive or Patch Contraceptive:
ethinyl estradiol	↓ ethinyl estradiol		Co-administration with ritonavir results in reduced ethinyl estradiol concentrations. Dosage increase or alternate contraceptive measures should be considered. An additional, non-hormonal method of contraception should be considered during the 5 days of PAXLOVID treatment and until one menstrual cycle after stopping PAXLOVID.
PDE5 Inhibitors (erectile dysfunction agents):
sildenafil, tadalafil, vardenafil	↑ sildenafil		Particular caution should be used when prescribing PDE5 inhibitors for the treatment of erectile dysfunction in patients receiving PAXLOVID. Co-administration of PAXLOVID with these drugs is expected to substantially increase their concentrations and may result in increase in associated adverse events, such as hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 Inhibitors for Erectile Dysfunction Sildenafil may be used with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Tadalafil may be used with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. Vardenafil should not be used with PAXLOVID (see 2 CONTRAINDICATIONS). Use of PDE5 Inhibitors for Pulmonary Arterial Hypertension Coadministration of PAXLOVID and tadalafil for the treatment of pulmonary arterial hypertension is not recommended. The use of sildenafil or vardenafil is contraindicated with PAXLOVID (see 2 CONTRAINDICATIONS).
PDE5 Inhibitors (pulmonary hypertension agents):
sildenafil (Revatio^®)	↑sildenafil		Co-administration of sildenafil with PAXLOVID is contraindicated due to the potential for sildenafil associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope (see 2 CONTRAINDICATIONS).
tadalafil (Adcirca^®)	↑tadalafil		Avoid concomitant use of tadalafil with PAXLOVID.
sGC stimulators (pulmonary hypertension agents):
riociguat	↑riociguat		Dosage adjustment is recommended for riociguat. Refer to the riociguat product label for more information.
Serotonin receptor 1A agonist/ serotonin receptor 2A antagonist:
flibanserin	↑flibanserin		Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression (see 2 CONTRAINDICATIONS).
Stimulants:
Methamphetamine	↑methamphetamine		Ritonavir dosed as a pharmacokinetic enhancer is not expected to result in any clinically meaningful increases in CYP2D6 substrates. Therefore, PAXLOVID should be used with caution, dose reduction of these drugs may be needed.
Vasopressin receptor antagonists:
tolvaptan	↑tolvaptan		Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia (see 2 CONTRAINDICATIONS).

Table 5: Drug Interactions: Pharmacokinetic Parameters for Nirmatrelvir in the Presence of the Co-administered Drugs
Co-administered Drug	Dose (Schedule)		N	Ratio (in combination with Co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI); No Effect=100
Co-administered Drug	Co-administered Drug	Nirmatrelvir/ Ritonavir		C_max	AUC^a
Carbamazepine^b	300 mg twice daily (16 doses)	300 mg/100 mg twice daily (5 doses)	9	56.82 (47.04, 68.62)	44.50 (33.77, 58.65)
Itraconazole	200 mg once daily (8 doses)	300 mg/100 mg twice daily (5 doses)	11	118.57 (112.50, 124.97)	138.82 (129.25, 149.11)
Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; C_max=maximum plasma concentrations. a. For carbamazepine, AUC=AUC_inf, for itraconazole, AUC=AUC_tau. b. Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7).