Paxlovid

• •
  PAXLOVID includes ritonavir, a strong CYP3A inhibitor, which may lead to greater exposure of certain concomitant medications, resulting in potentially severe, life-threatening, or fatal events

  [see

  4 CONTRAINDICATIONS

  PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions [e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome] to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product.

  PAXLOVID is contraindicated with drugs that are primarily metabolized by CYP3A and for which elevated concentrations are associated with serious and/or life-threatening reactions and drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. There are certain other drugs for which concomitant use with PAXLOVID should be avoided and/or dose adjustment, interruption, or therapeutic monitoring is recommended. Drugs listed in this section are a guide and not considered a comprehensive list of all drugs that may be contraindicated 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 like PAXLOVID

  [see Drug Interactions (7.3)]

  :

  • ➢Drugs that are primarily metabolized by CYP3A for which elevated concentrations are associated with serious and/or life-threatening reactions
    [see Drug Interactions (7.3)]
    :
    • •Alpha 1-adrenoreceptor antagonist: alfuzosin
    • •Antianginal: ranolazine
    • •Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
    • •Anti-gout: colchicine (in patients with renal and/or hepatic impairment
      [see
      Table 2
      , Drug Interactions (7.3)]
      )
    • •Antipsychotics: lurasidone, pimozide
    • •Benign prostatic hyperplasia agents: silodosin
    • •Cardiovascular agents: eplerenone, ivabradine
    • •Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
    • •HMG-CoA reductase inhibitors: lovastatin, simvastatin (these drugs can be temporarily discontinued to allow PAXLOVID use
      [see
      Table 2
      , Drug Interactions (7.3)]
      )
    • •Immunosuppressants: voclosporin
    • •Microsomal triglyceride transfer protein inhibitor: lomitapide
    • •Migraine medications: eletriptan, ubrogepant
    • •Mineralocorticoid receptor antagonists: finerenone
    • •Opioid antagonists: naloxegol
    • •PDE5 inhibitor: sildenafil (Revatio^®) when used for pulmonary arterial hypertension (PAH)
    • •Sedative/hypnotics: triazolam, oral midazolam
    • •Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin
    • •Vasopressin receptor antagonists: tolvaptan
  • ➢Drugs that are strong CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer
    [see Drug Interactions (7.3)]
    :
    • •Anticancer drugs: apalutamide
      , enzalutamide
    • •Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin
    • •Antimycobacterials: rifampin, rifapentine
    • •Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor
    • •Herbal products: St. John's Wort (
      hypericum perforatum
      )

  • •History of clinically significant hypersensitivity reactions to the active ingredients (nirmatrelvir or ritonavir) or any other components.
  • •Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
  • •Co-administration with potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.

  ,

  5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

  Initiation of PAXLOVID, which contains ritonavir, a strong 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. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:

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

  Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (e.g., tacrolimus, cyclosporine), followed by calcium channel blockers.

  Prior to prescribing PAXLOVID, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors)

  [see Contraindications (4)and Drug Interactions (7)]

  . See Table 2for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID.

  Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed

  [see Drug Interactions (7)and Clinical Studies (14)]

  .

  , and

  7 DRUG INTERACTIONS

  Co-administration of PAXLOVID can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PAXLOVID. Consider the potential for drug interactions prior to and during PAXLOVID therapy and review concomitant medications during PAXLOVID therapy.

  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
  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.
  	dabigatranSee Pharmacokinetics, Clinical Drug Interaction Studies (12.3).	↑ 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)] .

  ].
• •
  Prior to prescribing PAXLOVID: 1) Review all medications taken by the patient to assess potential drug-drug interactions with a strong CYP3A inhibitor like PAXLOVID and 2) Determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring

  [see

  7 DRUG INTERACTIONS

  Co-administration of PAXLOVID can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PAXLOVID. Consider the potential for drug interactions prior to and during PAXLOVID therapy and review concomitant medications during PAXLOVID therapy.

  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
  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.
  	dabigatranSee Pharmacokinetics, Clinical Drug Interaction Studies (12.3).	↑ 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)] .

  ].
• •
  Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed

  [see

  5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

  Initiation of PAXLOVID, which contains ritonavir, a strong 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. Medications that induce CYP3A may decrease concentrations of PAXLOVID. These interactions may lead to:

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

  Severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with PAXLOVID. The most commonly reported concomitant medications resulting in serious adverse reactions were calcineurin inhibitors (e.g., tacrolimus, cyclosporine), followed by calcium channel blockers.

  Prior to prescribing PAXLOVID, review all medications taken by the patient to assess potential drug-drug interactions and determine if concomitant medications require a dose adjustment, interruption, and/or additional monitoring (e.g., calcineurin inhibitors)

  [see Contraindications (4)and Drug Interactions (7)]

  . See Table 2for clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 2 are a guide and not considered a comprehensive list of all possible drugs that may interact with PAXLOVID.

  Consider the benefit of PAXLOVID treatment in reducing hospitalization and death, and whether the risk of potential drug-drug interactions for an individual patient can be appropriately managed

  [see Drug Interactions (7)and Clinical Studies (14)]

  .

  ,

  7 DRUG INTERACTIONS

  Co-administration of PAXLOVID can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PAXLOVID. Consider the potential for drug interactions prior to and during PAXLOVID therapy and review concomitant medications during PAXLOVID therapy.

  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
  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.
  	dabigatranSee Pharmacokinetics, Clinical Drug Interaction Studies (12.3).	↑ 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)] .

  , and

  14 CLINICAL STUDIES

  14.1 Efficacy in Subjects at High Risk of Progression to Severe COVID-19 (EPIC-HR)

  EPIC-HR (NCT04960202) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Subjects with COVID-19 symptom onset of ≤5 days were included in the study. Subjects were randomized (1:1) to receive PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The trial excluded individuals with a history of prior COVID-19 infection or vaccination and excluded individuals taking any medications with clinically significant drug interactions with PAXLOVID. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set [all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days).

  A total of 2,113 subjects were randomized to receive either PAXLOVID or placebo. At baseline, mean age was 45 years; 51% were male; 71% were White, 15% were Asian, 9% were American Indian or Alaska Native, 4% were Black or African American, and 1% was missing or unknown; 41% were Hispanic or Latino; 67% of subjects had onset of symptoms ≤3 days before initiation of study treatment; 49% of subjects were serological negative at baseline; the mean (SD) baseline viral RNA in nasopharyngeal samples was 4.71 log₁₀copies/mL (2.89); 27% of subjects had a baseline viral RNA of ≥10^7 (log₁₀copies/mL); 6% of subjects either received or were expected to receive COVID-19 therapeutic monoclonal antibody treatment at the time of randomization and were excluded from the mITT and mITT1 analyses.

  The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups.

  The proportions of subjects who discontinued treatment due to an adverse event were 2.0% in the PAXLOVID group and 4.2% in the placebo group.

  Table 9 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for PAXLOVID compared to placebo was 86% (95% CI: 72%, 93%).

  Table 9: COVID-19 Related Hospitalization or Death from Any Cause Through Day 28 in Non-Hospitalized Adults with COVID-19 (mITT1 Analysis Set): EPIC-HR

  	PAXLOVID (N=977)	Placebo (N=989)
  Abbreviations: CI=confidence interval; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT1=modified intent-to-treat 1 (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment). The determination of primary efficacy was based on a planned interim analysis of 754 subjects in mITT population. The estimated risk reduction was -6.5% with a 95% CI of (-9.3%, -3.7%) and 2-sided p-value <0.0001.
  COVID-19 Related Hospitalization or Death from Any Cause Through Day 28
  n (%)	9 (0.9%)	64 (6.5%)
  Reduction Relative to PlaceboThe estimated cumulative proportion of subjects hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalization and death status through Day 28 were censored at the time of study discontinuation.(95% CI), %	-5.6 (-7.3, -4.0)
  COVID-19 Related Hospitalization Through Day 28, %	9 (0.9%)	63 (6.4%)
  All-cause Mortality Through Day 28For the secondary endpoint of all-cause mortality through Week 24, there were 0 and 15 (1%) events in the PAXLOVID arm and placebo arm, respectively., %	0	12 (1.2%)

  Consistent results were observed in the mITT and mITT2 analysis populations.

  Similar trends have been observed across subgroups of subjects

  (see Figure 1)

  .

  Figure 1: Subgroup Analysis of Adults with COVID-19 Dosed within 5 Days of Symptom Onset with COVID-19 Related Hospitalization or Death from Any Cause Through Day 28: EPIC-HR

  Abbreviations: BMI=body mass index; COVID-19=coronavirus disease 2019; mAb=monoclonal antibody; mITT=modified intent-to-treat; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. N=number of subjects in the category of the analysis set. All categories are based on mITT1 population except for COVID-19 mAb treatment which is based on mITT2 population. Seropositivity was defined if results were positive in either Elecsys anti-SARS-CoV-2 S or Elecsys anti-SARS-CoV-2 (N) assay. The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on normal approximation of the data are presented.

  Among subjects who were SARS-CoV-2 seropositive at baseline, 1/490 (0.2%) PAXLOVID recipients versus 8/479 (1.7%) placebo recipients met the primary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 [reduction relative to placebo -1.47% (-2.70%, -0.25%)].

  Figure 1

  14.2 Trial in Unvaccinated Subjects Without a Risk Factor for Progression to Severe COVID-19 or Subjects Fully Vaccinated Against COVID-19 With at Least One Factor for Progression to Severe COVID-19 (EPIC-SR)

  PAXLOVID is not indicated for the treatment of COVID-19 in patients without a risk factor for progression to severe COVID-19.

  EPIC-SR (NCT05011513) was a Phase 2/3, randomized, double-blind, placebo-controlled trial in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e., completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR. Through the December 19, 2021, data cutoff, a total of 1,075 subjects were randomized (1:1) to receive PAXLOVID or placebo orally every 12 hours for 5 days; of these, 59% were fully vaccinated high-risk subjects.

  The primary endpoint in this trial, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among PAXLOVID versus placebo recipients, was not met.

  In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction relative to placebo for the secondary endpoint of COVID-19 related hospitalization or death from any cause through Day 28 was observed.

  14.3 Post-Exposure Prophylaxis Trial

  PAXLOVID is not indicated for the post-exposure prophylaxis of COVID-19.

  In a double-blind, double-dummy, placebo-controlled trial, the efficacy of PAXLOVID when administered for 5 or 10 days as post-exposure prophylaxis of COVID-19 was evaluated. Eligible subjects were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at baseline and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2,736 subjects were randomized (1:1:1) to receive PAXLOVID orally every 12 hours for 5 days, PAXLOVID orally every 12 hours for 10 days, or placebo.

  The primary endpoint for this trial was not met. The primary endpoint was the risk reduction between the 5-day and 10-day PAXLOVID regimens versus placebo in the proportion of subjects who developed RT-PCR or RAT-confirmed symptomatic SARS-CoV-2 infection through Day 14 who had a negative SARS-CoV-2 RT-PCR result at baseline. The proportion of subjects who had events through Day 14 was 2.6% for the 5-day PAXLOVID regimen, 2.4% for the 10-day PAXLOVID regimen, and 3.9% for placebo. There was not a statistically significant risk reduction versus placebo for either the 5-day or 10-day PAXLOVID regimen.

  ].

Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect.

The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider's discretion.

If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.

PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food

PAXLOVID is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. (

Nirmatrelvir must be co-administered with ritonavir. (

• •Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. (
  2.1 Important Dosage and Administration Information

  PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are three different dose packs available:

  • •PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg
    [see Dosage and Administration (2.2)]
    .
  • •PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment
    [see Dosage and Administration (2.3)].
  • •
    PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg (Day 1) and 150 mg;100 mg (Days 2-5) for patients with severe renal impairment

    [see Dosage and Administration (2.3)]

    .

  Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect.

  Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID [see Dosage and Administration (2.2, 2.3)].

  Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2.

  The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider's discretion.

  If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.

  PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food

  [see Clinical Pharmacology (12.3)]

  . The tablets should be swallowed whole and not chewed, broken, or crushed.
  )
• •Administer orally with or without food. (
  2.1 Important Dosage and Administration Information

  PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. There are three different dose packs available:

  • •PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg
    [see Dosage and Administration (2.2)]
    .
  • •PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 150 mg;100 mg for patients with moderate renal impairment
    [see Dosage and Administration (2.3)].
  • •
    PAXLOVID (nirmatrelvir; ritonavir) co-packaged for oral use 300 mg;100 mg (Day 1) and 150 mg;100 mg (Days 2-5) for patients with severe renal impairment

    [see Dosage and Administration (2.3)]

    .

  Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are insufficient to achieve the desired therapeutic effect.

  Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID [see Dosage and Administration (2.2, 2.3)].

  Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2.

  The 5-day treatment course of PAXLOVID should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. Should a patient require hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, the patient should complete the full 5-day treatment course per the healthcare provider's discretion.

  If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.

  PAXLOVID (both nirmatrelvir and ritonavir tablets) can be taken with or without food

  [see Clinical Pharmacology (12.3)]

  . The tablets should be swallowed whole and not chewed, broken, or crushed.
  )
• •Administer at approximately the same time each day. (
  2.2 Recommended Dosage

  The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily in the morning and at bedtime for 5 days.
  ,
  2.3 Dosage in Patients with Renal Impairment

  Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID.

  Providers should counsel patients about renal dosing instructions

  [see Patient Counseling Information (17)]

  .

  No dosage adjustment is

  recommended in patients

  with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥60 to <90 mL/min].

  In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min) or

  with severe renal impairment (eGFR <30 mL/min)

  including those requiring hemodialysis, the dosage of PAXLOVID should be reduced as shown in Table 1. PAXLOVID should be administered at approximately the same time each day for 5 days. On days

  patients with severe renal impairment

  undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and How Supplied/Storage and Handling (16)]

  .

  Table 1: Recommended Dose and Regimen for Patients with Renal Impairment

  Abbreviation: eGFR=estimated glomerular filtration rate.
  Renal Function	Days of Treatment	Dose and Dose Frequency PAXLOVID should be administered at approximately the same time each day for 5 days.
  Moderate renal impairment (eGFR ≥30 to <60 mL/min)	Days 1-5	150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily
  Severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis.	Day 1	300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once
  	Days 2-5	150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily
  )
• •Dosage: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all 3 tablets taken together twice daily for 5 days. (
  2.2 Recommended Dosage

  The recommended dosage for PAXLOVID is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) with all 3 tablets taken together orally twice daily in the morning and at bedtime for 5 days.
  )
• •
  Dose Reduction for Renal Impairment
  (
  2.3 Dosage in Patients with Renal Impairment

  Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID.

  Providers should counsel patients about renal dosing instructions

  [see Patient Counseling Information (17)]

  .

  No dosage adjustment is

  recommended in patients

  with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥60 to <90 mL/min].

  In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min) or

  with severe renal impairment (eGFR <30 mL/min)

  including those requiring hemodialysis, the dosage of PAXLOVID should be reduced as shown in Table 1. PAXLOVID should be administered at approximately the same time each day for 5 days. On days

  patients with severe renal impairment

  undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis

  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and How Supplied/Storage and Handling (16)]

  .

  Table 1: Recommended Dose and Regimen for Patients with Renal Impairment

  Abbreviation: eGFR=estimated glomerular filtration rate.
  Renal Function	Days of Treatment	Dose and Dose Frequency PAXLOVID should be administered at approximately the same time each day for 5 days.
  Moderate renal impairment (eGFR ≥30 to <60 mL/min)	Days 1-5	150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) twice daily
  Severe renal impairment (eGFR <30 mL/min) including those requiring hemodialysis On days of hemodialysis, the PAXLOVID dose should be administered after hemodialysis.	Day 1	300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once
  	Days 2-5	150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily
  ,
  8.6 Renal Impairment

  Renal impairment increases nirmatrelvir exposure, which may increase the risk of PAXLOVID adverse reactions. No dosage adjustment is recommended in patients with mild renal impairment (eGFR ≥60 to <90 mL/min). Reduce the PAXLOVID dosage in patients with moderate renal impairment (eGFR ≥30 to <60 mL/min). Reduce the PAXLOVID dose and dose frequency in patients with severe renal impairment (eGFR <30 mL/min), including those requiring hemodialysis. On days when patients undergo hemodialysis, the PAXLOVID dose should be administered after hemodialysis

  [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]

  .

  Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID

  . Providers should counsel patients about renal dosing instructions

  [see Patient Counseling Information (17)]

  .
  ,
  12.3 Pharmacokinetics

  The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19.

  Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir. Nirmatrelvir steady state was achieved on Day 2 following administration of the approved recommended dosage and the mean accumulation ratio was approximately 2-fold.

  The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 3.

  Table 3: Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects

  	Nirmatrelvir (When Given With Ritonavir)	Ritonavir
  Abbreviations: CL/F=apparent clearance; hr=hour; L/hr=liters per hour; T½=terminal elimination half-life; Tmax=the time to reach Cmax; Vz/F=apparent volume of distribution.
  Absorption
  Tmax(hr), median	3.00Represents data after a single dose of 300 mg nirmatrelvir (2 × 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.	3.98
  Food effect	Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinfand Cmaxfor nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively.Following a single oral dose of nirmatrelvir 300 mg boosted ritonavir 100 mg at -12 hours, 0 hours and 12 hours, administered under fed (high fat and high calorie meal) or fasted conditions.
  Distribution
  % bound to human plasma proteins	69%	98–99%
  Blood-to-plasma ratio	0.60	0.14Red blood cell to plasma ratio.
  Vz/F (L), mean	104.7300 mg nirmatrelvir (oral suspension formulation) co-administered with 100 mg ritonavir (tablet formulation) twice daily for 3 days.	112.4
  Elimination
  Major route of elimination	Renal elimination	Hepatic metabolism
  Half-life (T½) (hr), mean	6.05	6.15
  Oral clearance (CL/F) (L/hr), mean	8.99	13.92
  Metabolism
  Metabolic pathways	Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal.	Major CYP3A, Minor CYP2D6
  Excretion
  % drug-related material in feces	35.3%Determined by19F-NMR analysis following 300 mg nirmatrelvir oral suspension administered at 0 hr enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.	86.4%Determined by14C analysis following 600 mg14C-ritonavir oral solution (6 times the approved ritonavir dose).
  % of dose excreted as total (unchanged drug) in feces	27.5%	33.8%
  % drug-related material in urine	49.6%	11.3%
  % of dose excreted as total (unchanged drug) in urine	55.0%	3.5%

  The predicted Day 5 nirmatrelvir exposure parameters in adult subjects with mild-to-moderate COVID-19 who were treated with PAXLOVID in EPIC-HR are presented in Table 4.

  Table 4: Predicted Day 5 Nirmatrelvir Exposure Parameters Following Administration of Nirmatrelvir/Ritonavir 300 mg/100 mg Twice Daily in Subjects with Mild-to-Moderate COVID-19

  Pharmacokinetic Parameter (units) Data presented as geometric mean (10thand 90thpercentile).	Nirmatrelvir Based on 1,017 subjects with their post hoc PK parameters.
  Abbreviations: Cmax=predicted maximal concentration; Cmin=predicted minimal concentration (Ctrough).
  Cmax(µg/mL)	3.29 (1.93, 5.40)
  AUCtau(µg*hr/mL)AUCtau=predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing.	28.3 (12.5, 52.5)
  Cmin(µg/mL)	1.40 (0.48, 3.45)

  Effect of Food

  No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1,000 calories; 50% fat) to healthy subjects.

  Specific Populations

  There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity.

  Pediatric Patients

  The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.

  Patients with Renal Impairment

  The pharmacokinetics of nirmatrelvir in subjects with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg were determined. Compared to healthy controls with no renal impairment, the C_maxand AUC of nirmatrelvir in subjects with mild renal impairment was 30% and 24% higher, in subjects with moderate renal impairment was 38% and 87% higher, and in subjects with severe renal impairment was 48% and 204% higher, respectively.

  The pharmacokinetics of nirmatrelvir in subjects with mild-to-moderate COVID-19 and severe renal impairment (eGFR<30 mL/min) either requiring intermittent hemodialysis (n=12) or not requiring hemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of 5 doses.

  The administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 in subjects with severe renal impairment, either requiring intermittent hemodialysis or not requiring hemodialysis resulted in comparable exposures on Day 1 and at steady-state (AUC_0-24and C_max) compared to those observed in subjects with normal renal function receiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days. During a 4-hour hemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared through dialysis. Hemodialysis clearance was 1.83 L/h.

  Patients with Hepatic Impairment

  The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied.

  Clinical Drug Interaction Studies

  Table 5 describes the effect of other drugs on the C_maxand AUC of nirmatrelvir.

  Table 5: The Effect of Other Drugs on the Pharmacokinetic Parameters of Nirmatrelvir

  Co-administered Drug	Dose (Schedule)		N	Percent Ratio (in combination with co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI); No Effect=100
  	Co-administered Drug	Nirmatrelvir/ Ritonavir		Cmax	AUC For carbamazepine, AUC=AUCinf; for itraconazole, AUC=AUCtau.
  Abbreviations: AUC=area under the plasma concentration-time curve; AUCinf=area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUCtau=area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; Cmax=observed maximum plasma concentrations.
  CarbamazepineCarbamazepine 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).	300 mg twice daily (16 doses)	300 mg/100 mg once daily (2 doses)	10	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)

  Table 6 describes the effect of nirmatrelvir/ritonavir on the C_maxand AUC_infof other drugs.

  Table 6: Effect of Nirmatrelvir/Ritonavir on Pharmacokinetics of Other Drugs

  Co-administered Drug	Dose (Schedule)		N	Percent Ratio of Test/Reference of Geometric Means (90% CI); No Effect=100
  	Co-administered Drug	Nirmatrelvir/ Ritonavir		Cmax	AUCinf
  Abbreviations: AUCinf=area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; Cmax=observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein.
  MidazolamFor midazolam, Test=nirmatrelvir/ritonavir plus midazolam, Reference=Midazolam. Midazolam is an index substrate for CYP3A4. For dabigatran, Test=nirmatrelvir/ritonavir plus dabigatran, Reference=Dabigatran. Dabigatran is an index substrate for P-gp. For rosuvastatin, Test=nirmatrelvir/ritonavir plus rosuvastatin, Reference=Rosuvastatin. Rosuvastatin is an index substrate for OATP1B1.	2 mg (1 dose)	300 mg/100 mg twice daily (9 doses)	10	368.33 (318.91, 425.41)	1430.02 (1204.54, 1697.71)
  Dabigatran	75 mg (1 dose)	300 mg/100 mg twice daily (4 doses)	24	233.06 (172.14, 315.54)	194.47 (155.29, 243.55)
  Rosuvastatin	10 mg (1 dose)	300 mg/100 mg twice daily (3 doses)	12	212.44 (174.31, 258.90)	131.18 (115.89, 148.48)

  In Vitro Studies

  Cytochrome P450 (CYP) Enzymes:

  • •Nirmatrelvir is a reversible and time-dependent inhibitor of CYP3A, but not an inhibitor CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Nirmatrelvir is an inducer of CYP2B6, 2C8, 2C9, and 3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these CYP enzymes at the proposed therapeutic dose.
  • •Ritonavir is a substrate of CYP2D6 and CYP3A. Ritonavir is an inducer of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A.

  Transporter Systems:

  Nirmatrelvir is an inhibitor of P-gp and OATP1B1. Nirmatrelvir is a substrate for P-gp, but not BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATP1B1, OATP1B3, OATP2B1, or OATP4C1.
  )

• •PAXLOVID is not recommend in patients with severe hepatic impairment (Child-Pugh Class C). (
  2.4 Use in Patients with Hepatic Impairment

  No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

  No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment; therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment

  [see Use in Specific Populations (8.7)]

  .
  ,
  8.7 Hepatic Impairment

  No dosage adjustment of PAXLOVID is recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment, therefore, PAXLOVID is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment

  [see Warnings and Precautions (5.3)and Clinical Pharmacology (12.3)].
  )

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets

• •Nirmatrelvir is supplied as oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side. Each tablet contains 150 mg of nirmatrelvir.
• •Ritonavir is supplied as white or white to off-white film-coated tablets uniquely identified by the color, shape, and debossing. Each tablet contains 100 mg of ritonavir.

Available data on the use of nirmatrelvir during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug associated risk of miscarriage

In an embryo-fetal development study with nirmatrelvir, reduced fetal body weights following oral administration of nirmatrelvir to pregnant rabbits were observed at systemic exposures (AUC) approximately 11 times higher than clinical exposure at the approved human dose of PAXLOVID. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures (AUC) greater than or equal to 3 times higher than clinical exposure at the approved human dose of PAXLOVID

In embryo-fetal developmental studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at systemic exposures (AUC) 5 (rat) or 8 (rabbits) times higher than clinical exposure at the approved human dose of PAXLOVID

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.