PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets) Drug Interactions

(nirmatrelvir tablets; ritonavir tablets)

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Drug Interactions

7 DRUG INTERACTIONS

7.1 Potential for PAXLOVID to Affect Other Drugs

PAXLOVID (nirmatrelvir co-packaged with ritonavir) is a strong inhibitor of CYP3A, and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse events. 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 Contraindications (4) and Drug Interactions (7.3) Table 2]. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 2.

7.2 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 PAXLOVID therapeutic effect [see Contraindications (4) and Drug Interactions (7.3) Table 2].

7.3 Established and Other Potentially Significant Drug Interactions

Table 2 provides a listing of clinically significant drug interactions, including contraindicated drugs [see Contraindications (4) and Warnings and Precautions (5.1)]. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID. The healthcare provider should consult other appropriate resources such as the prescribing information for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir.

Table 2: Established and Other Potentially Significant Drug Interactions
Drug Class	Drugs within Class	Effect on Concentration	Clinical Comments
* See Pharmacokinetics, Clinical Drug Interaction Studies (12.3).
Alpha 1- adrenoreceptor antagonist	alfuzosin	↑ alfuzosin	Co-administration contraindicated due to potential hypotension [see Contraindications (4)].
Alpha 1- adrenoreceptor antagonist	tamsulosin	↑ tamsulosin	Avoid concomitant use with PAXLOVID.
Antianginal	ranolazine	↑ ranolazine	Co-administration contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].
Antiarrhythmics	amiodarone, dronedarone, flecainide, propafenone, quinidine	↑ antiarrhythmic	Co-administration contraindicated due to potential for cardiac arrhythmias [see Contraindications (4)].
Antiarrhythmics	lidocaine (systemic), disopyramide	↑ antiarrhythmic	Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics if available.
Anticancer drugs	apalutamide, enzalutamide	↓ nirmatrelvir/ritonavir	Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
Anticancer drugs	abemaciclib, ceritinib, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine	↑ anticancer drugs	Avoid co-administration of encorafenib or ivosidenib due to potential risk of serious adverse events such as QT interval prolongation. Avoid use of neratinib, venetoclax or ibrutinib. Co-administration of vincristine and vinblastine may lead to significant hematologic or gastrointestinal side effects. For further information, refer to individual product label for anticancer drug.
Anticoagulants	warfarin	↑↓ warfarin	Closely monitor international normalized ratio (INR) if co-administration with warfarin is necessary.
	rivaroxaban	↑ rivaroxaban	Increased bleeding risk with rivaroxaban. Avoid concomitant use.
	dabigatran*	↑ dabigatran	Increased bleeding risk with dabigatran. Depending on dabigatran indication and renal function, reduce dose of dabigatran or avoid concomitant use. Refer to the dabigatran product label for further information.
	apixaban	↑ apixaban	Combined P-gp and strong CYP3A 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.
Anticonvulsants	carbamazepine*, phenobarbital, primidone, phenytoin	↓ nirmatrelvir/ritonavir	Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
Anticonvulsants	clonazepam	↑ anticonvulsant	A dose decrease may be needed for clonazepam when co-administered with PAXLOVID and clinical monitoring is recommended.
Antidepressants	bupropion	↓ bupropion and active metabolite hydroxy-bupropion	Monitor for an adequate clinical response to bupropion.
	trazodone	↑ trazodone	Adverse reactions of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. Refer to trazadone product label for further information.
Antifungals	voriconazole	↓ voriconazole	Avoid concomitant use of voriconazole.
	ketoconazole, isavuconazonium sulfate, itraconazole*	↑ ketoconazole ↑ isavuconazonium sulfate ↑ itraconazole	Refer to ketoconazole, isavuconazonium sulfate, and itraconazole product labels for further information.
		↑ nirmatrelvir/ritonavir	A nirmatrelvir/ritonavir dose reduction is not needed.
Anti-gout	colchicine	↑ colchicine	Co-administration contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4)].
Anti-HIV protease inhibitors	atazanavir, darunavir, tipranavir	↑ protease inhibitor	For further information, refer to the respective protease inhibitors' prescribing information. Patients on ritonavir- or cobicistat-containing HIV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or protease inhibitor adverse events.
Anti-HIV	efavirenz, maraviroc, nevirapine, zidovudine, bictegravir/ emtricitabine/ tenofovir	↑ efavirenz ↑ maraviroc ↑ nevirapine ↓ zidovudine ↑ bictegravir ↔ emtricitabine ↑ tenofovir	For further information, refer to the respective anti-HIV drugs prescribing information.
Anti-infective	clarithromycin, erythromycin	↑ clarithromycin ↑ erythromycin	Refer to the respective prescribing information for anti-infective dose adjustment.
Antimycobacterial	rifampin, rifapentine	↓ nirmatrelvir/ritonavir	Co-administration contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered [see Contraindications (4)].
Antimycobacterial	bedaquiline	↑ bedaquiline	Refer to the bedaquiline product label for further information.
	rifabutin	↑ rifabutin	Refer to rifabutin product label for further information on rifabutin dose reduction.
Antipsychotics	lurasidone, pimozide	↑ lurasidone ↑ pimozide	Co-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Antipsychotics	quetiapine	↑ quetiapine	If co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations.
	clozapine	↑ clozapine	If co-administration is necessary, consider reducing the clozapine dose and monitor for adverse reactions.
Benign prostatic hyperplasia agents	silodosin	↑ silodosin	Co-administration contraindicated due to potential for postural hypotension [see Contraindications (4)].
Calcium channel blockers	amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil	↑ calcium channel blocker	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PAXLOVID. If co-administered, refer to individual product label for calcium channel blocker for further information.
Cardiac glycosides	digoxin	↑ digoxin	Caution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels. Refer to the digoxin product label for further information.
Cardiovascular agents	eplerenone	↑ eplerenone	Co-administration with eplerenone is contraindicated due to potential for hyperkalemia [see Contraindications (4)].
	ivabradine	↑ ivabradine	Co-administration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances [see Contraindications (4)].
Cardiovascular agents	aliskiren, ticagrelor, vorapaxar clopidogrel	↑ aliskiren ↑ ticagrelor ↑ vorapaxar ↓ clopidogrel active metabolite	Avoid concomitant use with PAXLOVID.
	cilostazol	↑ cilostazol	Dosage adjustment of cilostazol is recommended. Refer to the cilostazol product label for more information.
Corticosteroids primarily metabolized by CYP3A	betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone	↑ corticosteroid	Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. However, the risk of Cushing’s syndrome and adrenal suppression associated with short-term use of a strong CYP3A inhibitor is low. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone should be considered.
Cystic fibrosis transmembrane conductance regulator potentiators	lumacaftor/ivacaftor	↓ nirmatrelvir/ritonavir	Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
Cystic fibrosis transmembrane conductance regulator potentiators	ivacaftor elexacaftor/tezacaftor/ ivacaftor tezacaftor/ivacaftor	↑ ivacaftor ↑ elexacaftor/tezacaftor/ ivacaftor ↑ tezacaftor/ivacaftor	Reduce dosage when co-administered with PAXLOVID. Refer to individual product labels for more information.
Dipeptidyl peptidase 4 (DPP4) inhibitors	saxagliptin	↑ saxagliptin	Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin product label for more information.
Endothelin receptor antagonists	bosentan	↑ bosentan ↓ nirmatrelvir/ritonavir	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	↑ 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 Contraindications (4)].
Hepatitis C direct acting antivirals	elbasvir/grazoprevir	↑ antiviral	Increased grazoprevir concentrations can result in alanine transaminase (ALT) elevations.
	glecaprevir/pibrentasvir		Avoid concomitant use of glecaprevir/pibrentasvir with PAXLOVID.
	ombitasvir/paritaprevir/ ritonavir and dasabuvir		Refer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information.
	sofosbuvir/velpatasvir/ voxilaprevir		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.
Herbal products	St. John's Wort (hypericum perforatum)	↓ nirmatrelvir/ritonavir	Co-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
HMG-CoA reductase inhibitors	lovastatin, simvastatin	↑ lovastatin ↑ simvastatin	Co-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)]. If treatment with PAXLOVID is considered medically necessary, 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.
HMG-CoA reductase inhibitors	atorvastatin	↑ atorvastatin	Consider temporary discontinuation of atorvastatin during treatment with PAXLOVID. Atorvastatin does not need to be withheld prior to or after completing PAXLOVID.
Hormonal contraceptive	ethinyl estradiol	↓ ethinyl estradiol	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.
Immunosuppressants	voclosporin	↑ voclosporin	Co-administration contraindicated due to potential for acute and/or chronic nephrotoxicity [see Contraindications (4)].
Immunosuppressants	calcineurin inhibitors: cyclosporine, tacrolimus	↑ cyclosporine ↑ tacrolimus	Avoid concomitant use of calcineurin inhibitors with PAXLOVID when close monitoring of immunosuppressant concentrations is not feasible. If co-administered, dose adjustment of the immunosuppressant and close and regular monitoring for immunosuppressant concentrations and adverse reactions are recommended during and after treatment with PAXLOVID. Obtain expert consultation to appropriately manage the complexity of this co-administration [see Warnings and Precautions (5.1)].
	mTOR inhibitors: everolimus, sirolimus	↑ everolimus ↑ sirolimus	Avoid concomitant use of everolimus and sirolimus and PAXLOVID. Refer to the individual immunosuppressant product label and latest guidelines for further information.
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-administration of upadacitinib with PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib product label for more information.
Long-acting beta-adrenoceptor agonist	salmeterol	↑ salmeterol	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.
Microsomal triglyceride transfer protein (MTTP) inhibitor	lomitapide	↑ lomitapide	Co-administration contraindicated due to potential for hepatotoxicity and gastrointestinal adverse reactions [see Contraindications (4)].
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 Contraindications (4)].
	ubrogepant	↑ ubrogepant	Co-administration of ubrogepant with PAXLOVID is contraindicated due to potential for serious adverse reactions [see Contraindications (4)].
Migraine medications	rimegepant	↑ rimegepant	Avoid concomitant use with PAXLOVID.
Mineralocorticoid receptor antagonists	finerenone	↑ finerenone	Co-administration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension, and hyponatremia [see Contraindications (4)].
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.
Narcotic analgesics	fentanyl, hydrocodone, oxycodone, meperidine	↑ fentanyl ↑ hydrocodone ↑ oxycodone ↑ meperidine	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.
	methadone	↓ methadone	Monitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
Neuropsychiatric agents	suvorexant	↑ suvorexant	Avoid concomitant use of suvorexant with PAXLOVID.
	aripiprazole, brexpiprazole, cariprazine, iloperidone, lumateperone, pimavanserin	↑ 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 Contraindications (4)].
Pulmonary hypertension agents (PDE5 inhibitors)	sildenafil (Revatio®)	↑ sildenafil	Co-administration of sildenafil with PAXLOVID is contraindicated for use in pulmonary hypertension due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope [see Contraindications (4)].
Pulmonary hypertension agents (PDE5 inhibitors)	tadalafil (Adcirca®)	↑ tadalafil	Avoid concomitant use of tadalafil with PAXLOVID for pulmonary hypertension.
Pulmonary hypertension agents (sGC stimulators)	riociguat	↑ riociguat	Dosage adjustment is recommended for riociguat when used for pulmonary hypertension. Refer to the riociguat product label for more information.
Erectile dysfunction agents (PDE5 inhibitors)	avanafil	↑ avanafil	Do not use PAXLOVID with avanafil because a safe and effective avanafil dosage regimen has not been established.
	sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Dosage adjustment is recommended for use of sildenafil, tadalafil or vardenafil with PAXLOVID when used for erectile dysfunction. Refer to individual product label for more information.
Sedative/hypnotics	triazolam, oral midazolam*	↑ triazolam ↑ midazolam	Co-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4)].
Sedative/hypnotics	buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem	↑ sedative/hypnotic	A dose decrease may be needed for these drugs when co-administered with PAXLOVID and monitoring for adverse events.
	midazolam (administered parenterally)	↑ midazolam	Co-administration of midazolam (parenteral) 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. Refer to the midazolam product label for further information.
Serotonin receptor 1A agonist/ serotonin receptor 2A antagonist	flibanserin	↑ flibanserin	Co-administration contraindicated due to potential for hypotension, syncope, and CNS depression [see Contraindications (4)].
Vasopressin receptor antagonists	tolvaptan	↑ tolvaptan	Co-administration contraindicated due to potential for dehydration, hypovolemia and hyperkalemia [see Contraindications (4)].

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