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Generic Name: Atazanavir Sulfate
Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: (3S,8S,9S,12S) - 3,12 - Bis(1,1 - dimethylethyl) - 8 - hydroxy - 4,11 - dioxo - 9 - (phenylmethyl) - 6 - {[4 - (2 - pyridinyl)phenyl]methyl{ - 2,5,6,10,13 - pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1)
Molecular Formula: C38H52N6O7•H2SO4
CAS Number: 22997597-7

Introduction

Antiretroviral; HIV protease inhibitor (PI).1

Uses for Reyataz

Treatment of HIV Infection

Atazanavir with low-dose ritonavir (ritonavir-boosted atazanavir): Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥3 months of age;1 used in conjunction with other antiretrovirals.1 28 29 200 201

Atazanavir with cobicistat (cobicistat-boosted atazanavir): Treatment of HIV-1 infection in adults;238 239 used in conjunction with other antiretrovirals.200 238 239

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat): Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥3 months of age;1 used in conjunction with other antiretrovirals.1 2 3 4 7 14

Atazanavir usually used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 200 201 238 239 Pharmacokinetic enhancer (pharmacokinetic booster) used to improve atazanavir's pharmacokinetic profile.1 200 238 239 Low-dose ritonavir and cobicistat are not interchangeable in antiretroviral regimens;200 238 239 these pharmacokinetic enhancers have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions.200 238 239

When ritonavir-boosted atazanavir used, single-entity atazanavir is given with single-entity ritonavir.1

When cobicistat-boosted atazanavir used, fixed combination containing both drugs (atazanavir/cobicistat) can be used;238 alternatively, single-entity atazanavir is given with single-entity cobicistat.239 Assess estimated Clcr in all patients prior to initiation of cobicistat-boosted atazanavir (see Renal Effects under Cautions).238 239

For initial treatment in antiretroviral-naive adults and adolescents, experts state that ritonavir-boosted atazanavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is an alternative PI-based regimen.200 These experts state that cobicistat-boosted atazanavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) is another alternative PI-based regimen for initial treatment in antiretroviral-naive adults, but use only in those with pretreatment estimated Clcr ≥70 mL/minute.200 Ritonavir-boosted atazanavir or cobicistat-boosted atazanavir in conjunction with abacavir and lamivudine (or emtricitabine) are other PI-based options for initial treatment in antiretroviral-naive adults when recommended or alternative regimens cannot be used, but use only in those who are human leukocyte antigen (HLA)-B*5701 negative and only in those with pretreatment viral load <100,000 copies/mL.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that ritonavir-boosted atazanavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a preferred PI-based regimen in those ≥6 years of age and an alternative PI-based regimen in those 3 months through 5 years of age weighing ≥10 kg.201

Experts state that unboosted atazanavir is not recommended for initial treatment in antiretroviral-naive adults, adolescents, or children because it is less potent than boosted atazanavir,200 201 but can be used in special circumstances in antiretroviral-naive adolescents ≥13 years of age weighing ≥40 kg who cannot tolerate ritonavir.201

Unboosted atazanavir should not be used in antiretroviral-experienced (previously treated) patients with prior virologic failure.1 200 If using ritonavir-boosted atazanavir or cobicistat-boosted atazanavir in antiretroviral-experienced patients, treatment should be guided by number of baseline primary PI resistance substitutions.1 238

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199

USPHS recommends a 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV.199 Ritonavir-boosted atazanavir and 2 NRTIs is one of several alternative regimens.199 Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF; alternatives are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Reyataz Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted atazanavir) once daily with food.1

Alternatively, administer orally in conjunction with oral cobicistat (cobicistat-boosted atazanavir) once daily with food.238 239

Has been administered orally unboosted (i.e., without low-dose ritonavir or cobicistat) once daily with food.1

If used concomitantly with certain drugs (e.g., antacids, buffered medications, didanosine, histamine H2-receptor antagonists, proton-pump inhibitors), dosage adjustments may be needed and/or doses of atazanavir and the other drug may need to be given at separate times.1 238 239 (See Specific Drugs under Interactions.)

Atazanavir Capsules

Swallow capsules whole; do not open.1

Used in adults, adolescents, and pediatric patients ≥6 years of age.1

Usually administered with low-dose ritonavir (ritonavir-boosted atazanavir);1 200 201 may be used without low-dose ritonavir in adults and adolescents ≥13 years of age weighing ≥40 kg who are unable to tolerate ritonavir.1

Atazanavir Oral Powder

Provided in single-use packets containing 50 mg of atazanavir as an oral powder;1 must be mixed with food or beverage prior to administration.1

Used in pediatric patients ≥3 months of age weighing 10 kg to <25 kg.1

Must be administered with low-dose ritonavir (ritonavir-boosted atazanavir).1

Store atazanavir powder in original packet; do not open until ready to use.1 Mixing the powder with food (e.g., applesauce, yogurt) is preferred; may mix with beverage (e.g., milk, infant formula, water) for infants able to drink from a cup.1 For infants <6 months of age not able to eat solid food or drink from a cup, mix with infant formula and administer using oral dosing syringe.1 Administration with infant bottle not recommended since full dose may not be delivered.1

Administer entire dose within 1 hour after mixing with food or beverage; may be left at room temperature (20–30°C) for up to 1 hour after mixing.1

Mixing with food: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets with ≥1 tablespoon of food (e.g., applesauce, yogurt) in a small container (e.g., cup, bowl); feed mixture to patient.1 Add and mix additional 1 tablespoon of food to the small container; feed residual mixture to patient.1

Mixing with a beverage: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets in a small drinking cup with ≥30 mL of beverage; give mixture to patient to drink.1 Add and mix additional 15 mL of beverage to drinking cup; give residual mixture to patient to drink.1 If water is used as the beverage, patient also should eat food at time of administration.1

Mixing with liquid infant formula: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets in a small medicine cup with 10 mL of prepared liquid infant formula.1 Draw entire mixture into oral dosing syringe and administer into infant's right or left inner cheek.1 Pour and mix additional 10 mL of infant formula into medicine cup to rinse off any remaining powder.1 Draw residual mixture into oral dosing syringe and administer into infant's right or left inner cheek.1

Ritonavir-boosted Atazanavir

When atazanavir capsules used, give at same time as single-entity ritonavir capsules, tablets, or oral solution.1 200

When atazanavir oral powder used, administer single-entity ritonavir immediately following atazanavir dose.1

Cobicistat-boosted Atazanavir

Administer fixed-combination tablets containing both drugs (atazanavir/cobicistat).238 Alternatively, administer single-entity atazanavir as capsules at same time as single-entity cobicistat tablets.239

Dosage

Single-entity atazanavir available as capsules or oral powder containing atazanavir sulfate;1 dosage expressed in terms of atazanavir.1

Atazanavir/cobicistat available as fixed-combination tablets containing atazanavir sulfate (300 mg of atazanavir) and cobicistat (150 mg).238

Pediatric Patients

Treatment of HIV Infection
Antiretroviral-naive or Antiretroviral-experienced Pediatric Patients
Oral

Pediatric patients ≥3 months of age weighing 10 kg to <25 kg (oral powder): Dosage is based on weight.1 (See Table 1.) Oral powder must be used with low-dose ritonavir (ritonavir-boosted atazanavir).1

Table 1. Dosage of Ritonavir-boosted Atazanavir for Pediatric Patients ≥3 Months of Age Weighing 10 kg to <25 kg1

Body Weight

Atazanavir Dosage (Oral Powder)

Ritonavir Dosage (Oral Solution)

10 to <15 kg

200 mg (4 packets) once daily

80 mg once daily

15 to <25 kg

250 mg (5 packets) once daily

80 mg once daily

Pediatric patients 6 years to <18 years of age (capsules): Dosage is based on weight.1 (See Table 2.) Capsules usually used with low-dose ritonavir (ritonavir-boosted atazanavir).1

Table 2. Dosage of Ritonavir-boosted Atazanavir for Pediatric Patients 6 Years to <18 Years of Age1

Body Weight

Atazanavir Dosage (Capsules)

Ritonavir Dosage

<15 kg

Capsules not recommended

15 to <20 kg

150 mg once daily

100 mg once daily

20 to <40 kg

200 mg once daily

100 mg once daily

≥40 kg

300 mg once daily

100 mg once daily

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) in antiretroviral-naive adolescents ≥13 years of age weighing ≥40 kg unable to tolerate ritonavir: 400 mg once daily.1 Do not use unboosted atazanavir in antiretroviral-experienced adolescents.1

Adults

Treatment of HIV Infection
Antiretroviral-naive Adults
Oral

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: 1 tablet of atazanavir/cobicistat (300 mg of atazanavir and 150 mg of cobicistat) once daily.238 Alternatively, single-entity atazanavir 300 mg (one 300-mg atazanavir capsule) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Unboosted atazanavir (adults unable to tolerate ritonavir): 400 mg once daily.1

Antiretroviral-experienced Adults
Oral

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: 1 tablet of atazanavir/cobicistat (300 mg of atazanavir and 150 mg of cobicistat) once daily.238 Alternatively, single-entity atazanavir 300 mg (one 300-mg atazanavir capsule) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Oral

400 mg once daily.198 Use in conjunction with other antiretrovirals.198 If tenofovir included in the regimen, use 300 mg of atazanavir once daily with low-dose ritonavir.198

Initiate nPEP as soon as possible following nonoccupational exposure to HIV (preferably ≤72 hours after exposure); continue for 28 days.198

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Do not exceed adult dosage.1

Ritonavir-boosted atazanavir (children ≥6 years of age): Maximum 300 mg once daily with low-dose ritonavir (100 mg once daily).1

Unboosted atazanavir (antiretroviral-naive adolescents ≥13 years of age weighing ≥40 kg): Maximum 400 mg once daily (without low-dose ritonavir).1

Special Populations

Hepatic Impairment

Oral

Unboosted atazanavir in treatment-naive adults with mild hepatic impairment (Child-Pugh class A): 400 mg once daily.1

Unboosted atazanavir in treatment-naive adults with moderate hepatic impairment (Child-Pugh class B): 300 mg once daily.1 200

Unboosted atazanavir in severe hepatic impairment (Child-Pugh class C): Do not use.1 200

Ritonavir-boosted atazanavir or cobicistat-boosted atazanavir: Do not use in patients with any degree of hepatic impairment.1 238 239

Renal Impairment

Oral

Ritonavir-boosted atazanavir or unboosted atazanavir in patients with renal impairment not undergoing hemodialysis: Dosage adjustments not needed.1

Ritonavir-boosted atazanavir in antiretroviral-naive adults with end-stage renal disease undergoing hemodialysis: 300 mg once daily with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: Assess estimated Clcr prior to initiation of fixed-combination atazanavir/cobicistat or, alternatively, single-entity atazanavir with single-entity cobicistat.238 239 Experts state dosage adjustments of cobicistat-boosted atazanavir not necessary in patients with renal impairment who do not require hemodialysis.200 However, these experts and manufacturer state do not use cobicistat-boosted atazanavir in conjunction with tenofovir DF in patients with estimated Clcr <70 mL/minute.200 238 239

Antiretroviral-experienced adults with end-stage renal disease undergoing hemodialysis: Do not use ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.1 238 239

Geriatric Patients

Dosage adjustments based solely on age not required in patients ≥65 years of age.1

Pregnant and Postpartum Women

Use ritonavir-boosted atazanavir;1 202 do not use unboosted atazanavir.1 202 Monitor closely for adverse effects, especially during first 2 months after delivery.1 (See Pregnancy under Cautions.)

Ritonavir-boosted atazanavir: Manufacturer states usually recommended adult dosage can be used during pregnancy or postpartum period unless used concomitantly with certain drugs.1 Experts recommend using increased atazanavir dosage of 400 mg once daily with low-dose ritonavir (100 mg once daily) during second and third trimesters.202

Ritonavir-boosted atazanavir: Antiretroviral-experienced pregnant women in second or third trimester also receiving either a histamine H2-receptor antagonist or tenofovir: Increase atazanavir dosage to 400 mg once daily with low-dose ritonavir (100 mg once daily).1 Not recommended in antiretroviral-experienced pregnant women receiving both a histamine H2-receptor antagonist and tenofovir.1

Cautions for Reyataz

Contraindications

  • History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to atazanavir or any ingredient in the formulation.1 238

  • Concomitant use of ritonavir-boosted or cobicistat-boosted atazanavir with drugs highly dependent on CYP3A or uridine diphosphate-glucuronosyltransferase (UGT) 1A1 for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, indinavir, irinotecan, lovastatin, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).1 238 239 In addition, concomitant use of cobicistat-boosted atazanavir and colchicine, dronedarone, lurasidone, or ranolazine is contraindicated.238 239 (See Specific Drugs under Interactions.)

    Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with drugs that are potent inducers of CYP3A (e.g., nevirapine, rifampin, St. John’s wort [Hypericum perforatum], triazolam) since such use may decrease atazanavir exposures resulting in possible loss of virologic response.1 238 239 (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Rash (generally mild to moderate maculopapular eruptions) reported frequently.1 238 Median time to onset 7.3 weeks; median duration 1.4 weeks.1 238 Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, reported.1 238

Discontinue in patients who develop severe rash.1 238

Cardiovascular Effects

Abnormalities in AV conduction (including prolongation of PR interval) reported.1 238 Cardiac conduction abnormalities generally are asymptomatic and limited to first-degree AV block.1 238

Because of limited clinical experience in patients with preexisting cardiac conduction abnormalities (e.g., marked first-degree AV block; second- or third-degree AV block), consider ECG monitoring in such patients.1 238

Caution advised if used with other drugs that prolong PR interval (e.g., some β-adrenergic blocking agents, some calcium-channel blocking agents, digoxin, fixed combination of lopinavir and ritonavir [lopinavir/ritonavir]).1 207 (See Specific Drugs under Interactions.)

Renal Effects

Cobicistat decreases estimated Clcr by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function;238 239 consider this effect when interpreting changes in estimated Clcr in patients receiving cobicistat-boosted atazanavir, particularly those needing Clcr monitoring due to a medical condition or other concomitant drugs.238 239

Assess estimated Clcr prior to initiating cobicistat-boosted atazanavir.238 239 Although cobicistat may cause only modest increases in Scr and modest declines in estimated Clcr without affecting renal glomerular function, closely monitor patient for renal safety if Scr increases >0.4 mg/dL from baseline during cobicistat-boosted atazanavir therapy.238 239

Manufacturer states dosage recommendations not available for drugs requiring dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted atazanavir;238 239 consider alternative concomitant drugs that do not require dosage adjustments based on renal impairment.238 239

New-onset or worsening renal impairment, including acute renal failure and Fanconi syndrome, reported in patients receiving cobicistat in an antiretroviral regimen that also includes tenofovir DF.238 239 Concomitant use of cobicistat-boosted atazanavir and tenofovir DF not recommended in patients with estimated Clcr <70 mL/minute.238 239 Whenever cobicistat-boosted atazanavir and tenofovir DF are used concomitantly, document urine glucose and urine protein at baseline and monitor estimated Clcr, urine glucose, and urine protein throughout concomitant therapy.238 239 In addition, monitor serum phosphorus in those with or at risk for renal impairment.238 239 Concomitant use of a nephrotoxic agent not recommended in patients receiving an antiretroviral regimen that includes cobicistat-boosted atazanavir and tenofovir DF.238 239

Hyperbilirubinemia

Reversible, asymptomatic elevations in indirect (unconjugated) bilirubin occur in most patients since atazanavir is a competitive inhibitor of UGT 1A1 (an enzyme that catalyzes glucuronidation of bilirubin).1 238

Total bilirubin concentrations ≥2.6 times ULN reported in 35–49% of patients; long-term safety data not available for patients with persistent elevations in total bilirubin >5 times ULN.1 238

If increases in serum AST and/or ALT occur with hyperbilirubinemia, evaluate for etiologies other than hyperbilirubinemia.1 238

If jaundice or scleral icterus resulting from elevated bilirubin causes cosmetic concerns, alternative antiretroviral can be considered; reduction of atazanavir dosage not recommended since efficacy data not available.1 238

Hyperbilirubinemia reported in pregnant women receiving atazanavir.1 Neonates exposed in utero also at risk; monitor for severe hyperbilirubinemia during first few days of life.1

Phenylketonuria

Atazanavir oral powder contains aspartame (NutraSweet),1 which is metabolized in the GI tract to phenylalanine.104 105

Each packet of oral powder (50 mg of atazanavir) contains 35 mg of phenylalanine.1 Atazanavir capsules do not contain phenylalanine.1

Hepatic Effects

Risk of further transaminase elevations or hepatic decompensation in HIV-infected patients with HBV or HCV coinfection or elevated hepatic enzymes prior to initiation of atazanavir.1 238 Evaluate hepatic function prior to and during atazanavir treatment in these patients.1 238 (See Hepatic Impairment under Cautions.)

Nephrolithiasis and Cholelithiasis

Postmarketing reports of nephrolithiasis and cholelithiasis; some patients required hospitalization for additional management or experienced complications.1 238

If nephrolithiasis or cholelithiasis occurs, temporary interruption or discontinuation of atazanavir may be considered.1 238

Interactions

Atazanavir usually used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 200 238 239 When ritonavir-boosted or cobicistat-boosted atazanavir used, consider cautions, precautions, contraindications, and drug interactions associated with atazanavir and the pharmacokinetic enhancer.1 200 238 239

Concomitant use of ritonavir-boosted or cobicistat-boosted atazanavir with certain drugs is contraindicated or requires particular caution.1 200 238 239 Concomitant use with some drugs may result in clinically important adverse effects due to higher exposures of the concomitant drug or higher exposures of atazanavir and/or the pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 200 238 239 Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted or cobicistat-boosted atazanavir and possible development of resistance.1 200 238 239 Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.1 200 238 239

Consider that concomitant use of cobicistat-boosted atazanavir with other drugs may result in different drug interactions than those observed or expected with ritonavir-boosted atazanavir due to complex or unknown mechanisms of drug interactions.238 239

Concomitant use of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir with other antiretroviral drugs administered in conjunction with a pharmacokinetic enhancer (e.g., ritonavir-boosted HIV PIs, ritonavir-boostedparitaprevir, elvitegravir) not recommended.200 238 239 Dosage recommendations for such combinations not established;238 concomitant use of more than one pharmacokinetic enhancer may result in complex drugs interactions, including decreased plasma concentrations of the antiretroviral leading to loss of therapeutic effect and development of resistance.200 238 238

Atazanavir, ritonavir, and cobicistat are all available as single-entity preparations.1 209 239 In addition, fixed-combination atazanavir/cobicistat is commercially available.238 Ensure that therapy is not duplicated; do not use atazanavir/cobicistat concomitantly with any other preparations containing atazanavir, cobicistat, or ritonavir.238 239

Consider potential drug interactions prior to and during use of ritonavir-boosted or cobicistat-boosted atazanavir.1 238 239 Monitor for adverse effects associated with drugs used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir.1 238 239 (See Interactions.)

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with HIV PIs; diabetic ketoacidosis has occurred.1 238

Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.1 238

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.1 238

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 238

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.1 Mechanisms and long-term consequences unknown; causal relationship not established.1 238

Hemophilia A and B

Increased bleeding, including spontaneous hematomas and hemarthrosis, reported with HIV PIs; causal relationship not established.1 238

Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1 238

HIV Resistance

Possibility of HIV-1 resistant to atazanavir.1 9 11

Varying degrees of cross-resistance occur among the various HIV PIs.1 Resistance to atazanavir may not preclude subsequent use of other HIV PIs.1

Specific Populations

Pregnancy

Ritonavir-boosted atazanavir and cobicistat-boosted atazanavir: Category B.1 238

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat): Do not use in pregnant or postpartum women.1 202

Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum.1 Available human and animal data suggest atazanavir does not increase risk of major birth defects overall compared to background rate.1 Because studies cannot rule out possibility of harm, use during pregnancy only if clearly needed.1

Use cobicistat-boosted atazanavir during pregnancy only if potential benefits to the woman justify potential risks to fetus.238 239 Do not use cobicistat-boosted atazanavir in treatment-experienced pregnant women receiving a histamine H2-receptor antagonist and/or tenofovir DF.238

Experts state that ritonavir-boosted atazanavir in conjunction with 2 NRTIs is a preferred PI-based regimen for initial treatment in antiretroviral-naive pregnant women.202 Dosage adjustments may be necessary.1 (See Pregnant and Postpartum Women under Dosage and Administration.)

Lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia reported in pregnant women receiving atazanavir in conjunction with NRTIs.1 238

Hyperbilirubinemia reported in pregnant women receiving atazanavir.1 238 Bilirubin concentrations ≥4 mg/dL reported within 24 hours of birth in some neonates born to women who received ritonavir-boosted atazanavir during pregnancy.1 Monitor neonates exposed to atazanavir in utero for development of severe hyperbilirubinemia during first few days of life.1 238

Monitor postpartum women closely for adverse effects during first 2 months after delivery; atazanavir concentrations and AUC may be increased during postpartum period.1 (See Special Populations under Pharmacokinetics: Absorption.)

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Lactation

Atazanavir distributed into milk in low concentrations.202 Not known whether ritonavir209 or cobicistat238 239 distributed into human milk; cobicistat is distributed into milk in rats.239

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 238

Pediatric Use

Do not use ritonavir-boosted or unboosted atazanavir in neonates and infants <3 months of age because of risk of kernicterus.1 201 Closely monitor any infant exposed to atazanavir in utero.1 (See Pregnancy under Cautions.)

Safety, efficacy, and pharmacokinetic profile of ritonavir-boosted atazanavir and unboosted atazanavir evaluated in pediatric patients ≥3 months of age weighing ≥10 kg.1 Adverse effects in children 6 years to <18 years of age receiving the capsules generally similar to those reported in adults;1 adverse effects in pediatric patients weighing 10 kg to <25 kg receiving the oral powder generally similar to those reported in pediatric patients receiving capsules.1

Safety and efficacy of cobicistat-boosted atazanavir (administered as atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat) not established in pediatric patients <18 years of age.238 239

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 238

Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 238

Hepatic Impairment

Atazanavir principally metabolized and eliminated by the liver; increased plasma atazanavir concentrations expected in patients with moderate to severe hepatic impairment.1

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat): Dosage adjustments recommended in those with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Do not use in those with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration.)

Ritonavir-boosted or cobicistat-boosted atazanavir: Do not use in those with any degree of hepatic impairment.1 238

HIV-infected patients with HBV or HCV coinfection and those with marked increases in AST or ALT prior to atazanavir therapy may be at increased risk for further elevations in hepatic enzymes or for hepatic decompensation.1 (See Hepatotoxicity under Cautions.)

Renal Impairment

Plasma concentrations of atazanavir in individuals with severe renal impairment not undergoing dialysis generally are similar to those in individuals with normal renal function.1 Dosage adjustments not needed.1

Ritonavir-boosted atazanavir can be used in antiretroviral-naive patients with end-stage renal disease who are undergoing hemodialysis.1

Do not use ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir in antiretroviral-experienced patients with end-stage renal disease undergoing hemodialysis.1 200 238

Common Adverse Effects

Ritonavir-boosted atazanavir or unboosted atazanavir in adults: Headache, nausea, jaundice/scleral icterus, abdominal pain, rash, vomiting, diarrhea, insomnia, peripheral neurologic symptoms, dizziness, myalgia, depression, fever.1

Ritonavir-boosted atazanavir or unboosted atazanavir in pediatric patients 6 years to <18 years of age: Elevated total bilirubin, cough, fever, jaundice/scleral icterus, rash, vomiting, diarrhea, neutropenia, headache, peripheral edema, extremity pain, nasal congestion, oropharyngeal pain, wheezing, rhinorrhea, hypoglycemia.1

Cobicistat-boosted atazanavir in adults: Jaundice, ocular icterus, nausea.238

Interactions for Reyataz

Atazanavir, ritonavir, and cobicistat metabolized by CYP3A.1 209 238 239

Atazanavir, ritonavir, and cobicistat inhibit CYP3A.1 238

Atazanavir inhibits CYP2C8 and UGT1A1.1

Ritonavir and cobicistat inhibit CYP2D6.209 238

Cobicistat inhibits P-glycoprotein (P-gp) transport system,238 239 breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1 and 1B3.238 239

When atazanavir is used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat), consider drug interactions associated with both atazanavir and the pharmacokinetic enhancer.1 200 238 239 Interactions reported or expected with ritonavir-boosted atazanavir may differ from those reported or expected with cobicistat-boosted atazanavir.1 200 238 239

The following drug interactions are based on studies using ritonavir-boosted atazanavir or unboosted atazanavir1 or studies using cobicistat alone.238 239 Drug interaction studies not available to date using cobicistat-boosted atazanavir administered either as fixed-combination atazanavir/cobicistat or as single-entity atazanavir given with single-entity cobicistat.238 239

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A inducers: Potential pharmacokinetic interactions with ritonavir-boosted, cobicistat-boosted, and unboosted atazanavir (increased clearance of atazanavir, ritonavir, or cobicistat; possible loss of antiretroviral efficacy and development of resistance).1 238 239

CYP3A inhibitors: Potential pharmacokinetic interactions with ritonavir-boosted, cobicistat-boosted, and unboosted atazanavir (increased plasma concentrations of atazanavir, ritonavir, or cobicistat).1 238 239

CYP3A, 2C8, or 2D6 substrates: Potential pharmacokinetic interactions with ritonavir-boosted, cobicistat-boosted, and unboosted atazanavir (altered metabolism of these substrates).1 238 239

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase 1A1

UGT 1A1 substrates: Potential pharmacokinetic interactions with ritonavir-boosted, cobicistat-boosted, and unboosted atazanavir.1 238

Drugs Affecting or Affected by Other Membrane Transporters

BCRP, OATP1B1, or OATP1B3 substrates: Potential pharmacokinetic interactions with cobicistat-boosted atazanavir (increased plasma concentrations of such substrates; possible increased or prolonged therapeutic effects and increased risk of associated adverse effects).238 239

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Acetaminophen

Pharmacokinetic interactions unlikely1 238

Alfuzosin

Possible increased alfuzosin concentrations; may result in hypotension1 238 239

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Antacids

Possible decreased atazanavir concentrations1 238

Administer ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir at least 2 hours before or 1–2 hours after antacids1 200 238

Antiarrhythmic agents (amiodarone, disopyramide, dofetilide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine)

Amiodarone, dofetilide, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine: Possible increased antiarrhythmic agent concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir; potential for serious and/or life-threatening effects1 200 238 239

Disopyramide, mexiletine: Possible increased antiarrhythmic agent concentrations if used with cobicistat-boosted atazanavir238 239

Disopyramide, dofetilide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Use concomitantly with caution; monitor serum concentrations of antiarrhythmic agent1 200 238 239

Amiodarone: Experts state monitor for amiodarone toxicity if used with ritonavir-boosted or cobicistat-boosted atazanavir;200 consider monitoring ECG and amiodarone concentrations200

Dronedarone: Concomitant use with cobicistat-boosted atazanavir contraindicated;238 239 experts state do not use concomitantly with ritonavir-boosted or unboosted atazanavir200

Anticoagulants, oral (apixaban, dabigatran, rivaroxaban, warfarin)

Apixaban: Possible increased apixaban concentrations200 238

Dabigatran: Possible increased dabigatran concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir200 238

Rivaroxaban: Possible increased rivaroxaban concentrations; may increase bleeding risk200 238 239

Warfarin: Potential for increased or decreased warfarin concentrations and serious and/or life-threatening bleeding episodes if used with ritonavir-boosted or unboosted atazanavir;1 200 effect of cobicistat-boosted atazanavir on warfarin concentrations unknown200 238 239

Apixaban: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir not recommended200 238

Dabigatran: Concomitant use with ritonavir-boosted or cobicistat-boosted atazanavir not recommended in certain patients with renal impairment;200 238 experts state avoid concomitant use in those with Clcr <50 mL/minute200

Rivaroxaban: Avoid concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200 238 239

Warfarin: Monitor INR if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239 (especially when initiating or discontinuing atazanavir) and adjust warfarin dosage accordingly;200 if ritonavir-boosted atazanavir switched to cobicistat-boosted atazanavir, effect on warfarin concentrations not expected to be equivalent200

Anticonvulsants (carbamazepine, clonazepam, ethosuximide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine: Possible decreased atazanavir concentrations and increased carbamazepine concentrations if used with ritonavir-boosted atazanavir;1 200 possible decreased atazanavir and cobicistat concentrations and increased carbamazepine concentrations if used with cobicistat-boosted atazanavir;238 239 decreased atazanavir concentrations if used with unboosted atazanavir1 200

Clonazepam: Possible increased clonazepam concentrations if used with cobicistat-boosted atazanavir238 239

Ethosuximide: Possible increased ethosuximide concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Lamotrigine: Decreased lamotrigine concentrations and AUC if used with ritonavir-boosted atazanavir;1 200 effect of cobicistat-boosted atazanavir on lamotrigine concentrations unknown;200 238 interaction not expected with unboosted atazanavir1 200

Oxcarbazepine: Possible decreased atazanavir and cobicistat concentrations if used with cobicistat-boosted atazanavir238 239

Phenobarbital, phenytoin: Possible decreased concentrations of atazanavir and the anticonvulsant if used with ritonavir-boosted atazanavir;1 200 possible decreased atazanavir and cobicistat concentrations and unknown effects on anticonvulsant concentrations is used with cobicistat-boosted atazanavir;238 239 decreased atazanavir concentrations if used with unboosted atazanavir1 200

Carbamazepine: Concomitant use with unboosted atazanavir not recommended;1 200 consider alternative anticonvulsant in patients receiving ritonavir-boosted or cobicistat-boosted atazanavir;200 if used with ritonavir-boosted or cobicistat-boosted atazanavir, consider that anticonvulsant dosage adjustment may be needed, monitor serum concentrations of both drugs, and assess virologic response200 238 239

Clonazepam: Clinical monitoring recommended if used with cobicistat-boosted atazanavir238 239

Ethosuximide: Monitor for ethosuximide toxicities if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Lamotrigine: Increased lamotrigine dosage may be needed and consider monitoring lamotrigine concentrations if used with ritonavir-boosted atazanavir or consider alternative anticonvulsant;1 200 monitor lamotrigine concentrations if used with cobicistat-boosted atazanavir or consider alternative anticonvulsant;200 238 dosage adjustments not needed if used with unboosted atazanavir1 200

Oxcarbazepine: Monitor for lack or loss of antiretroviral response if used with cobicistat-boosted atazanavir or consider alternative anticonvulsant238 239

Phenobarbital, phenytoin: Concomitant use with unboosted atazanavir not recommended;1 200 consider alternative anticonvulsants in patients receiving ritonavir-boosted or cobicistat-boosted atazanavir;200 if used with ritonavir-boosted or cobicistat-boosted atazanavir, consider that anticonvulsant dosage adjustment may be needed, monitor serum concentrations of both drugs, and assess virologic response200 238 239

Antifungals, azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Fluconazole: No clinically important pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted atazanavir1 238

Itraconazole: Possible increased itraconazole, atazanavir, and cobicistat concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Ketoconazole: No clinically important pharmacokinetic interactions with unboosted atazanavir;1 possible increased ketoconazole, atazanavir, and cobicistat concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir1 238 239

Posaconazole: Increased atazanavir concentrations if used with ritonavir-boosted or unboosted atazanavir;32 200 possible pharmacokinetic interactions if used with cobicistat-boosted atazanavir200

Voriconazole: Decreased atazanavir and voriconazole concentrations if used with ritonavir-boosted atazanavir in patients with functional CYP2C19 allele and decreased atazanavir concentrations and increased voriconazole concentrations in those without functional CYP2C19 allele;1 200 effect of cobicistat-boosted atazanavir on voriconazole concentrations unknown;200 238 239 possible altered atazanavir and voriconazole concentrations if used with unboosted atazanavir1 200

Fluconazole: Dosage adjustments not needed if used with ritonavir-boosted or cobicistat-boosted atazanavir200

Itraconazole: Consider monitoring itraconazole concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and adjust itraconazole dosage accordingly;200 caution advised if itraconazole dosage >200 mg daily is used with ritonavir-boosted atazanavir;1 specific dosage recommendations not available for use with cobicistat-boosted atazanavir;238 239 some experts state itraconazole dosages >200 mg daily not recommended with ritonavir-boosted or cobicistat-boosted atazanavir unless itraconazole concentrations used to guide antifungal dosage200

Ketoconazole: Caution advised if ketoconazole dosage >200 mg daily used with ritonavir-boosted atazanavir;1 specific dosage recommendations not available for use with cobicistat-boosted atazanavir238 239

Posaconazole: Monitor for atazanavir-associated adverse effects if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir32 200

Voriconazole: Do not use with ritonavir-boosted or cobicistat-boosted atazanavir unless potential benefits outweigh risks;1 200 238 239 if used with ritonavir-boosted or cobicistat-boosted atazanavir, monitor for voriconazole-associated adverse effects and loss of voriconazole or atazanavir efficacy and consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly;1 200 if used with unboosted atazanavir, monitor for toxicities200

Antimalarial agents

Fixed combination of atovaquone and proguanil (atovaquone/proguanil): Decreased atovaquone and proguanil concentrations if used with ritonavir-boosted atazanavir200

Atovaquone/proguanil: Consider alternative antimalarial, if possible200

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Possible increased bedaquiline concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir;200 clinical importance unknown

Rifabutin: Increased concentrations and AUC of rifabutin and its metabolite if used with ritonavir-boosted or unboosted atazanavir;1 200 increased rifabutin concentrations expected if used with cobicistat-boosted atazanavir, but effects on atazanavir and cobicistat concentrations unknown238 239

Rifampin: Substantially decreased atazanavir concentrations; possible loss of virologic response and development of resistance1 238

Rifapentine: Possible decreased atazanavir concentrations with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with loss of antiretroviral effect and development of resistance1 200 238

Bedaquiline: If potential benefits outweigh risks, use with ritonavir-boosted or cobicistat-boosted atazanavir with caution and monitor for QTc interval prolongation and liver dysfunction200

Rifabutin: If used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, reduce rifabutin dosage to 150 mg once every other day or 3 times weekly;1 200 238 239 some experts suggest rifabutin 150 mg once daily or 300 mg 3 times weekly;200 monitor for rifabutin-associated adverse effects (e.g., neutropenia, uveitis);1 238 239 monitor for antimycobacterial response and consider therapeutic drug monitoring200

Rifampin: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Rifapentine: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir not recommended200

Antineoplastic agents (dasatinib, irinotecan, nilotinib, paclitaxel, vinblastine, vincristine)

Dasatinib, nilotinib: Possible increased antineoplastic concentrations if used with cobicistat-boosted atazanavir 238 239

Irinotecan: Possible interference with metabolism of irinotecan and increased risk of irinotecan toxicity if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 238 239

Paclitaxel: Possible increased paclitaxel concentrations if used with unboosted atazanavir;1 clinically important interactions not expected if used with ritonavir-boosted atazanavir1

Vinblastine, vincristine: Possible increased antineoplastic concentrations if used with cobicistat-boosted atazanavir238 239

Dasatinib, nilotinib: If used with cobicistat-boosted atazanavir, decreased dosage of the antineoplastic may be needed238 239

Irinotecan: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Paclitaxel: Caution advised if used with unboosted atazanavir;1 concomitant use with cobicistat-boosted atazanavir not recommended238

Vinblastine, vincristine: Monitor for adverse hematologic or GI effects if used with cobicistat-boosted atazanavir238

Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)

Lurasidone: Potential for serious and/or life-threatening adverse effects if used with cobicistat-boosted atazanavir238

Perphenazine, risperidone, thioridazine: Possible increased antipsychotic agent concentrations if used with cobicistat-boosted atazanavir238 239

Pimozide: Potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias) if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 238 239

Quetiapine: Increased quetiapine concentrations expected if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Lurasidone: Concomitant use with cobicistat-boosted atazanavir contraindicated;238 experts state do not use with ritonavir-boosted or unboosted atazanavir200

Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed if used with cobicistat-boosted atazanavir238 239

Pimozide: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Quetiapine: Consider alternative antiretroviral;1 238 239 if ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine efficacy and adverse effects;1 200 238 239 if quetiapine necessary in patient receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, experts state initiate using lowest quetiapine dosage and titrate as needed200

Avanafil

Possible increased avanafil concentrations and AUC183 200 238 239

Do not use concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir;183 200 238 239 experts state that unboosted atazanavir can be used if avanafil dosage does not exceed 50 mg once every 24 hours200

Benzodiazepines

Alprazolam: Possible increased alprazolam concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Diazepam: Possible increased diazepam concentrations If used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir 200 238 239

Midazolam or triazolam: Possible increased concentrations of midazolam or triazolam and potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression) if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 238 239

Lorazepam, oxazepam, temazepam: No data, but may have less potential for pharmacokinetic interactions with PIs compared with other benzodiazepines200

Alprazolam: Consider alternative benzodiazepine with less potential for interactions (e.g., lorazepam, oxazepam, temazepam)200

Diazepam: If used with cobicistat-boosted atazanavir, decreased diazepam dosage may be needed and monitor for adverse effects;238 239 experts state consider alternative (e.g., lorazepam, oxazepam, temazepam)200

Oral midazolam or triazolam: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Parenteral midazolam: Use concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with caution and in monitored setting where respiratory depression and/or prolonged sedation can be managed;1 238 239 consider reduced midazolam dosage, especially if multiple midazolam doses are given;1 238 239 experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation200

β-Adrenergic blocking agents (atenolol, carvedilol, labetalol, metoprolol, nadolol, timolol, sotalol)

Atenolol: No clinically important interactions when used with unboosted atazanavir;1 pharmacokinetic interactions not expected if used with cobicistat-boosted atazanavir238

Carvedilol, metoprolol, timolol: Possible increased concentrations of the β-blocker if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200 238 239

Carvedilol, metoprolol, timolol: Clinical monitoring recommended and reduced dosage of the β-blocker may be needed if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir;200 238 239 experts state consider use of alternatives not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol)200

Bosentan

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased bosentan concentrations and decreased atazanavir and cobicistat concentrations1 200 238

Unboosted atazanavir: Do not use concomitantly with bosentan1 200

In patients already receiving ritonavir-boosted or cobicistat-boosted atazanavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 200 238 239

In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted or cobicistat-boosted atazanavir; after ≥10 days of ritonavir-boosted or cobicistat-boostedatazanavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 200 238 239

If ritonavir-boosted atazanavir is switched to cobicistat-boosted atazanavir, maintain current bosentan dosage238 239

Buprenorphine, buprenorphine/naloxone

Ritonavir-boosted or unboosted atazanavir: Increased buprenorphine and norbuprenorphine concentrations;1 when used with unboosted atazanavir, decreased atazanavir concentrations also possible1

Cobicistat-boosted atazanavir: Data not available regarding use with buprenorphine/naloxone200 238 239

Unboosted atazanavir: Concomitant use with buprenorphine not recommended1

Ritonavir-boosted atazanavir: Monitor for sedation and adverse cognitive effects; consider reduced buprenorphine dosage1

Cobicistat-boosted atazanavir: If initiating buprenorphine or buprenorphine/naloxone in patient already receiving cobicistat-boosted atazanavir, use lowest possible dosage and carefully titrate to desired therapeutic effect;200 238 239 if initiating cobicistat-boosted atazanavir in patient already receiving buprenorphine or buprenorphine/naloxone, monitor patient and consider that dosage adjustments may be needed238 239

Buspirone

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased buspirone concentrations200 238

Titration of buspirone dosage recommended, consider lower buspirone dosage and monitor patient for prolonged or adverse effects238

Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Possible increased calcium-channel blocking agent concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Diltiazem: Increased diltiazem concentrations and AUC if used with unboosted atazanavir;1 200 use with ritonavir-boosted or cobicistat-boosted atazanavir expected to result in greater increases in diltiazem concentrations200 238 239

Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Use concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with caution; dosage titration of the calcium-channel blocking agent and clinical and ECG monitoring recommended1 200 238 239

Diltiazem: Use concomitantly with caution;1 if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, consider reducing diltiazem dosage by 50%; ECG monitoring recommended1 200

Cisapride

Possible increased cisapride concentrations and potential for serious and/or life-threatening effects (e.g., cardiac arrhythmias)1 238 239

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

Cobicistat

Increased atazanavir concentrations and AUC;200 238 239 used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (cobicistat-boosted atazanavir)200 238 239

Colchicine

Increased colchicine concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Patients with renal or hepatic impairment: Concomitant use of colchicine and ritonavir-boosted or unboosted atazanavir not recommended;1 200 concomitant use with cobicistat-boosted atazanavir contraindicated238

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 238

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 238

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 238

Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisolone, prednisone, triamcinolone)

Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected200

Budesonide, fluticasone, or mometasone (orally inhaled, intranasal): Increased corticosteroid concentrations;1 200 238 239 may result in adrenal insufficiency or Cushing's syndrome200 238 239

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency or Cushing's syndrome200

Budesonide or prednisone (systemic): Increased corticosteroid concentrations;200 may result in adrenal insufficiency or Cushing's syndrome200

Dexamethasone (systemic): Possible decreased atazanavir concentrations and decreased antiretroviral efficacy and development of atazanavir resistance200 238 239

Budesonide, fluticasone, or mometasone (orally inhaled, intranasal): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir unless potential benefits of inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects;200 238 239 consider alternative (e.g., beclomethasone;1 238 239 use fluticasone and unboosted atazanavir concomitantly with caution1

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required,200 use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir)200

Budesonide or prednisone (systemic): Do not use concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir unless potential benefits outweigh risks of systemic corticosteroid adverse effects200

Dexamethasone (systemic): Use concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with caution; consider alternative corticosteroid for long-term use200

Co-trimoxazole

Pharmacokinetic interactions unlikely1 238

Daclatasvir

Ritonavir-boosted or unboosted atazanavir: Increased daclatasvir concentrations expected178

Ritonavir-boosted atazanavir: Decrease daclatasvir dosage to 30 mg once daily178

Unboosted atazanavir: Monitor for daclatasvir-associated adverse effects178

Dapsone

Pharmacokinetic interactions unlikely1 238

Darunavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir204

Ritonavir-boosted atazanavir: Concomitant use with ritonavir-boosted darunavir not recommended204

Delavirdine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Didanosine

Buffered didanosine: Decreased atazanavir concentrations and AUC;1 238 decreased didanosine concentrations and AUC1 238

Didanosine delayed-release capsules: Decreased didanosine concentrations and AUC if given with atazanavir and food;1 200 no change in atazanavir concentrations200

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Administer atazanavir (with food) 2 hours before or 1 hour after buffered or delayed-release didanosine preparations (without food)1 200 238

Digoxin

Increased digoxin concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir200 238 239

Use concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir with caution;1 titrate digoxin dosage and monitor digoxin concentrations200 238 239

Dolutegravir

Ritonavir-boosted or unboosted atazanavir: Increased dolutegravir concentrations and AUC200

Cobicistat-boosted atazanavir: Data not available200

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state dosage adjustments not needed200

Efavirenz

Ritonavir-boosted atazanavir: Possible increased atazanavir concentrations and AUC depending on specific regimen1 213

Cobicistat-boosted atazanavir: Decreased atazanavir and cobicistat concentrations; no change in efavirenz concentrations200 238 239

Unboosted atazanavir: Substantially decreased atazanavir concentrations and AUC;1 200 213 no clinically important change in efavirenz concentrations200

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Ritonavir-boosted atazanavir in antiretroviral-naive adults: Use atazanavir 400 mg and ritonavir 100 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime)1 200 213

Cobicistat-boosted atazanavir in antiretroviral-naive adults: Use single-entity atazanavir 400 mg and single-entity cobicistat 150 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime)200 239

Ritonavir-boosted or cobicistat-boosted atazanavir in antiretroviral-experienced adults: Concomitant use not recommended1 200 238 239

Unboosted atazanavir: Do not use with efavirenz1 200

Elvitegravir

Elvitegravir: Decreased elvitegravir concentrations if used with ritonavir-boosted atazanavir;200 data not available regarding use with cobicistat-boosted atazanavir200

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir, cobicistat, and/or atazanavir when used concomitantly with ritonavir-boosted or unboosted atazanavir200

Elvitegravir: If used concomitantly with ritonavir-boosted atazanavir, experts recommend dosage of atazanavir 300 mg and ritonavir 100 mg once daily with single-entity elvitegravir 85 mg once daily;200 do not use single-entity elvitegravir concomitantly with cobicistat-boosted atazanavir200

EVG/COBI/TDF/FTC: Do not use concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Emtricitabine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possible increased concentrations of ergot alkaloids and potential for serious and/or life-threatening effects such as ergot toxicity (peripheral vasospasm, ischemia of the extremities and other tissues)1 238 239

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated1 238 239

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving atazanavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Estrogens/progestins

Oral hormonal contraceptives containing ethinyl estradiol and norgestimate or norethindrone: Possible increased or decreased concentrations of ethinyl estradiol and increased progestin concentrations if used with ritonavir-boosted or unboosted atazanavir;1 200 data not available regarding use with cobicistat-boosted atazanavir200 238 239

Etonogestrel-releasing subdermal implant contraceptive or transdermal ethinyl estradiol/norelgestromin contraceptive: Data not available regarding use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Ritonavir-boosted atazanavir: Caution advised in patients using oral contraceptives; use oral contraceptive containing at least 35 mcg of ethinyl estradiol1

Unboosted atazanavir: Caution advised in patients using oral contraceptives; use oral contraceptive containing no more than 30 mcg of ethinyl estradiol1

Use additional or alternative nonhormonal contraception or consider alternative antiretroviral regimen in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200 238 239

Etonogestrel-releasing subdermal implant contraceptive or transdermal ethinyl estradiol/norelgestromin contraceptive: Use alternative or additional method of contraception or use alternative antiretroviral regimen200

Etravirine

Ritonavir-boosted or unboosted atazanavir: Increased etravirine concentrations and AUC, decreased atazanavir concentrations and AUC; possible decreased antiretroviral efficacy200 214

Cobicistat-boosted atazanavir: Decreased atazanavir and cobicistat concentrations200 238 239

No in vitro evidence of antagonistic antiretroviral effects with atazanavir214

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Do not use concomitantly with etravirine;200 238 239 if ritonavir-boosted atazanavir used, some experts recommend atazanavir 300 mg once daily and ritonavir 100 mg once daily with usual etravirine dosage200

Fentanyl

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased fentanyl concentrations200 238 239

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Carefully monitor patient for fentanyl therapeutic and adverse effects, including potentially fatal respiratory depression200 238 239

Fosamprenavir

Ritonavir-boosted fosamprenavir: Decreased atazanavir concentrations and AUC; no change in concentrations and AUC of amprenavir (active metabolite of fosamprenavir)205

Fosamprenavir (without low-dose ritonavir): No data205

In vitro evidence of synergistic antiretroviral effects with atazanavir205

Fosamprenavir (with or without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established205

Histamine H2-receptor antagonists

Famotidine: Decreased atazanavir concentrations with possible loss of therapeutic effect and development of resistance if unboosted atazanavir administered at same time as the histamine H2-receptor antagonist; 1 if used with ritonavir-boosted or cobicistat-boosted atazanavir, possible alterations in atazanavir pharmacokinetics1 238 239

Ritonavir-boosted atazanavir in antiretroviral-naive adults: Administer atazanavir 300 mg and ritonavir 100 mg once daily with food simultaneously with and/or at least 10 hours after the histamine H2-receptor antagonist;1 dosage of histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent)1

Cobicistat-boosted atazanavir in antiretroviral-naive adults: Administer atazanavir 300 mg once daily with cobicistat 150 mg once daily simultaneously with and/or at least 10 hours after the histamine H2-receptor antagonist;238 239 dosage of histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent)238 239

Unboosted atazanavir in antiretroviral-naive adults: Administer atazanavir 400 mg once daily at least 2 hours before and 10 hours after the histamine H2-receptor antagonist;1 dosage of the histamine H2-receptor antagonist should not exceed famotidine 40 mg daily (or equivalent) and single doses should not exceed famotidine 20 mg (or equivalent)1

Antiretroviral-experienced patients receiving tenofovir DF and a histamine H2-receptor antagonist: Fixed-combination atazanavir/cobicistat not recommended238

Antiretroviral-experienced patients receiving tenofovir DF and a histamine H2-receptor antagonist: Regimen of atazanavir 400 mg, tenofovir DF 300 mg, and ritonavir 100 mg once daily with food recommended;1 200 alternatively, atazanavir 400 mg and cobicistat 150 mg once daily with food239

Antiretroviral-experienced patients receiving ritonavir-boosted or cobicistat-boosted atazanavir: Dosage of histamine H2-receptor antagonist should not exceed famotidine 20 mg twice daily (or equivalent)1 238 239

Antiretroviral-experienced pregnant women in second or third trimester receiving ritonavir-boosted atazanavir and a histamine H2-receptor antagonist: Increase dosage of atazanavir to 400 mg once daily with ritonavir 100 mg once daily1

Dosage recommendations not available for antiretroviral-experienced pregnant women receiving atazanavir and both tenofovir and a histamine H2-receptor antagonist 1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin: Possible increased concentrations and AUC of the statin if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 200 238 239

Pitavastatin: Increased pitavastatin concentrations and AUC; no clinically important effect on atazanavir concentrations200

Atorvastatin: Carefully titrate atorvastatin dosage and use lowest necessary dosage1 200 238 239

Fluvastatin: If used with cobicistat-boosted atazanavir, carefully titrate fluvastatin dosage and use lowest necessary dosage238

Lovastatin: Concomitant use contraindicated1 186 238 239

Pitavastatin: Dosage adjustments not necessary186 200

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily;1 186 200 238 carefully titrate rosuvastatin dosage and use lowest necessary dosage1 200 238 239

Simvastatin: Concomitant use contraindicated1 186 200 238 239

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Potential for increased concentrations of cyclosporine, everolimus, sirolimus, or tacrolimus1 200 238 239

Monitor plasma concentrations of the immunosuppressive agent if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Indinavir

Potential for additive hyperbilirubinemia1 200 238

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use with indinavir contraindicated1 238

Lamivudine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Ledipasvir

Ritonavir-boosted or cobicistat-boosted atazanavir: Clinically important pharmacokinetic interactions not expected if used with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir)181 200

Ritonavir-boosted or cobicistat-boosted atazanavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Possible increased tenofovir concentrations;181 200 safety of increased tenofovir concentrations not established181 200

Ritonavir-boosted or cobicistat-boosted atazanavir: Dosage adjustments not needed if used with ledipasvir/sofosbuvir200

Ritonavir-boosted or cobicistat-boosted atazanavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Consider alternative treatment regimen or alternative antiretroviral regimen;181 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects181 200

Lopinavir/ritonavir

Prolonged PR interval reported with both atazanavir and lopinavir207

In vitro evidence of additive to synergistic antiretroviral effects with atazanavir;207 no in vitro evidence of antagonism1

Use concomitantly with caution and clinical monitoring207

Macrolides (azithromycin, clarithromycin, erythromycin, telithromycin)

Azithromycin: Pharmacokinetic interactions unlikely1 238

Clarithromycin: If used with ritonavir-boosted or unboosted atazanavir, increased concentrations and AUC of atazanavir and increased clarithromycin concentrations and decreased 14-hydroxyclarithromycin concentrations;1 increased clarithromycin concentrations may cause QTc prolongation1

Erythromycin: If used with cobicistat-boosted atazanavir, increased atazanavir, cobicistat, and erythromycin concentrations;238 239 if used with unboosted atazanavir, pharmacokinetic interactions unlikely1

Telithromycin: If used with cobicistat-boosted atazanavir, increased atazanavir, cobicistat, and telithromycin concentrations238 239

Clarithromycin: Consider reducing clarithromycin dosage by 50% if used with ritonavir-boosted or unboosted atazanavir;1 consider alternative anti-infective (e.g., azithromycin)1 200

Erythromycin or telithromycin: Consider alternative anti-infective in patients receiving cobicistat-boosted atazanavir238 239

Maraviroc

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased maraviroc concentrations and AUC200 224 238 239

No in vitro evidence of antagonistic antiretroviral effects with atazanavir224

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Recommended maraviroc dosage is 150 mg twice daily200 238 239

Methadone

Unboosted atazanavir: Pharmacokinetic interactions unlikely1 200

Ritonavir-boosted atazanavir: Decreased R-methadone (active isomer) concentrations200

Cobicistat-boosted atazanavir: Data not available regarding concomitant use with methadone200 238 239

Unboosted atazanavir: Adjustment of methadone dosage not needed200

Ritonavir-boosted atazanavir: Adjustments of methadone dosage not needed; closely monitor for signs of opiate withdrawal and adjust methadone dosage if needed200

Cobicistat-boosted atazanavir: Initiate methadone at lowest possible dosage and titrate carefully to desired therapeutic effect;200 238 239 if initiating cobicistat-boosted atazanavir in patients already receiving methadone, clinically monitor patient and adjust methadone dosage if needed238 239

Nelfinavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Nevirapine

Ritonavir-boosted or unboosted atazanavir: Decreased atazanavir concentrations and AUC with possible loss of therapeutic effect and development of resistance; increased nevirapine concentrations and AUC and increased risk of nevirapine-associated adverse effects1 200 215

Cobicistat-boosted atazanavir: Decreased cobicistat concentrations200 238 239

In vitro evidence of additive to synergistic antiretroviral effects with atazanavir;215 no in vitro evidence of antagonistic antiretroviral effects1

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use contraindicated1 238 239

Paritaprevir

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir): Substantially increased paritaprevir concentrations if used with ritonavir-boosted or unboosted atazanavir179

Fixed combination of ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Increased paritaprevir concentrations if used with ritonavir-boosted atazanavir but no substantial effect on atazanavir concentrations;180 data not available regarding use with cobicistat-boosted atazanavir200

Fixed-combination ombitasvir/paritaprevir/ritonavir: Manufacturer of the HCV drug states concomitant use with ritonavir-boosted or unboosted atazanavir not recommended179

Fixed-combination ombitasvir/paritaprevir/ritonavir with dasabuvir: If used with unboosted atazanavir, give atazanavir 300 mg once daily in the morning at same time as morning dose of the HCV drug;180 200 do not use ritonavir-boosted or cobicistat-boosted atazanavir during HCV treatment, but can replace unboosted atazanavir after HCV treatment completed200

Proton-pump inhibitors (PPIs)

Omeprazole: Substantially decreased atazanavir concentrations and possible loss of virologic response and development of atazanavir resistance1 238 239

Unboosted atazanavir: Concomitant use with PPIs not recommended;1 200 use alternative acid-reducing agent or use ritonavir-boosted or cobicistat-boosted atazanavir200

Ritonavir-boosted atazanavir in antiretroviral-naive adults receiving a PPI: Use regimen of atazanavir 300 mg once daily with ritonavir 100 mg once daily with food;1 administer the PPI approximately 12 hours before ritonavir-boosted atazanavir;1 200 dosage of PPI should not exceed omeprazole 20 mg daily (or equivalent)1 200

Cobicistat-boosted atazanavir in antiretroviral-naive adults receiving a PPI: Use regimen of atazanavir 300 mg once daily with cobicistat 150 mg once daily with food;238 239 administer the PPI approximately 12 hours before cobicistat-boosted atazanavir;200 238 239 dosage of PPI should not exceed omeprazole 20 mg daily (or equivalent)200 238 239

Antiretroviral-experienced patients: Do not use PPIs concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir1 200 238 239

Raltegravir

Ritonavir-boosted or unboosted atazanavir: Increased raltegravir concentrations and AUC;200 225 data not available regarding use with cobicistat-boosted atazanavir200

In vitro evidence of additive to synergistic antiretroviral effects with atazanavir225

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed200 225

Ranolazine

Cobicistat-boosted atazanavir: Potential serious and/or life-threatening adverse effects238

Cobicistat-boosted atazanavir: Concomitant use contraindicated238

Ritonavir-boosted or unboosted atazanavir: Concomitant use not recommended200

Repaglinide

Unboosted atazanavir: Possible increased repaglinide concentrations1

Ritonavir-boosted atazanavir: Clinically important interactions not expected1

Unboosted atazanavir: Use concomitantly with caution1

Cobicistat-boosted atazanavir: Concomitant use not recommended238

Rilpivirine

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased rilpivirine concentrations; not expected to affect atazanavir concentrations200 226

No in vitro evidence of antagonistic antiretroviral effects with atazanavir226

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed200

Ritonavir

Increased atazanavir concentrations and AUC;1 200 low-dose ritonavir (100 mg once daily) used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (ritonavir-boosted atazanavir)1 13 200

Possibility of additional pharmacokinetic interactions if ritonavir-boosted atazanavir used with other HIV PIs1

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Safety and efficacy of concomitant use of ritonavir dosages >100 mg once daily with atazanavir not established;1 such dosages not recommended1

Ritonavir-boosted atazanavir: Concomitant use with other HIV PIs not recommended1

Ritonavir or ritonavir-containing preparations: Concomitant use with cobicistat-boosted atazanavir not recommended238

St. John’s wort (Hypericum perforatum)

Possible decreased atazanavir concentrations; possible loss of virologic response and increased risk of atazanavir resistance1 238 239

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use contraindicated1 238 239

Salmeterol

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, and sinus tachycardia1 238 239

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use not recommended1 238 239

Saquinavir

Ritonavir-boosted saquinavir: Increased saquinavir concentrations and AUC; no change in atazanavir concentrations210

Prolonged PR interval reported with both drugs; potential additive effects on PR interval210

In vitro evidence of synergistic antiretroviral effects with atazanavir;210 no in vitro evidence of antagonism1

Appropriate dosage for concomitant use with respect to safety and efficacy not established1

Ritonavir-boosted saquinavir: Use concomitantly with caution and clinical monitoring210

Selective serotonin-reuptake inhibitors (SSRIs)

Fluvoxamine: Possible altered (increased or decreased) fluvoxamine concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir200

Data not available regarding possible effect of ritonavir-boosted or cobicistat-boosted atazanavir on concentrations of other SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)200 238 239

Ritonavir-boosted atazanavir: Carefully titrate SSRI dosage based on clinical response200

Cobicistat-boosted atazanavir: Carefully titrate SSRI dosage based on clinical response;200 238 239 use lowest possible initial or maintenance dosage238 239

Fluvoxamine: Experts state consider alternative treatment in patients receiving ritonavir-boosted or cobicistat-boosted atazanavir200

Sildenafil

Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (hypotension, syncope, visual disturbances, priapism)1 200 238 239

Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated;1 238 239 safe and effective dosages for concomitant use not established1

Sildenafil for treatment of erectile dysfunction: Use with caution and with reduced sildenafil dosage (do not exceed 25 mg every 48 hours) in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir;1 238 239 closely monitor for sildenafil-associated adverse effects1 238 239

Simeprevir

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible altered (increased or decreased) simeprevir concentrations187 238 239

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use not recommended187 200 238 239

Sofosbuvir

Elevated total bilirubin in 94% of HCV-infected patients coinfected with HIV receiving atazanavir and other antiretrovirals, but in only 1.5% of those not receiving atazanavir188

Stavudine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Suvorexant

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased suvorexant concentrations200

Avoid concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Tadalafil

Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (hypotension, syncope, visual disturbances, priapism)1 238 239

Tadalafil for treatment of PAH in patients who have been receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, increase dosage to 40 mg once daily1 238 239

Patients already receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir; after ≥1 week of the antiretroviral, may resume tadalafil at a dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily;1 238 239 if ritonavir-boosted atazanavir switched to cobicistat-boosted atazanavir, maintain current tadalafil dosage238 239

Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir; use with caution and closely monitor for adverse effects1 238 239

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Telaprevir

Ritonavir-boosted atazanavir: Decreased telaprevir concentrations and AUC; increased atazanavir trough concentrations and AUC184 200

Ritonavir-boosted atazanavir: Dosage adjustments not needed200

Tenofovir

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Decreased atazanavir concentrations and AUC; increased tenofovir concentrations and AUC and possible increased risk of tenofovir-associated adverse effects, including renal disorders1 200 221 238

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Unboosted atazanavir: Do not use concomitantly with tenofovir DF1 200 221

Ritonavir-boosted atazanavir: Use atazanavir 300 mg, ritonavir 100 mg, and tenofovir DF 300 mg once daily with food;1 200 221 monitor for tenofovir toxicity;1 200 221 discontinue tenofovir if tenofovir-associated adverse effects occur221

Ritonavir-boosted atazanavir used concomitantly with tenofovir and a histamine H2-receptor antagonist in antiretroviral-experienced adults: Use atazanavir 400 mg and ritonavir 100 mg, and tenofovir DF 300 mg once daily with food1 200

Cobicistat-boosted atazanavir: Use atazanavir 300 mg, cobicistat 150 mg, and tenofovir DF 300 mg once daily with food;200 monitor for tenofovir toxicity;200 238 assess baseline estimated Clcr, urine glucose, and urine protein;238 239 monitor serum phosphorus in those with or at risk for renal impairment;238 239 not recommended in patients with estimated Clcr <70 mL/minute238 239

Cobicistat-boosted atazanavir used concomitantly with tenofovir and a histamine H2-receptor antagonist in antiretroviral-experienced adults: Experts state use single-entity atazanavir 400 mg and single-entity cobicistat 150 mg once daily with food200

Antiretroviral-experienced pregnant women in second or third trimester receiving ritonavir-boosted atazanavir and either a histamine H2-receptor antagonist or tenofovir: Use atazanavir 400 mg and ritonavir 100 mg once daily with food1

Dosage recommendations not available for antiretroviral-experienced pregnant women receiving ritonavir-boosted atazanavir and both tenofovir and a histamine H2-receptor antagonist1

Ticagrelor

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased ticagrelor concentrations expected200

Avoid concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Tipranavir

Ritonavir-boosted atazanavir: Decreased atazanavir concentrations and AUC; increased tipranavir concentrations and AUC211

In vitro evidence of additive to antagonistic antiretroviral effects with atazanavir211

Ritonavir-boosted or unboosted atazanavir: Concomitant use not recommended211

Tramadol

Cobicistat-boosted atazanavir: Increased tramadol concentrations238 239

Cobicistat-boosted atazanavir: Decreased tramadol dosage may be needed238 239

Trazodone

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased trazodone concentrations;1 238 239 adverse effects (nausea, dizziness, hypotension, syncope) reported when trazodone and ritonavir used concomitantly1

Use concomitantly with caution; consider using decreased trazodone dosage;1 238 239 monitor for therapeutic response and trazodone adverse effects (e.g., CNS effects, cardiovascular effects)200 238 239

Tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, nortriptyline)

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased concentrations of tricyclic antidepressants and potential for serious and/or life-threatening effects1 200 238 239

Monitor tricyclic antidepressant concentrations;1 200 use lowest possible antidepressant dosage; titrate antidepressant dosage based on plasma antidepressant concentrations and/or clinical assessment200

Vardenafil

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (hypotension, syncope, visual disturbances, priapism)1 200

Ritonavir-boosted or cobicistat-boosted atazanavir in patients receiving vardenafil for treatment of erectile dysfunction: Use with caution; do not exceed vardenafil dosage of 2.5 mg once every 72 hours and closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 238 239

Unboosted atazanavir in patients receiving vardenafil for treatment of erectile dysfunction: Use with caution; do not exceed vardenafil dosage of 2.5 mg once every 24 hours and closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1

Vorapaxar

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased vorapaxar concentrations200

Avoid concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir200

Zidovudine

No change in zidovudine AUC; possible decreased trough zidovudine concentrations200

No in vitro evidence of antagonistic antiretroviral effects with atazanavir1

Clinical importance unknown200

Zolpidem

Ritonavir-boosted or cobicistat-boosted atazanavir: Possible increased zolpidem concentrations200 238

Ritonavir-boosted or cobicistat-boosted atazanavir: Titrate zolpidem dosage, consider lower zolpidem dosage, and monitor for adverse effects200 238

Reyataz Pharmacokinetics

Absorption

Bioavailability

Unboosted atazanavir: Rapidly absorbed following oral administration;1 peak plasma concentrations attained approximately 2–2.5 hours after a dose.1

Ritonavir-boosted atazanavir: Peak plasma concentrations attained approximately 2.7–3 hours after a dose.1

Cobicistat-boosted atazanavir: Peak plasma concentrations attained approximately 3.5 hours after a dose.238

Food

Food increases bioavailability and reduces pharmacokinetic variability.1

Administration of unboosted atazanavir with a light meal increases peak plasma concentration by 57% and AUC by 70% compared with fasting.1 A high-fat meal increases AUC by 35% with no increase in peak plasma concentration.1

Administration of ritonavir-boosted atazanavir with a light meal increases atazanavir peak plasma concentrations by 40% and AUC by 33% compared with fasting.1 A high-fat meal does not affect AUC compared with fasting.1

Administration of cobicistat-boosted atazanavir with a light meal increases atazanavir peak plasma concentrations by 42% and AUC by 28% compared with fasting;238 a high-fat meal did not affect atazanavir AUC but decreased peak plasma concentrations by 14%.238

Plasma Concentrations

Nonlinear pharmacokinetics with greater than dose-proportional increases in plasma concentrations and AUC.1

Unboosted atazanavir: Steady-state concentrations attained between days 4–8 with an accumulation of approximately 2.3-fold.1

Special Populations

Unboosted atazanavir in hepatic impairment: Following a single 400-mg dose of atazanavir, AUC increased 42% in adults with moderate to severe hepatic impairment (Child-Pugh class B and C) compared with healthy adults.1

Unboosted atazanavir in renal impairment: Plasma concentrations in adults with severe renal impairment not undergoing dialysis generally are similar to those in adults with normal renal function.1 When administered before or after dialysis, plasma concentrations are lower than those in adults with normal renal function (mechanism of this change unknown).1

Ritonavir-boosted atazanavir in postpartum women: Atazanavir steady-state peak plasma concentrations and AUC are approximately 28–43% higher during postpartum period (4–12 weeks) compared with historical data in HIV-infected, nonpregnant patients.1

Distribution

Extent

Low concentrations of atazanavir attained in CSF and semen after oral administration.1

Atazanavir distributed into cord blood in low concentrations.1 202 When ritonavir-boosted atazanavir used in pregnant women, atazanavir concentrations in cord blood approximately 12–19% of maternal plasma concentrations at delivery.1

Distributed into milk in low concentrations.202

Plasma Protein Binding

86% bound to serum proteins; binding independent of concentration.1

Binds to both α-1-acid glycoprotein (89%) and albumin (86%).1

Elimination

Metabolism

Extensively metabolized and eliminated in liver.1 CYP3A involved in metabolism of the drug.1

Elimination Route

Approximately 79% of a dose eliminated in feces and 13% eliminated in urine as metabolites and unchanged drug.1

Not removed by hemodialysis.1

Half-life

Unboosted atazanavir: 6.5–7.9 hours.1

Ritonavir-boosted atazanavir: 8.6–18.1 hours.1

Cobicistat-boosted atazanavir: 7.5 hours.238

Special Populations

No clinically important differences in pharmacokinetics in those >65 years of age compared with younger adults.1

Atazanavir: Half-life is 12.1 hours in those with moderate to severe hepatic impairment.1

Stability

Storage

Oral

Capsules

Atazanavir: 25°C (may be exposed to 15–30°C).1

Powder

Atazanavir: <30°C in original packet.1 After mixing with food or beverage, may store for up to 1 hour at room temperature (20–30°C).1

Tablets

Atazanavir/cobicistat: 25°C (may be exposed to 15–30°C).238

Actions and Spectrum

  • Active against HIV-1;1 has some in vitro activity against HIV-2.1 40

  • Inhibits replication of HIV-1 by interfering with HIV protease.1

  • Atazanavir may be administered with low-dose ritonavir (ritonavir-boosted atazanavir) or with cobicistat (cobicistat-boosted atazanavir) resulting in increased exposures to atazanavir.1 200 201 238 239

  • Antiretroviral activity of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir due to atazanavir.1 238

  • HIV-1 with reduced susceptibility to atazanavir have been selected in vitro and have emerged during therapy with the drug.1 11

  • Varying degrees of cross-resistance occur among HIV PIs.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 238 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 238

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1 200 238

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 238 Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1 238

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 238 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 238

  • Importance of reading patient information provided by the manufacturer.1 238 239

  • Importance of taking with food to enhance absorption.1 238 239

  • If atazanavir oral powder used, importance of caregivers following mixing and administration instructions.1

  • When using ritonavir-boosted atazanavir, importance of taking single-entity atazanavir with food at the same time as single-entity ritonavir.1

  • When using cobicistat-boosted atazanavir, importance of taking the fixed-combination tablet containing both drugs (atazanavir/cobicistat) with food238 or importance of taking single-entity atazanavir with food and at the same time as single-entity cobicistat.239

  • If a dose of atazanavir is missed, take the dose as soon as it is remembered and take the next dose at the regularly scheduled time; if a dose is skipped, do not double the next dose.1

  • If a dose of cobicistat-boosted atazanavir is missed by <12 hours, take the dose as soon as it is remembered and take the next dose at the regularly scheduled time.238 239 If a dose of cobicistat-boosted atazanavir is missed by >12 hours, omit the dose and take the next dose at the regularly scheduled time.238 Do not take a double dose to make up for a missed dose.238 239

  • If atazanavir oral powder used, advise caregivers of patients with phenylketonuria that the powder contains phenylalanine.1

  • Advise patients that ECG changes (PR prolongation) have occurred; importance of consulting clinician if dizziness or lightheadedness occurs.1 238

  • Possibility of asymptomatic increases in indirect bilirubin that may be accompanied by yellowing of the skin or whites of the eyes;1 238 alternative antiretroviral therapy can be considered if these cosmetic changes are a concern.1 238

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 238

  • Advise patients that mild rash and severe skin reactions, including Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, have occurred.1 238 Importance of immediately discontinuing ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and contacting clinician if manifestations of severe skin reactions or hypersensitivity occur (e.g., severe rash or rash accompanied by shortness of breath, fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema).1 238

  • Advise patients that kidney stones and/or gallstones have been reported and some patients required hospitalization or experienced complications;1 238 discontinuance of the drug may be necessary.1 238

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1 238

  • Advise patients receiving a selective PDE5 inhibitor (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged penile erection) and that any symptoms should be promptly reported to clinician.1 238 Should not be used in patients receiving avanafil for treatment of erectile dysfunction183 or sildenafil for treatment of PAH.1 238

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 238 Advise HIV-infected women not to breast-feed.1 238

  • Importance of advising patients of other important precautionary information.1 238 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Atazanavir Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Powder

50 mg (of atazanavir) per packet

Reyataz

Bristol-Myers Squibb

Capsules

150 mg (of atazanavir)

Reyataz

Bristol-Myers Squibb

200 mg (of atazanavir)

Reyataz

Bristol-Myers Squibb

300 mg (of atazanavir)

Reyataz

Bristol-Myers Squibb

Atazanavir Sulfate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg (of atazanavir) with Cobicistat 150 mg

Evotaz

Bristol-Myers Squibb

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules and oral powder prescribing information. Princeton, NJ; 2015 Mar.

2. Sanne I, Piliero P, Squires K et al. Results of a phase 2 clinical trial at 48 weeks (A1424-007); a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003; 32:18-29. [IDIS 492665] [PubMed 12514410]

3. Haas DW, Zala C, Schrader S et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS. 2003; 17:1339-49. [PubMed 12799555]

4. Piliero PJ. Atazanavir: a novel HIV-1 protease inhibitor. Expert Opin Investig Drugs. 2002; 11:1295-1301 [PubMed 12225250]

7. Squires K, Lazzarin A, Gatell JM et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004; 36:1011-9. [PubMed 15247553]

8. Wood R, Phanuphak P, Cahn P et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr. 2004; 36:684-92. [PubMed 15167287]

9. Murphy RL. Reviving protease inhibitors: new data and more options. J Acquir Immune Defic Syndr. 2003; 33(suppl 1):S43-52. [IDIS 511780] [PubMed 12946064]

11. Colonno RJ, Thiry A, Limoli K et al. Activities of atazanavir 9BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother. 2003; 47:1324-3. [PubMed 12654666]

12. Reddy SS. Dear healthcare professional letter. Results of pharmacokinetic study in healthy volunteers given Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. West Point, PA: Merck; 2012 Feb 6.

13. Hodder S. Dear healthcare provider letter: important new pharmacokinetic data for Reyataz (atazanavir sulfate) in combination with Viread (tenofovir disoproxil fumarate). Princeton, NJ: Bristol-Myers Squibb; 2003 Aug 8.

14. Goldsmith DR, Perry CM. Atazanavir. Drugs. 2003; 63:1679-93. [PubMed 12904086]

17. Food and Drug Administration. FDA drug safety communication: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. 2012 Feb 8. From FDA website. Accessed 2012 Apr 23.

18. Food and Drug Administration. FDA drug safety communication: Updated information on drug interactions between Victrelis (boceprevir) and certain boosted HIV protease inhibitor drugs. 2012 Apr 26. From FDA website. Accessed 2012 Jul 9.

28. Molina JM, Andrade-Villanueva J, Echevarria J et al. Once-daily atazanavir/ritonavir versus twice daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1 infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008; 372:646-55. [PubMed 18722869]

29. Molina JM, Andrade-Villanueva J, Echevarria J et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010; 53:323-32. [PubMed 20032785]

30. Johnson M, Grinsztejn B, Rodriguez C et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005; 19:685-94. [PubMed 15821394]

31. Johnson M, Grinsztejn B, Rodriguez C et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS. 2006; 20:711-8. [PubMed 16514301]

32. Schering Corp. Noxafil (posaconazole) oral solution prescribing information. Whitehouse Station, NJ; 2012 Jun.

35. Murphy RL, Sanne I, Cahn P et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS. 2003; 17:2603-14. [PubMed 14685054]

40. Desbois D, Roquebert B, Peytavin G et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. 2008; 52:1545-8. [PubMed 18227188]

41. Gallant JE, Koenig E, Andrade-Villanueva J et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis. 2013; 208:32-9. [PubMed 23532097]

104. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376 82.

105. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1 2.

178. Bristol-Myers Squibb Company. Daklinza (daclatasvir) tablets prescribing information. Princeton, NJ. 2015 Jul.

179. AbbVie, Inc. Technivie (ombitasvir, paritaprevir, and ritonavir) tablets prescribing information. North Chicago, IL; 2015 Jul.

180. AbbVie, Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) tablets prescribing information. North Chicago, IL; 2015 Mar.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.

183. Vivus. Stendra (avanafil) tablets prescribing information. Mountain View, CA; 2012 Apr.

184. Vertex Pharmaceuticals. Incivek (telaprevir) tablets prescribing information. Cambridge, MA; 2012 Jun.

185. Merck & Co. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23.

187. Janssen Products LP. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.

188. Gilead Sciences, Inc. Sovaldi (sofosbuvir) prescribing information. Foster City, CA; 2013 Dec.

198. Center for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Morb Mortal Wkly Rep. 2005; 54(No. RR-2):1-19. [PubMed 15647722]

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 8, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (March 5, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

204. Janssen Therapeutics. Prezista (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2015 May.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2013 Apr.

207. AbbVie Inc. Kaletra (lopinavir/ritonavir) film-coated oral tablets and oral solution prescribing information. North Chicago, IL; 2013 Nov.

209. Abbott Laboratories. Norvir (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

210. Genentech USA. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2014 Apr.

213. Bristol-Myers Squibb. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2012 Jun.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

215. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.

221. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Jan.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Janssen Therapeutics. Edurant (rilpivirine) tablets prescribing information. Titusville, NJ; 2014 May.

238. Bristol-Myers Squibb. Evotaz (atazanavir/cobicistat) tablets prescribing information. Princeton, NJ; 2015 May.

239. Gilead Sciences. Tybost (cobicistat) tablets prescribing information. Foster City, CA; 2014 Sep.

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