Nirmatrelvir And Ritonavir

1 INDICATIONS AND USAGE 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 which includes nirmatrelvir, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro : also referred to as 3CL pro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, 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. ( 1 ) Limitations of Use PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19. ( 1 ) Limitations of Use PAXLOVID is not approved for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19 [see Clinical Studies (14.3) ] .

2 DOSAGE AND ADMINISTRATION 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) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥1% and greater incidence than in the placebo group) are dysgeusia and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PAXLOVID is based on two Phase 2/3 randomized, placebo-controlled trials in symptomatic adult subjects 18 years of age and older with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Subjects in both studies received PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo every 12 hours for 5 days for the treatment of mild-to-moderate COVID-19 within 5 days of symptom onset [see Clinical Studies (14) ] : • Trial C4671005 (EPIC-HR) enrolled subjects who were at high risk for progression to severe disease. • Trial C4671002 (EPIC-SR) enrolled subjects who were at standard risk for progression to severe disease (previously unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease). Adverse reactions were those reported while subjects were on study medication and through 28 days after the last dose of study treatment. In Trial C4671005 (EPIC-HR), 1,038 subjects received PAXLOVID and 1,053 subjects received placebo. The most common adverse reactions (≥1% incidence in the PAXLOVID group and occurring at a greater frequency than in the placebo group) were dysgeusia (5% and <1%, respectively) and diarrhea (3% and 2%, respectively). Among vaccinated or unvaccinated subjects at standard risk or fully vaccinated subjects with at least 1 risk factor for progression to severe disease in Trial C4671002 (EPIC-SR), 540 subjects received PAXLOVID and 528 subjects received placebo. The adverse reactions observed were consistent with those observed in EPIC-HR. Trial C4671028 (EPIC-SRI) was a Phase 1, open-label trial that evaluated the effects of severe renal impairment on the pharmacokinetics, safety, and tolerability of PAXLOVID in non-hospitalized adult participants with COVID-19 and severe renal impairment. A total of 15 subjects with severe renal impairment were enrolled in this trial, with 12 subjects receiving intermittent hemodialysis and 3 subjects not on hemodialysis. Subjects received nirmatrelvir/ritonavir 300 mg/100 mg once on Day 1 followed by nirmatrelvir/ritonavir 150 mg/100 mg once daily from Days 2-5. The safety profile of PAXLOVID in subjects with severe renal impairment, including those requiring hemodialysis, was consistent with the safety profile observed in the Phase 2/3 randomized, placebo-controlled trials. Emergency Use Authorization Experience in Subjects with COVID-19 The following adverse reactions have been identified during use of PAXLOVID under Emergency Use Authorization. Immune System Disorders: Anaphylaxis, hypersensitivity reactions [see Warnings and Precautions (5.2) ] Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome [see Warnings and Precautions (5.2) ] Nervous System Disorders: Headache Vascular Disorders: Hypertension Gastrointestinal Disorders: Abdominal pain, nausea, vomiting General Disorders and Administration Site Conditions: Malaise

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.