Atazanavir

1 INDICATIONS AND USAGE REYATAZ ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. Limitations of Use: • REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4) ] . • Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4) ] . REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1)

2 DOSAGE AND ADMINISTRATION • Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2) • Treatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3) • Treatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3) • Pediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4) • REYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than 5 kg. (2.5) • Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6) • Dosing modifications: may be required for concomitant therapy ( 2.3 , 2.4 , 2.5 , 2.6) , renal impairment (2.7) , and hepatic impairment. (2.8) 2.1 Overview • REYATAZ capsules and oral powder must be taken with food. • Do not open the capsules. • The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2 -receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3 , 2.4 , 2.5 , and 2.6 ) and Drug Interactions (7) ] . • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) ] . • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.5) ] . • Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir. 2.2 Testing Prior to Initiation and During Treatment with REYATAZ Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5 , 5.6) ] . Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see Warnings and Precautions (5.4) ] . 2.3 Dosage of REYATAZ in Adult Patients Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H 2 -receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended. Table 1: Recommended REYATAZ and Ritonavir Dosage in Adults a,b a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir. REYATAZ Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg 2.4 Dosage of REYATAZ Capsules in Pediatric Patients The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2). Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age) a,b a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir. Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experienced c Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir. Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg) a,b a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ. Body Weight Daily Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir Oral Solution 5 kg to less than 15 kg 200 mg (4 packets) c,d 80 mg 15 kg to less than 25 kg 250 mg (5 packets) d 80 mg When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use] • Determine the number of packets (3, 4, 5 or 6 packets) that are needed. • Prior to mixing, tap the packet to settle the powder. • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered. • Use a clean pair of scissors to cut each packet along the dotted line. • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture. • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time. • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant. • Administer ritonavir immediately following REYATAZ powder administration. • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture. 2.6 Dosage Adjustments in Pregnant Patients Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1) ] . Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patients a a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA. REYATAZ Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF b In combination with EITHER H2RA OR tenofovir DF 400 mg 100 mg 2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7) ] . 2.8 Dosage Adjustments in Patients with Hepatic Impairment Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended. Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment REYATAZ Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) REYATAZ with or without ritonavir is not recommended

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • cardiac conduction abnormalities [see Warnings and Precautions (5.1) ] • rash [see Warnings and Precautions (5.2) ] • hyperbilirubinemia [see Warnings and Precautions (5.8) ] • chronic kidney disease [see Warnings and Precautions (5.5) ] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Adverse Reactions in Treatment-Naive Adult Participants The safety profile of REYATAZ in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants received REYATAZ 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive participants receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424-138 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. 96 weeks c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d 400 mg / 100 mg (twice daily) and tenofovir DF/emtricitabine e (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced participants receiving REYATAZ with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, b Study AI424-045 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. 48 weeks c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively. Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424-138 a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. 96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d Variable Limit e (n=441) (n=437) Chemistry High SGOT/AST ≥5.1 × ULN 3% 1% SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limit d (n=404) (n=401) (n=279) (n=191) Chemistry High SGOT/AST ≥5.1 × ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Change d mg/dL Change d mg/dL mg/dL Change d mg/dL Change d (n=428 e ) (n=372 e ) (n=372 e ) (n=342 e ) (n=342 e ) (n=424 e ) (n=335 e ) (n=335 e ) (n=291 e ) (n=291 e ) LDL-Cholesterol f 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol f 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol f 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides f 126 145 +15% 140 +13% 129 194 +52% 184 +50% Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ a,b efavirenz b,c Baseline mg/dL (n=383 e ) Week 48 mg/dL (n=283 e ) Week 48 Change d (n=272 e ) Baseline mg/dL (n=378 e ) Week 48 mg/dL (n=264 e ) Week 48 Change d (n=253 e ) LDL-Cholesterol f 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides f 138 124 −9% 129 168 +23% Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045 a a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. 48 weeks b 48 weeks b REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI Variable Limit c (n=119) (n=118) Chemistry High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b Lopinavir/ritonavir b,c Baseline mg/dL (n=111 e ) Week 48 mg/dL (n=75 e ) Week 48 Change d (n=74 e ) Baseline mg/dL (n=108 e ) Week 48 mg/dL (n=76 e ) Week 48 Change d (n=73 e ) LDL-Cholesterol f 108 98 −10% 104 103 +1% HDL-Cholesterol 40 39 −7% 39 41 +2% Total Cholesterol 188 170 −8% 181 187 +6% Triglycerides f 215 161 −4% 196 224 +30% Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric participants with HIV-1 (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric participants were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 participants weighing at least 5 kg to less than 35 kg, including 134 participants exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric participants with HIV-1 (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir. In Study AI424-045, 20 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 participants treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the participants treated with REYATAZ, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with REYATAZ, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [see Warnings and Precautions (5.8) ] . 6.2 Postmarketing Experience The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1) ] Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6) ] , cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9) ] Musculoskeletal System: arthralgia Renal System: nephrolithiasis [see Warnings and Precautions (5.6) ] , interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5) ] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2) ] , pruritus, angioedema

12.3 Pharmacokinetics The pharmacokinetics of atazanavir were evaluated in adult participants who either were healthy, or with HIV-1, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17). Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Participants or Participants with HIV-1 in the Fed State a n=26. b n=12. 400 mg once daily 300 mg with ritonavir 100 mg once daily Parameter Healthy Participants (n=14) Participants with HIV-1 (n=13) Healthy Participants (n=28) Participants with HIV-1 (n=10) C max (ng/mL) Geometric mean (CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) T max (h) Median 2.5 2.0 2.7 3.0 AUC (ng•h/mL) Geometric mean (CV%) 28132 (28) 14874 (91) 57039 (37) 46073 (66) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2) a 8.6 (2.3) C min (ng/mL) Geometric mean (CV%) 159 (88) 120 (109) 1227 (53) 636 (97) Mean (SD) 218 (191) 273 (298) b 1441 (757) 862 (838) Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in adult participants with HIV-1. Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for Adult Participants with HIV-1 Absorption Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Food Effect Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T max increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in participants with HIV-1 dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following a single 400-mg dose of 14 C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy participants (n=214) and adult participants with HIV-1 (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Specific Populations Renal Impairment In healthy participants, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult participants with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max was 9% lower, AUC was 19% higher, and C min was 96% higher in participants with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched participants with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C max , AUC, and C min were approximately 25% to 43% lower compared to participants with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) ] . Hepatic Impairment REYATAZ has been studied in adult participants with moderate-to-severe hepatic impairment (14 with Child-Pugh B and 2 with Child-Pugh C) after a single 400-mg dose. The mean AUC(0- ∞ ) was 42% greater in participants with impaired hepatic function than in healthy participants. The mean half-life of atazanavir in hepatically impaired participants was 12.1 hours compared to 6.4 hours in healthy participants. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in participants with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) ] . Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5) ] . Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) [n] atazanavir with ritonavir Dose (mg) C max ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) C min ng/mL Geometric Mean (CV%) 5 to <10 [20] 150/80 4131 (55%) 32503 (61%) 336 (76%) 5 to <10 [10] 200/80 4466 (59%) 39519 (54%) 550 (60%) 10 to <15 [18] 200/80 5197 (53%) 50305 (67%) 572 (111%) 15 to <25 [32] 250/80 5394 (46%) 55687 (45%) 686 (68%) 25 to <35 [8] 300/100 4209 (52%) 44329 (63%) 468 (104%) The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4) ]. Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) atazanavir with ritonavir Dose (mg) C max ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) C min ng/mL Geometric Mean (CV%) 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) ≥35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 receiving REYATAZ Capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 in the Fed State a Available data during the 2nd trimester are limited. b Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in, non-pregnant patients with HIV-1. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1. c C min is concentration 24 hours post-dose. Atazanavir 300 mg with ritonavir 100 mg Pharmacokinetic Parameter 2nd Trimester (n=5 a ) 3rd Trimester (n=20) Postpartum b (n=34) C max ng/mL Geometric mean (CV%) 3078.85 (50) 3291.46 (48) 5721.21 (31) AUC ng•h/mL Geometric mean (CV%) 27657.1 (43) 34251.5 (43) 61990.4 (32) C min ng/mL c Geometric mean (CV%) 538.70 (46) 668.48 (50) 1462.59 (45) Drug Interaction Data Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K inact value of 0.05 to 0.06 min −1 and K i value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (K i =1.9 µM) and CYP2C8 (K i =2.1 µM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, C max , and C min are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7) . Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs a Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 C max AUC C min atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.00 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) clarithromycin 500 mg BID, d 7–10 (n=29) and d 18–21 400 mg QD, d 1–10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T) b ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=31) 400 mg × 1 dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=32) 400 mg × 1 dose 1 h after ddI + d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, d 7–20 (n=27) 400 mg QD, d 1–20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, d 7–20 (n=13) 400 mg QD, d 1–6 (n=23) then 300 mg with ritonavir 100 mg QD, 2 h before efavirenz, d 7–20 (n=13) 1.14 (0.83, 1.58) 1.39 (1.02, 1.88) 1.48 (1.24, 1.76) 600 mg QD, d 11–24 (pm) (n=14) 300 mg QD with ritonavir 100 mg QD, d 1–10 (pm) (n=22), then 400 mg QD with ritonavir 100 mg QD, d 11–24 (pm), (simultaneously with efavirenz) (n=14) 1.17 (1.08, 1.27) 1.00 (0.91, 1.10) 0.58 (0.49, 0.69) famotidine 40 mg BID, d 7–12 (n=15) 400 mg QD, d 1–6 (n=45), d 7–12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, d 7–12 (n=14) 400 mg QD (pm), d 1–6 (n=14), d 7–12 (10 h after, 2 h before famotidine) (n=14) 1.08 (0.82, 1.41) 0.95 (0.74, 1.21) 0.79 (0.60, 1.04) 40 mg BID, d 11–20 (n=14) c 300 mg QD with ritonavir 100 mg QD, d 1–10 (n=46), d 11–20 d (simultaneous administration) (n=14) 0.86 (0.79, 0.94) 0.82 (0.75, 0.89) 0.72 (0.64, 0.81) 20 mg BID, d 11–17 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), d 11–17 (am) (simultaneous administration with am famotidine) (n=18) d,e 0.91 (0.84, 0.99) 0.90 (0.82, 0.98) 0.81 (0.69, 0.94) 40 mg QD (pm), d 18–24 (n=20) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), d 18–24 (am) (12 h after pm famotidine) (n=20) e 0.89 (0.81, 0.97) 0.88 (0.80, 0.96) 0.77 (0.63, 0.93) 40 mg BID, d 18–24 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), d 18–24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18) e 0.74 (0.66, 0.84) 0.79 (0.70, 0.88) 0.72 (0.63, 0.83) 40 mg BID, d 11–20 (n=15) 300 mg QD with ritonavir 100 mg QD, d 1–10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD, d 11–20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/elbasvir grazoprevir 200 mg QD d 1–35 (n = 11) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD d 1–35 (n = 8) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 8) 1.02 (0.96, 1.08) 1.07 (0.98,1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, d 7–13 (n=14) 400 mg QD, d 1–13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapine f,g 200 mg BID, d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then 400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23) h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, d 7–12 (n=16) i 400 mg QD, d 1–6 (n=48), d 7–12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, d 11 –20 (n=15) i 300 mg QD with ritonavir 100 mg QD, d 1–20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, d 17–23 (am) (n=13) 300 mg QD with ritonavir 100 mg QD, d 7–16 (pm) (n=27), d 17–23 (pm) (n=13) j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, d 17–23 (am) (n=14) 300 mg QD with ritonavir 100 mg QD, d 7–16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD, d 17–23 (am) (n=14) l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, d 15–28 (n=7) 400 mg QD, d 1–28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) rifampin 600 mg QD, d 17–26 (n=16) 300 mg QD with ritonavir 100 mg QD, d 7–16 (n=48), d 17–26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavir n 100 mg QD, d 11–20 (n=28) 300 mg QD, d 1–20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DF o 300 mg QD, d 9–16 (n=34) 400 mg QD, d 2–16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, d 15–42 (n=10) 300 mg with ritonavir 100 mg QD, d 1–42 (n=10) 0.72 p (0.50, 1.05) 0.75 p (0.58, 0.97) 0.77 p (0.54, 1.10) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 0.81 (0.66, 1.00) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) a Data provided are under fed conditions unless otherwise noted. b All drugs were given under fasted conditions. c REYATAZ 300 mg with ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean C max that was similar and AUC and C min values that were 1.79- and 4.46-fold higher relative to REYATAZ 400 mg once daily alone. d Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg with ritonavir 100 mg and tenofovir DF 300 mg. e Coadministration of atazanavir with ritonavir and tenofovir DF was administered after a light meal. f Study was conducted in participants with HIV-1. g Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg. h Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Participants were treated with nevirapine prior to study entry. i Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ. j Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and REYATAZ 300 mg with ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole. k REYATAZ 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and C min (2.4-fold), with a decrease in C max (29%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). l Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and REYATAZ 400 mg with ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. m REYATAZ 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and C min (3.3-fold), with a decrease in C max (26%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). n Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir geometric mean values of C max , AUC, and C min by 18%, 103%, and 671%, respectively. o Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours. p Ratio of atazanavir with ritonavir and tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o ). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: C max = 3190 ng/mL, AUC = 34459 ng•h/mL, and C min = 491 ng/mL. Study was conducted in participants with HIV-1. NA = not available. Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ a Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 C max AUC C min a Data provided are under fed conditions unless otherwise noted. b 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19. c Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. d Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for C max , AUC, and C min were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. e All participants were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen ® . Ortho Tri-Cyclen ® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen ® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. f 17-deacetyl norgestimate is the active component of norgestimate. g Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported. h (R)-methadone is the active isomer of methadone. i Study was conducted in participants with HIV-1. j Participants were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20. l Not the recommended therapeutic dose of atazanavir. m When compared to rifabutin 150 mg QD alone d1–10 (n=14). Total of rifabutin and 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). n Rosiglitazone used as a probe substrate for CYP2C8. o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the C max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir DF and REYATAZ was separated by 12 hours. r Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours. NA = not available. acetaminophen 1 g BID, d 1–20 (n=10) 300 mg QD with ritonavir 100 mg QD, d 11–20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) clarithromycin 500 mg BID, d 7–10 (n=21) and d 18–21 400 mg QD, d 1–10 (n=21) 1.50 (1.32, 1.71) OH-clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (enteric-coated [EC] capsules) b 400 mg d 1 (fasted), d 8 (fed) (n=34) 400 mg QD, d 2–8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg d 1 (fasted), d 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, d 9–19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) diltiazem 180 mg QD, d 7–11 (n=28) and d 19–23 400 mg QD, d 1–11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol & norethindrone c Ortho-Novum ® 7/7/7 QD, d 1–29 (n=19) 400 mg QD, d 16–29 (n=19) ethinyl estradiol: 1.15 (0.99, 1.32) norethindrone: 1.67 (1.42, 1.96) ethinyl estradiol: 1.48 (1.31, 1.68) norethindrone: 2.10 (1.68, 2.62) ethinyl estradiol: 1.91 (1.57, 2.33) norethindrone: 3.62 (2.57, 5.09) ethinyl estradiol & norgestimate d Ortho Tri-Cyclen ® QD, d 1–28 (n=18), then Ortho Tri-Cyclen ® LO QD, d 29–42 e (n=14) 300 mg QD with ritonavir 100 mg QD, d 29–42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) 17-deacetyl norgestimate: f 1.68 (1.51, 1.88) ethinyl estradiol: 0.81 (0.75, 0.87) 17-deacetyl norgestimate: f 1.85 (1.67, 2.05) ethinyl estradiol: 0.63 (0.55, 0.71) 17-deacetyl norgestimate: f 2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥4.06 g (3.15, 5.23) ≥6.53 g (5.24, 8.14) ≥14.3 g (9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥1.29 g (1.15, 1.45) ≥1.64 g (1.48, 1.82) ≥2.29 g (1.95, 2.68) grazoprevir/elbasvir grazoprevir 200 mg QD d 1–35 (n=12) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD d 1–35 (n=10) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, d 1–15 (n=16) 400 mg QD, d 2–15 (n=16) (R)-methadone h 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadone h 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadone h 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapine i,j 200 mg BID, d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then 400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23) 1.17 (1.09, 1.25) 1.21 (1.11, 1.32) 1.25 (1.17, 1.34) 1.26 (1.17, 1.36) 1.32 (1.22, 1.43) 1.35 (1.25, 1.47) omeprazole k 40 mg single dose, d 7 and d 20 (n=16) 400 mg QD, d 1–12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, d 1–10 then 150 mg QD, d 11–20 (n=3) 600 mg QD, l d 11–20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl-rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl-rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl-rifabutin: 75.6 (30.1, 190.0) 150 mg twice weekly, d 1–15 (n=7) 300 mg QD with ritonavir 100 mg QD, d 1–17 (n=7) 2.49 m (2.03, 3.06) 25-O-desacetyl-rifabutin: 7.77 (6.13, 9.83) 1.48 m (1.19, 1.84) 25-O-desacetyl-rifabutin: 10.90 (8.14, 14.61) 1.40 m (1.05, 1.87) 25-O-desacetyl-rifabutin: 11.45 (8.15, 16.10) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazone n 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d 2–7, then 300 mg QD with ritonavir 100 mg QD, d 8–17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QD with ritonavir 100 mg QD for 7 days ↑ 7-fold o ↑ 3-fold o NA saquinavir p (soft gelatin capsules) 1200 mg QD, d 1–13 (n=7) 400 mg QD, d 7–13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DF q 300 mg QD, d 9–16 (n=33) and d 24–30 (n=33) 400 mg QD, d 2–16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 300 mg QD, d 1–7 (pm) (n=14) d 25–34 (pm) (n=12) 300 mg QD with ritonavir 100 mg QD, d 25–34 (am) (n=12) r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, d 1–12 (n=19) 400 mg QD, d 7–12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1.00 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08) Reyataz Fig 1