Atazanavir Drug Information

Atazanavir capsules are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg. Limitations of Use: Atazanavir capsules are not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus . Use of atazanavir capsules with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions . Atazanavir capsules are 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 6 years and older weighing at least 15 kg.

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 atazanavir in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received atazanavir 300 mg with ritonavir 100 mg and 1089 participants received atazanavir 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 atazanavir 300 mg with ritonavir 100 mg and atazanavir 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 96 weeks c atazanavir 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% * 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 atazanavir. 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. 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 Study AI424-034 Studies AI424-007, -008 64 weeks c atazanavir 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 atazanavir 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% * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing atazanavir. 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. Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of atazanavir 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 atazanavir 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 48 weeks c atazanavir 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% * * 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 atazanavir. c Median time on therapy. d As a fixed-dose product. Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including atazanavir 300 mg with ritonavir 100 mg or atazanavir 400 mg (without ritonavir) with Grade 3 to 4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.

Table 10: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424-138 Variable Limit e 96 weeks b atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c (n=441) 96 weeks b lopinavir/ritonavir 400 mg/100 mg c (twice daily) and tenofovir DF/emtricitabine d (n=437) Chemistry High SGOT/AST ≥5.1 x ULN 3% 1% SGPT/ALT ≥5.1 x ULN 3% 2% Total Bilirubin ≥2.6 x ULN 44% <1% Lipase ≥2.1 x ULN 2% 2% Creatine Kinase ≥5.1 x ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% a Based on the regimen containing atazanavir. 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. Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 Variable Limit d 64 weeks b atazanavir 400 mg once daily and lamivudine/ zidovudine e (n=404) 64 weeks b efavirenz 600 mg once daily and lamivudine/ zidovudine e (n=401) 120 weeks b,c atazanavir 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine (n=279) 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine (n=191) Chemistry High SGOT/AST ≥5.1 x ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 x ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 x ULN 35% <1% 47% 3% Amylase ≥2.1 x ULN * * 14% 10% Lipase ≥2.1 x ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 x 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% * None reported in this treatment arm. a Based on regimen(s) containing atazanavir. 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. 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 atazanavir with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL (n=428 e ) mg/dL (n=372 e ) Change d (n=372 e ) mg/dL (n=342 e ) Change d (n=342 e ) mg/dL (n=424 e ) mg/dL (n=335 e ) Change d (n=335 e ) mg/dL (n=291 e ) Change d (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% a Atazanavir 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 atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir with ritonavir arm.

Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir 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. Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 atazanavir 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% a Atazanavir 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 atazanavir arm.

Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the atazanavir 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. Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including atazanavir with ritonavir having Grade 3 to 4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045 a Variable Limit c 48 weeks b atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks b lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) Chemistry High SGOT/AST ≥5.1 x ULN 3% 3% SGPT/ALT ≥5.1 x ULN 4% 3% Total Bilirubin ≥2.6 x ULN 49% <1% Lipase ≥2.1 x ULN 5% 6% Creatine Kinase ≥5.1 x 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% a Based on regimen(s) containing atazanavir. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. 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 atazanavir 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 atazanavir 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% a Atazanavir 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 atazanavir with ritonavir arm.

Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir 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. Adverse Reactions in Pediatric Participants with HIV-1: Atazanavir Capsules The safety and tolerability of atazanavir 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 atazanavir 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 atazanavir in adults. The most common Grade 2 to 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 to 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 to 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 atazanavir 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 atazanavir 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 atazanavir with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir.

In Study AI424-045, 20 participants administered atazanavir 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 atazanavir 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 atazanavir with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir.

In Studies AI424-008 and AI424-034, 74 participants treated with atazanavir 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 atazanavir, 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 atazanavir, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir.

Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants .

Postmarketing Experience

The following events have been identified during postmarketing use of atazanavir. 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 Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis , cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia Musculoskeletal System: arthralgia Renal System: nephrolithiasis, interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema

Potential for Atazanavir to Affect Other Drugs Atazanavir is an inhibitor of

CYP3A and UGT1A1. Coadministration of atazanavir 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 atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected. The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir.

See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

Potential for Other Drugs to Affect Atazanavir Atazanavir is a

CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir’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 atazanavir.

Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations

in adults as a result of drug interactions with atazanavir. 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 Atazanavir with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations.

Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir 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 atazanavir 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 atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking atazanavir with ritonavir and tenofovir DF, see Dosage and Administration . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If atazanavir is combined with efavirenz, Atazanavir 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 atazanavir with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of atazanavir 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 . 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 atazanavir 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy . indinavir Coadministration of atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. ritonavir ↑ atazanavir If atazanavir is coadministered with ritonavir, it is recommended that atazanavir 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 atazanavir with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of atazanavir with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations. voxilaprevir/sofosbuvir/ velpatasvir ↑ voxilaprevir Coadministration with atazanavir is not recommended.

Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of atazanavir with alfuzosin is contraindicated due to risk for hypotension. Antacids and buffered medications: ↓ atazanavir Atazanavir 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 atazanavir with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias.

Coadministration with atazanavir 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 atazanavir without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with atazanavir 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 atazanavir 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 Atazanavir with ritonavir ↑ rivaroxaban Coadministration of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding.

Atazanavir ↑ rivaroxaban Coadministration of atazanavir, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when atazanavir is coadministered with rivaroxaban. apixaban Atazanavir with ritonavir ↑ apixaban Atazanavir ↑ apixaban Concomitant use of atazanavir 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.

Concomitant use of atazanavir, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with atazanavir. Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with atazanavir 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 atazanavir. 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 atazanavir, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: carbamazepine ↓ atazanavir ↑ carbamazepine Coadministration of atazanavir (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance .. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of atazanavir (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance. 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 rifabutin­associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan apalutamide ivosidenib encorafenib ↑ irinotecan ↓ atazanavir ↓ atazanavir ↑ ivosidenib ↓ atazanavir ↑ encorafenib Coadministration of atazanavir with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.

Coadministration of atazanavir (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 . Coadministration of ivosidenib with atazanavir (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. Coadministration of encorafenib with atazanavir (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 clopidogrel ↑ ticagrelor ↓ clopidogrel active metabolite Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor.

Coadministration of atazanavir (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 atazanavir with pimozide is contraindicated.

This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias. lurasidone Atazanavir with ritonavir ↑ lurasidone Atazanavir ↑ lurasidone Atazanavir with ritonavir Coadministration of lurasidone with atazanavir with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions. Atazanavir 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 atazanavir 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 atazanavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with atazanavir can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. 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 atazanavir 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 atazanavir 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 Atazanavir ↓ atazanavir Atazanavir with ritonavir ↑ bosentan Coadministration of bosentan and atazanavir without ritonavir is not recommended. For adult patients who have been receiving atazanavir 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 atazanavir with ritonavir.

At least 10 days after starting atazanavir 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 atazanavir 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.

GI Motility Agents: cisapride ↑ cisapride Coadministration of atazanavir with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix ↓ atazanavir ↑ elagolix Coadministration of elagolix and atazanavir 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 200 mg twice daily with atazanavir with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with atazanavir (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 atazanavir is contraindicated. This may result in loss of therapeutic effect of atazanavir and the development of resistance. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with atazanavir (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 atazanavir with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis. 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 atazanavir, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of atazanavir 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. H 2 -Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance.

In HIV-treatment-naive adult patients: Atazanavir 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 atazanavir 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, atazanavir 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 atazanavir without ritonavir in pregnant patients is not recommended.

In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving atazanavir with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the atazanavir with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. Atazanavir 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. Atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. Atazanavir 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. Atazanavir is not recommended for pregnant patients during the second and third trimester taking atazanavir 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 atazanavir or atazanavir with ritonavir. If atazanavir with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol.

If atazanavir 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 atazanavir or atazanavir 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 atazanavir. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with atazanavir is not recommended.

Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone Atazanavir ↑ fluticasone Atazanavir with ritonavir ↑ fluticasone Concomitant use of fluticasone propionate and atazanavir without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long­term use.

With concomitant use of fluticasone propionate and atazanavir 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 atazanavir with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects . 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 atazanavir. 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 atazanavir with ritonavir and clarithromycin has not been studied. Opioids: buprenorphine Atazanavir or atazanavir with ritonavir ↑ buprenorphine ↑ norbuprenorphine Atazanavir ↓ atazanavir Coadministration of atazanavir with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.

The coadministration of atazanavir and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with atazanavir 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 atazanavir with REVATIO ® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated . The following dose adjustments are recommended for the use of ADCIRCA ® (tadalafil) with atazanavir: Coadministration of ADCIRCA ® in patients on atazanavir (with or without ritonavir): For patients receiving atazanavir (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 atazanavir (with or without ritonavir) in patients on ADCIRCA ® : Avoid the use of ADCIRCA ® when starting atazanavir (with or without ritonavir). Stop ADCIRCA ® at least 24 hours before starting atazanavir (with or without ritonavir). At least one week after starting atazanavir (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. Atazanavir 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.

Atazanavir: 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 atazanavir 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 atazanavir 300 mg with ritonavir 100 mg dose.

In HIV-treatment-experienced adult patients: Coadministration of atazanavir with PPIs is not recommended. a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 . b See Contraindications, 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.

Drugs with No Observed Interactions with Atazanavir No clinically significant drug interactions

were observed when atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine .

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to atazanavir 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 . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7 to 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 . Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period Atazanavir must be administered with ritonavir in pregnant patients. For pregnant patients, no dosage adjustment is required for atazanavir with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an H 2 -receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend an atazanavir 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 . Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir , including those who are pregnant . Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life . Data Human Data In Study AI424-182, atazanavir 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 atazanavir with ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir 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 to 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 Atazanavir capsules are indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 6 years of age and older weighing at least 15 kg. Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus . All atazanavir contraindications, warnings, and precautions apply to pediatric patients . The safety, pharmacokinetic profile, and virologic response of atazanavir in pediatric patients at least 6 years of age and older weighing at least 15 kg were established in an open-label, multicenter clinical trial: PACTG 1020A . 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 atazanavir capsules.

• Atazanavir 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 atazanavir capsules . 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 Atazanavir (Information in the table applies to Atazanavir with or without ritonavir, unless otherwise indicated) Drug Class Drugs within class that are contraindicated with Atazanavir Alpha 1-adrenoreceptor antagonist Alfuzosin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Anticonvulsants Carbamazepine, phenobarbital, phenytoin 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 a See Drug Interactions, Table 16 for parenterally administered midazolam. b See Drug Interactions, Table 16 for sildenafil when dosed as VIAGRA ® for erectile dysfunction. In patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of atazanavir capsules. Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. 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.

Human experience of acute overdose with atazanavir 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 atazanavir 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 atazanavir 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 atazanavir 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 atazanavir.

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.