PAXLOVID (nirmatrelvir tablets; ritonavir tablets)

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).

Analgesics, Narcotic:

fentanyl

tramadol

propoxyphene^a

↑ fentanyl

↑ tramadol

↑ propoxyphene

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 respiratory depression) is

recommended when ritonavir is

co-administered with fentanyl, including

extended-release, transdermal or transmucosal

preparations. Use tramadol and propoxyphene

with caution, dose reduction of these drugs

may be needed.

methadone

↓ methadone

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:

abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, 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 with ritonavir should be avoided due to potential increase in encorafenib exposure potentially increasing the 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).

Concomitant use of ritonavir with apalutamide is contraindicated.

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).

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:

rivaroxaban

↑ rivaroxaban

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.

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

↑ carbamazepine

↓ phenytoin

↓ ritonavir

↓nirmatrelvir

Co-administration of PAXLOVID with carbamazepine, phenobarbital or phenytoin is contraindicated (see 2 CONTRAINDICATIONS)

Antidepressants:

amitriptyline, clomipramine, fluoxetine, imipramine, maprotiline, nefazodone, 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

Bupropion is primarily metabolized by CYP2B6. Concurrent administration of bupropion with repeated doses of ritonavir decreases bupropion levels.

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

↑ 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

↑ ketoconazole

High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.

itraconazole

↑ itraconazole

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 CONTRAINDICATIONS).

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

↑ clarithromycin

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.

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 (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:

midazolam, oral^a

↑ 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 of oral midazolam with PAXLOVID is contraindicated (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.

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:

diltiazem, 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.

Corticosteroids:

fluticasone propionate, budesonide, 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.

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.

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:

ombitasvir/paritaprevir/ ritonavir with or without dasabuvir^a

↑ paritaprevir

Exposures of paritaprevir may be increased when co-administered with ritonavir, therefore, co-administration is not recommended.

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.

glecaprevir/pibrentasvir

↑ glecaprevir

Coadministration with ritonavir is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure.

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

↓ 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.

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.

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.

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.

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, everolimus, tacrolimus,  rapamycin^a

↑ immunosuppressants

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).

Neuroleptics/Antipsychotics:

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.

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:

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).

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.