Evotaz

DESCRIPTION

EVOTAZ® is a fixed-dose combination tablet for oral administration containing the active ingredients atazanavir and cobicistat. Atazanavir is anHIV-1protease 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,silicondioxide, 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-(2pyridinyl)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 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-4yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C₄₀H₅₃N₇O₅S₂and a molecular weight of 776.0. It has the following structural formula:

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

• 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” symptoms
  • fever
  • muscle or joint aches
  • swelling of your face
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • blisters
  • mouth sores
  • painful, warm, or red lump under your skin
• 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 stoneshave 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 disordershave 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:
  • pain in the right or middle upper stomach area
  • fever
  • 恶心想吐and vomiting
  • your 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:
  • your skin or the white part of your eyes turns yellow
  • dark (tea-colored) urine
  • light colored stools
  • 恶心想吐
  • itching
  • stomach-area pain

INDICATIONS

Indications

EVOTAZ^®is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in the following populations [seeDOSAGE AND ADMINISTRATION]:

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

Limitations Of Use

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

DOSAGE AND ADMINISTRATION

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警告AND PRECAUTIONS]. Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see警告AND PRECAUTIONS].

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警告AND PRECAUTIONS].

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警告AND PRECAUTIONS].

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 [seeCLINICAL PHARMACOLOGY] in HIV-1-infected treatment-naïve and treatment-experienced:

• Adult patients
• Pediatric patients weighing at least 35 kg

Administer EVOTAZ in conjunction with other antiretroviral agents [seeDRUG INTERACTIONS]. Dose separation may be required when taken with H₂-receptor antagonists or proton-pump inhibitors [seeDRUG INTERACTIONS].

Dosage In Patients With Renal Impairment

EVOTAZ is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [seeUse In Specific PopulationsandCLINICAL PHARMACOLOGY].

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警告AND PRECAUTIONSandADVERSE REACTIONS].

Not Recommended In Patients With Any Degree Of Hepatic Impairment

EVOTAZ is not recommended in patients with any degree of hepatic impairment [see警告AND PRECAUTIONS,Use In Specific Populations, andCLINICAL PHARMACOLOGY].

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 [seeUse In Specific Populations].

HOW SUPPLIED

Dosage Forms And Strengths

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.

Storage And Handling

EVOTAZ^®tablets, 300 mgatazanavir 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.

Manufactured for: Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Revised: Jul 2020

SIDE EFFECTS

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

• cardiac conduction abnormalities [see警告AND PRECAUTIONS]
• rash [see警告AND PRECAUTIONS]
• effects on serum creatinine [see警告AND PRECAUTIONS]
• new onset or worsening renal impairment when used with tenofovir DF [see警告AND PRECAUTIONS]
• chronic kidney disease [see警告AND PRECAUTIONS]
• nephrolithiasis and cholelithiasis [see警告AND PRECAUTIONS]
• hepatotoxicity [see警告AND PRECAUTIONS]
• hyperbilirubinemia [see警告AND PRECAUTIONS]

atazanavir为额外的安全信息and cobicistat, consult the full prescribing information for these individual products.

Clinical Trial Experience

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

Adverse Reactions From Clinical Trial Experience In Adult Subjects

The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study GS-US-216-0114, in which 692 antiretroviral treatment-naive subjects with HIV-1 infection received:

• atazanavir coadministered cobicistat和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 GS-US-216-0114.

Table 2: Selected Adverse Reactions^a(Grades 2-4) Reported in ≥2% of Treatment-Naive Adults with HIV-1 Infection in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis)

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

Less Common Adverse Reactions

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

肌肉骨骼和结缔组织疾病:rhabdomyolysis

Psychiatric Disorders:depression, abnormal dreams, insomnia

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

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114 is presented in Table 3.

Table 3: Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of HIV-1-Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis)

Laboratory Parameter Abnormality	144 weeks Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344)	144 weeks Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF (n=348)
Total Bilirubin (>2.5 × ULN)	73%	66%
Creatine Kinase (≥10.0 × ULN)	8%	9%
Urine RBC (Hematuria) (>75 RBC/HPF)	6%	3%
ALT (>5.0 × ULN)	6%	3%
AST (>5.0 × ULN)	4%	3%
GGT (>5.0 × ULN)	4%	2%
Serum Amylasea(>2.0 × ULN)	4%	2%
Urine Glucose (Glycosuria ≥1000 mg/dL)	3%	3%
Neutrophils (<750/mm3)	3%	2%
Serum Glucose (Hyperglycemia) (≥250 mg/dL)	2%	2%
aFor subjects with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively.

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警告AND PRECAUTIONSandCLINICAL PHARMACOLOGY]. In Study GS-US-216-0114, 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.

Serum Lipids

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.

Table 4: Lipid Values, Mean Change from Baseline, Reported in Treatment-Naive Adults with HIV-1 Infection Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study GS-US-216-0114 (Week 144 analysis)

	Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF		Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF
	Baseline mg/dL	Week 144 change from baselinea	Baseline mg/dL	Week 144 change from baselinea
Total Cholesterol (fasted)	163 [N=219]	+11 [N=219]	165 [N=227]	+13 [N=227]
HDL-cholesterol (fasted)	43 [N=218]	+7 [N=218]	43 [N=228]	+6 [N=228]
低密度脂蛋白胆固醇(禁食)	102 [N=218]	+11 [N=218]	104 [N=228]	+16 [N=228]
Triglycerides (fasted)	130 [N=219]	+14 [N=219]	131 [N=227]	+14 [N=227]
aThe change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug.

Adverse Reactions From Clinical Trial Experience In Pediatric Subjects

Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed subjects with HIV-1 infection between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128) [seeClinical Studies]. Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.

Postmarketing Experience

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

DRUG INTERACTIONS

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 [seeCONTRAINDICATIONS]. 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) [seeCLINICAL PHARMACOLOGY,Table 7].

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) [seeDOSAGE AND ADMINISTRATION].

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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONS, andCLINICAL PHARMACOLOGY].

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions

Concomitant Drug Class: Specific Drugs	Effectbon Concentration	Clinical Comment
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警告AND PRECAUTIONS].
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 [seeCONTRAINDICATIONS].
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 [seeCONTRAINDICATIONS]. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
ritonavir or products containing ritonavi	↑ atazanavir	Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A [see警告AND PRECAUTIONS].
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 [seeCONTRAINDICATIONS].
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 [seeCONTRAINDICATIONS].
Antiarrhythmics:
dronedarone	↑ronedarone	Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [seeCONTRAINDICATIONS].
amiodarone, quinidine lidocaine (systemic), . disopyramide, flecainide mexiletine, propafenone	↑ other antiarrhythmics	Clinical monitoring is recommended upon coadministration with antiarrhythmics.
digoxin	↑ digoxin	When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Antibacterials (macrolide or ketolide antibiotics):
clarithromycin	↑ atazanavir ↑ cobicistat	Consider alternative antibiotics.
erythromycin	↑ clarithromycin
telithromycin	↑ erythromycin ↑ telithromycin
Anticancer Agents:
irinotecan	↑ irinotecan	Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity [seeCONTRAINDICATIONS].
(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	↓ atazanavir ↓ cobicistat	Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance [seeCONTRAINDICATIONS].
Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine)	↓ atazanavir ↓ cobicistat	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: effect unknown	Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine)	SSRIs: effect 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	effect 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 [seeCONTRAINDICATIONS]. 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 [seeCONTRAINDICATIONS].
Antipsychotics:
lurasidone	↑lurasidone	Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions [seeCONTRAINDICATIONS].
pimozide	↑pimozide	共同服用哌咪清禁忌due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [seeCONTRAINDICATIONS].
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	临床监测beta-block时建议ers that are metabolized by CYP2D6 are coadministered with EVOTAZ.
Calcium channel blockers:
(e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil)	↑ calcium channel blocker	临床监测是coadministr推荐ation with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.
糖皮质激素(所有航线皮除外):
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 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.
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.
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 [seeCONTRAINDICATIONS].
GI Motility Agents
cisapride	↑ cisapride	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 [seeCONTRAINDICATIONS].
Hepatitis C Direct-Acting Antivirals
elbasvir/grazoprevir	↑ grazoprevir	Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [seeCONTRAINDICATIONS].
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of EVOTAZ with glecaprevir/pibrentasvir is contraindicated due to increased risk of ALT elevations [seeCONTRAINDICATIONS].
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 [seeCONTRAINDICATIONS].
H2-Receptor antagonists (H2RA):
(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 [seeCONTRAINDICATIONS].
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 [seeCONTRAINDICATIONS].
Other HMG-CoA reductase inhibitors:
atorvastatin, fluvastatin, pravastatin, rosuvastatin	↑ HMG-CoA	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 [seeCONTRAINDICATIONS].
(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 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.
buprenorphine, naloxone, methadone		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:	↑ PDE-5 inhibitors	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
avanafil, sildenafil, tadalafil, vardenafil		Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope) [seeCONTRAINDICATIONS]. 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. Use of PDE-5 inhibitors for erectile dysfunction: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.
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 [seeCONTRAINDICATIONS].
Other Benzodiazepines
clorazepate	↑ 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.
diazepam
estazolam
flurazepam
parenterally administered midazolam
Other Sedatives/Hypnotics buspirone, zolpidem		With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.
aFor magnitude of interactions seeCLINICAL PHARMACOLOGY, Table 7. b↑ = Increase, ↓ = Decrease, ↔ = No change.

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 andacetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin [seeCLINICAL PHARMACOLOGY,Table 7].

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Cardiac Conduction Abnormalities

Atazanavir prolongs the PR interval of theelectrocardiogramin some patients. In healthy volunteers and in patients, abnormalities inatrioventricular(AV) conduction wereasymptomaticand generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [seeADVERSE REACTIONSandOVERDOSE]. 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 thirddegree AV block), considerECGmonitoring in these patients [seeCLINICAL PHARMACOLOGY].

Severe Skin Reactions

Cases ofStevens-Johnson syndrome,erythema multiforme, and toxic skin eruptions, including drug rash,eosinophiliaand systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [seeCONTRAINDICATIONSandADVERSE REACTIONS]. 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.

Effects On Serum Creatinine

Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Cardiac Conduction Abnormalities

Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [seeADVERSE REACTIONSandOVERDOSE]. In clinical trials of atazanavir in subjects with HIV-1 infection that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of subjects treated with atazanavir (n=920) and 5% of subjects (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 [seeCLINICAL PHARMACOLOGY].

Severe Skin Reactions

Cases of Stevens-Johnson syndrome,erythemamultiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [seeCONTRAINDICATIONSandADVERSE REACTIONS]. 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.

Effects On Serum Creatinine

Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renalglomerularfunction. 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 [seeDOSAGE AND ADMINISTRATION]. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment [seeADVERSE REACTIONS,DRUG INTERACTIONS, andCLINICAL PHARMACOLOGY]. 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.

New Onset Or Worsening Renal Impairment When Used With Tenofovir DF

Renal impairment, including cases ofacute renal failureand Fanconi syndrome, has been reported when cobicistat was used in anantiretroviralregimen 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 [seeDOSAGE AND ADMINISTRATION].

• 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 serumphosphorusin patients with or at risk for renal impairment.
• Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of anephrotoxicagent 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 withproximalrenal 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 treated with cobicistat, 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

Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatousinterstitialnephritisassociated with the deposition of atazanavir drug crystals in the renalparenchyma. 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, andurinalysiswithmicroscopicexamination) 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 [seeDOSAGE AND ADMINISTRATIONandADVERSE REACTIONS].

Nephrolithiasis And Cholelithiasis

Cases ofnephrolithiasisand/orcholelithiasishave been reported during postmarketing surveillance in patients with HIV-1 infection 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 [seeADVERSE REACTIONS].

Hepatotoxicity

Patients with underlyinghepatitis Bor 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 [seeDOSAGE AND ADMINISTRATIONandUse In Specific Populations].

风险严重的副词erse 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 [seeDRUG INTERACTIONS]. 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 [seeCONTRAINDICATIONSandDRUG INTERACTIONS].

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 [seeDRUG INTERACTIONSandCLINICAL PHARMACOLOGY].

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 HIVproteaseinhibitors 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.

SeeDRUG INTERACTIONSfor additional recommendations on use with other antiretroviral agents.

Hyperbilirubinemia

大多数病人服用atazanavir asympto经验matic elevations in indirect (unconjugated) bilirubin related to inhibition ofUDP-glucuronosyltransferase(UGT). Thishyperbilirubinemiais 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). Alternativeantiretroviral therapyto EVOTAZ may be considered ifjaundiceor scleralicterusassociated with bilirubin elevations presents cosmetic concerns for patients [seeADVERSE REACTIONS].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whoseimmune systemresponds may develop aninflammatory responseto indolent orresidualopportunistic infections (such asMycobacterium aviuminfection,cytomegalovirus,Pneumocystis jirovecipneumonia, ortuberculosis), which may necessitate further evaluation and treatment.

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

Diabetes Mellitus/Hyperglycemia

New-onsetdiabetes mellitus, exacerbation of preexistingdiabetesmellitus, andhyperglycemiahave been reported during postmarketing surveillance in patients with HIV-1 infection receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments ofinsulinor oralhypoglycemicagents for treatment of these events. In some cases,diabetic ketoacidosishas 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.

Fat Redistribution

Redistribution/accumulation of body fat including centralobesity, dorsocervical fat enlargement (buffalo hump), peripheralwasting, facial wasting, breast enlargement, and “cushingoidappearance” 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.

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas andhemarthrosis, in patients withhemophiliatype A and B treated with protease inhibitors. In some patients additionalfactor VIIIwas 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Instructions For Use

建议患者采取EVOTAZ食物每一天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 [seeDOSAGE AND ADMINISTRATION].

Drug Interactions

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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandDRUG INTERACTIONS].

Cardiac Conduction Abnormalities

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 orlightheadedness[see警告AND PRECAUTIONS].

Severe Skin Reactions

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, generalmalaise, muscle or joint aches, blisters, oral lesions,conjunctivitis, or facial edema) [see警告AND PRECAUTIONS].

Chronic Kidney Disease

Inform patients that treatment with EVOTAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking EVOTAZ [see警告AND PRECAUTIONS].

Nephrolithiasis And Cholelithiasis

Inform patients that kidney stones and/orgallstoneshave been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications [see警告AND PRECAUTIONS].

Hyperbilirubinemia

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警告AND PRECAUTIONS].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV-1 infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV-1 treatment is started [see警告AND PRECAUTIONS].

Fat Redistribution

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警告AND PRECAUTIONS].

Not Recommended During Pregnancy

Advise patients that EVOTAZ is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking EVOTAZ [seeUse In Specific Populations].

Pregnancy Registry

Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant individuals exposed to EVOTAZ during pregnancy [seeUse In Specific Populations].

Lactation

Advise individuals 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 [seeUse In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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 thethyroid glandwas 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 andthyroid hormoneimbalance, 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.

Mutagenesis

Atazanavir

Atazanavir tested positive in anin vitroclastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in thein vitroAmes reverse-mutation assay,in vivomicronucleus andDNA repairtests in rats, andin vivoDNA damage test in ratduodenum(comet assay).

Cobicistat

Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouselymphomaor rat micronucleus assays.

Impairment Of Fertility

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.

Use In Specific Populations

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 [seeDOSAGE AND ADMINISTRATION]; 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.

Prospectivepregnancy data from the APR are not sufficient to adequately assess the risk of birth defects ormiscarriage. 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 AtlantaCongenitalDefects Program (MACDP) (seeData). 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 (seeData). 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 (seeData).

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 (seeRisk Summary).

Maternal Adverse Reactions

Atazanavir

Reports oflactic acidosissyndrome, 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 lacticacidosissyndrome.

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 atazanavirin uteromay develop severe hyperbilirubinemia during the first few days of life.

Data

Human Data

Atazanavir

4月已经收到了未来的生活irths following exposure to atazanavircontaining 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 backgroundbirth defectrate of 2.7% in the U.S. reference population of the MACDP.

Cobicistat

4月已经收到了未来的生活irths following exposure to cobicistatcontaining 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是怀孕的大鼠口服药物s 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-implantationloss 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.

Lactation

Risk Summary

TheCenters for Disease Control and Preventionrecommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

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 (seeData). 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-1 transmission (in HIV-1 negative infants), (2) developing viral resistance (in HIV-1 positive infants), and (3) adverse reactions in a breastfed infant, instruct individuals with HIV-1 infection not to breastfeed.

Data

Animal Data

Cobicistat:During theprenataland postnatal developmenttoxicologystudy 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.

Females And Males Of Reproductive Potential

Contraception

Atazanavir and cobicistat, components of EVOTAZ, interact with certain oral contraceptives [seeCONTRAINDICATIONSandDRUG INTERACTIONS]. Nonhormonal forms of contraceptive should be considered.

Pediatric Use

The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects 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 anopen-label trialof components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults [seeADVERSE REACTIONS,CLINICAL PHARMACOLOGY, andClinical Studies].

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 ofkernicterus.

Geriatric Use

Clinical studies with the components of EVOTAZ did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 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 [seeCLINICAL PHARMACOLOGY].

Renal Impairment

在treatment-exp EVOTAZ不建议使用erienced patients with HIV-1 infection who haveend-stage renal diseasemanaged withhemodialysis[seeDOSAGE AND ADMINISTRATION,警告AND PRECAUTIONS, andCLINICAL PHARMACOLOGY].

Hepatic Impairment

EVOTAZ is not recommended for use in patients with any degree of hepatic impairment [seeDOSAGE AND ADMINISTRATION,警告AND PRECAUTIONS, andCLINICAL PHARMACOLOGY].

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 [seeDOSAGE AND ADMINISTRATION]. Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment [seeADVERSE REACTIONS,DRUG INTERACTIONS, andCLINICAL PHARMACOLOGY]. 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.

New Onset Or Worsening Renal Impairment When Used With Tenofovir DF

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

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

In a clinical trial over 144 weeks (N=692), 10 (2.9%) 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 treated with cobicistat, 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

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 [seeDOSAGE AND ADMINISTRATIONandADVERSE REACTIONS].

Nephrolithiasis And Cholelithiasis

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 [seeADVERSE REACTIONS].

Hepatotoxicity

Patients with underlyinghepatitisB 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 [seeDOSAGE AND ADMINISTRATIONandUse In Specific Populations].

风险严重的副词erse 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 [seeDRUG INTERACTIONS]. 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 [seeCONTRAINDICATIONSandDRUG INTERACTIONS].

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 [seeDRUG INTERACTIONS, andCLINICAL PHARMACOLOGY].

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.

SeeDRUG INTERACTIONSfor additional recommendations on use with other antiretroviral agents.

Hyperbilirubinemia

大多数病人服用atazanavir asympto经验matic 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 [seeADVERSE REACTIONS].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such asMycobacterium aviuminfection, cytomegalovirus,Pneumocystis jirovecipneumonia, 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.

Diabetes Mellitus/Hyperglycemia

最近诊断为糖尿病,preex恶化isting 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, diabeticketoacidosishas 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.

Fat Redistribution

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

Hemophilia

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

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Instructions For Use

建议患者采取EVOTAZ食物每一天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 [seeDOSAGE AND ADMINISTRATION].

Drug Interactions

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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandDRUG INTERACTIONS].

Cardiac Conduction Abnormalities

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警告AND PRECAUTIONS].

Severe Skin Reactions

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警告AND PRECAUTIONS].

Chronic Kidney Disease

Inform patients that treatment with EVOTAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking EVOTAZ [see警告AND PRECAUTIONS].

Nephrolithiasis And Cholelithiasis

告知患者肾结石和/或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警告AND PRECAUTIONS].

Hyperbilirubinemia

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警告AND PRECAUTIONS].

Immune Reconstitution Syndrome

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警告AND PRECAUTIONS].

Fat Redistribution

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警告AND PRECAUTIONS].

Not Recommended During Pregnancy

Advise patients that EVOTAZ is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking EVOTAZ [seeUse In Specific Populations].

Pregnancy Registry

Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant individuals exposed to EVOTAZ during pregnancy [seeUse In Specific Populations].

Lactation

Advise individuals 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 [seeUse In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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 thethyroidglandwas 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.

Mutagenesis

Atazanavir

Atazanavir tested positive in anin vitroclastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in thein vitroAmes reverse-mutation assay,in vivomicronucleus and DNA repair tests in rats, andin vivoDNA 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.

Impairment Of Fertility

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.

Use In Specific Populations

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 [seeDOSAGE AND ADMINISTRATION]; 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) (seeData). 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 (seeData). 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 (seeData).

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 (seeRisk 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 atazanavirin uteromay develop severe hyperbilirubinemia during the first few days of life.

Data

Human Data

Atazanavir

4月已经收到了未来的生活irths following exposure to atazanavircontaining 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

4月已经收到了未来的生活irths following exposure to cobicistatcontaining 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是怀孕的大鼠口服药物s 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.

Lactation

Risk Summary

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 (seeData). 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 individuals with HIV-1 infection 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.

Females And Males Of Reproductive Potential

Contraception

Atazanavir and cobicistat, components of EVOTAZ, interact with certain oral contraceptives [seeCONTRAINDICATIONSandDRUG INTERACTIONS]. Nonhormonal forms of contraceptive should be considered.

Pediatric Use

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.

Geriatric Use

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 [seeCLINICAL PHARMACOLOGY].

Renal Impairment

EVOTAZ is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [seeDOSAGE AND ADMINISTRATION,警告AND PRECAUTIONS, andCLINICAL PHARMACOLOGY].

Hepatic Impairment

EVOTAZ is not recommended for use in patients with any degree of hepatic impairment [seeDOSAGE AND ADMINISTRATION,警告AND PRECAUTIONS, andCLINICAL PHARMACOLOGY].

OVERDOSE

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 specificantidotefor 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 orperitoneal dialysis.

Atazanavir

Human experience of acute overdose with atazanavir is limited. A single self-administered overdose of 29.2 g of atazanavir in apatient with HIV-1 infection (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警告AND PRECAUTIONSandCLINICAL PHARMACOLOGY].

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警告AND PRECAUTIONS,DRUG INTERACTIONSandCLINICAL PHARMACOLOGY].

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警告AND PRECAUTIONS].
• 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).
• when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1).
• For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [seeDRUG INTERACTIONS].

Table 1: Drugs Contraindicated with EVOTAZ

Drug Class	Drugs within class that are contraindicated with EVOTAZ
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	irinotecan
Antipsychotics	lurasidone, pimozide
Ergot Derivatives	dihydroergotamine, ergotamine, methylergonovine
GI Motility Agent	cisapride
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	sildenafilawhen administered for the treatment of pulmonary arterial hypertension
Protease Inhibitors	indinavir
Sedative/hypnotics	triazolam, orally administered midazolamb
aRefer to Table 5 for sildenafil when administered for erectile dysfunction [seeDRUG INTERACTIONS]. bRefer to Table 5 for parenterally administered midazolam [seeDRUG INTERACTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

EVOTAZ is a fixed-dose tablet consisting of the HIV-1 antiretroviral drug, atazanavir and the CYP3A inhibitor, cobicistat [seeMicrobiology].

Pharmacodynamics

Cardiac Electrophysiology

Atazanavir

In a thorough QT/QTc study in 72 healthy subjects (Study AI424-076), 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 (Cmax and AUCtau) observed in this healthy subject study exceeded those observed in subjects 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警告AND PRECAUTIONS].

In 1793 subjects with HIV-1 infection receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir-containing and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see警告AND PRECAUTIONS].

Cobicistat

In a thorough QT/QTc study conducted in 48 healthy subjects (Study GS-US-2160107), 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.

Effects On Serum Creatinine

The effect of cobicistat on serum creatinine was investigated in Study GS-US-216-0121, conducted in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-tomoderate 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_CGwere 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 ofprobedrug 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警告AND PRECAUTIONS].

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 subjects (Study AI424-511). Results are summarized in Table 6.

Table 6: Pharmacokinetic Properties of the Components of EVOTAZ

	Atazanavir	Cobicistat
Absorption
Tmax (h)	2.0	2.0
Effect of light meal (relative to fasting) AUC ratiob	1.28 (1.17,1.40)	1.24 (1.15,1.34)
Effect of high fat meal (relative to fasting) AUC ratiob	0.96 (0.81,1.13)	1.12 (1.01,1.23)
Effect of light meal (relative to fasting) C24 ratiob	1.35 (1.22,1.50)	ND
Effect of high fat meal (relative to fasting) C24 ratiob	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
t1/2 (h)	7.2a	3.5
% Of dose excreted in urine	ND	8.2c
% Of dose excreted in feces	ND	86.2c
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.

The pharmacokinetics of atazanavir was evaluated in subjects with HIV-1 infection 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 [seeClinical Studies].

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
Cmax (μg/mL)	3.91 ± 1.94
Ctau (μg/mL)	0.80 ± 0.72

Specific Populations

Pediatric

In pediatric subjects aged 12 to less than 18 years who received atazanavir 300 mg coadministered with cobicistat 150 mg (N=12), atazanavir exposures (AUCtau, Cmax, and Ctau) 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 Subjects with HIV-1 Infection Weighing at Least 35 kg

Atazanavir PK Parameter	Geometric Mean (CV%)
	Pediatric subjects (N=12)a	Adult subjects (N=30)b
AUCtau (μg/hr/mL)	49.48 (49.1)	39.96 (52.1)
Cmax (μg/mL)	4.32 (49.9)	3.54 (45.8)
Ctau (μg/mL)	0.91 (96.4)	0.58 (84.7)
CV=Coefficient of Variation aFrom intensive PK analysis of Study GS-US-216-0128 bFrom pooled intensive PK analysis of trials with atazanavir + cobicistat.

Renal Impairment

Atazanavir

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. In study AI424-105, atazanavir was 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 Cmax was 9% lower, AUC was 19% higher, and Cmin 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-hourdialysissession, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. .he 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 in Study GS-US-216-0124 [seeUse In Specific Populations].

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 subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. (Study GS-US-183-0133). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [seeUse In Specific Populations].

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 shownin vivonot to induce its ownmetabolism,也增加一些博士的生物转化ugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio ofendogenous6β-OHcortisolto 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

			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	Cmax	AUC
atorvastatin	10 mg single dose (n=16)	150 mg QD (n=16)	18.85b (13.53, 26.27)	9.22b (7.58, 11.22)
desipramine	50毫克单剂量 (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)	1.12b (1.05, 1.19)	2.30b (2.00, 2.64)
	0.02 ethinyl estradiol single dose (n=14)	150 mg QD (n=14)	0.82b (0.76, 0.89)	0.78b (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)	10.58b (8.72, 12.83)	3.42b (2.87, 4.07)
aAll interaction studies conducted in healthy subjects. bStudies of cobicistat conducted in the presence of atazanavir 300 mg.

注意:下面列出的信息不是按压hensive 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.

Microbiology

Mechanism Of Action

EVOTAZ is a fixed-dose tablet of atazanavir and the CYP3A inhibitor cobicistat. Atazanavir is an azapeptide HIV-1 protease inhibitor 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.

Antiviral Activity In Cell Culture

Atazanavir exhibits anti−HIV-1 activity with a mean 50% effective concentration (EC₅₀value) 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. Atazanavir has activity against HIV-1 Group M subtypevirusesA, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀values above the EC₅₀values of failure isolates. Two-drug combinationantiviralactivity studies with atazanavir showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1fusion inhibitorenfuvirtide, and two compounds used in the treatment ofviral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Cobicistat does not inhibitrecombinantHIV-1 protease in abiochemicalassay and has no detectable antiviral activity in cell culture against HIV-1, hepatitis B or C virus. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.

Resistance

In Cell Culture

HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir coadministered with ritonavir. HIV-1 isolates with 93-to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir 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 protease inhibitor substitutions were growth impaired and displayed increased susceptibility in cell culture to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir 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 Adult Subjects Receiving Atazanavir 300 mg Coadministered with Cobicistat 150 mg

在分析成人受试者收到atazanavir coadministered with cobicistat through Week 144 (Study GS-US-216-0114), 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 resistance-associated substitution M184V. No subject developed the tenofovir resistance-associated 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 resistance-associated substitution M184V with no tenofovir or protease inhibitor resistance-associated substitutions.

Clinical Study of Pediatric Subjects Receiving Atazanavir Coadministered with Cobicistat

In an as-treated analysis of pediatric subjects between the ages of 12 to less than 18 years who received atazanavir coadministered with cobicistat plus two NRTIs in Study GS-US-216-0128, 3 of 14 subjects qualified for resistance analysis through Week 48; 1 had evaluable data and no significant resistance-associated substitutions in protease orreverse transcriptase[seeClinical Studies].

Cross-Resistance

抗力移转中蛋白酶抑制剂有蜜蜂n observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of protease inhibitor-experienced subjects with HIV-1 infection showed that isolates cross-resistant to multiple protease inhibitors were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other protease inhibitors with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, protease inhibitor-resistant viral isolates that developed the I50L substitution in addition to other protease inhibitor resistance-associated substitution were also cross-resistant to other protease inhibitors.

国际艾滋病协会(IAS)定义的蛋白酶inhibitor resistance substitutions, depending on the number and type, may confer a reduced virologic response to atazanavir. Please refer to the “BaselineGenotype/Phenotypeand Virologic Outcome Analyses” section in the atazanavir full prescribing information.

Clinical Studies

Clinical Trial Results In Treatment-Naive Adult Subjects With HIV-1 Infection – Study GS-US-216-0114

The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study GS-US-216-0114 [NCT01108510]) in treatment-naive subjects with HIV-1 infection with baseline estimated creatinine clearance above 70 mL/min (N=692). 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.Randomizationwas 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 log₁₀copies/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 GS-US-216-0114 through Week 144 are presented in Table 10. In Study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm³in patients receiving atazanavir coadministered with cobicistat and 297 cells/mm³in patients receiving atazanavir coadministered with ritonavir.

Table 10: Virologic Outcomes of Randomized Treatment of Study GS-US216- 0114 in Treatment-Naive Adults with HIV-1 Infection at Week 144^a

	Atazanavir 300 mg coadministered with cobicistat 150 mg (once daily) + emtricitabine/ tenofovir disoproxil fumarate (n=344)	Atazanavir 300 mg coadministered with ritonavir 100 mg + emtricitabine/ tenofovir disoproxil fumarate (n=348)
HIV-1 RNA <50 copies/mL	72%	74%
Treatment Difference	−2.1% (95% CI = −8.7%, 4.5%)
HIV-1 RNA ≥50 copies/mLb	8%	5%
No Virologic Data at Week 48 Window	20%	21%
Discontinued Study Drug Due to AE or Deathc	11%	11%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLd	8%	10%
Missing Data During Window, but on Study Drug	<1%	<1%
aWeek 144 window is between Day 967 and 1050 (inclusive). bIncludes subjects who had ≥50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. cIncludes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. There were no deaths reported in Study GS-US-216-0114. dIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy (e.g., withdrew consent, lost to follow-up, etc).

Clinical Trial Results In Virologically Suppressed Pediatric Subjects With HIV-1 Infection – Study GS-US-216-0128

Study GS-US-216-0128 (NCT02016924) was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of atazanavir coadministered with cobicistat in pediatric subjects ages 12 years and older with HIV-1 infection who were virologically suppressed and had a baseline estimated creatinine clearance ≥90 mL/min/1.73 m². Subjects were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to cobicistat 150 mg once daily and continued atazanavir (N=14) and 2 NRTIs.

The mean age of subjects was 14 years (range 12–17 years); median weight was 53 kg; 71% were male, 57% were Asian, 29% were White, 14% were Black, and 71% were not Hispanic or Latino. At baseline, 13/14 subjects had plasma HIV-1 RNA <50 copies/mL and 1 subject had plasma HIV-1 RNA of 50 copies/mL.

In subjects who switched to atazanavir coadministered with cobicistat, 93% (13/14) of subjects remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject experienced virologic failure at Week 48. From a median baseline CD4+ cell count and CD4+% of 770 cells/mm³(range 486 to 1765 cells/mm³) and 33% (range 23% to 45%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -60 cells/mm³(range -500 to 705 cells/mm³) and -0.3% (range -6% to 8%), respectively.

PATIENT INFORMATION

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

What is EVOTAZ?

EVOTAZ is a prescription medicine that is used with other HIV-1 medicines to treat HIV-1 infection in adults and children weighing at least 77 pounds (35 kg).

HIV-1 is the virus that causesAcquired Immunodeficiency Syndrome(AIDS).

EVOTAZ contains the prescription medicines atazanavir and cobicistat.

It is not known if EVOTAZ is safe and effective in children who weigh less than 77 pounds (35 kg).

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:
  • alfuzosin
  • carbamazepine
  • cisapride
  • colchicine, if you have liver or kidney problems
  • dronedarone hydrochloride
  • drospirenone and ethinyl estradiol
  • elbasvir and grazoprevir
  • ergot-containing medicines:
    • dihydroergotamine
    • ergotamine
    • methylergonovine
  • glecaprevir and pibrentasvir
  • indinavir
  • irinotecan
  • lovastatin
  • lomitapide
  • lurasidone
  • midazolam, when taken by mouth for sedation
  • nevirapine
  • phenobarbital
  • phenytoin
  • pimozide
  • ranolazine
  • rifampin
  • sildenafil, when used for the treatment ofpulmonary arterial hypertension(PAH)
  • simvastatin
  • St. John’s wort (Hypericum perforatum), or a product that contains St. John’s wort
  • triazolam

Before taking EVOTAZ, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems
• have liver problems, including hepatitis B or C virus infection
• have kidney problems
• have diabetes
• have hemophilia
• are pregnant or plan to become pregnant. It is not known if EVOTAZ will harm your unborn baby.
  • EVOTAZ should not be used during pregnancy, because the EVOTAZ levels in your blood may be lower during pregnancy and may not control your HIV-1.
  • Tell your healthcare provider right away if you become pregnant during treatment with EVOTAZ.
  • Your healthcare provider may prescribe different medicines if you become pregnant during treatment with EVOTAZ.
  • People who are pregnant have developed a serious condition called lactic acidosis (a build-up of lactic acid in the blood) when taking EVOTAZ with other HIV-1 medicines called nucleoside analogues.
  • Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patches, 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.
  • Pregnancy Registry.There is a pregnancy registry for people who take HIV-1 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.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take EVOTAZ.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Talk 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 HIV-1 medicines.
• Take EVOTAZ 1 time a day with food.
• Do not miss a dose of EVOTAZ.
• When your EVOTAZ supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to EVOTAZ and become harder to treat.
• 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 “flulike” symptoms
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • fever
  • blisters
  • muscle or joint aches
  • mouth sores
  • swelling of your face
  • painful, warm, or red lump under your skin
• Kidney problems.EVOTAZ用其他药物时,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 stoneshave 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 disordershave happened in some people who take atazanavir, one of the medicines in EVOTAZ. Tell your healthcare provider right away if you get symptoms ofgallbladderproblems, which may include:
  • pain in the right or middle upper stomach area
  • 恶心想吐and vomiting
  • fever
  • your 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:
  • your skin or the white part of your eyes turns yellow
  • 恶心想吐
  • dark (tea-colored) urine
  • itching
  • light colored stools
  • stomach-area pain
• Yellowing of the skin or the white part of your eyesis 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. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking EVOTAZ.
• Changes in body fatcan 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 hemophiliahave happened when taking protease inhibitors including EVOTAZ.

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

These are not all the possible side effects of EVOTAZ.

Call your doctor for medical advice about side effects. You may report side effects to 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 the safe and effective use of 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.

You can ask your pharmacist or healthcare provider for information about EVOTAZ that is written for health professionals.

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.