Reyataz Drug Information

• ® 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)

• 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

• Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4 , 7 , 12.3) 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3) ] . The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 7.2 Potential for Other Drugs to Affect REYATAZ Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect ( see Table 16 ). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with REYATAZ [see Dosage and Administration ( 2.3 , 2.4 , 2.5 and 2.6) ] . 7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6) . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) ] . Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ] . indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ] . ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ] . glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4) ] . voxilaprevir/sofosbuvir/velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ] . Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban REYATAZ with ritonavir ↑ rivaroxaban Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. REYATAZ ↑ rivaroxaban Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. apixaban REYATAZ with ritonavir ↑ apixaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. REYATAZ ↑ apixaban Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: carbamazepine ↓ atazanavir ↑ carbamazepine Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. Antifungals: ketoconazole, itraconazole REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir. voriconazole REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day . If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day . Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterials: rifampin ↓ atazanavir Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ] . rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan ↑ irinotecan Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4) ] . apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4) ] . ivosidenib ↓ atazanavir ↑ ivosidenib Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. encorafenib ↓ atazanavir ↑ encorafenib Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets: ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. lurasidone REYATAZ with ritonavir ↑ lurasidone REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. REYATAZ ↑ lurasidone REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. quetiapine ↑ quetiapine Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ]. parenterally administered midazolam b ↑ midazolam Coadministration with parenteral midazolam 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. Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Corticosteroids: dexamethasone and other corticosteroids (all routes of administration) ↓ atazanavir ↑ corticosteroids Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor antagonists: bosentan REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4) ]. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix ↓ atazanavir ↑ elagolix Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. Herbal Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4) ]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ]. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4) ]. H 2 - Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H 2 -receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.
• REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA.
• REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA.
• REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol ↑ norgestimate c ↑ ethinyl estradiol ↑ norethindrone d Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone REYATAZ ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. REYATAZ with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and REYATAZ with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ] . Macrolide antibiotics: clarithromycin ↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied. Opioids: buprenorphine REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. REYATAZ ↓ atazanavir The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO ® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4) ] . The following dose adjustments are recommended for the use of ADCIRCA ® (tadalafil) with REYATAZ: Coadministration of ADCIRCA ® in patients on REYATAZ (with or without ritonavir):
• For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA ® :
• Avoid the use of ADCIRCA ® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA ® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA ® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS ® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ : Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended. 7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3) ] .

• Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data ] . Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period
• REYATAZ must be administered with ritonavir in pregnant patients.
• For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:
• For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H 2 -receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H 2 -receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.
• No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ] . Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8) ] , including those who are pregnant [see Data ] . Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to REYATAZ in utero , should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data ] . Data Human Data In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.

Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus . All REYATAZ contraindications, warnings, and precautions apply to pediatric patients . The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 . The safety profile in pediatric patients was generally similar to that observed in adults . See Dosage and Administration for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.

• is contraindicated:
• in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2) ] .
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
• when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA ® for erectile dysfunction. Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Antimycobacterials Rifampin Antineoplastics Apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics Lurasidone (with ritonavir), pimozide Benzodiazepines Orally administered midazolam a , triazolam Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility Agent Cisapride Hepatitis C Direct-Acting Antivirals Elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum ) Lipid-Modifying Agents: Lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil b when dosed as REVATIO ® for the treatment of pulmonary arterial hypertension Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine
• In patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ. (4)
• Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. ( 4 )
• Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. ( 4 )

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy participants without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation.

These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed . Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage.

Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.