ATAZANAVIR: 5,434 Adverse Event Reports & Safety Profile

EVOTAZ ® is a fixed-dose tablet for oral administration containing the active ingredients atazanavir and cobicistat. Atazanavir is an HIV-1 protease inhibitor. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. EVOTAZ tablets contain 342 mg of atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat, as well as the following inactive ingredients in the tablet core: croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium starch glycolate, and stearic acid. The tablets are film-coated with a coating material containing the following inactive ingredients: hypromellose, red iron oxide, talc, titanium dioxide, triacetin. Atazanavir: Atazanavir is present as the sulfate salt. The chemical name for atazanavir sulfate is (3 S ,8 S ,9 S ,12 S )-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C 38 H 52 N 6 O 7

• H 2 SO 4 , which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C. Cobicistat: The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0. It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20°C. atazanavir chemical structure cobicistat chemical structure

AND USAGE EVOTAZ is a two-drug combination of atazanavir, a human immunodeficiency virus (HIV-1) protease inhibitor, and cobicistat, a CYP3A inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV‑1 infection in adults and pediatric patients weighing at least 35 kg. (1) Limitations of Use Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions. (1)

1.1 Indications EVOTAZ ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in the following populations <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3) ]</span> :

• Adult patients
• Pediatric patients weighing at least 35 kg.

1.2 Limitations of Use Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.4) ]</span> .

AND ADMINISTRATION

• Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2)
• Treatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3)
• Treatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3)
• Pediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4)
• REYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than 5 kg. (2.5)
• Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6)
• Dosing modifications: may be required for concomitant therapy ( 2.3 , 2.4 , 2.5 , 2.6) , renal impairment (2.7) , and hepatic impairment. (2.8)

2.1 Overview

• REYATAZ capsules and oral powder must be taken with food.
• Do not open the capsules.
• The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2 -receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3 , 2.4 , 2.5 , and 2.6 ) and Drug Interactions (7) ] .
• REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) ] .
• REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.5) ] .
• Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.

2.2 Testing Prior to Initiation and During Treatment with REYATAZ Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5 , 5.6) ]</span> . Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

2.3 Dosage of REYATAZ in Adult Patients Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults.

Table

1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H 2 -receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.

Table

1: Recommended REYATAZ and Ritonavir Dosage in Adults a,b a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.

Reyataz

Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg

2.4 Dosage of REYATAZ Capsules in Pediatric Patients The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).

Table

2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age) a,b a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients.

See Drug

Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir. Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experienced c Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards.

Table

3 displays the recommended dosage of REYATAZ oral powder and ritonavir.

Table

3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg) a,b a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients.

See Drug

Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ.

Body Weight Daily

Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir Oral Solution 5 kg to less than 15 kg 200 mg (4 packets) c,d 80 mg 15 kg to less than 25 kg 250 mg (5 packets) d 80 mg When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]

• Determine the number of packets (3, 4, 5 or 6 packets) that are needed.
• Prior to mixing, tap the packet to settle the powder.
• It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
• Use a clean pair of scissors to cut each packet along the dotted line.
• Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.
• Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.
• Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
• Administer ritonavir immediately following REYATAZ powder administration.
• Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.

2.6 Dosage Adjustments in Pregnant Patients Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .

Table

4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patients a a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA.

Reyataz

Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF b In combination with EITHER H2RA OR tenofovir DF 400 mg 100 mg

2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span> .

2.8 Dosage Adjustments in Patients with Hepatic Impairment Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.

Table

5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment REYATAZ Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) REYATAZ with or without ritonavir is not recommended

The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Warnings and Precautions (5.8 , 5.9) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]. EVOTAZ is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product [see Warnings and Precautions (5.2) ] .
• when coadministered with drugs that strongly induce CYP3A4, which may lead to lower exposure of EVOTAZ resulting in potential loss of efficacy and development of possible resistance (Table 5).
• 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 5). For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [see Drug Interactions (7.3) ] . Coadministration is contraindicated with, but not limited to, the following drugs: Table 1: Drugs Contraindicated with EVOTAZ Drug Class Drugs within class that are contraindicated with EVOTAZ a Refer to Table 5 for sildenafil when administered for erectile dysfunction [see Drug Interactions (7.3) ]. b Refer to Table 5 for parenterally administered midazolam [see Drug Interactions (7.3) ].

Alpha

1-adrenoreceptor antagonist alfuzosin Antianginal ranolazine Antiarrhythmics dronedarone Anticonvulsants carbamazepine, phenobarbital, phenytoin Antigout colchicine (when used in patients with hepatic and/or renal impairment) Antimycobacterials rifampin Antineoplastics apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics lurasidone, pimozide Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine Hepatitis C Direct-Acting Antivirals elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum )

Hormonal

Contraceptives drospirenone/ethinyl estradiol Lipid-modifying Agents lomitapide, lovastatin, simvastatin Non-nucleoside Reverse Transcriptase Inhibitor nevirapine Phosphodiesterase-5 (PDE-5) Inhibitor sildenafil a when administered for the treatment of pulmonary arterial hypertension Protease Inhibitors indinavir Sedative/hypnotics triazolam, orally administered midazolam b

• EVOTAZ is contraindicated in patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)
• EVOTAZ is contraindicated with drugs that are strong inducers of CYP3A4 due to the potential for loss of therapeutic effect and development of possible resistance. (4)
• EVOTAZ is contraindicated with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4)

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:

• cardiac conduction abnormalities [see Warnings and Precautions (5.1) ]
• rash [see Warnings and Precautions (5.2) ]
• hyperbilirubinemia [see Warnings and Precautions (5.8) ]
• chronic kidney disease [see Warnings and Precautions (5.5) ]
• nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse

Reactions in Treatment-Naive Adult Participants The safety profile of REYATAZ in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants received REYATAZ 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive participants receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table

7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424-138 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. 96 weeks c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d 400 mg / 100 mg (twice daily) and tenofovir DF/emtricitabine e (n=437)

Digestive System Nausea

4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced participants receiving REYATAZ with ritonavir are presented in Table 9.

Table

9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, b Study AI424-045 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. 48 weeks c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.

Table

10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424-138 a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. 96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d Variable Limit e (n=441) (n=437)

Chemistry

High SGOT/AST ≥5.1 × ULN 3% 1% SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limit d (n=404) (n=401) (n=279) (n=191)

Chemistry

High SGOT/AST ≥5.1 × ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table

12: Lipid Values, Mean Change from Baseline, Study AI424-138 a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm.

Through Week

48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm.

Through Week

96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Change d mg/dL Change d mg/dL mg/dL Change d mg/dL Change d (n=428 e ) (n=372 e ) (n=372 e ) (n=342 e ) (n=342 e ) (n=424 e ) (n=335 e ) (n=335 e ) (n=291 e ) (n=291 e ) LDL-Cholesterol f 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol f 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol f 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides f 126 145 +15% 140 +13% 129 194 +52% 184 +50% Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm.

Through Week

48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ a,b efavirenz b,c Baseline mg/dL (n=383 e )

Week

48 mg/dL (n=283 e )

Week

48 Change d (n=272 e ) Baseline mg/dL (n=378 e )

Week

48 mg/dL (n=264 e )

Week

48 Change d (n=253 e ) LDL-Cholesterol f 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides f 138 124 −9% 129 168 +23% Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14.

Table

14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045 a a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. 48 weeks b 48 weeks b REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI Variable Limit c (n=119) (n=118)

Chemistry

High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

Table

15: Lipid Values, Mean Change from Baseline, Study AI424-045 a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm.

Through Week

48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b Lopinavir/ritonavir b,c Baseline mg/dL (n=111 e )

Week

48 mg/dL (n=75 e )

Week

48 Change d (n=74 e ) Baseline mg/dL (n=108 e )

Week

48 mg/dL (n=76 e )

Week

48 Change d (n=73 e ) LDL-Cholesterol f 108 98 −10% 104 103 +1% HDL-Cholesterol 40 39 −7% 39 41 +2% Total Cholesterol 188 170 −8% 181 187 +6% Triglycerides f 215 161 −4% 196 224 +30% Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric participants with HIV-1 (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric participants were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse

Reactions in Pediatric Participants with HIV-1: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 participants weighing at least 5 kg to less than 35 kg, including 134 participants exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric participants with HIV-1 (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse

Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir.

In

Study AI424-045, 20 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir.

In

Studies AI424-008 and AI424-034, 74 participants treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the participants treated with REYATAZ, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with REYATAZ, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [see Warnings and Precautions (5.8) ] .

6.2 Postmarketing Experience The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>

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

AND PRECAUTIONS

• Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. Consider ECG monitoring in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. ( 5.1 , 6 , 7.3 , 12.2 , 17 )
• Severe skin reactions: Discontinue if severe rash develops. ( 5.2 , 6.1 , 17 )
• Assess creatinine clearance (CLcr) before initiating treatment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. ( 5.3 )
• When cobicistat, a component of EVOTAZ, is used in combination with a tenofovir disoproxil fumarate (tenofovir DF)-containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. ( 5.4 )
• When used with tenofovir DF, assess urine glucose and urine protein at baseline and monitor CLcr, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. Coadministration with tenofovir DF is not recommended in patients with CLcr below 70 mL/min or in patients also receiving a nephrotoxic agent. ( 5.4 )
• Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment with EVOTAZ. Consider discontinuation of EVOTAZ in patients with progressive renal disease. ( 5.5 )
• Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. ( 5.6 , 6 )
• Hepatotoxicity: Patients with hepatitis B or C are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. ( 2.5 , 5.7 , 8.7 )
• Antiretrovirals that are not recommended: EVOTAZ is not recommended for use with ritonavir or products containing ritonavir, or in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other protease inhibitors and elvitegravir). ( 5.9 )
• Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. ( 5.10 , 6 )
• Patients receiving EVOTAZ may develop immune reconstitution syndrome ( 5.11 ), new onset or exacerbations of diabetes mellitus/hyperglycemia ( 5.12 , 6 ), and redistribution/accumulation of body fat ( 5.13 ).
• Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. ( 5.14 )

5.1 Cardiac Conduction Abnormalities Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) and Overdosage (10) ]</span> . In clinical trials of atazanavir in participants with HIV-1 that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of participants treated with atazanavir (n=920) and 5% of participants (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block), consider ECG monitoring in these patients <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> .

5.2 Severe Skin Reactions Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir <span class="opacity-50 text-xs">[see Contraindications (4) and Adverse Reactions (6.1) ]</span> . EVOTAZ should be discontinued if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation.

5.3 Effects on Serum Creatinine Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.2) ]</span> . Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.

5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir DF Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

• When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment.
• Measure serum phosphorus in patients with or at risk for renal impairment.
• Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. In a clinical trial over 144 weeks (N=692), 10 (2.9%) participants treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) participants treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants treated with cobicistat, with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any participant.

5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3 ) and Adverse Reactions (6.1) ]</span>.

5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 , 6.1 )]</span> .

5.7 Hepatotoxicity Patients with underlying hepatitis B or C virus or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with EVOTAZ and during treatment <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Use in Specific Populations (8.7) ]</span> .

5.8 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions Initiation of EVOTAZ, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving EVOTAZ, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ, respectively. Increased concentrations of EVOTAZ may lead to:

• clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications.
• clinically significant adverse reactions from higher exposures of EVOTAZ. Decreased concentrations of EVOTAZ may lead to:
• loss of therapeutic effect of EVOTAZ and possible development of resistance.

See Table

5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7.3) ] . Consider the potential for drug interactions prior to and during EVOTAZ therapy; review concomitant medications during EVOTAZ therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . When used with concomitant medications, EVOTAZ may result in different drug interactions than those observed or expected with atazanavir coadministered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with atazanavir coadministered with ritonavir to certain EVOTAZ interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] .

5.9 Antiretrovirals that are Not Recommended EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance. EVOTAZ is not recommended in combination with ritonavir or products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

See Drug

Interactions (7) for additional recommendations on use with other antiretroviral agents.

5.10 Hyperbilirubinemia Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin greater than 5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to EVOTAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.11 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium , cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.12 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

5.13 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.14 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

INTERACTIONS Coadministration of atazanavir 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 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 (e.g., paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected <span class="opacity-50 text-xs">[see Clinical Pharmacology, Table 22 (12.3) ]</span> . 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.

7.2 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&apos;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4 , and 2.6) ]</span> .

7.3 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 (2.6) . 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 [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 atazanavir 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 atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ]. 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 [see Contraindications (4) ]. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of atazanavir 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 atazanavir is not recommended.

Other Agents Alpha

1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of atazanavir with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ]. 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 [see Contraindications (4) ]. 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 apixaban Atazanavir with ritonavir ↑ rivaroxaban Atazanavir ↑ rivaroxaban Atazanavir with ritonavir ↑ apixaban Atazanavir ↑ apixaban 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. 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. 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 [see Contraindications (4) ]. 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 [see Contraindications (4) ]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and atazanavir with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with atazanavir without ritonavir. Antifungals: ketoconazole, itraconazole Atazanavir with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with atazanavir 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 atazanavir with ritonavir. voriconazole Atazanavir with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir Atazanavir with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving atazanavir 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 atazanavir with ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of atazanavir with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with atazanavir: 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 atazanavir 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% (e.g., 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 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 [see Contraindications (4) ]. 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 [see Contraindications (4) ]. 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 [see Contraindications (4) ]. lurasidone quetiapine Atazanavir with ritonavir ↑ lurasidone Atazanavir ↑ lurasidone ↑ quetiapine 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 [see Contraindications (4) ]. Atazanavir without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. 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 [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 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 [see Contraindications (4) ]. 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 [see Contraindications (4) ]. 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 [see Contraindications (4) ]. 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 [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 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 [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: 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 (e.g., 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 Concomitant use of fluticasone propionate and atazanavir without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Atazanavir with ritonavir ↑ fluticasone 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 [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 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 [see Contraindications (4) ] . 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 (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.

7.4 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology, Tables 21 and 22 (12.3) ]</span>.