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Atazanavir

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: 229975-97-7

Medically reviewed by Drugs.com on May 12, 2021. Written by ASHP.

Introduction

Antiretroviral; HIV protease inhibitor (PI).

Uses for Atazanavir

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; used in conjunction with other antiretrovirals.

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

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat): Treatment of HIV-1 infection in adults and adolescents ≥13 years of age; used in conjunction with other antiretrovirals.

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

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

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

For initial treatment in antiretroviral-naive adults and adolescents, experts state that ritonavir-boosted atazanavir in conjunction with tenofovir alafenamide fumarate (TAF) and emtricitabine or ritonavir-boosted atazanavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are alternative PI-based regimens. These experts state that cobicistat-boosted atazanavir in conjunction with TAF and emtricitabine or cobicistat-boosted atazanavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative PI-based regimens for initial treatment in antiretroviral-naive adults and adolescents. Ritonavir-boosted or cobicistat-boosted atazanavir in conjunction with abacavir and lamivudine are other regimen options for initial treatment in antiretroviral-naive patients when recommended or alternative regimens cannot be used, but use only in those with baseline plasma HIV RNA levels <100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.

For initial treatment in antiretroviral-naive pediatric patients, experts state that ritonavir-boosted atazanavir in conjunction with 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a preferred regimen in those ≥3 years of age and an alternative regimen in those 3 months to <3 years of age weighing 5–25 kg.

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.

Unboosted atazanavir should not be used in antiretroviral-experienced (previously treated) patients with prior virologic failure. 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.

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

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.

USPHS recommends a 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV. Ritonavir-boosted atazanavir and 2 NRTIs is one of several alternative regimens. 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.

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. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

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

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada); recommended alternative regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

CDC states that ritonavir-boosted atazanavir is an alternative antiretroviral that can be used in nPEP regimens.

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.

Atazanavir Dosage and Administration

Administration

Oral Administration

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

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

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

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. (See Specific Drugs under Interactions.)

Atazanavir Capsules

Swallow capsules whole; do not open.

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

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

Atazanavir Oral Powder

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

Used in pediatric patients ≥3 months of age weighing ≥5 kg.

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

Store atazanavir powder in original packet; do not open until ready to use. 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. 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. Administration with infant bottle not recommended since full dose may not be delivered.

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.

Mixing with food: Tap packet to settle powder; cut packet along dotted line with clean scissors. 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. Add and mix additional 1 tablespoon of food to the small container; feed residual mixture to patient.

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

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

Ritonavir-boosted Atazanavir

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

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

Cobicistat-boosted Atazanavir

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

Dosage

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

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

Pediatric Patients

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

Pediatric patients ≥3 months of age weighing ≥5 kg (oral powder): Dosage is based on weight. (See Table 1.) Oral powder must be used with low-dose ritonavir (ritonavir-boosted atazanavir).

In patients weighing 5 to <10 kg who do not tolerate 200 mg (4 packets) of atazanavir oral powder and have not previously received an HIV PI, atazanavir oral powder in a dosage of 150 mg (3 packets) once daily may be used with close HIV viral load monitoring.

Table 1. Dosage of Ritonavir-boosted Atazanavir for Pediatric Patients ≥3 Months of Age Weighing ≥5 kg1

Body Weight

Atazanavir Dosage (Oral Powder)

Ritonavir Dosage (Oral Solution)

5 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

≥25 kg and not able to swallow capsules

300 mg (6 packets) once daily

100 mg once daily

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

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. Do not use unboosted atazanavir in antiretroviral-experienced adolescents.

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).

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

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

Antiretroviral-experienced Adults
Oral

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

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

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)†
Oral

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

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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Do not exceed adult dosage.

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

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

Special Populations

Hepatic Impairment

Oral

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

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

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

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

Renal Impairment

Oral

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

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).

Cobicistat-boosted atazanavir: Assess estimated Clcr prior to initiation of fixed-combination atazanavir/cobicistat or, alternatively, single-entity atazanavir with single-entity cobicistat. Experts state dosage adjustments of cobicistat-boosted atazanavir not necessary in patients with renal impairment who do not require hemodialysis. 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.

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

Geriatric Patients

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

Pregnant and Postpartum Women

Use ritonavir-boosted atazanavir; do not use unboosted atazanavir. Monitor closely for adverse effects, especially during first 2 months after delivery. (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. Experts recommend using increased atazanavir dosage of 400 mg once daily with low-dose ritonavir (100 mg once daily) during second and third trimesters.

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). Not recommended in antiretroviral-experienced pregnant women receiving both a histamine H2-receptor antagonist and tenofovir.

Cautions for Atazanavir

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.

  • 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, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam). In addition, concomitant use of cobicistat-boosted atazanavir and colchicine, dronedarone, lurasidone, or ranolazine is contraindicated. (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. (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

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

Discontinue in patients who develop severe rash.

Cardiovascular Effects

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

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.

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]). (See Specific Drugs under Interactions.)

Renal Effects

Cobicistat decreases estimated Clcr by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function; 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.

Assess estimated Clcr prior to initiating cobicistat-boosted atazanavir. 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.

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

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. Concomitant use of cobicistat-boosted atazanavir and tenofovir DF not recommended in patients with estimated Clcr <70 mL/minute. 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. In addition, monitor serum phosphorus in those with or at risk for renal impairment. Concomitant use of a nephrotoxic agent not recommended in patients receiving an antiretroviral regimen that includes cobicistat-boosted atazanavir and tenofovir DF.

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).

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.

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

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.

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

Phenylketonuria

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

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

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. Evaluate hepatic function prior to and during atazanavir treatment in these patients. (See Hepatic Impairment under Cautions.)

Nephrolithiasis and Cholelithiasis

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

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

Interactions

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

Concomitant use of ritonavir-boosted or cobicistat-boosted atazanavir with certain drugs is contraindicated or requires particular caution. 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). 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. Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.

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.

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. Dosage recommendations for such combinations not established; 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.

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

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

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

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.

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

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.

Mechanisms and long-term consequences of adipogenic effects unknown; causal relationship not established.

Hemophilia A and B

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

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

HIV Resistance

Possibility of HIV-1 resistant to atazanavir.

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

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Data to date indicate that atazanavir does not increase risk of major birth defects overall compared to background rate. No treatment-related malformations observed in rats and rabbits at atazanavir exposures 0.7–1.2 times those reported with usual human dosage of ritonavir-boosted atazanavir (300 mg of atazanavir once daily with ritonavir 100 mg once daily).

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

Cobicistat-boosted atazanavir: Manufacturer states use during pregnancy only if potential benefits to the woman justify potential risks to fetus; do not use cobicistat-boosted atazanavir in treatment-experienced pregnant women receiving a histamine H2-receptor antagonist and/or tenofovir DF. Experts state data insufficient to date to recommend routine use of cobicistat-boosted atazanavir for initial treatment in antiretroviral-naive pregnant women.

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

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

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

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

Lactation

Atazanavir distributed into milk in low concentrations. Not known whether ritonavir or cobicistat distributed into human milk; cobicistat is distributed into milk in rats.

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

Pediatric Use

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

Ritonavir-boosted or unboosted atazanavir: Safety, efficacy, and pharmacokinetic profile evaluated in pediatric patients ≥3 months of age weighing ≥5 kg. Adverse effects in children 6 years to <18 years of age receiving the capsules generally similar to those reported in adults; adverse effects in pediatric patients weighing ≥5 kg receiving the oral powder generally similar to those reported in pediatric patients receiving capsules.

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

Geriatric Use

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

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

Hepatic Impairment

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

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). Do not use in those with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Dosage and Administration.)

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

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. (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. Dosage adjustments not needed.

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

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

Common Adverse Effects

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

Ritonavir-boosted 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.

Ritonavir-boosted atazanavir in pediatric patients 3 months to 10 years of age: Neutropenia; elevated amylase, ALT, total bilirubin, and lipase.

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

Interactions for Atazanavir

Atazanavir, ritonavir, and cobicistat metabolized by CYP3A.

Atazanavir, ritonavir, and cobicistat inhibit CYP3A.

Atazanavir inhibits CYP2C8 and UGT1A1.

Ritonavir and cobicistat inhibit CYP2D6.

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

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. Interactions reported or expected with ritonavir-boosted atazanavir may differ from those reported or expected with cobicistat-boosted atazanavir.

The following drug interactions are based on studies using ritonavir-boosted or unboosted atazanavir or studies using cobicistat alone. 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.

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).

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

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

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase 1A1

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

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).

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Acetaminophen

Pharmacokinetic interactions unlikely

Alfuzosin

Possible increased alfuzosin concentrations; may result in hypotension

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

Antacids

Possible decreased atazanavir concentrations

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

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 effects

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

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

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

Dronedarone: Concomitant use with cobicistat-boosted atazanavir contraindicated; experts state concomitant use with ritonavir-boosted or unboosted atazanavir also contraindicated

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

Apixaban: Increased apixaban concentrations expected

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

Edoxaban: Increased edoxaban concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir

Rivaroxaban: Possible increased rivaroxaban concentrations; may increase bleeding risk

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

Apixaban, edoxaban, rivaroxaban: Avoid concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

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

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

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

Carbamazepine: Possible decreased atazanavir concentrations and increased carbamazepine concentrations if used with ritonavir-boosted atazanavir; possible decreased atazanavir and cobicistat concentrations if used with cobicistat-boosted atazanavir; decreased atazanavir concentrations if used with unboosted atazanavir

Eslicarbazepine: Possible decreased atazanavir and cobicistat concentrations if used with cobicistat-boosted atazanavir

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

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

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

Phenobarbital, phenytoin: Possible decreased concentrations of atazanavir and the anticonvulsant if used with ritonavir-boosted atazanavir; possible decreased atazanavir and cobicistat concentrations may result in loss of therapeutic effect and development of resistance if used with cobicistat-boosted atazanavir; decreased atazanavir concentrations if used with unboosted atazanavir

Carbamazepine: Concomitant use with unboosted atazanavir not recommended; consider alternative anticonvulsant in patients receiving ritonavir-boosted atazanavir; if used with ritonavir-boosted atazanavir, consider that reduced anticonvulsant dosage may be needed, monitor serum concentrations of both drugs, assess virologic response; concomitant use with cobicistat-boosted atazanavir contraindicated

Eslicarbazepine: Consider alternative anticonvulsant or alternative antiretroviral; if used concomitantly with cobicistat-boosted atazanavir, monitor for lack or loss of antiretroviral response

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

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

Oxcarbazepine: Consider alternative anticonvulsant or alternative antiretroviral; if used concomitantly with cobicistat-boosted atazanavir, monitor for lack or loss of antiretroviral response

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

Antifungals, azoles

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

Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and altered atazanavir concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

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

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

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

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; effect of cobicistat-boosted atazanavir on voriconazole concentrations unknown; possible altered atazanavir and voriconazole concentrations if used with unboosted atazanavir

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

Isavuconazonium: Monitor for atazanavir-associated adverse effects and virologic efficacy if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir; consider monitoring isavuconazole concentrations

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

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

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

Voriconazole: Do not use with ritonavir-boosted or cobicistat-boosted atazanavir unless potential benefits outweigh risks; 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; if used with unboosted atazanavir, monitor for toxicities

Antimalarial agents

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

Atovaquone/proguanil: Consider alternative antimalarial, if possible

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

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

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

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

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

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

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; some experts suggest rifabutin 150 mg once daily or 300 mg 3 times weekly; monitor for rifabutin-associated adverse effects (e.g., neutropenia, uveitis); monitor for antimycobacterial response and consider therapeutic drug monitoring

Rifampin: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

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

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

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

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

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

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

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

Irinotecan: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

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

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

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

Lurasidone: Possible increased lurasidone concentrations if used with ritonavir-boosted or unboosted atazanavir; potential for serious and/or life-threatening adverse effects if used with ritonavir-boosted or cobicistat-boosted atazanavir

Perphenazine, risperidone, thioridazine: Possible increased antipsychotic agent concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir

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

Quetiapine: Increased quetiapine concentrations expected if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

Lurasidone: Concomitant use with ritonavir-boosted or cobicistat-boosted atazanavir contraindicated; experts state do not use concomitantly with unboosted atazanavir; if concomitant use with unboosted atazanavir necessary, reduce lurasidone dosage

Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed if used with ritonavir-boosted or cobicistat-boosted atazanavir; experts state initiate antipsychotic at lowest dosage, adjust maintenance dosage as needed, and monitor for antipsychotic-associated toxicities

Pimozide: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

Quetiapine: Consider alternative antiretroviral; 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; if quetiapine necessary in patient receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, experts state initiate using lowest quetiapine dosage and titrate as needed

Atovaquone

Ritonavir-boosted atazanavir: No effect on atovaquone concentrations

Ritonavir-boosted atazanavir: Dosage adjustments not needed

Avanafil

Possible increased avanafil concentrations and AUC

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

Benzodiazepines

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

Clonazepam: Possible increased clonazepam concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

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

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 atazanavir

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

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

Clonazepam: Clinical monitoring recommended if used with cobicistat-boosted atazanavir; experts state consider alternative (e.g., lorazepam, oxazepam, temazepam)

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

Oral midazolam or triazolam: Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

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; consider reduced midazolam dosage, especially if multiple midazolam doses are given; experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation

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

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

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

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; experts state consider use of alternatives not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol)

Bosentan

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

Unboosted atazanavir: Do not use concomitantly with bosentan

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 tolerability

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 tolerability

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

Buprenorphine, buprenorphine/naloxone

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

Cobicistat-boosted atazanavir: Data not available regarding use with buprenorphine/naloxone

Unboosted atazanavir: Concomitant use with buprenorphine not recommended

Ritonavir-boosted atazanavir: Monitor for sedation and adverse cognitive effects; consider reduced buprenorphine dosage; in those with a buprenorphine subdermal implant, removal of the implant and switch to a different buprenorphine formulation that permits dosage adjustments may be needed

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; if initiating cobicistat-boosted atazanavir in patient already receiving buprenorphine or buprenorphine/naloxone, monitor patient and consider that dosage adjustments may be needed; in those with a buprenorphine subdermal implant, removal of the implant and switch to a different buprenorphine formulation that permits dosage adjustments may be needed

Buspirone

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

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

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 atazanavir

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

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 recommended

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

Cisapride

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

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

Cobicistat

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

Colchicine

Increased colchicine concentrations if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

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

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 later

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 daily

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)

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

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

Budesonide, fluticasone, or mometasone (orally inhaled, intranasal): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome

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

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

Dexamethasone (systemic): Possible decreased atazanavir concentrations and decreased antiretroviral efficacy and development of atazanavir resistance

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; consider alternative (e.g., beclomethasone; use fluticasone and unboosted atazanavir concomitantly with caution

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, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir)

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 effects

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

Co-trimoxazole

Pharmacokinetic interactions unlikely

Daclatasvir

Ritonavir-boosted atazanavir: Increased daclatasvir concentrations and AUC

Cobicistat-boosted atazanavir: Increased daclatasvir concentrations

Unboosted atazanavir: Clinically important changes in daclatasvir concentrations not expected

Ritonavir-boosted or cobicistat-boosted atazanavir: Use daclatasvir dosage of 30 mg once daily

Unboosted atazanavir: Dosage adjustments not needed

Dapsone

Pharmacokinetic interactions unlikely

Darunavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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

Delavirdine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Didanosine

Buffered didanosine: Decreased atazanavir concentrations and AUC; decreased didanosine concentrations and AUC

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

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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)

Digoxin

Increased digoxin concentrations if used with ritonavir-boosted or cobicistat-boosted atazanavir

Use concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir with caution; titrate digoxin dosage and monitor digoxin concentrations

Dolutegravir

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

Cobicistat-boosted atazanavir: Data not available

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

Efavirenz

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

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

Unboosted atazanavir: Substantially decreased atazanavir concentrations and AUC; no clinically important change in efavirenz concentrations

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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)

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)

Ritonavir-boosted or cobicistat-boosted atazanavir in antiretroviral-experienced adults: Concomitant use not recommended

Unboosted atazanavir: Do not use with efavirenz

Elbasvir and grazoprevir

Ritonavir-boosted atazanavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations; may increase risk of elevated ALT concentrations

Cobicistat-boosted or unboosted atazanavir: Increased grazoprevir concentrations expected; may increase risk of elevated ALT concentrations

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use with fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) contraindicated

Elvitegravir

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

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

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; do not use single-entity elvitegravir concomitantly with cobicistat-boosted atazanavir

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

Emtricitabine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Eplerenone

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased eplerenone concentrations expected

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state concomitant use contraindicated

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)

Concomitant use with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir contraindicated

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 possible

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; data not available regarding use with cobicistat-boosted atazanavir

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

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

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

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

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

Etravirine

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

Cobicistat-boosted atazanavir: Decreased atazanavir and cobicistat concentrations

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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

Fentanyl

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased fentanyl concentrations

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

Flibanserin

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased flibanserin concentrations expected

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state concomitant use contraindicated

Fosamprenavir

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

Fosamprenavir (without low-dose ritonavir): No data

In vitro evidence of synergistic antiretroviral effects with atazanavir

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

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; if used with ritonavir-boosted or cobicistat-boosted atazanavir, possible alterations in atazanavir pharmacokinetics

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; dosage of histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent)

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; dosage of histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent)

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; 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)

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

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; alternatively, atazanavir 400 mg and cobicistat 150 mg once daily with food

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)

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 daily

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

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 rhabdomyolysis

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

Atorvastatin: Carefully titrate atorvastatin dosage and use lowest necessary dosage

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

Lovastatin: Concomitant use contraindicated

Pitavastatin: Dosage adjustments not necessary

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily; carefully titrate rosuvastatin dosage and use lowest necessary dosage

Simvastatin: Concomitant use contraindicated

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Potential for increased concentrations of cyclosporine, everolimus, sirolimus, or tacrolimus

Monitor plasma concentrations of the immunosuppressive agent if used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

Indinavir

Potential for additive hyperbilirubinemia

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

Ivabradine

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased ivabradine concentrations expected

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state concomitant use with ivabradine contraindicated

Lamivudine

Unboosted atazanavir: No clinically important interactions

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Ledipasvir and sofosbuvir

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

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

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

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

Lopinavir/ritonavir

Prolonged PR interval reported with both atazanavir and lopinavir

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

Use concomitantly with caution and clinical monitoring

Macrolides (azithromycin, clarithromycin, erythromycin, telithromycin)

Azithromycin: Pharmacokinetic interactions unlikely

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

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

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

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

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

Maraviroc

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased maraviroc concentrations and AUC

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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

Methadone

Unboosted atazanavir: Pharmacokinetic interactions unlikely

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

Cobicistat-boosted atazanavir: Data not available regarding concomitant use with methadone

Unboosted atazanavir: Adjustment of methadone dosage not needed

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

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

Nelfinavir

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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 effects

Cobicistat-boosted atazanavir: Decreased cobicistat concentrations

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

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use contraindicated

Ombitasvir, paritaprevir, and ritonavir

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir: Substantially increased paritaprevir concentrations if used with ritonavir-boosted or unboosted atazanavir but no substantial effect on atazanavir, dasabuvir, or ombitasvir concentrations; data not available regarding use with cobicistat-boosted atazanavir

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Concomitant use with ritonavir-boosted or unboosted atazanavir not recommended

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; ritonavir-boosted or cobicistat-boosted atazanavir can replace unboosted atazanavir after HCV treatment completed

Proton-pump inhibitors (PPIs)

Omeprazole: Substantially decreased atazanavir concentrations and possible loss of virologic response and development of atazanavir resistance

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

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; administer the PPI approximately 12 hours before ritonavir-boosted atazanavir; dosage of PPI should not exceed omeprazole 20 mg daily (or equivalent)

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; administer the PPI approximately 12 hours before cobicistat-boosted atazanavir; dosage of PPI should not exceed omeprazole 20 mg daily (or equivalent)

Antiretroviral-experienced patients: Do not use PPIs concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir

Raltegravir

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

In vitro evidence of additive to synergistic antiretroviral effects with atazanavir

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

Ranolazine

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

Cobicistat-boosted atazanavir: Concomitant use contraindicated

Ritonavir-boosted or unboosted atazanavir: Concomitant use contraindicated

Repaglinide

Unboosted atazanavir: Possible increased repaglinide concentrations

Ritonavir-boosted atazanavir: Clinically important interactions not expected

Unboosted atazanavir: Use concomitantly with caution

Cobicistat-boosted atazanavir: Concomitant use not recommended

Rilpivirine

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

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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

Ritonavir

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

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

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

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

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

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

St. John’s wort (Hypericum perforatum)

Possible decreased atazanavir concentrations; possible loss of virologic response and increased risk of atazanavir resistance

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use contraindicated

Salmeterol

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

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use not recommended

Saquinavir

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

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

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

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

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

Selective serotonin-reuptake inhibitors (SSRIs)

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

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)

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

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

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

Sildenafil

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

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

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; closely monitor for sildenafil-associated adverse effects

Simeprevir

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

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Concomitant use not recommended

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 atazanavir

Sofosbuvir and velpatasvir

Ritonavir-boosted atazanavir: No clinically important pharmacokinetic interactions with fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir)

HIV antiretroviral regimen of ritonavir-boosted atazanavir in conjunction with fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF): Increased velpatasvir and tenofovir concentrations and AUC if used with sofosbuvir/velpatasvir

HIV antiretroviral regimens that include ritonavir-boosted atazanavir and tenofovir DF: Monitor for tenofovir-associated adverse effects if used with sofosbuvir/velpatasvir

Stavudine

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Suvorexant

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Increased suvorexant concentrations expected

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state concomitant use with suvorexant not recommended

Tadalafil

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

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 daily

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; if ritonavir-boosted atazanavir switched to cobicistat-boosted atazanavir, maintain current tadalafil dosage

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 effects

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 atazanavir

Tenofovir alafenamide

Ritonavir-boosted atazanavir: Increased tenofovir alafenamide AUC

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

Tenofovir DF

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 disorders

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Unboosted atazanavir: Do not use concomitantly with tenofovir DF

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

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 food

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

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 food

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 food

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

Ticagrelor

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

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Experts state avoid concomitant use with ticagrelor

Tipranavir

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

In vitro evidence of additive to antagonistic antiretroviral effects with atazanavir

Ritonavir-boosted or unboosted atazanavir: Concomitant use not recommended

Tramadol

Cobicistat-boosted atazanavir: Increased tramadol concentrations

Cobicistat-boosted atazanavir: Decreased tramadol dosage may be needed; monitor for efficacy and tramadol-associated adverse effects

Trazodone

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

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

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 effects

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

Vardenafil

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

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)

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)

Vorapaxar

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

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

Zidovudine

Unboosted atazanavir: No clinically important interactions

No in vitro evidence of antagonistic antiretroviral effects with atazanavir

Zolpidem

Ritonavir-boosted or cobicistat-boosted atazanavir: Possible increased zolpidem concentrations

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

Atazanavir Pharmacokinetics

Absorption

Bioavailability

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

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

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

Food

Food increases bioavailability and reduces pharmacokinetic variability.

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

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

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

Plasma Concentrations

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

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

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.

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. When administered before or after dialysis, plasma concentrations are lower than those in adults with normal renal function (mechanism of this change unknown).

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.

Distribution

Extent

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

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

Distributed into milk in low concentrations.

Plasma Protein Binding

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

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

Elimination

Metabolism

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

Elimination Route

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

Not removed by hemodialysis.

Half-life

Unboosted atazanavir: 6.5–7.9 hours.

Ritonavir-boosted atazanavir: 8.6–18.1 hours.

Cobicistat-boosted atazanavir: 7.5 hours.

Special Populations

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

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

Stability

Storage

Oral

Capsules

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

Powder

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

Tablets

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

Actions and Spectrum

  • Active against HIV-1; has some in vitro activity against HIV-2.

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

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

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

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

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

Advice to Patients

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

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

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

  • 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. 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.

  • Importance of reading patient information provided by the manufacturer.

  • Importance of taking with food to enhance absorption.

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

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

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

  • When using unboosted atazanavir, importance of taking with food.

  • 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.

  • 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. 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. Do not take a double dose to make up for a missed dose.

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

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

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

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

  • Advise patients that mild rash and severe skin reactions, including Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, have occurred. 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).

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

  • 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.

  • 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. Should not be used in patients receiving avanafil for treatment of erectile dysfunction or sildenafil for treatment of PAH.

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

  • Importance of advising patients of other important precautionary information. (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 2021, Selected Revisions May 22, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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