Nirmatrelvir and Ritonavir

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. ( 2.1 ) Nirmatrelvir must be co-administered with ritonavir. ( 2.1 )

• Initiate PAXLOVID treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. ( 2.1 )
• Administer orally with or without food. ( 2.1 )
• Administer at approximately the same time each day. ( 2.2 , 2.3 )
• 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 )
• Dose Reduction for Renal Impairment ( 2.3 , 8.6 , 12.3 ) 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
• PAXLOVID is not recommend in patients with severe hepatic impairment (Child-Pugh Class C). ( 2.4 , 8.7 )

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.

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 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) ] .

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. ( 4 , 5.1 , 7 , 12.3 )

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 the individual product prescribing information for anticancer drug. Anticoagulants warfarin ↑↓ warfarin Closely monitor international normalized ratio (INR) if co-administration with warfarin is necessary. rivaroxaban ↑ rivaroxaban Increased bleeding risk with rivaroxaban. Avoid concomitant use. dabigatran See 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 prescribing information 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 prescribing information 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 the trazadone prescribing information for further information. Antifungals voriconazole ↓ voriconazole Avoid concomitant use of voriconazole. ketoconazole, isavuconazonium sulfate, itraconazole ↑ ketoconazole ↑ isavuconazonium sulfate ↑ itraconazole Refer to the ketoconazole, isavuconazonium sulfate, and itraconazole prescribing information 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 prescribing information for further information. rifabutin ↑ rifabutin Refer to the rifabutin prescribing information 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 the individual product prescribing information 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 prescribing information 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 prescribing information for more information. mavacamten ↑ mavacamten Co-administration with mavacamten may increase mavacamten plasma concentration and increase the risk of heart failure. Discontinue mavacamten for the duration of PAXLOVID treatment. Resumption of mavacamten within 5 days of completing PAXLOVID may result in higher exposure of mavacamten. Refer to the mavacamten prescribing information 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 the individual product prescribing information for more information. Dipeptidyl peptidase 4 (DPP4) inhibitors saxagliptin ↑ saxagliptin Dosage adjustment of saxagliptin is recommended. Refer to the saxagliptin prescribing information 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 prescribing information 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 prescribing information 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 prescribing information and latest guidelines for further information. Janus kinase (JAK) inhibitors tofacitinib ↑ tofacitinib Dosage adjustment of tofacitinib is recommended. Refer to the tofacitinib prescribing information for more information. upadacitinib ↑ upadacitinib Dosing recommendations for co-administration of upadacitinib with PAXLOVID depends on the upadacitinib indication. Refer to the upadacitinib prescribing information 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 prescribing information 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 prescribing information 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 the individual product prescribing information for more information. Non-opioid analgesic (selective blocker of Na v 1.8 sodium channels) suzetrigine ↑ suzetrigine and active metabolite M6‑SUZ Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions [see Contraindications (4) ] . 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 prescribing information 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 the individual product prescribing information 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 prescribing information 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) ] .

8.1 Pregnancy Risk Summary 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 (see Data ). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ). 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 (see Data ) . 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 (see Data ) . 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. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data Human Data Ritonavir Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,500 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.4% [95% confidence interval (CI): 1.9%, 2.9%] following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%, 3.5%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Animal Data Nirmatrelvir Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and GD 7 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC 24 ) in rats was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC 24 ) in rabbits was approximately 11 times higher than clinical exposures at the approved human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC 24 ) approximately 3 times higher than clinical exposures at the approved human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 showed no adverse findings. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir-treated versus control animals, a decrease in the body weight of offspring was observed on Postnatal Day (PND) 17 (8% decrease) and PND 21 (up to 7% decrease) in the absence of maternal toxicity. No significant differences in offspring body weight were observed from PND 28 to PND 56. The maternal systemic exposure (AUC 24 ) at 1,000 mg/kg/day was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, where maternal systemic exposure (AUC 24 ) was approximately 6 times higher than clinical exposures at the approved human dose of PAXLOVID. Ritonavir Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 in rats and GD 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5 (rats) or 8 (rabbits) times higher than exposure at the approved human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures (AUC) approximately 10 times higher than exposure at the approved human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8 times higher than exposure at the approved human dose of PAXLOVID. In a PPND study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through PND 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10 times the exposure at the approved human dose of PAXLOVID.

8.2 Lactation Risk Summary Nirmatrelvir and ritonavir are present in human breast milk in small amounts (less than 2%). In a clinical lactation study in 8 lactating women, nirmatrelvir and ritonavir were estimated to be present in human milk at a mean weight-normalized infant daily dose of 0.16 mg/kg/day (1.8% of maternal weight-adjusted daily dose) and 0.006 mg/kg/day (0.2% of maternal weight-adjusted daily dose), respectively (see Data ) . There are no available data on the effects of nirmatrelvir or ritonavir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19. Data In a clinical pharmacokinetics study, 8 healthy lactating women who were at least 12 weeks postpartum were administered 3 oral doses every 12 hours (steady state dosing) of 300 mg/100 mg nirmatrelvir/ritonavir. The mean daily amount of nirmatrelvir and ritonavir recovered in breast milk was 0.752 mg and 0.027 mg, respectively, representing 0.13% and 0.014% of the corresponding administered daily maternal doses (unadjusted for weight). The estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 0.16 mg/kg/day and 0.006 mg/kg/day, 1.8% and 0.2% of the maternal dose, respectively, for nirmatrelvir and ritonavir.

8.3 Females and Males of Reproductive Potential Contraception Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3) ] .

8.4 Pediatric Use The optimal dose of PAXLOVID has not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of PAXLOVID include subjects 65 years of age and older and their data contributes to the overall assessment of safety and efficacy [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . Of the total number of subjects in the integrated dataset consisting of EPIC-HR and EPIC-SR who were randomized to and received PAXLOVID (N=1,578), 165 (10%) were 65 years of age and older and 39 (2%) were 75 years of age and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in safety between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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) ] .

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) ].

Risk Summary 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 (see Data ). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ). 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 (see Data ) . 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 (see Data ) . 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. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death. Data Human Data Ritonavir Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,500 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.4% [95% confidence interval (CI): 1.9%, 2.9%] following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%, 3.5%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Animal Data Nirmatrelvir Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and GD 7 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC 24 ) in rats was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC 24 ) in rabbits was approximately 11 times higher than clinical exposures at the approved human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC 24 ) approximately 3 times higher than clinical exposures at the approved human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 showed no adverse findings. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir-treated versus control animals, a decrease in the body weight of offspring was observed on Postnatal Day (PND) 17 (8% decrease) and PND 21 (up to 7% decrease) in the absence of maternal toxicity. No significant differences in offspring body weight were observed from PND 28 to PND 56. The maternal systemic exposure (AUC 24 ) at 1,000 mg/kg/day was approximately 9 times higher than clinical exposures at the approved human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, where maternal systemic exposure (AUC 24 ) was approximately 6 times higher than clinical exposures at the approved human dose of PAXLOVID. Ritonavir Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 in rats and GD 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5 (rats) or 8 (rabbits) times higher than exposure at the approved human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures (AUC) approximately 10 times higher than exposure at the approved human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8 times higher than exposure at the approved human dose of PAXLOVID. In a PPND study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through PND 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10 times the exposure at the approved human dose of PAXLOVID.

12.1 Mechanism of Action Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4) ]. Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 M pro . Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

12.2 Pharmacodynamics Cardiac Electrophysiology At 3 times the steady state peak plasma concentration (C max ) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

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; T ½ =terminal elimination half-life; T max =the time to reach C max ; V z /F=apparent volume of distribution. Absorption T max (hr), median 3.00 Represents 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) AUC inf and C max for 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 0.14 Red blood cell to plasma ratio. V z /F (L), mean 104.7 300 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 (T ½ ) (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 by 19 F-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 by 14 C analysis following 600 mg 14 C-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 (10 th and 90 th percentile). Nirmatrelvir Based on 1,017 subjects with their post hoc PK parameters. Abbreviations: C max =predicted maximal concentration; C min =predicted minimal concentration (C trough ). C max (µg/mL) 3.29 (1.93, 5.40) AUC tau (µg*hr/mL) AUC tau =predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing. 28.3 (12.5, 52.5) C min (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 max and 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 0-24 and 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 max and 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 C max AUC For carbamazepine, AUC=AUC inf ; for itraconazole, AUC=AUC tau . Abbreviations: AUC=area under the plasma concentration-time curve; AUC inf =area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUC tau =area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; C max =observed maximum plasma concentrations. Carbamazepine Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7). 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 max and AUC inf of 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 C max AUC inf Abbreviations: AUC inf =area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; C max =observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein. Midazolam For 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.

12.4 Microbiology Mechanism of Action Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (M pro ), also referred to as 3C-like protease (3CL pro ) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 M pro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 M pro in a biochemical assay with a K i value of 3.1 nM and an IC 50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 M pro active site by X-ray crystallography. Antiviral Activity Cell Culture Antiviral Activity Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC 50 and EC 90 values of 62 nM (31 ng/mL) and 181 nM (90 ng/mL), respectively, after 3 days of drug exposure. The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, XBB.1.5, EG.5, and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC 50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC 50 value fold changes ≤1.8 relative to the USA-WA1/2020 isolate. In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC 50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC 50 value fold change of 3.7 relative to USA-WA1/2020. The other variants had EC 50 value fold changes ≤1.1 relative to USA-WA1/2020. Clinical Antiviral Activity In clinical trial EPIC-HR, which enrolled subjects who were primarily infected with the SARS-CoV-2 Delta variant, PAXLOVID treatment was associated with a 0.83 log 10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5 (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); similar results were observed in the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). In the EPIC-SR trial, which included subjects who were infected with SARS-CoV-2 Delta (79%) or Omicron (19%) variants, PAXLOVID treatment was associated with a 1.05 log 10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5, with similar declines observed in subjects infected with Delta or Omicron variants. The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR. Antiviral Resistance In Cell Culture and Biochemical Assays SARS-CoV-2 M pro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with M pro substitutions, and biochemical assays with recombinant SARS-CoV-2 M pro containing amino acid substitutions. Table 7 indicates M pro substitutions and combinations of M pro substitutions that have been observed in SARS-CoV-2 under nirmatrelvir selective pressure in cell culture. Individual M pro substitutions are listed regardless of whether they occurred alone or in combination with other M pro substitutions. Note that the M pro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of M pro . Substitutions at other M pro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown. Abbreviation: ND=no data. Table 7: SARS-CoV-2 M pro Amino Acid Substitutions Selected by Nirmatrelvir in Cell Culture EC 50 value fold change ranges are shown in instances where multiple data points have been reported. Single Substitutions (EC 50 value fold change in cell culture) T21I (1.1-4.8), S46F (ND), L50F (1.2-4.2), P108S (ND), T135I (ND), F140L (4.1), S144A (2.2-5.3), C160F (2.1), E166A (3.3), E166V (25‑288), L167F (1.9-2.5), T169I (ND), H172Y (15), A173V (0.9-2.3), V186A (ND), R188G (ND), A191V (0.7-1.5), A193P (ND), P252L (5.9), S301P (ND), and T304I (1.4-5.5). ≥2 Substitutions (EC 50 value fold change in cell culture) T21I+S144A (9.4), T21I+E166V (83-250), T21I+A173V (3.1-8.9), T21I+T304I (3.0-7.9), L50F+E166V (34-175), L50F+T304I (5.9), T135I+T304I (3.8), F140L+A173V (10-17), H172Y+P252L (ND), A173V+T304I (5.8-20), T21I+L50F+A193P+S301P (29), T21I+S144A+T304I (11-28), T21I+C160F+A173V+V186A+T304I (28-29), T21I+A173V+T304I (15-16), and L50F+F140L+L167F+T304I (43-55). Table 8 indicates M pro substitutions and combinations of M pro substitutions that have been found to reduce nirmatrelvir activity ≥3-fold (based on IC 50 or K i values) in biochemical assays using recombinant SARS-CoV-2 M pro . Note that these M pro substitutions were laboratory engineered and most were not observed in PAXLOVID-treated subjects in clinical trials. In addition, according to public sequence databases, most of these substitutions have not been observed in clinical isolates or have been observed but with global cumulative frequencies ≤0.002%. Thus, the clinical relevance of these substitutions is unclear. The following M pro substitutions and combinations of M pro substitutions emerged in cell culture in the presence of nirmatrelvir but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I, S46F, L50F, P108S, T135I, C160F, T169I, V186A, A191V, A193P, P252L, S301P, T304I, T21I+T304I, and L50F+T304I. Table 8: SARS-CoV-2 M pro Amino Acid Substitutions That Reduce Nirmatrelvir Activity ≥3-Fold in Biochemical Assays Single Substitutions (IC 50 /K i value fold change in biochemical assay) Y54A/C (3.0-25), F140A/L/S (1.2-230), G143S (3.6-148), S144A/F/G/M/W/Y (1.2-76), S144D/E/H/Q/T/V (81-480), S144K/L/P/R (1,165->5,319), H164N (1.9-6.7), M165D/F/G/T (5.7-51), M165H/K/P/R/W (>384), M165Y (3,838), E166A/G/K/L/Q (4.5-77), E166D/H/I/N/V/Y (143-708), E166R/V (>1,538-7,700), L167F (1.4-4.5), P168del (4.5-9.3), H172D/F/G/K/Q/Y (10-91), H172A/C/E/M/N/R/V/Y (114-858), H172I/L/S/T (1,172-6,740), A173S/V (4.1-52), R188G (38), Q189E/K (1.6-16), Q192A/C/D/E/F/G/H/I/K/L/P/R/S/T/V/W (5.0-61), Q192Y (>384), A260V (0.6-3.3), and V297A (3.0). ≥2 Substitutions (IC 50 /K i value fold change in biochemical assay) T21I+S144A (20), T21I+E166V (120-11,000), T21I+A173V (15), L50F+E166V (100-4,500), T135I+T304I (5.1), F140L+A173V (95), S144A+T304I (28), E166V+L232R (5,700), P168del+A173V (170-536), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (52-180), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28). In Clinical Trials Treatment-emergent substitutions were evaluated among subjects in clinical trials EPIC-HR/SR with sequence data available at both baseline and post-baseline visits (n=907 PAXLOVID-treated subjects, n=946 placebo-treated subjects). SARS-CoV-2 M pro amino acid changes were classified as PAXLOVID treatment-emergent substitutions if they occurred at the same amino acid position in 3 or more PAXLOVID-treated subjects and were ≥2.5-fold more common in PAXLOVID-treated subjects than placebo-treated subjects. The following PAXLOVID treatment-emergent M pro substitutions were observed: T98I/R/del(n=4), E166V (n=3), and W207L/R/del (n=4). In biochemical assays, the T98I and W207L/R substitutions did not affect nirmatrelvir activity (K i value fold changes were 0.3 and 0.7/0.3, respectively), whereas the E166V substitution (which occurs at a M pro -nirmatrelvir contact residue) reduced nirmatrelvir activity 187-7,700-fold. Within the M pro cleavage sites, the following PAXLOVID treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific M pro substitutions. In a cell culture replicon assay, the A5328S/V and S6799A substitutions did not affect nirmatrelvir activity (EC 50 value fold changes were 0.3/0.2 and 0.7, respectively). None of the treatment-emergent substitutions listed above in M pro or M pro cleavage sites occurred in PAXLOVID-treated subjects who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown. Viral RNA Rebound and Treatment-Emergent Substitutions EPIC-HR and EPIC-SR were not designed to evaluate COVID-19 rebound; exploratory analyses were conducted to assess the relationship between PAXLOVID use and rebound in viral RNA shedding levels. Post-treatment increases in SARS-CoV-2 RNA shedding levels in nasopharyngeal samples were observed on Day 10 and/or Day 14 in a subset of PAXLOVID and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral RNA rebound varied according to analysis parameters, but was generally similar among PAXLOVID and placebo recipients. A similar or smaller percentage of placebo recipients compared to PAXLOVID recipients had nasopharyngeal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods. In EPIC-HR, of 59 PAXLOVID-treated subjects identified with post-treatment viral RNA rebound and with available viral sequence data, treatment-emergent substitutions in M pro potentially reducing nirmatrelvir activity were detected in 2 (3%) subjects, including E166V in 1 subject and T304I in 1 subject. Both subjects had viral RNA shedding levels <LLOQ by Day 14. Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 following the single 5-day course of PAXLOVID treatment. The clinical relevance of post-treatment increases in viral RNA following PAXLOVID or placebo treatment is unknown. Cross-Resistance Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not M pro inhibitors).

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; T ½ =terminal elimination half-life; T max =the time to reach C max ; V z /F=apparent volume of distribution. Absorption T max (hr), median 3.00 Represents 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) AUC inf and C max for 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 0.14 Red blood cell to plasma ratio. V z /F (L), mean 104.7 300 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 (T ½ ) (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 by 19 F-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 by 14 C analysis following 600 mg 14 C-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 (10 th and 90 th percentile). Nirmatrelvir Based on 1,017 subjects with their post hoc PK parameters. Abbreviations: C max =predicted maximal concentration; C min =predicted minimal concentration (C trough ). C max (µg/mL) 3.29 (1.93, 5.40) AUC tau (µg*hr/mL) AUC tau =predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing. 28.3 (12.5, 52.5) C min (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 max and 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 0-24 and 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 max and 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 C max AUC For carbamazepine, AUC=AUC inf ; for itraconazole, AUC=AUC tau . Abbreviations: AUC=area under the plasma concentration-time curve; AUC inf =area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUC tau =area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; C max =observed maximum plasma concentrations. Carbamazepine Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7). 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 max and AUC inf of 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 C max AUC inf Abbreviations: AUC inf =area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; C max =observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein. Midazolam For 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.