Evotaz Tablet
FDA Label NDC 0003-3641

EVOTAZ^® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults.

Limitations of Use:

• Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)].

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 [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)].

EVOTAZ is a fixed-dose combination product containing 300 mg of atazanavir and 150 mg of cobicistat. In treatment-naive and -experienced adults, the recommended dosage of EVOTAZ is one tablet taken once daily orally with food [see Clinical Pharmacology (12.3)]. Administer EVOTAZ in conjunction with other antiretroviral agents [see Drug Interactions (7)].

When coadministered with H₂-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Drug Interactions (7)].

EVOTAZ is not recommended in HIV-1 treatment-experienced patients with 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)].

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)].

EVOTAZ tablets contain 342 mg atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat and are oval, biconvex, pink, film-coated, and debossed with “3641” on one side and plain on the other side.

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 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 1).
• when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1).

Table 1 displays drugs that are contraindicated with EVOTAZ.

Table 1: Drugs that are Contraindicated with EVOTAZ

Drug Class	Drugs within class that are contraindicated with EVOTAZ	Clinical Comment
a  See Drug Interactions, Table 5 (7) for parenterally administered midazolam. b  See Drug Interactions, Table 5 (7) for sildenafil when administered for erectile dysfunction.
Alpha 1-Adrenoreceptor Antagonist	Alfuzosin	Potential for increased alfuzosin concentrations, which can result in hypotension.
Antianginal	Ranolazine	Potential for serious and/or life-threatening reactions.
Antiarrhythmics	Dronedarone	Potential for increased dronedarone concentrations.
Anticonvulsants	Carbamazepine, phenobarbital, phenytoin	Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Antigout	Colchicine	Contraindicated in patients with renal and/or hepatic impairment due to the potential for serious and/or life-threatening reactions.
Antimycobacterials	Rifampin	Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
Antineoplastics	Irinotecan	Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Antipsychotic	Lurasidone Pimozide	Potential for serious and/or life-threatening reactions. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Benzodiazepines	Triazolam, orally administered midazolama	Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with atazanavir may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Ergot Derivatives	Dihydroergotamine, ergotamine, methylergonovine	Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Hepatitis C Direct-Acting Antivirals	Elbasvir/grazoprevir	May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.
	Glecaprevir/pibrentasvir	May increase the risk of ALT elevations due to an increase in glecaprevir and pibrentasvir concentrations.
Herbal Products	St. John’s wort (Hypericum perforatum)	Coadministration of products containing St. John’s wort and EVOTAZ may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for serious reactions such as myopathy including rhabdomyolysis.
Hormonal Contraceptives	Drospirenone/ethinyl estradiol	Potential for increased drospirenone concentrations, which can result in hyperkalemia.
Non-nucleoside Reverse Transcriptase Inhibitors	Nevirapine	Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures.
Phosphodiesterase-5 (PDE-5) Inhibitors	Sildenafilb when administered for the treatment of pulmonary arterial hypertension	Potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Protease Inhibitors	Indinavir	Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10)]. In clinical trials of atazanavir that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of atazanavir-treated patients (n=920) and 5% of patients (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block), consider ECG monitoring in these patients [see Clinical Pharmacology (12.2)].

Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [see Contraindications (4) and Adverse Reactions (6.1)]. EVOTAZ should be discontinued if severe rash develops.

Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation.

Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.

Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance [see Dosage and Administration (2.1)]. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.

Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.

Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min [see Dosage and Administration (2.3)].

• When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment.
• Measure serum phosphorus in patients at risk for renal impairment.
• Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.

In a clinical trial over 144 weeks (N=692), 10 (2.9%) subjects treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) subjects treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any subject.

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered [see Dosage and Administration (2.1 and 2.3) and Adverse Reactions (6.2)].

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.1, 6.2)].

Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with EVOTAZ and during treatment [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

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)]. 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)].

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.

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

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

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

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

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

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

• cardiac conduction abnormalities [see Warnings and Precautions (5.1)]
• rash [see Warnings and Precautions (5.2)]
• effects on serum creatinine [see Warnings and Precautions (5.3)]
• new onset or worsening renal impairment when used with tenofovir DF [see Warnings and Precautions (5.4)]
• chronic kidney disease [see Warnings and Precautions (5.5)]
• nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)]
• hepatotoxicity [see Warnings and Precautions (5.7)]
• hyperbilirubinemia [see Warnings and Precautions (5.10)]

For additional safety information about atazanavir and cobicistat, consult the full prescribing information for these individual products.

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

The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naive subjects received:

• atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or
• atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348).

The most common adverse reactions (Grades 2-4) and reported in ≥5% of subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%).

The proportion of subjects who discontinued study treatment due to adverse events regardless of severity was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups. Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114.

Table 2: Selected Adverse Reactions^a (Grades 2-4) Reported in ≥2% of HIV-1 Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144 analysis)

	Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=344)	Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (n=348)
a  Frequencies of adverse reactions are based on Grades 2-4 adverse events attributed to study drugs. b  Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria.
Jaundice	6%	3%
Rashb	5%	4%
Ocular icterus	4%	2%
Nausea	2%	2%
Diarrhea	2%	1%
Headache	2%	1%

Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF are listed below. These events have been included because of investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with atazanavir coadministered with cobicistat, and reported with greater frequency compared with the atazanavir coadministered with ritonavir group.

Gastrointestinal Disorders: vomiting, upper abdominal pain

General Disorders and Administration Site Conditions: fatigue

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Psychiatric Disorders: depression, abnormal dreams, insomnia

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis

The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study 114 is presented in Table 3.

Increase in Serum Creatinine: Cobicistat, a component of EVOTAZ, has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)]. In Study 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment in the atazanavir coadministered with cobicistat group, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was −15.1 ± 16.5 mL/min in the atazanavir coadministered with cobicistat group and −8.0 ± 16.8 mL/min in the atazanavir coadministered with ritonavir group.

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. In both groups, mean values for serum lipids remained within the normal range for each laboratory test. The clinical significance of these changes is unknown.

See the full prescribing information for atazanavir for postmarketing information on atazanavir.

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, Table 7 (12.3)].

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 Dosage and Administration (2.1)].

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)].

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, Table 7 (12.3)].

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Cobicistat use in women during pregnancy has not been evaluated; however, atazanavir use during pregnancy has been evaluated in a limited number of women. The pharmacokinetics of EVOTAZ have not been evaluated in pregnant patients. Available data from the APR show no difference 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].

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].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production.

Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk [see Data]. There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct women not to breastfeed.

Data

Animal Data

Cobicistat: During the prenatal and postnatal development toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10.

Dose Adjustment During Pregnancy and the Postpartum Period

Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of EVOTAZ cannot be predicted from studies of other atazanavir-containing products in pregnant women.

Maternal Adverse Reactions

Atazanavir

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.

Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.

Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions

Atazanavir

All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life. Advise pregnant women of the potential risk to newborn infants. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.

Data

Human Data

Atazanavir

Based on prospective reports from the interim APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference in the overall rate for birth defects for atazanavir (2.3%) compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Based on prospective reports to the APR, the prevalence of birth defects in live births was 2.1% following first trimester exposure to atazanavir-containing regimens.

Cobicistat

Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.

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.

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 safety and efficacy of EVOTAZ in pediatric patients 3 months to less than 18 years of age have not been established.

Clinical studies with the components of EVOTAZ did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

EVOTAZ is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

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)].

Treatment for overdosage with EVOTAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. There is no specific antidote for overdose with EVOTAZ. Since atazanavir is extensively metabolized by the liver and both atazanavir and cobicistat are highly bound plasma proteins, it is unlikely that EVOTAZ will be significantly removed by hemodialysis or peritoneal dialysis.

Atazanavir: Human experience of acute overdose with atazanavir is limited. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (73 times the 400-mg recommended dose of atazanavir administered without a CYP3A inhibitor) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At atazanavir doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.10) and Clinical Pharmacology (12.2)].

EVOTAZ^® is a fixed-dose combination tablet for oral administration containing the active ingredients atazanavir and cobicistat. Atazanavir is an HIV-1 protease inhibitor. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. EVOTAZ tablets contain 342 mg of atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat, as well as the following inactive ingredients in the tablet core: croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium starch glycolate, and stearic acid. The tablets are film-coated with a coating material containing the following inactive ingredients: hypromellose, red iron oxide, talc, titanium dioxide, triacetin.

Atazanavir: Atazanavir is present as the sulfate salt. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C₃₈H₅₂N₆O₇•H₂SO₄, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

Atazanavir Chemical Structure (Atazanavir Structure)

Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C.

Cobicistat: The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C₄₀H₅₃N₇O₅S₂ and a molecular weight of 776.0. It has the following structural formula:

Cobicistat Chemical Structure (Cobicistat Structure)

Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20°C.

EVOTAZ is a fixed-dose combination of the HIV-1 antiretroviral drug, atazanavir and the CYP3A inhibitor, cobicistat [see Microbiology (12.4)].

Atazanavir: In a thorough QT/QTc study in 72 healthy subjects, atazanavir 400 mg and 800 mg (Cmax was 1.2 times and 2.4 times the Cmax observed with the recommended dosage of EVOTAZ, respectively) without a CYP3A inhibitor did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving atazanavir. The mean (±SD) maximum change in PR interval from the predose for atazanavir 400 mg (n=65), atazanavir 800 mg (n=66), and placebo (n=67) was 24 (±15) msec, 60 (±25) msec, and 13 (±11) msec, respectively. Steady state atazanavir exposures (C_max and AUC_tau) observed in this healthy volunteer study exceeded those observed in patients treated with atazanavir coadministered with cobicistat. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1)].

In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir-containing and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, cobicistat 250 mg (1.7 times the recommended dosage in EVOTAZ) and 400 mg (2.7 times the recommended dosage in EVOTAZ) did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg dose of cobicistat.

The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change in estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFR_CG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFR_CG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR_CG, without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.3)].

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 volunteers. Results are summarized in Table 6.

The pharmacokinetics of atazanavir was evaluated in HIV-1 infected subjects 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)].

Atazanavir: In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects (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_max was 9% lower, AUC was 19% higher, and C_min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C_max, AUC, and C_min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown.

Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance <30 mL/min, using the Cockcroft-Gault method) and healthy subjects [see Use in Specific Populations (8.6)].

EVOTAZ has not been studied in patients with hepatic impairment.

Atazanavir: Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function.

Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. 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)].

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.

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 8.

EVOTAZ is a fixed-dose combination of atazanavir (ATV) and the CYP3A inhibitor cobicistat. ATV is an azapeptide HIV-1 protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of the CYP3A substrate atazanavir.

Atazanavir exhibits anti−HIV-1 activity with a mean 50% effective concentration (EC₅₀ value) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT‑2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀ values above the EC₅₀ values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.

In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir coadministered with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies: Resistance to EVOTAZ is driven by atazanavir as cobicistat lacks antiviral activity. For the complete atazanavir resistance-associated substitutions, refer to the atazanavir full prescribing information.

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 300 mg Coadministered with Cobicistat 150 mg: In an analysis of treatment-failure subjects who received atazanavir coadministered with cobicistat in Study 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in this group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 subjects, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir- or protease inhibitor-associated resistance substitutions.

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.

International AIDS Society (IAS)-defined PI resistance substitutions, depending on the number and type, may confer a reduced virologic response to atazanavir. Please refer to the “Baseline Genotype/Phenotype and Virologic Outcome Analyses” section in the atazanavir full prescribing information.

Atazanavir: Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir coadministered with 100 mg/day ritonavir, nonpregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.

Atazanavir: Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Cobicistat: Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

Atazanavir: At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir coadministered with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

Cobicistat: Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naive subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg coadministered with cobicistat 150 mg once daily or atazanavir 300 mg coadministered with ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as a single tablet. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).

The mean age of subjects was 37 years (range: 19-70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀ copies/mL (range: 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm³ (range: 1-1455) and 17% had CD4+ cell counts ≤200 cells/mm³. Forty percent (40%) of patients had baseline viral loads >100,000 copies/mL.

Virologic outcomes in Study 114 through Week 144 are presented in Table 9. In Study 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm3 in patients receiving atazanavir coadministered with cobicistat and 297 cells/mm3 in patients receiving atazanavir coadministered with ritonavir.

EVOTAZ^® tablets, 300 mg atazanavir and 150 mg cobicistat, are oval, biconvex, pink, film-coated, debossed with “3641” on one side and plain on the other side. Each bottle contains 30 tablets (NDC-0003-3641-11), a silica gel desiccant and is closed with a child-resistant closure.

Store EVOTAZ tablets at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise patients to take EVOTAZ with food every day and that EVOTAZ must always be used in combination with other antiretroviral drugs. Inform patients to avoid missing doses as it can result in development of resistance, and not to discontinue therapy without consulting with their healthcare provider. Advise patients if a dose of EVOTAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped, the patient should not double the next dose [see Dosage and Administration (2.2)].

EVOTAZ may interact with many drugs; therefore, inform patients of the potential for serious drug interactions with EVOTAZ, and that some drugs are contraindicated with EVOTAZ and other drugs require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Instruct patients receiving hormonal contraceptives to use additional or alternative non-hormonal contraceptive measures during therapy with EVOTAZ because no data are available to make recommendations regarding use of hormonal contraceptives and atazanavir coadministered with cobicistat [see Contraindications (4), Warnings and Precautions (5.8, 5.9) and Drug Interactions (7)].

Inform patients that EVOTAZ may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)].

Inform patients that mild rashes without other symptoms have been reported with atazanavir use. These rashes go away within two weeks with no change in treatment. However, inform patients there have been reports of severe skin reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with atazanavir use. Advise patients to seek medical evaluation immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, or facial edema) [see Warnings and Precautions (5.2)].

Inform patients that treatment with EVOTAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking EVOTAZ [see Warnings and Precautions (5.5)].

Inform patients that kidney stones and/or gallstones have been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications [see Warnings and Precautions (5.6)].

Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving atazanavir, a component of EVOTAZ. Tell patients this may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if they have cosmetic concerns [see Warnings and Precautions (5.10)].

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.11)].

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.13)].

Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant women exposed to EVOTAZ [see Use in Specific Populations (8.1)].

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk. Atazanavir, a component of EVOTAZ, can also be passed to the baby in breast milk, and it is not known whether it could harm the baby [see Use in Specific Populations (8.2)].

EVOTAZ^® (EV-oh-taz)
(atazanavir and cobicistat)
tablet

Read this Patient Information before you start taking EVOTAZ and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is EVOTAZ?

EVOTAZ is a prescription HIV-1 (Human Immunodeficiency Virus) medicine used with other antiretroviral medicines to treat HIV-1 infection in adults. HIV is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

EVOTAZ contains the prescription medicines REYATAZ^® (atazanavir) and TYBOST^® (cobicistat).

It is not known if EVOTAZ is safe and effective in children under 18 years of age.

When used with other antiretroviral medicines to treat HIV-1 infection, EVOTAZ may help:

• reduce the amount of HIV-1 in your blood. This is called “viral load.”
• increase the number of CD4+ (T) cells in your blood that help to fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

EVOTAZ does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

• Do not share or reuse needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

Who should not take EVOTAZ?

Do not take EVOTAZ if you:

• are allergic to any of the ingredients in EVOTAZ. See the end of this leaflet for a complete list of ingredients in EVOTAZ.
• are taking any of the following medicines. EVOTAZ may cause serious life-threatening side effects or death when used with these medicines:
  • oalfuzosin (UROXATRAL^®)
  • ocarbamazepine (CARBATROL^®, EPITOL^®, EQUETRO^®, TEGRETOL^®)
  • ocisapride (PROPULSID^®, PROPULSID^® QUICKSOLV^®)
  • ocolchicine (COLCRYS^®, MITIGARE™), if you have liver or kidney problems
  • odronedarone hydrochloride (MULTAQ^®)
  • odrospirenone/ethinyl estradiol (BEYAZ^®, SAFYRAL^®, YASMIN^®, YAZ^®)
  • oelbasvir/grazoprevir (ZEPATIER^®)
  • oergot-containing medicines:
    • ▪dihydroergotamine mesylate (D.H.E. 45^®, EMBOLEX^®, MIGRANAL^®)
    • ▪ergotamine tartrate (CAFERGOT^®, MIGERGOT^®, ERGOMAR^®, ERGOSTAT^®, MEDIHALER^®, WIGRAINE^®, WIGRETTES^®)
    • ▪methylergonovine (METHERGINE^®)
    • oglecaprevir/pibrentasvir (MAVYRET^®)
    • oindinavir (CRIXIVAN^®)
    • oirinotecan (CAMPTOSAR^®)
    • olovastatin (ADVICOR^®, ALTOPREV^®, MEVACOR^®)
    • olurasidone (LATUDA^®)
    • omidazolam (VERSED^®), when taken by mouth for sedation
    • onevirapine (VIRAMUNE^®, VIRAMUNE XR^®)
    • ophenobarbital (LUMINAL^®)
    • ophenytoin (DILANTIN^®, PHENYTEK^®)
    • opimozide (ORAP^®)
    • oranolazine (RANEXA^®)
    • orifampin (RIMACTANE^®, RIFADIN^®, RIFATER^®, RIFAMATE^®)
    • osildenafil (REVATIO^®), when used for the treatment of pulmonary arterial hypertension (PAH)
    • osimvastatin (ZOCOR^®, VYTORIN^®, SIMCOR^®)
    • oSt. John’s wort (Hypericum perforatum), or a product that contains St. John’s wort
    • otriazolam (HALCION^®)

    What should I tell my healthcare provider before taking EVOTAZ?

    Before taking EVOTAZ, tell your healthcare provider if you:

    • have heart problems
    • have liver problems, including hepatitis B or C virus infection
    • have kidney problems
    • have diabetes
    • have hemophilia
    • have any other medical conditions
    • are pregnant or plan to become pregnant. It is not known if EVOTAZ will harm your unborn baby. Pregnant women have developed a serious condition called lactic acidosis (a build-up of lactic acid in the blood) when taking EVOTAZ with other HIV medicines called nucleoside analogues.
      • oHormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with EVOTAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with EVOTAZ.
      • oPregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
      • oAfter your baby is born, tell your healthcare provider if your baby’s skin or the white part of his/her eyes turns yellow.
      • are breastfeeding or plan to breastfeed. Do not breastfeed if you take EVOTAZ.
        • oYou should not breastfeed if you have HIV because of the risk of passing HIV to your baby.
        • oIt is not known if EVOTAZ passes into your breast milk.
        • oTalk to your healthcare provider about the best way to feed your baby.

        Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with EVOTAZ. Keep a list of your medicines to show your healthcare provider and pharmacist.

        • You can ask your healthcare provider or pharmacist for a list of medicines that interact with EVOTAZ.
        • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take EVOTAZ with other medicines.

        How should I take EVOTAZ?

        • Take EVOTAZ exactly as your healthcare provider tells you.
        • Do not change your dose or stop taking EVOTAZ without talking to your healthcare provider.
        • EVOTAZ must be used with other antiretroviral medicines.
        • Take EVOTAZ 1 time a day with food.
        • If you miss a dose of EVOTAZ, take the dose as soon as possible and then return to your normal schedule.
        • If a dose of EVOTAZ is missed, do not double the next dose.
        • If you take too much EVOTAZ, call your healthcare provider or go to the nearest hospital emergency room right away.

        What are the possible side effects of EVOTAZ?

        EVOTAZ can cause serious side effects, including:

        • A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
        • Skin rash. Skin rash is common with EVOTAZ but can sometimes be severe. Skin rash usually goes away within 2 weeks without any change in treatment. Severe rash may develop with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, call your healthcare provider or go to the nearest hospital emergency room right away:
        general feeling of discomfort or “flu-like” symptomsred or inflamed eyes, like “pink eye” (conjunctivitis)feverblistersmuscle or joint achesmouth soresswelling of your facepainful, warm, or red lump under your skin

        o

        o

        o

        o

        o

        o

        o

        o

        • Kidney problems. EVOTAZ, when taken with certain other medicines, can cause new or worse kidney problems, including kidney failure. Your healthcare provider should check your kidneys before you start and while you are taking EVOTAZ.
        • Chronic kidney disease. EVOTAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start EVOTAZ and during treatment.
        • Kidney stones have happened in some people who take atazanavir, one of the medicines in EVOTAZ. Tell your healthcare provider right away if you get symptoms of kidney stones, which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate.
        • Gallbladder disorders have happened in some people who take atazanavir, one of the medicines in EVOTAZ. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include:
          • opain in the right or middle upper stomach area
          • ofever
          • onausea and vomiting
          • oyour skin or the white part of your eyes turns yellow
          • Liver problems. If you have liver problems, including hepatitis B or C infection, your liver problems may get worse when you take EVOTAZ. Your healthcare provider will do blood tests to check your liver before you start EVOTAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:
            • oyour skin or the white part of your eyes turns yellow
            • odark (tea-colored) urine
            • olight colored stools
            • onausea
            • oitching
            • ostomach-area pain
            • Yellowing of the skin or the white part of your eyes is common with EVOTAZ but may be a symptom of a serious problem. These effects may be due to increases in bilirubin levels in the blood (bilirubin is made by the liver). Although these effects may not be damaging to your liver, skin, or eyes, tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.
            • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting your HIV-1 medicine.
            • Diabetes and high blood sugar (hyperglycemia) have happened and worsened in some people who take protease inhibitor medicines like EVOTAZ. Some people have had to start taking medicine to treat diabetes or have had to change their diabetes medicine.
            • Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
            • Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors including EVOTAZ.

            The most common side effects of EVOTAZ were yellowing of the skin and rash.

            Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

            These are not all the possible side effects of EVOTAZ. For more information ask your healthcare provider or pharmacist.

            Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

            How should I store EVOTAZ?

            • Store EVOTAZ tablets at room temperature between 68°F and 77°F (20°C and 25°C).
            • Keep tablets in a tightly closed container.

            Keep EVOTAZ and all medicines out of the reach of children.

            General information about EVOTAZ

            Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EVOTAZ for a condition for which it was not prescribed. Do not give EVOTAZ to other people, even if they have the same symptoms that you have. It may harm them.

            If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about EVOTAZ that is written for health professionals.

            For more information, call 1‑800‑321‑1335.

            What are the ingredients in EVOTAZ?

            Active ingredients: atazanavir and cobicistat

            Inactive ingredients: croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium starch glycolate, and stearic acid. The film-coating contains hypromellose, red iron oxide, talc, titanium dioxide, triacetin.

            
            This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

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Revised: March 2018

REYATAZ and EVOTAZ are trademarks of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

See HOW SUPPLIED section for a complete list of available packages of EVOTAZ.

NDC 0003-3641-11
30 Tablets
EVOTAZ™
(atazanavir and cobicistat) tablets
300 mg/150 mg
Rx only
Take with food.
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that should NOT be taken with EVOTAZ™