What is mechanism of action?

mechanism of action is Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA], Breast Cancer Resistance Protein Inhibitors [MoA], P-Glycoprotein Inhibitors [MoA], Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA], Cytochrome P450 2D6 Inhibitors [MoA], Cytochrome P450 3A Inhibitors [MoA] or Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA]

Evotaz

(Atazanavir And Cobicistat)

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Dosage & Administration

* •

Pretreatment testing:

Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ.

2.1 Laboratory Testing Prior to Initiation and During Treatment with EVOTAZ

Renal Testing

Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Renal laboratory testing should include estimated creatinine clearance, serum creatinine, and urinalysis with microscopic examination

[see Warnings and Precautions (5.5, 5.6)]

. Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function

[see Warnings and Precautions (5.3)]

When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline and routinely monitor during treatment. In patients with chronic kidney disease, also monitor serum phosphorus

[see Warnings and Precautions (5.4)]

Hepatic Testing

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ

[see Warnings and Precautions (5.7)].

* •

Recommended dosage:

One tablet once daily, taken orally with food in adults and pediatric patients weighing at least 35 kg.

2.2 Recommended Dosage

EVOTAZ is a fixed-dose tablet containing 300 mg of atazanavir and 150 mg of cobicistat. The recommended dosage of EVOTAZ is one tablet taken once daily orally with food

[see Clinical Pharmacology (12.3)]

in both treatment-naive and treatment-experienced patients with HIV-1:

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

Administer EVOTAZ in conjunction with other antiretroviral agents

[see Drug Interactions (7)]

. Dose separation may be required when taken with H₂-receptor antagonists or proton-pump inhibitors

[see Drug Interactions (7.2, 7.3)]

* •

Renal impairment:

EVOTAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis.

2.3 Dosage in Patients with Renal Impairment

EVOTAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis

[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]

EVOTAZ coadministered with tenofovir DF is not recommended in patients with estimated creatinine clearance below 70 mL/min. Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended

[see Warnings and Precautions (5.4)and Adverse Reactions (6.1)]

8.6 Renal Impairment

EVOTAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis

[see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]

* •

Hepatic impairment:

EVOTAZ is not recommended in patients with any degree of hepatic impairment.

2.4 Not Recommended in Patients with Any Degree of Hepatic Impairment

EVOTAZ is not recommended in patients with any degree of hepatic impairment

[see

Warnings and Precautions (5.7)

, Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]

8.7 Hepatic Impairment

EVOTAZ is not recommended for use in patients with any degree of hepatic impairment

[see Dosage and Administration (2.4),

Warnings and Precautions (5.7)

, and Clinical Pharmacology (12.3)]

Evotaz Prescribing Information

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:

•
Contraindications ( 4 CONTRAINDICATIONS 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:

Table 1: Drugs Contraindicated with EVOTAZ
Drug Class	Drugs within class that are contraindicated with EVOTAZ
^aRefer to Table 5 for sildenafil when administered for erectile dysfunction [see Drug Interactions (7.3)].
^bRefer 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^awhen 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)

)

05/2025

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 INDICATIONS AND USAGE

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

[see Dosage and Administration (2.2 , 2.3)]

•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

[see

Clinical Pharmacology (12.4)

]

Limitations of Use

Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions.

1 INDICATIONS AND USAGE

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

[see Dosage and Administration (2.2 , 2.3)]

•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

[see

Clinical Pharmacology (12.4)

]

•
Pretreatment testing:
Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ.
2.1 Laboratory Testing Prior to Initiation and During Treatment with EVOTAZ
Renal Testing
Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Renal laboratory testing should include estimated creatinine clearance, serum creatinine, and urinalysis with microscopic examination
[see Warnings and Precautions (5.5, 5.6)]
. Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function
[see Warnings and Precautions (5.3)]
.
When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline and routinely monitor during treatment. In patients with chronic kidney disease, also monitor serum phosphorus
[see Warnings and Precautions (5.4)]
.
Hepatic Testing
Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ
[see Warnings and Precautions (5.7)].
•
Recommended dosage:
One tablet once daily, taken orally with food in adults and pediatric patients weighing at least 35 kg.
2.2 Recommended Dosage
EVOTAZ is a fixed-dose tablet containing 300 mg of atazanavir and 150 mg of cobicistat. The recommended dosage of EVOTAZ is one tablet taken once daily orally with food
[see Clinical Pharmacology (12.3)]
in both treatment-naive and treatment-experienced patients with HIV-1:
- •Adult patients
- •Pediatric patients weighing at least 35 kg
Administer EVOTAZ in conjunction with other antiretroviral agents
[see Drug Interactions (7)]
. Dose separation may be required when taken with H₂-receptor antagonists or proton-pump inhibitors
[see Drug Interactions (7.2, 7.3)]
.
•
Renal impairment:
EVOTAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis.
2.3 Dosage in Patients with Renal Impairment
EVOTAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis
[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]
.
EVOTAZ coadministered with tenofovir DF is not recommended in patients with estimated creatinine clearance below 70 mL/min. Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended
[see Warnings and Precautions (5.4)and Adverse Reactions (6.1)]
.
,
8.6 Renal Impairment
EVOTAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis
[see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]
.
•
Hepatic impairment:
EVOTAZ is not recommended in patients with any degree of hepatic impairment.
2.4 Not Recommended in Patients with Any Degree of Hepatic Impairment
EVOTAZ is not recommended in patients with any degree of hepatic impairment
[see
Warnings and Precautions (5.7)
, Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]
.
,
8.7 Hepatic Impairment
EVOTAZ is not recommended for use in patients with any degree of hepatic impairment
[see Dosage and Administration (2.4),
Warnings and Precautions (5.7)
, and Clinical Pharmacology (12.3)]
.

•
Pregnancy:
EVOTAZ is not recommended during pregnancy and should not be initiated in pregnant individuals; use of an alternative regimen is recommended.
2.5 Not Recommended During Pregnancy
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals due to substantially lower exposures of cobicistat and consequently, lower exposures of atazanavir, during the second and third trimesters. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ
[see Use in Specific Populations (8.1)]
.
,
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals
[see Dosage and Administration (2.5)]
; use of an alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ. Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposures during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component, atazanavir.
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Atazanavir use during pregnancy has been evaluated in a limited number of individuals. Available data from the APR show no increase in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)
(see Data)
. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15−20%.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits
(see Data)
. During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg
(see Data)
.
Clinical Considerations
EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ
(see Risk Summary)
.
Maternal Adverse Reactions
Atazanavir
Reports of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant individuals 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 pregnant individuals. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.
Fetal/Neonatal Adverse Reactions
Atazanavir
Infants exposed to atazanavir
in utero
may develop severe hyperbilirubinemia during the first few days of life.
Data
Human Data
Atazanavir
The APR has received prospective reports of live births following exposure to atazanavir-containing regimens during pregnancy, including 1361 exposures in the first trimester and 737 exposures in second/third trimester. Birth defects occurred in live births in 30 of 1361 (2.2%, 95% CI: 1.5% to 3.1%) with first trimester exposure to atazanavir-containing regimens and 17 of 737 (2.3%, 95% CI: 1.3% to 3.7%) with second/third trimester exposure to atazanavir-containing regimens. There was no increase in the overall rate of birth defects for atazanavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
Cobicistat
The APR has received prospective reports of live births following exposure to cobicistat-containing regimens during pregnancy, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Birth defects occurred in 13 of 347 (3.7%, 95% CI: 2.0% to 6.3%) live births with first trimester exposure and 1 of 79 (1.3%, 95% CI: 0.0% to 6.9%) with second/third trimester exposure to cobicistat-containing regimens. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. There was no increase in the overall rate of birth defects for cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Animal Data
Atazanavir
Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD.
Cobicistat
Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD.
In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.
•
Pediatrics:
EVOTAZ is not recommended for patients weighing less than 35 kg.
8.4 Pediatric Use
The safety and effectiveness of EVOTAZ for the treatment of HIV-1 in pediatric participants weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric participants with HIV-1 aged 12 years and older. The safety in these participants through 48 weeks was similar to that in antiretroviral treatment-naive adults
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]
.
Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.

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

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.

7 DRUG INTERACTIONS

Coadministration of EVOTAZ can alter the concentration of other drugs and other drugs may alter the concentration of EVOTAZ, which may result in known or potentially significant drug interactions. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3)

7.1 Potential for EVOTAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1 and a weak inhibitor of CYP2C8. Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3.

Coadministration of EVOTAZ with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated

[see Contraindications (4)]

. Coadministration of EVOTAZ and drugs primarily metabolized by CYP3A, UGT1A1 and/or CYP2D6 or drugs that are substrates of P-gp, BCRP, OATP1B1 and/or OATP1B3 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic effects and adverse reactions which may require dose adjustments and/or additional monitoring as shown in Table 5. Use of EVOTAZ is not recommended when coadministered with drugs highly dependent on CYP2C8 for clearance with narrow therapeutic indices (e.g., paclitaxel, repaglinide)

[see

Clinical Pharmacology (12.3; Table 7)

]

7.2 Potential for Other Drugs to Affect EVOTAZ

Atazanavir and cobicistat are CYP3A4 substrates; therefore, drugs that induce CYP3A4 may decrease atazanavir and cobicistat plasma concentrations and reduce the therapeutic effect of EVOTAZ, leading to development of resistance to atazanavir (see Table 5). Cobicistat is also metabolized by CYP2D6 to a minor extent.

Coadministration of EVOTAZ with other drugs that inhibit CYP3A4 may increase the plasma concentrations of cobicistat and atazanavir (see Table 5).

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H₂-receptor antagonists are administered with EVOTAZ (see Table 5)

[see

Dosage and Administration (2.2)

]

7.3 Established and Other Potentially Significant Drug Interactions

Table 5 provides dosing recommendations as a result of drug interactions with the components of EVOTAZ. These recommendations are based either on observed drug interactions in studies of cobicistat, atazanavir, or atazanavir coadministered with ritonavir or predicted drug interactions based on the expected magnitude of interaction and potential for serious events or loss of therapeutic effect of EVOTAZ

[see Contraindications (4),

Warnings and Precautions (5.8)

, and Clinical Pharmacology (12.3)]

Tadalafil

: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ:

Initiation of tadalafil in patients taking EVOTAZ:For patients receiving EVOTAZ for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.Initiation of EVOTAZ in patients taking tadalafil:Avoid the use of tadalafil when starting EVOTAZ. Stop tadalafil at least 24 hours before starting EVOTAZ. At least one week after starting EVOTAZ, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.Patients switching from atazanavir coadministered with ritonavir to EVOTAZ:Maintain tadalafil dose.

Avanafil

: Not recommended because a safe and effective dose of avanafil has not been established.

Sildenafil

: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions.

Tadalafil

: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions.

Vardenafil

: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor Predicted Interactions
Concomitant Drug Class: Specific Drugs	Effect^bon Concentration	Clinical Comment
^aFor magnitude of interactions see Clinical Pharmacology (12.3; Table 7) . ^b↑ = Increase, ↓ = Decrease, ↔ = No change.
HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs)
didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times.
tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions [see Warnings and Precautions (5.4)] .
HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions [see Contraindications (4)] .
efavirenz	↓ atazanavir ↓ cobicistat ↔ efavirenz	Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to atazanavir.
etravirine	↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.
HIV Antiretroviral Agents: CCR5 Antagonist
maraviroc	↑ maraviroc	When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily.
HIV Antiretroviral Agents: Protease Inhibitor
indinavir		Coadministration with indinavir is contraindicated [see Contraindications (4)] . Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
ritonavir or products containing ritonavir	↑ atazanavir	Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see Warnings and Precautions (5.9) ] .
Hepatitis C Antiviral Agents
sofosbuvir/velpatasvir/ voxilaprevir	↑ voxilaprevir	Coadministration with EVOTAZ is not recommended.
Other Agents
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension [see Contraindications (4)] .
Antacids and buffered medications (please also see H₂-receptor antagonists and proton-pump inhibitors below)	↓ atazanavir	With concomitant use, administer a minimum of 2 hours apart.
Antianginal: ranolazine	↑ ranolazine	Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
Antiarrhythmics: dronedarone	↑ dronedarone	Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin	↑ other antiarrhythmics ↑ digoxin	Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin	↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin	Consider alternative antibiotics.
Anticancer Agents: irinotecan	↑ irinotecan	Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [see Contraindications (4)] .
(e.g., dasatinib, nilotinib, vinblastine, vincristine)	↑ other anticancer agents	A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.
Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information.
rivaroxaban	↑ rivaroxaban	Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk.
betrixaban dabigatran etexilate edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	warfarin: effect unknown	Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine)	↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] . Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.
Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam)	↑ clonazepam	Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration.
Other anticonvulsants (e.g., lamotrigine)	lamotrigine: effects unknown	Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine)	SSRIs: effects unknown	When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline)	↑ TCAs
Other Antidepressants (e.g., trazodone)	↑ trazodone
Antifungals: ketoconazole, itraconazole	↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole	Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole.
voriconazole	effects unknown	Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.
Antigout: colchicine	↑ colchicine	Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] . Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 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: Rifabutin	atazanavir: effect unknown cobicistat: effect unknown ↑ 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 and uveitis, is warranted.
rifampin	↓ atazanavir ↓ cobicistat	Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
Antineoplastics: apalutamide	↓ atazanavir ↓cobicistat	Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide.
ivosidenib	↓ atazanavir ↓ cobicistat ↑ ivosidenib	Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib.
encorafenib	↓ atazanavir ↓ cobicistat ↑ encorafenib	Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib.
Antiplatelets: ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.
prasugrel	↔ prasugrel active metabolite	No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat.
Antipsychotics: lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
quetiapine	↑ quetiapine	Initiation of EVOTAZ 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 EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
(e.g., perphenazine, risperidone, thioridazine)	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ.
Beta-agonist (inhaled): salmeterol	↑ salmeterol	Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Beta-Blockers: (e.g., metoprolol, carvedilol, timolol)	↔ atazanavir ↑ beta-blockers	Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ.
Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil)	↑ calcium channel blocker	Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.
Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone	↓ atazanavir ↓ cobicistat ↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Kinase inhibitors: fostamatinib	↑ R406 active metabolite of fostamatinib	Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↓ cobicistat ↑ bosentan	Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose.
Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix	↓ atazanavir ↓ cobicistat ↑ elagolix	Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure.
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Coadministration of EVOTAZ with ergot derivatives is contraindicated 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)] .
Hepatitis C Direct-Acting Antivirals : elbasvir/grazoprevir	↑ grazoprevir	Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
Herbal Products : St. John’s wort ( Hypericum perforatum)	↓ atazanavir ↓ cobicistat	Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
H ₂ ‑Receptor antagonists (H ₂ RA ) : (e.g., famotidine)	↓ atazanavir	Coadministration of EVOTAZ with tenofovir DF and an H₂RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H₂RA. The dose of the H₂RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients.
Lipid-modifying agents: Other lipid-modifying agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity [see Contraindications (4)] .
HMG-CoA reductase inhibitors : lovastatin simvastatin	↑lovastatin ↑simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)] .
Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day.
Hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone	Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia [see Contraindications (4)].
(e.g., progestin/estrogen)	progestin and estrogen: effects unknown	No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.
Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ.
Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone	buprenorphine or buprenorphine/naloxone: effects unknown methadone: effects unknown	Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.
fentanyl	↑ fentanyl	When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended.
tramadol	↑ tramadol	When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed.
Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ PDE-5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [see Contraindications (4)] .





		Use of PDE-5 inhibitors for erectile dysfunction:
Proton-pump inhibitors (PPI): (e.g., omeprazole)	↓ atazanavir	In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended.
Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4)] .
Other Benzodiazepines : clorazepate diazepam estazolam flurazepam parenterally administered midazolam	↑ sedatives/hypnotics	Parenterally administered midazolam: Coadministration 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.
Other Sedatives/Hypnotics: buspirone, zolpidem		With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.

7.4 Drugs with No Observed or Predicted Interactions with the Components of EVOTAZ

Based on known metabolic profiles, clinically significant drug interactions are not expected between EVOTAZ and acetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin

[see

Clinical Pharmacology (12.3; Table 7)

, and

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of EVOTAZ (atazanavir 300 mg and cobicistat 150 mg) were evaluated in healthy adult participants (Study AI424-511). Results are summarized in Table 6.

Table 6: Pharmacokinetic Properties of the Components of EVOTAZ
	Atazanavir	Cobicistat
^aFollowing EVOTAZ dosing under fasted conditions. ^bValues refer to geometric mean ratio (fed / fasted) and (90% confidence interval). ^cDosing in mass balance study: cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days). ND = not determined.
Absorption
T_max(h)	2.0	2.0
Effect of light meal (relative to fasting) AUC ratio^b	1.28 (1.17,1.40)	1.24 (1.15,1.34)
Effect of high fat meal (relative to fasting) AUC ratio^b	0.96 (0.81,1.13)	1.12 (1.01,1.23)
Effect of light meal (relative to fasting) C24 ratio^b	1.35 (1.22,1.50)	ND
Effect of high fat meal (relative to fasting) C24 ratio^b	1.23 (1.02,1.48)	ND
Distribution
% Bound to human plasma proteins	86	~98
Source of protein binding data	In vitro	In vitro
Blood-to-plasma ratio	ND	0.5
Metabolism
Metabolism	CYP3A (major) Glucuronidation, N-dealkylation, hydrolysis, oxygenation with dehydrogenation (minor)	CYP3A (major) CYP2D6 (minor)
Elimination
Major route of elimination	Metabolism	Metabolism
t_1/2(h)	7.2^a	3.5
% Of dose excreted in urine	ND	8.2^c
% Of dose excreted in feces	ND	86.2^c

The pharmacokinetics of atazanavir was evaluated in participants with HIV-1 who received atazanavir 300 mg coadministered with cobicistat 150 mg in combination with emtricitabine/tenofovir DF. The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat are shown in Table 7

[see Clinical Studies (14)]

Table 7: Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in the Pharmacokinetic Substudy of Study GS-US-216-0114
Parameter	Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=22)
AUC (µg•h/mL)	46.13 ± 26.18
C_max(µg/mL)	3.91 ± 1.94
C_tau(µg/mL)	0.80 ± 0.72

Specific Populations

Pediatric

In pediatric participants aged 12 to less than 18 years who received atazanavir 300 mg coadministered with cobicistat 150 mg (N=12), atazanavir exposures (AUC_tau, C_max, and C_tau) were 20-60% higher than in adults; the increases were not considered clinically significant (Table 8).

Table 8: Multiple Dose Pharmacokinetic Parameters of Atazanavir Following Coadministration of Atazanavir with Cobicistat in Pediatric Participants with HIV-1 Weighing at Least 35 kg
Atazanavir PK Parameter	Geometric Mean (CV%)
Atazanavir PK Parameter	Pediatric participants (N=12)^a	Adult participants (N=30)^b
CV=Coefficient of Variation ^aFrom intensive PK analysis of Study GS-US-216-0128 ^bFrom pooled intensive PK analysis of trials with atazanavir + cobicistat.
AUC_tau(µg/hr/mL)	49.48 (49.1)	39.96 (52.1)
C_max(µg/mL)	4.32 (49.9)	3.54 (45.8)
C_tau(µg/mL)	0.91 (96.4)	0.58 (84.7)

Renal Impairment

Atazanavir:

In healthy participants, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. In study AI424-105, atazanavir was studied in adult participants (n=20) with severe renal impairment (estimated creatinine clearance <30 mL/min, using 24-hour urinary creatinine and serum creatinine levels), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C_maxwas 9% lower, AUC was 19% higher, and C_minwas 96% higher in participants with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched participants with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C_max, AUC, and C_minwere approximately 25% to 43% lower compared to participants with normal renal function. The mechanism of this decrease is unknown.

Cobicistat:

No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with severe renal impairment (estimated creatinine clearance <30 mL/min, using the Cockcroft-Gault method) and healthy participants in Study GS-US-216-0124

[see Use in Specific Populations (8.6)]

Hepatic Impairment

EVOTAZ has not been studied in patients with hepatic impairment.

Atazanavir:

Increased concentrations of atazanavir are expected in those with moderately or severely impaired hepatic function (Study AI424-015).

Cobicistat:

No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with moderate hepatic impairment (Child-Pugh Class B) and healthy participants (Study GS-US-183-0133). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied

[see Use in Specific Populations (8.7)]

Pregnancy and Postpartum

Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposures during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component, atazanavir.

Gender, Age, and Race

Atazanavir:

No clinically important differences in atazanavir pharmacokinetics were observed based on age or gender.

Cobicistat:

No clinically relevant differences in cobicistat pharmacokinetics were observed based on race or gender.

Assessment of Drug Interactions

Atazanavir has been shown

in vivo

not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

The effects of cobicistat on the exposure of coadministered drugs are summarized in Table 9.

Table 9: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat^a,b
Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat-containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information.
Coadministered Drug	Coadministered Drug Dose/Schedule	Cobicistat Dose/Schedule	Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without cobicistat; No effect = 1.00
Coadministered Drug	Coadministered Drug Dose/Schedule	Cobicistat Dose/Schedule	C_max	AUC
^aAll interaction studies conducted in healthy participants. ^bStudies of cobicistat conducted in the presence of atazanavir 300 mg.
atorvastatin	10 mg single dose (n=16)	150 mg QD (n=16)	18.85^b (13.53, 26.27)	9.22^b (7.58, 11.22)
desipramine	50 mg single dose (n=8)	150 mg QD (n=8)	1.24 (1.08, 1.44)	1.65 (1.36, 2.02)
digoxin	0.5 mg single dose (n=22)	150 mg QD (n=22)	1.41 (1.29, 1.55)	1.08 (1.00, 1.17)
drospirenone/ ethinyl estradiol	3 mg drospirenone single dose (n=14)	150 mg QD (n=14)	1.12^b (1.05, 1.19)	2.30^b (2.00, 2.64)
drospirenone/ ethinyl estradiol	0.02 ethinyl estradiol single dose (n=14)	150 mg QD (n=14)	0.82^b (0.76, 0.89)	0.78^b (0.73, 0.85)
efavirenz	600 mg single dose (n=17)	150 mg QD (n=17)	0.87 (0.80, 0.94)	0.93 (0.89, 0.97)
rosuvastatin	10 mg single dose (n=16)	150 mg QD (n=16)	10.58^b (8.72, 12.83)	3.42^b (2.87, 4.07)

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

7.3 Established and Other Potentially Significant Drug Interactions

[see Contraindications (4),

Warnings and Precautions (5.8)

, and Clinical Pharmacology (12.3)]

Tadalafil

: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ:

Avanafil

: Not recommended because a safe and effective dose of avanafil has not been established.

Sildenafil

: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions.

Tadalafil

: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions.

Vardenafil

: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor Predicted Interactions
Concomitant Drug Class: Specific Drugs	Effect^bon Concentration	Clinical Comment
^aFor magnitude of interactions see Clinical Pharmacology (12.3; Table 7) . ^b↑ = Increase, ↓ = Decrease, ↔ = No change.
HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs)
didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times.
tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions [see Warnings and Precautions (5.4)] .
HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions [see Contraindications (4)] .
efavirenz	↓ atazanavir ↓ cobicistat ↔ efavirenz	Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to atazanavir.
etravirine	↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.
HIV Antiretroviral Agents: CCR5 Antagonist
maraviroc	↑ maraviroc	When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily.
HIV Antiretroviral Agents: Protease Inhibitor
indinavir		Coadministration with indinavir is contraindicated [see Contraindications (4)] . Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
ritonavir or products containing ritonavir	↑ atazanavir	Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see Warnings and Precautions (5.9) ] .
Hepatitis C Antiviral Agents
sofosbuvir/velpatasvir/ voxilaprevir	↑ voxilaprevir	Coadministration with EVOTAZ is not recommended.
Other Agents
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension [see Contraindications (4)] .
Antacids and buffered medications (please also see H₂-receptor antagonists and proton-pump inhibitors below)	↓ atazanavir	With concomitant use, administer a minimum of 2 hours apart.
Antianginal: ranolazine	↑ ranolazine	Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
Antiarrhythmics: dronedarone	↑ dronedarone	Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin	↑ other antiarrhythmics ↑ digoxin	Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin	↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin	Consider alternative antibiotics.
Anticancer Agents: irinotecan	↑ irinotecan	Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [see Contraindications (4)] .
(e.g., dasatinib, nilotinib, vinblastine, vincristine)	↑ other anticancer agents	A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.
Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information.
rivaroxaban	↑ rivaroxaban	Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk.
betrixaban dabigatran etexilate edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	warfarin: effect unknown	Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine)	↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] . Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.
Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam)	↑ clonazepam	Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration.
Other anticonvulsants (e.g., lamotrigine)	lamotrigine: effects unknown	Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine)	SSRIs: effects unknown	When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline)	↑ TCAs
Other Antidepressants (e.g., trazodone)	↑ trazodone
Antifungals: ketoconazole, itraconazole	↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole	Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole.
voriconazole	effects unknown	Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.
Antigout: colchicine	↑ colchicine	Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] . Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 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: Rifabutin	atazanavir: effect unknown cobicistat: effect unknown ↑ 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 and uveitis, is warranted.
rifampin	↓ atazanavir ↓ cobicistat	Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
Antineoplastics: apalutamide	↓ atazanavir ↓cobicistat	Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide.
ivosidenib	↓ atazanavir ↓ cobicistat ↑ ivosidenib	Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib.
encorafenib	↓ atazanavir ↓ cobicistat ↑ encorafenib	Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib.
Antiplatelets: ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.
prasugrel	↔ prasugrel active metabolite	No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat.
Antipsychotics: lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
quetiapine	↑ quetiapine	Initiation of EVOTAZ 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 EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
(e.g., perphenazine, risperidone, thioridazine)	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ.
Beta-agonist (inhaled): salmeterol	↑ salmeterol	Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Beta-Blockers: (e.g., metoprolol, carvedilol, timolol)	↔ atazanavir ↑ beta-blockers	Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ.
Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil)	↑ calcium channel blocker	Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.
Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone	↓ atazanavir ↓ cobicistat ↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Kinase inhibitors: fostamatinib	↑ R406 active metabolite of fostamatinib	Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↓ cobicistat ↑ bosentan	Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose.
Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix	↓ atazanavir ↓ cobicistat ↑ elagolix	Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure.
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Coadministration of EVOTAZ with ergot derivatives is contraindicated 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)] .
Hepatitis C Direct-Acting Antivirals : elbasvir/grazoprevir	↑ grazoprevir	Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
Herbal Products : St. John’s wort ( Hypericum perforatum)	↓ atazanavir ↓ cobicistat	Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
H ₂ ‑Receptor antagonists (H ₂ RA ) : (e.g., famotidine)	↓ atazanavir	Coadministration of EVOTAZ with tenofovir DF and an H₂RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H₂RA. The dose of the H₂RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients.
Lipid-modifying agents: Other lipid-modifying agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity [see Contraindications (4)] .
HMG-CoA reductase inhibitors : lovastatin simvastatin	↑lovastatin ↑simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)] .
Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day.
Hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone	Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia [see Contraindications (4)].
(e.g., progestin/estrogen)	progestin and estrogen: effects unknown	No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.
Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ.
Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone	buprenorphine or buprenorphine/naloxone: effects unknown methadone: effects unknown	Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.
fentanyl	↑ fentanyl	When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended.
tramadol	↑ tramadol	When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed.
Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ PDE-5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [see Contraindications (4)] .





		Use of PDE-5 inhibitors for erectile dysfunction:
Proton-pump inhibitors (PPI): (e.g., omeprazole)	↓ atazanavir	In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended.
Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4)] .
Other Benzodiazepines : clorazepate diazepam estazolam flurazepam parenterally administered midazolam	↑ sedatives/hypnotics	Parenterally administered midazolam: Coadministration 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.
Other Sedatives/Hypnotics: buspirone, zolpidem		With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.

]

Coadministration is contraindicated with, but not limited to, the following drugs:

Drug Class

Drugs within class that are contraindicated with EVOTAZ

^a Refer to Table 5 for sildenafil when administered for erectile dysfunction [see

7.3 Established and Other Potentially Significant Drug Interactions

[see Contraindications (4),

Warnings and Precautions (5.8)

, and Clinical Pharmacology (12.3)]

Tadalafil

: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ:

Avanafil

: Not recommended because a safe and effective dose of avanafil has not been established.

Sildenafil

: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions.

Tadalafil

: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions.

Vardenafil

: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor Predicted Interactions
Concomitant Drug Class: Specific Drugs	Effect^bon Concentration	Clinical Comment
^aFor magnitude of interactions see Clinical Pharmacology (12.3; Table 7) . ^b↑ = Increase, ↓ = Decrease, ↔ = No change.
HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs)
didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times.
tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions [see Warnings and Precautions (5.4)] .
HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions [see Contraindications (4)] .
efavirenz	↓ atazanavir ↓ cobicistat ↔ efavirenz	Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to atazanavir.
etravirine	↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.
HIV Antiretroviral Agents: CCR5 Antagonist
maraviroc	↑ maraviroc	When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily.
HIV Antiretroviral Agents: Protease Inhibitor
indinavir		Coadministration with indinavir is contraindicated [see Contraindications (4)] . Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
ritonavir or products containing ritonavir	↑ atazanavir	Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see Warnings and Precautions (5.9) ] .
Hepatitis C Antiviral Agents
sofosbuvir/velpatasvir/ voxilaprevir	↑ voxilaprevir	Coadministration with EVOTAZ is not recommended.
Other Agents
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension [see Contraindications (4)] .
Antacids and buffered medications (please also see H₂-receptor antagonists and proton-pump inhibitors below)	↓ atazanavir	With concomitant use, administer a minimum of 2 hours apart.
Antianginal: ranolazine	↑ ranolazine	Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
Antiarrhythmics: dronedarone	↑ dronedarone	Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin	↑ other antiarrhythmics ↑ digoxin	Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin	↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin	Consider alternative antibiotics.
Anticancer Agents: irinotecan	↑ irinotecan	Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [see Contraindications (4)] .
(e.g., dasatinib, nilotinib, vinblastine, vincristine)	↑ other anticancer agents	A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.
Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information.
rivaroxaban	↑ rivaroxaban	Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk.
betrixaban dabigatran etexilate edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	warfarin: effect unknown	Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine)	↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] . Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.
Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam)	↑ clonazepam	Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration.
Other anticonvulsants (e.g., lamotrigine)	lamotrigine: effects unknown	Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine)	SSRIs: effects unknown	When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline)	↑ TCAs
Other Antidepressants (e.g., trazodone)	↑ trazodone
Antifungals: ketoconazole, itraconazole	↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole	Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole.
voriconazole	effects unknown	Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.
Antigout: colchicine	↑ colchicine	Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] . Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 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: Rifabutin	atazanavir: effect unknown cobicistat: effect unknown ↑ 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 and uveitis, is warranted.
rifampin	↓ atazanavir ↓ cobicistat	Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
Antineoplastics: apalutamide	↓ atazanavir ↓cobicistat	Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide.
ivosidenib	↓ atazanavir ↓ cobicistat ↑ ivosidenib	Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib.
encorafenib	↓ atazanavir ↓ cobicistat ↑ encorafenib	Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib.
Antiplatelets: ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.
prasugrel	↔ prasugrel active metabolite	No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat.
Antipsychotics: lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
quetiapine	↑ quetiapine	Initiation of EVOTAZ 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 EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
(e.g., perphenazine, risperidone, thioridazine)	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ.
Beta-agonist (inhaled): salmeterol	↑ salmeterol	Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Beta-Blockers: (e.g., metoprolol, carvedilol, timolol)	↔ atazanavir ↑ beta-blockers	Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ.
Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil)	↑ calcium channel blocker	Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.
Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone	↓ atazanavir ↓ cobicistat ↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Kinase inhibitors: fostamatinib	↑ R406 active metabolite of fostamatinib	Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↓ cobicistat ↑ bosentan	Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose.
Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix	↓ atazanavir ↓ cobicistat ↑ elagolix	Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure.
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Coadministration of EVOTAZ with ergot derivatives is contraindicated 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)] .
Hepatitis C Direct-Acting Antivirals : elbasvir/grazoprevir	↑ grazoprevir	Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
Herbal Products : St. John’s wort ( Hypericum perforatum)	↓ atazanavir ↓ cobicistat	Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
H ₂ ‑Receptor antagonists (H ₂ RA ) : (e.g., famotidine)	↓ atazanavir	Coadministration of EVOTAZ with tenofovir DF and an H₂RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H₂RA. The dose of the H₂RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients.
Lipid-modifying agents: Other lipid-modifying agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity [see Contraindications (4)] .
HMG-CoA reductase inhibitors : lovastatin simvastatin	↑lovastatin ↑simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)] .
Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day.
Hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone	Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia [see Contraindications (4)].
(e.g., progestin/estrogen)	progestin and estrogen: effects unknown	No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.
Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ.
Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone	buprenorphine or buprenorphine/naloxone: effects unknown methadone: effects unknown	Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.
fentanyl	↑ fentanyl	When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended.
tramadol	↑ tramadol	When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed.
Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ PDE-5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [see Contraindications (4)] .





		Use of PDE-5 inhibitors for erectile dysfunction:
Proton-pump inhibitors (PPI): (e.g., omeprazole)	↓ atazanavir	In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended.
Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4)] .
Other Benzodiazepines : clorazepate diazepam estazolam flurazepam parenterally administered midazolam	↑ sedatives/hypnotics	Parenterally administered midazolam: Coadministration 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.
Other Sedatives/Hypnotics: buspirone, zolpidem		With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.

^b Refer to Table 5 for parenterally administered midazolam [see

7.3 Established and Other Potentially Significant Drug Interactions

[see Contraindications (4),

Warnings and Precautions (5.8)

, and Clinical Pharmacology (12.3)]

Tadalafil

: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ:

Avanafil

: Not recommended because a safe and effective dose of avanafil has not been established.

Sildenafil

: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions.

Tadalafil

: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions.

Vardenafil

: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^aor Predicted Interactions
Concomitant Drug Class: Specific Drugs	Effect^bon Concentration	Clinical Comment
^aFor magnitude of interactions see Clinical Pharmacology (12.3; Table 7) . ^b↑ = Increase, ↓ = Decrease, ↔ = No change.
HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs)
didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times.
tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions [see Warnings and Precautions (5.4)] .
HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions [see Contraindications (4)] .
efavirenz	↓ atazanavir ↓ cobicistat ↔ efavirenz	Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to atazanavir.
etravirine	↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.
HIV Antiretroviral Agents: CCR5 Antagonist
maraviroc	↑ maraviroc	When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily.
HIV Antiretroviral Agents: Protease Inhibitor
indinavir		Coadministration with indinavir is contraindicated [see Contraindications (4)] . Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
ritonavir or products containing ritonavir	↑ atazanavir	Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see Warnings and Precautions (5.9) ] .
Hepatitis C Antiviral Agents
sofosbuvir/velpatasvir/ voxilaprevir	↑ voxilaprevir	Coadministration with EVOTAZ is not recommended.
Other Agents
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension [see Contraindications (4)] .
Antacids and buffered medications (please also see H₂-receptor antagonists and proton-pump inhibitors below)	↓ atazanavir	With concomitant use, administer a minimum of 2 hours apart.
Antianginal: ranolazine	↑ ranolazine	Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
Antiarrhythmics: dronedarone	↑ dronedarone	Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin	↑ other antiarrhythmics ↑ digoxin	Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin	↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin	Consider alternative antibiotics.
Anticancer Agents: irinotecan	↑ irinotecan	Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [see Contraindications (4)] .
(e.g., dasatinib, nilotinib, vinblastine, vincristine)	↑ other anticancer agents	A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.
Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information.
rivaroxaban	↑ rivaroxaban	Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk.
betrixaban dabigatran etexilate edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	warfarin: effect unknown	Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine)	↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] . Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.
Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam)	↑ clonazepam	Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration.
Other anticonvulsants (e.g., lamotrigine)	lamotrigine: effects unknown	Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine)	SSRIs: effects unknown	When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline)	↑ TCAs
Other Antidepressants (e.g., trazodone)	↑ trazodone
Antifungals: ketoconazole, itraconazole	↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole	Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole.
voriconazole	effects unknown	Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.
Antigout: colchicine	↑ colchicine	Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] . Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 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: Rifabutin	atazanavir: effect unknown cobicistat: effect unknown ↑ 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 and uveitis, is warranted.
rifampin	↓ atazanavir ↓ cobicistat	Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
Antineoplastics: apalutamide	↓ atazanavir ↓cobicistat	Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide.
ivosidenib	↓ atazanavir ↓ cobicistat ↑ ivosidenib	Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib.
encorafenib	↓ atazanavir ↓ cobicistat ↑ encorafenib	Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation. [see Contraindications (4)] . Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib.
Antiplatelets: ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.
prasugrel	↔ prasugrel active metabolite	No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat.
Antipsychotics: lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [see Contraindications (4)] .
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] .
quetiapine	↑ quetiapine	Initiation of EVOTAZ 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 EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
(e.g., perphenazine, risperidone, thioridazine)	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ.
Beta-agonist (inhaled): salmeterol	↑ salmeterol	Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Beta-Blockers: (e.g., metoprolol, carvedilol, timolol)	↔ atazanavir ↑ beta-blockers	Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ.
Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil)	↑ calcium channel blocker	Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.
Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone	↓ atazanavir ↓ cobicistat ↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Kinase inhibitors: fostamatinib	↑ R406 active metabolite of fostamatinib	Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↓ cobicistat ↑ bosentan	Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose.
Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix	↓ atazanavir ↓ cobicistat ↑ elagolix	Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure.
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Coadministration of EVOTAZ with ergot derivatives is contraindicated 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)] .
Hepatitis C Direct-Acting Antivirals : elbasvir/grazoprevir	↑ grazoprevir	Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4)] .
Herbal Products : St. John’s wort ( Hypericum perforatum)	↓ atazanavir ↓ cobicistat	Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance [see Contraindications (4)] .
H ₂ ‑Receptor antagonists (H ₂ RA ) : (e.g., famotidine)	↓ atazanavir	Coadministration of EVOTAZ with tenofovir DF and an H₂RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H₂RA. The dose of the H₂RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients.
Lipid-modifying agents: Other lipid-modifying agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity [see Contraindications (4)] .
HMG-CoA reductase inhibitors : lovastatin simvastatin	↑lovastatin ↑simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)] .
Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin	↑ HMG-CoA reductase inhibitors	Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day.
Hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone	Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia [see Contraindications (4)].
(e.g., progestin/estrogen)	progestin and estrogen: effects unknown	No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.
Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ.
Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone	buprenorphine or buprenorphine/naloxone: effects unknown methadone: effects unknown	Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms.
fentanyl	↑ fentanyl	When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended.
tramadol	↑ tramadol	When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed.
Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ PDE-5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [see Contraindications (4)] .





		Use of PDE-5 inhibitors for erectile dysfunction:
Proton-pump inhibitors (PPI): (e.g., omeprazole)	↓ atazanavir	In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended.
Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4)] .
Other Benzodiazepines : clorazepate diazepam estazolam flurazepam parenterally administered midazolam	↑ sedatives/hypnotics	Parenterally administered midazolam: Coadministration 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.
Other Sedatives/Hypnotics: buspirone, zolpidem		With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.

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

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