Evotaz

Dosage Forms & Strengths

atazanavir/cobicistat

tablet

• 300mg/150mg

HIV-1 Infection

Indicated in combination with other antiretroviral (ART) agents for the treatment of human immunodeficiency virus type 1 (HIV-1) in adults

1 tablet (300 mg/150 mg) PO qDay with food

When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required

Dosage Modifications

Hepatic impairment: Do not use in patients with any degree of hepatic impairment

Renal impairment

• CrCl <70 mL/min: Coadministered with tenofovir disoproxil fumarate (DF) is not recommended
• ESRD managed with hemodialysis: Use not recommended
• Concomitant or recent use of nephrotoxic drug: atazanavir/cobicistat plus tenofovir DF is not recommended

Dosage Considerations

Limitations of use: Use in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions

Testing before initiating

• Renal testing
  • Creatinine clearance (CrCl): Before initiating, assess estimated CrCl because cobicistat decreases eCrCl, owing to inhibition of tubular secretion of creatinine, without affecting actual renal glomerular function
  • Coadministration with tenofovir DF: Assess eCrCl, urine glucose, and urine protein at baseline and routinely monitor during treatment
• Hepatic testing
  • Conduct hepatic laboratory testing prior to initiating therapy and during treatment in patients with underlying hepatitis B or C viral infections

<18 years: Safety and efficacy not established

Atazanavir, and therefore atazanavir/cobicistat, is not recommended for use in patients aged <3 months due to the risk of kernicterus

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Evotaz falls into category ­B. There are no well-done studies that have been done in humans with Evotaz. In animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with Evotaz. Talk to your healthcare provider about forms of birth control that may be used during treatment with Evotaz.

Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose and take your medicine at the next scheduled dose. Do not take extra medicine to make up the missed dose.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of atazanavir and cobicistat combination in the pediatric population. Safety and efficacy have not been established. Use is not recommended in children younger than 3 months of age because atazanavir may cause kernicterus.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of atazanavir and cobicistat combination in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution for patients receiving this medicine.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin
• Amifampridine
• Amisulpride
• Bepridil
• Carbamazepine
• Cisapride
• Colchicine
• Conivaptan
• Crizotinib
• Dihydroergotamine
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Eletriptan
• Eliglustat
• Enzalutamide
• Eplerenone
• Ergoloid Mesylates
• Ergonovine
• Ergotamine
• Flibanserin
• Fluconazole
• Fosphenytoin
• Grazoprevir
• Indinavir
• Irinotecan
• Irinotecan Liposome
• Isavuconazonium Sulfate
• Ivabradine
• Ketoconazole
• Lomitapide
• Lovastatin
• Lurasidone
• Maraviroc
• Mesoridazine
• Methylergonovine
• Methysergide
• Midazolam
• Mitotane
• Naloxegol
• Nelfinavir
• Nevirapine
• Pazopanib
• Phenobarbital
• Phenytoin
• Pimozide
• Piperaquine
• Primidone
• Ranolazine
• Rifampin
• Riociguat
• Romidepsin
• Saquinavir
• Sildenafil
• Silodosin
• Simvastatin
• Sparfloxacin
• St John's Wort
• Terfenadine
• Thioridazine
• Tolvaptan
• Triazolam
• Venetoclax
• Vinflunine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ado-Trastuzumab Emtansine
• Afatinib
• Alprazolam
• Amiodarone
• Amitriptyline
• Amlodipine
• Amprenavir
• Anagrelide
• Apixaban
• Aprepitant
• Aripiprazole
• Arsenic Trioxide
• Artemether
• Atorvastatin
• Avanafil
• Axitinib
• Bedaquiline
• Betrixaban
• Boceprevir
• Bosentan
• Bosutinib
• Brentuximab Vedotin
• Brexpiprazole
• Brigatinib
• Bromocriptine
• Budesonide
• Buprenorphine
• Buserelin
• Cabazitaxel
• Cabozantinib
• Calcifediol
• Cariprazine
• Ceritinib
• Cilostazol
• Cimetidine
• Clarithromycin
• Clomipramine
• Clozapine
• Cobimetinib
• Cyclophosphamide
• Cyclosporine
• Dabrafenib
• Daclatasvir
• Darunavir
• Dasabuvir
• Dasatinib
• Deflazacort
• Degarelix
• Delamanid
• Delavirdine
• Deslorelin
• Deutetrabenazine
• Dexamethasone
• Dexlansoprazole
• Diazepam
• Digoxin
• Diltiazem
• Disopyramide
• Docetaxel
• Domperidone
• Donepezil
• Efavirenz
• Eluxadoline
• Eplerenone
• Erlotinib
• Erythromycin
• Escitalopram
• Eslicarbazepine Acetate
• Esomeprazole
• Eszopiclone
• Etravirine
• Everolimus
• Famotidine
• Felodipine
• Fentanyl
• Flecainide
• Fluoxetine
• Fluticasone
• Fluvastatin
• Fosamprenavir
• Fosaprepitant
• Foscarnet
• Garlic
• Gonadorelin
• Goserelin
• Haloperidol
• Histrelin
• Hydrocodone
• Hydrocortisone
• Hydroxychloroquine
• Hydroxyzine
• Ibrutinib
• Idelalisib
• Ifosfamide
• Iloperidone
• Imipramine
• Irinotecan
• Irinotecan Liposome
• Itraconazole
• Ivabradine
• Ivacaftor
• Ixabepilone
• Ketoconazole
• Lacosamide
• Lamotrigine
• Lansoprazole
• Lapatinib
• Leuprolide
• Levofloxacin
• Levomilnacipran
• Lidocaine
• Lofepramine
• Lopinavir
• Lumefantrine
• Lurasidone
• Macitentan
• Manidipine
• Methadone
• Metronidazole
• Mexiletine
• Midostaurin
• Mifepristone
• Minocycline
• Morphine
• Morphine Sulfate Liposome
• Moxifloxacin
• Nafarelin
• Netupitant
• Nevirapine
• Nicardipine
• Nifedipine
• Nilotinib
• Nimodipine
• Nisoldipine
• Nizatidine
• Olaparib
• Omeprazole
• Ondansetron
• Orlistat
• Oxcarbazepine
• Oxycodone
• Palbociclib
• Panobinostat
• Pantoprazole
• Paritaprevir
• Pasireotide
• Pimavanserin
• Piperaquine
• Pitolisant
• Pixantrone
• Ponatinib
• Pravastatin
• Propafenone
• Quetiapine
• Quinidine
• Rabeprazole
• Ranitidine
• Reboxetine
• Regorafenib
• Repaglinide
• Retapamulin
• Ribociclib
• Rifabutin
• Rifapentine
• Ritonavir
• Rivaroxaban
• Rosuvastatin
• Ruxolitinib
• Salmeterol
• Saquinavir
• Sevoflurane
• Simeprevir
• Sirolimus
• Sonidegib
• Sulpiride
• Sunitinib
• Suvorexant
• Tacrolimus
• Tadalafil
• Tamoxifen
• Tamsulosin
• Telithromycin
• Temsirolimus
• Tenofovir Disoproxil Fumarate
• Thiotepa
• Ticagrelor
• Tipranavir
• Tolvaptan
• Topotecan
• Toremifene
• Trabectedin
• Tramadol
• Trazodone
• Trimipramine
• Triptorelin
• Valbenazine
• Vandetanib
• Vardenafil
• Vemurafenib
• Venetoclax
• Venlafaxine
• Verapamil
• Vilanterol
• Vilazodone
• Vinblastine
• Vincristine
• Vincristine Sulfate Liposome
• Vinflunine
• Vorapaxar
• Voriconazole
• Warfarin
• Zolpidem
• Zuclopenthixol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aripiprazole Lauroxil
• Atazanavir
• Cobicistat
• Dapsone
• Darunavir
• Desogestrel
• Didanosine
• Dienogest
• Drospirenone
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Indinavir
• Levonorgestrel
• Lopinavir
• Medroxyprogesterone Acetate
• Mestranol
• Methadone
• Nelfinavir
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Suvorexant
• Telaprevir
• Trazodone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Diabetes or
• Fanconi syndrome (kidney disease), history of or
• Gallbladder problems or
• Hemophilia (a bleeding problem) or
• Hyperglycemia (high blood sugar) or
• Kidney failure, history of or
• Liver disease (eg, hepatitis B or C)—Use with caution. May make these conditions worse.

• Heart block or
• Heart conduction problems (eg, prolonged PR interval)—May change the way your heart beats and increase your chance of getting side effects.

• Kidney disease, severe—Use is not recommended in these patients.

Your doctor will want to check your progress at regular visits, especially during the first few weeks that you take this medicine. Blood and urine tests may be needed to check for any unwanted effects.

This medicine should not be used together with alfuzosin (Uroxatral®), carbamazepine (Tegretol®), cisapride (Propulsid®), colchicine (Colcrys®), dronedarone (Multaq®), elbasvir/grazoprevir (Zepatier™), indinavir (Crixivan®), irinotecan (Camptosar®), lovastatin (Mevacor®), lurasidone (Latuda®), midazolam (Versed®), nevirapine (Viramune®), phenobarbital (Luminal®), phenytoin (Dilantin®), pimozide (Orap®), ranolazine (Ranexa®), rifampin (Rifadin®, Rimactane®), sildenafil (Revatio®), simvastatin (Zocor®), St John's wort, triazolam (Halcion®), or ergot medicines (such as dihydroergotamine, ergotamine, methylergonovine, Cafergot®, Ergomar®, Wigraine®).

This medicine may cause heart rhythm problems (eg, PR prolongation). Tell your doctor right away if you get dizzy or lightheaded.

Serious allergic and skin reactions can occur with this medicine. Check with your doctor right away if you have any of the following symptoms while using this medicine: severe rash, blistering, peeling, or loose skin, chills, cough, diarrhea, itching, joint or muscle pain, red skin lesions, often with a purple center, skin rash, sore throat, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

This medicine may increase your risk of having kidney stones or gallstones. Check with your doctor right away if you have blood in your urine, nausea and vomiting, pain in the groin or genitals, or sharp back pain just below the ribs, stomach fullness or pain, recurrent fever, or yellow eyes or skin.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Your immune system may get stronger when you start taking HIV medicines. Tell your doctor right away if you notice any changes in your health. Sometimes the immune system will start to fight infections that were hidden in your body, such as pneumonia, herpes, or tuberculosis. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) may also occur.

This medicine may increase blood sugar levels. Check with your doctor if you notice a change in the results of your blood or urine sugar tests.

This medicine does not decrease the risk of transmitting the HIV infection to others through sexual contact or by contaminated blood. Make sure you understand and practice safe sex, even if your partner also has HIV. Avoid sharing needles with anyone.

This medicine may cause you to have excess body fat. Tell your doctor if you notice changes in your body shape, such as an increased amount of fat in the upper back and neck, or around the chest and stomach area. You might also lose fat from the legs, arms, and face.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or non-prescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• dizziness
• fever
• headache
• itching or rash
• loss of appetite
• nausea
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

Incidence not known

• Abdominal or stomach fullness or tenderness
• black, tarry stools
• blistering, peeling, or loosening of the skin
• blood in the urine
• chest pain
• clay colored stools
• decreased appetite
• diarrhea
• gaseous abdominal or stomach pain
• joint or muscle pain
• pain in the groin or genitals
• painful or difficult urination
• recurrent fever
• red skin lesions, often with a purple center
• red, irritated eyes
• sharp back pain just below the ribs
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• swelling of the feet or lower legs
• swollen glands
• unusual bleeding or bruising

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

• It is used to treat HIV infection.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Evotaz, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Evotaz. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Evotaz (atazanavir and cobicistat).

Review Date: October 4, 2017

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

• cardiac conduction abnormalities [see Warnings and Precautions (5.1)] • rash [see Warnings and Precautions (5.2)] • effects on serum creatinine [see Warnings and Precautions (5.3)] • new onset or worsening renal impairment when used with tenofovir DF [see Warnings and Precautions (5.4)] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.5)] • hepatotoxicity [see Warnings and Precautions (5.6)] • hyperbilirubinemia [see Warnings and Precautions (5.9)]

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

Clinical Trial Experience in Adults

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

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

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

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

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

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

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

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

Musculoskeletal and Connective Tissue Disorders: 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 114 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 114 (Week 144 analysis)

	144 weeks Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF	144 weeks Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF
Laboratory Parameter Abnormality	(n=344)	(n=348)
a  For 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.
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%

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

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 HIV-1 Infected Treatment-Naive Adults Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study 114 (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
a  The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug.
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]
LDL-cholesterol (fasted)	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]

Postmarketing Experience

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

Mechanism of Action

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

Pharmacodynamics

Cardiac Electrophysiology

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

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

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

Effects on Serum Creatinine

The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change in estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) 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 eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.3)].

Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of Evotaz (atazanavir 300 mg and cobicistat 150 mg) were evaluated in healthy adult volunteers. Results are summarized in Table 6.

Table 6:      Pharmacokinetic Properties of the Components of Evotaz
	Atazanavir	Cobicistat
a     Following Evotaz dosing under fasted conditions. b     Values refer to geometric mean ratio (fed / fasted) and (90% confidence interval). c     Dosing in mass balance study: cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days). ND = not determined.
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

The pharmacokinetics of atazanavir was evaluated in HIV-1 infected subjects who received atazanavir 300 mg coadministered with cobicistat 150 mg in combination with emtricitabine/tenofovir DF. The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat are shown in Table 7 [see Clinical Studies (14)].

Table 7: Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in the Pharmacokinetic Substudy of Study 114

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

Renal Impairment

Atazanavir: In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), 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-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown.

Cobicistat: A study of the pharmacokinetics of cobicistat was performed in non−HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Specific Populations (8.6)].

Hepatic Impairment

Evotaz has not been studied in patients with hepatic impairment.

Atazanavir: Atazanavir is primarily metabolized and eliminated by the liver. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function.

Cobicistat: Cobicistat is primarily metabolized and eliminated by the liver. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7)].

Gender and Age

Atazanavir: There were no clinically important pharmacokinetic differences observed due to age or gender.

Cobicistat: No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.

Assessment of Drug Interactions

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

Drug interaction studies were not conducted for Evotaz or for atazanavir coadministered with cobicistat. Drug interaction studies of cobicistat were conducted with desipramine, digoxin, and efavirenz. Drug interaction studies of cobicistat coadministered with elvitegravir included rosuvastatin and rifabutin. The effects of cobicistat on the exposure of coadministered drugs are summarized in Table 8. For information regarding clinical recommendations, [see Drug Interactions (7)].

Table 8: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistata

Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat-containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information.
Coadministered Drug	Coadministered Drug Dose/Schedule	Cobicistat Dose/Schedule	Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without cobicistat; No Effect = 1.00
			Cmax	AUC	Cmin
a  All interaction studies conducted in healthy volunteers. NC = not calculated
desipramine	50 mg single dose (n=8)	150 mg QD (n=8)	1.24 (1.08, 1.44)	1.65 (1.36, 2.02)	NC
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)	NC
efavirenz	600 mg single dose (n=17)	150 mg QD (n=17)	0.87 (0.80, 0.94)	0.93 (0.89, 0.97)	NC

Microbiology

Mechanism of Action

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

Antiviral Activity in Cell Culture

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

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

Resistance

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

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

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

Cross-Resistance

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

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

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

Instructions for Use

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

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 [see Contraindications (4), Warnings and Precautions (5.6, 5.7) and Drug Interactions (7)].

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 Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.2)].

Nephrolithiasis and Cholelithiasis

Inform patients that kidney stones and/or gallstones have been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications [see Warnings and Precautions (5.5)].

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 Warnings and Precautions (5.9)].

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 Warnings and Precautions (5.12)].

Pregnancy Registry

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

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Serious drug interactions can occur when certain medicines are used together with Evotaz. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

Usual Adult Dose for HIV Infection:

1 tablet orally once a day with food

Comments:
-For therapy-naive and therapy-experienced patients
-The number of baseline primary protease inhibitor resistance substitutions should guide use in therapy-experienced patients.

Use: In combination with other antiretroviral agents, for the treatment of HIV-1 infection

Applies to atazanavir / cobicistat: oral tablet

General

In clinical trials, safety of this drug was evaluated in HIV-1-infected, antiretroviral therapy-naive patients using the individual components with other antiretrovirals for at least 48 weeks. In 1 trial, atazanavir and cobicistat were used with emtricitabine-tenofovir (cobicistat-boosted group); in another trial, atazanavir and ritonavir were used with emtricitabine-tenofovir (ritonavir-boosted group). In the cobicistat-boosted group, the most common side effects were jaundice, ocular icterus, and nausea; in the ritonavir-boosted group, the most common side effects were jaundice, ocular icterus, nausea, and diarrhea. Study treatment was discontinued due to side effects in 7% of patients in both the cobicistat- and the ritonavir-boosted groups. Most of the side effects included from clinical trials were of at least moderate intensity (grade 2 or higher).

The manufacturer product information for atazanavir and cobicistat should be consulted for additional safety information.[Ref]

Hepatic

Increases in total bilirubin greater than 2.5 times the upper limit of normal (2.5 x ULN) was reported in 65% of patients in the cobicistat-boosted group and 56% in the ritonavir-boosted group. Increased ALT (greater than 5 x ULN), AST (greater than 5 x ULN), and GGT (greater than 5 x ULN) were reported in 3%, 3%, and 2% of patients in the cobicistat-boosted group, respectively, and 2%, 2%, and 1% of patients in the ritonavir-boosted group, respectively.

Jaundice was reported in the cobicistat-boosted group (all grades: 13%; grades 2 to 4: 5%) and the ritonavir-boosted group (all grades: 11%; grades 2 to 4: 3%).

Most patients taking atazanavir experienced asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UGT. This hyperbilirubinemia was reversible upon discontinuation of atazanavir.[Ref]

Very common (10% or more): Increased total bilirubin (65%), jaundice (up to 13%)
Common (1% to 10%): Increased ALT, increased AST, increased GGT

Atazanavir:
-Very common (10% or more): Elevated indirect (unconjugated) bilirubin/hyperbilirubinemia, UDP-glucuronosyl transferase (UGT) inhibited, jaundice, increased total bilirubin
-Common (1% to 10%): Increased ALT, increased AST, increased GGT
-Postmarketing reports: Hepatic function abnormalities, cholelithiasis, cholecystitis, cholestasis[Ref]

Ocular

Ocular icterus was reported in the cobicistat-boosted group (all grades: 15%; grades 2 to 4: 3%) and the ritonavir-boosted group (all grades: 17%; grades 2 to 4: 1%).[Ref]

Very common (10% or more): Ocular icterus (up to 15%)

Atazanavir:
-Very common (10% or more): Ocular icterus[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 12%)
Common (1% to 10%): Increased lipase, increased serum amylase
Frequency not reported: Diarrhea, vomiting, upper abdominal pain

Atazanavir:
-Very common (10% or more): Nausea, diarrhea
-Common (1% to 10%): Increased lipase, increased serum amylase
-Postmarketing reports: Pancreatitis[Ref]

Nausea was reported in the cobicistat-boosted group (all grades: 12%; grades 2 to 4: 2%) and the ritonavir-boosted group (all grades: 11%; grades 2 to 4: 2%). Diarrhea (all grades) was reported in 11% of patients in the ritonavir-boosted group.

Increased serum amylase (greater than 2 x ULN) was reported in 4% and 2% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.

If serum amylase was greater than 1.5 x ULN, lipase was also measured. Increased lipase (grades 3 to 4) was reported in 9% and 6% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.[Ref]

Dermatologic

Common (1% to 10%): Rash (rash events included allergic dermatitis, drug hypersensitivity, generalized pruritus, eosinophilic pustular folliculitis, rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, urticaria)

Atazanavir:
-Common (1% to 10%): Rash events
-Frequency not reported: Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, mild-to-moderate maculopapular skin eruptions
-Postmarketing reports: Alopecia, maculopapular rash, pruritus, angioedema[Ref]

Rash events (grades 2 to 4) were reported in 5% and 4% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.[Ref]

Musculoskeletal

Common (1% to 10%): Increased creatine kinase
Frequency not reported: Rhabdomyolysis

Atazanavir:
-Common (1% to 10%): Increased creatine kinase
-Postmarketing reports: Arthralgia[Ref]

Increased creatine kinase (at least 10 x ULN) was reported in 5% and 6% of patients in the cobicistat-boosted and ritonavir-boosted groups, respectively.[Ref]

Renal

Nephrolithiasis has been reported with atazanavir. In clinical trials, nephrolithiasis was reported in 2% of patients in the cobicistat-boosted group and no patients in the ritonavir-boosted group. Onset of nephrolithiasis was about 24 weeks in the cobicistat-boosted group.

In clinical trials, serum creatinine increased and estimated CrCl decreases occurred early during therapy in the cobicistat-boosted group after which they stabilized. After 48 weeks of therapy, eGFR (based on CrCl) change averaged -13.4 mL/min in the cobicistat-boosted group and -9.1 mL/min in the ritonavir-boosted group.

Renal impairment (including acute renal failure and Fanconi syndrome) has been reported when cobicistat was used in a regimen containing tenofovir.

In clinical trials over 48 weeks (n=771), 6 (1.5%) patients using atazanavir, cobicistat, and tenofovir discontinued therapy due to a renal side effect; 5 patients had laboratory findings consistent with proximal renal tubulopathy. None of the 5 patients had baseline renal dysfunction (e.g., estimated CrCl less than 70 mL/min). Laboratory findings in these 5 patients improved but did not completely resolve in all patients when therapy was stopped. No patients required renal replacement therapy.[Ref]

Common (1% to 10%): Nephrolithiasis
Frequency not reported: Decreased estimated CrCl, increased serum creatinine, decreased estimated glomerular filtration rate (eGFR; based on CrCl), nephropathy, Fanconi syndrome, laboratory findings consistent with proximal renal tubulopathy

Atazanavir:
-Frequency not reported: Decreased eGFR
-Postmarketing reports: Nephrolithiasis, interstitial nephritis

Cobicistat:
-Frequency not reported: Decreased estimated CrCl, increased serum creatinine, tubular secretion of creatinine inhibited (actual renal glomerular function not affected), decreased eGFR, renal impairment (including acute renal failure, Fanconi syndrome)[Ref]

Genitourinary

Increased urine RBC (greater than 75 RBC/high power field) and urine glucose (at least 1000 mg/dL) have been reported in 3% and 3% of patients in the cobicistat-boosted group, respectively, and 2% and 1% of patients in the ritonavir-boosted group, respectively.[Ref]

Common (1% to 10%): Hematuria (increased urine RBC), glycosuria (increased urine glucose)

Atazanavir:
-Common (1% to 10%): Increased urine RBC, increased urine glucose[Ref]

Metabolic

Frequency not reported: Increased fasted total cholesterol, increased fasted high-density lipoprotein cholesterol, increased fasted low-density lipoprotein cholesterol, increased fasted triglycerides

Atazanavir:
-Postmarketing reports: New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, diabetic ketoacidosis

Combination antiretroviral therapy:
-Frequency not reported: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")[Ref]

Nervous system

Frequency not reported: Headache[Ref]

Other

Frequency not reported: Fatigue

Atazanavir:
-Postmarketing reports: Edema[Ref]

Psychiatric

Frequency not reported: Depression, abnormal dreams, insomnia[Ref]

Cardiovascular

Atazanavir:
-Common (1% to 10%): First-degree atrioventricular (AV) block
-Frequency not reported: Prolongation of the PR interval, abnormalities in AV conduction, other conduction abnormalities
-Postmarketing reports: Second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation[Ref]

Immunologic

Atazanavir:
-Frequency not reported: Immune reconstitution syndrome

Combination antiretroviral therapy:
-Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

Hematologic

Protease inhibitor therapy:
-Frequency not reported: Increased bleeding (including spontaneous skin hematomas, hemarthrosis) in hemophiliacs[Ref]

Some side effects of Evotaz may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.