Introduction ⬇
AHFS Class:
- HIV Protease Inhibitors 8:18.08.08
Generic Name(s):
Atazanavir sulfate, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1
Uses ⬆ ⬇
Treatment of HIV Infection 
Atazanavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naïve (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults, adolescents, and children 3 months of age or older weighing at least 5 kg.1,28,29,8,30,35 The manufacturer advises that use of ritonavir-boosted atazanavir in antiretroviral-experienced patients should be guided by the number of baseline primary HIV protease inhibitor (PI) resistance substitutions.1
Atazanavir is not recommended for use in patients younger than age 3 months because of the risk of kernicterus.1 Ritonavir-boosted or cobicistat-boosted atazanavir is used with a dual-nucleoside reverse transcriptase inhibitor (NRTI) “backbone” of a fully suppressive antiretroviral regimen; consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202
Atazanavir is commercially available as a single-entity preparation and in a fixed-dose combination preparation that also contains cobicistat; refer to the full prescribing information for administration of the combination product.1,10
Clinical Experience
Antiretroviral-naïve Adults and Adolescents
In an open-label, noninferiority study in antiretroviral-naïve adults (study AI424-138; CASTLE study), a regimen of ritonavir-boosted atazanavir given once daily in conjunction with tenofovir DF and emtricitabine demonstrated antiviral efficacy similar to that of a regimen of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) given twice daily in conjunction with tenofovir DF and emtricitabine.1,28,29 At week 48, 78 or 76% of adults receiving the regimen that included ritonavir-boosted atazanavir or the regimen that included lopinavir/ritonavir had plasma HIV-1 RNA levels less than 50 copies/mL, respectively.1 At week 96, 75 or 68% of adults receiving the regimen that included ritonavir-boosted atazanavir or the regimen that included lopinavir/ritonavir respectively, had plasma HIV-1 RNA levels less than 50 copies/mL.1,29
Safety and efficacy of unboosted atazanavir used in conjunction with other antiretroviral agents have been evaluated in 2 randomized multicenter studies in antiretroviral-naïve adults (study AI424-034 and AI424-008).1,7 In study AI424-034, 810 HIV-infected adults (mean age: 34 years; 65% male; 33% white; 36% Hispanic; mean baseline plasma HIV-1 RNA level: 4.8 log10 copies/mL; mean baseline CD4+ T-cell count: 321 cells/mm3) were randomized to receive atazanavir (400 mg once daily) or efavirenz (600 mg once daily) in conjunction with a fixed-combination preparation containing lamivudine and zidovudine (150 mg of lamivudine and 300 mg of zidovudine twice daily).1,7 Results of this study indicated that an initial regimen that includes atazanavir in conjunction with lamivudine and zidovudine is as effective as an initial regimen of efavirenz in conjunction with lamivudine and zidovudine.1,7 At week 48, 67 and 32% of adults receiving the regimen that included atazanavir and 62 and 37% of those receiving the regimen that included efavirenz had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 In patients with high viral titers at baseline (i.e., 100,000 copies/mL or greater), the proportion of patients responding at week 48 to the regimen that included atazanavir was similar to the proportion responding to the regimen that included efavirenz.1 At week 48, increases in CD4+ T-cell counts were greater in patients receiving the regimen that included atazanavir (increase of 176 cells/mm3) than in those receiving the regimen that included efavirenz (increase of 160 cells/mm3).1
In study AI424-008, 467 HIV-infected adults (mean age: 35 years; 63% male; 55% white; mean baseline plasma HIV-1 RNA level: 4.7 log10 copies/mL; mean baseline CD4+ T-cell count: 295 cells/mm3) were randomized to receive unboosted atazanavir (600 or 400 mg once daily) or nelfinavir (1250 mg twice daily) in conjunction with lamivudine (150 mg twice daily) and stavudine (40 mg twice daily).1 In this study, an initial regimen of atazanavir, lamivudine, and stavudine was as effective as an initial regimen of nelfinavir, lamivudine, and stavudine.1,35 At week 48, 67 and 33% of adults receiving the regimen that included atazanavir (400 mg once daily) and 59 and 38% of those receiving the regimen that included nelfinavir had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 At week 48, patients receiving the regimen that included atazanavir 400 mg once daily had greater increases in CD4+ T-cell counts than those receiving the regimen that included nelfinavir (mean increase of 234 and 211 cells/mm3, respectively).1 In an open-label extension study (study AI424-044), virologic response was maintained at a median of 108 weeks in patients receiving atazanavir, lamivudine, and stavudine.8
Antiretroviral-experienced Adults and Adolescents
If atazanavir is used in antiretroviral-experienced (previously treated) patients with prior virologic failure, ritonavir-boosted atazanavir or cobicistat-boosted atazanavir is used.1 Use of these regimens in antiretroviral-experienced patients should be guided by the number of baseline primary PI resistance substitutions.1 Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is not recommended in antiretroviral-experienced patients with prior virologic failure.1
Ritonavir-boosted atazanavir has been evaluated in a randomized, open-label, multicenter study (study AI424- 045) in 347 previously treated adults who experienced virologic failure with antiretroviral regimens that included HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), NRTIs, and/or PIs.1 Patients were randomized to receive ritonavir-boosted atazanavir (300 mg of atazanavir with 100 mg of ritonavir once daily), lopinavir/ritonavir (400 mg of lopinavir/100 mg of ritonavir twice daily) or atazanavir (400 mg once daily) with saquinavir (1.2 g once daily as soft gelatin capsules no longer commercially available in the US), each in conjunction with tenofovir DF 300 mg once daily and an additional NRTI.1,30 At 48 weeks, 55 or 38% of adults receiving the regimen that included ritonavir-boosted atazanavir and 57 or 45% of those receiving the regimen that included lopinavir/ritonavir had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 Administration of ritonavir-boosted atazanavir in conjunction with tenofovir DF and an additional NRTI resulted in a mean decrease in plasma HIV-1 RNA levels of 1.58 log10 copies/mL at 48 weeks.1 Similarly, administration of lopinavir/ritonavir in conjunction with tenofovir DF and an additional NRTI resulted in a mean decrease in plasma HIV-1 RNA levels of 1.7 log10 copies/mL.1 The regimen of atazanavir, saquinavir, tenofovir DF, and one NRTI was less effective than the regimens of ritonavir-boosted atazanavir or lopinavir/ritonavir with tenofovir DF and an additional NRTI in this group of patients.1,30 At 96 weeks, 44 or 33% of patients continuing a regimen containing ritonavir-boosted atazanavir maintained plasma HIV-1 RNA levels below 400 or 50 copies/mL, respectively.31 This was similar to 46 or 36%, respectively, of patients receiving a regimen containing lopinavir/ritonavir.31
Although no longer recommended for antiretroviral-experienced patients, unboosted atazanavir was evaluated in a randomized, open-label, multicenter study (study AI424-043) in 300 previously treated adults who experienced virologic failure to one (but not more than one) antiretroviral regimen that included a PI.1 Patients were randomized to receive unboosted atazanavir (400 mg once daily) in conjunction with 2 NRTIs or lopinavir/ritonavir (400 mg of lopinavir/100 mg of ritonavir twice daily) in conjunction with 2 NRTIs.1 At week 48, 49 and 35% of adults receiving the regimen that included atazanavir and 69 and 53% of those receiving the regimen that included lopinavir/ritonavir had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 Administration of atazanavir in conjunction with 2 NRTIs resulted in a mean decrease in viral load of 1.59 log10 copies/mL at 48 weeks; administration of lopinavir/ritonavir in conjunction with 2 NRTIs resulted in a mean decrease in viral load of 2.02 log10 copies/mL.1 Based on results of this study, a regimen that includes atazanavir without low-dose ritonavir is not recommended in adults who previously received a PI and experienced virologic failure.1
Pediatric Patients
Ritonavir-boosted atazanavir is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children 3 months of age or older weighing 5 kg or more.1
Efficacy and safety of atazanavir capsules (with or without low-dose ritonavir) were evaluated in an open-label trial in 105 HIV-infected children 6 years to less than 21 years of age (PACTG 1020A).1 At week 96, 51 or 47% of antiretroviral-naïve children and 34 or 24% of antiretroviral-experienced children had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 At week 96, the median increase in absolute CD4+ T-cell count from baseline was 335 cells/mm3 in antiretroviral-naïve children and 220 cells/mm3 in antiretroviral-experienced children.1
Efficacy and safety of ritonavir-boosted atazanavir oral powder were evaluated in 2 open-label, multicenter trials that included 134 pediatric patients 3 months to less than 11 years of age weighing 5 kg to less than 35 kg (PRINCE I and PRINCE II).1 Patients weighing 5 kg to less than 10 kg received either 150 or 200 mg of atazanavir (oral powder) and 80 mg of ritonavir (oral solution);1 those weighing 10 kg to less than 15 kg received 200 mg of atazanavir (oral powder) and 80 mg of ritonavir (oral solution);1 those weighing 15 kg to less than 25 kg received 250 mg of atazanavir (oral powder) and 80 mg of ritonavir (oral solution);1 and those weighing 25 kg to less than 35 kg received 300 mg of atazanavir (oral powder) and 100 of ritonavir.1 At 48 weeks, 79 or 54% of antiretroviral-naïve children and 62 or 50% of antiretroviral-experienced children had achieved plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively.1 The median increase in absolute CD4+ T-cell count from baseline was 215 cells/mm3 in antiretroviral-naïve children and 133 cells/mm3 in antiretroviral-experienced children;1 the median increase in T-cell percentage from baseline was 6 and 4%, respectively.1
Clinical Perspective
Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202
The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200
Atazanavir boosted with cobicistat or ritonavir (a boosted PI) is used with a dual-NRTI “backbone” plus tenofovir alafenamide or tenofovir disoproxil fumarate plus emtricitabine or lamivudine.200 In the 2023 HHS adult and adolescent HIV treatment guideline, boosted atazanavir is included among alternative initial regimens in certain clinical situations.200 The guideline states that boosted darunavir is generally preferred over boosted atazanavir.200
In the 2023 HHS pediatric HIV treatment guideline, atazanavir is included in various antiretroviral regimens.201 Atazanavir boosted with ritonavir plus a dual-NRTI backbone is recommended as an alternative PI-based regimen in children ≥3 months of age.201 Atazanavir boosted with cobicistat is an alternative regimen for children weighing ≥35 kg.201 Unboosted atazanavir is not recommended.201
In the 2023 HHS perinatal HIV treatment guideline, ritonavir-boosted atazanavir is included in various antiretroviral regimens.202 Ritonavir-boosted atazanavir is listed as an alternative regimen for pregnant patients initiating antiretrovirals for the first time, who have received ART in the past and are restarting antiretrovirals, who are on a regimen that is not well-tolerated, or are not pregnant and trying to conceive.202 Ritonavir-boosted atazanavir should be continued in patients who become pregnant on a fully suppressive, well-tolerated regimen.202 The guideline states that a higher dose of atazanavir/ritonavir 400 mg/100 mg should be used in the second or third trimester, although some recommend this for patients receiving tenofovir disoproxil or histamine-receptor agonists.202 Use of atazanavir with cobicistat is associated with lower plasma drug exposures during the second and third trimesters, which may pose a risk of virologic failure.200 Cobicistat-boosted atazanavir is generally not recommended.202
Postexposure Prophylaxis following HIV Occupational Exposure
Atazanavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199
The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir®), or zidovudine and emtricitabine.199 Ritonavir-boosted atazanavir is included among alternatives to raltegravir.199
Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199
Dosage and Administration ⬆ ⬇
General
Pretreatment Screening
- Perform renal laboratory testing (serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) in all patients prior to initiation of atazanavir.1
- Perform hepatic laboratory testing in patients with underlying liver disease prior to initiation of atazanavir.1
Patient Monitoring
- Perform renal laboratory testing (serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) during treatment with atazanavir.1
- Perform hepatic laboratory testing in patients with underlying liver disease during treatment with atazanavir.1
- Monitor ECG in patients with preexisting conduction system disease or when atazanavir is administered with other drugs that may prolong the PR interval.1
- Monitor liver enzymes in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection.1
Dispensing and Administration Precautions
- Atazanavir is commercially available as a single entity and in a fixed-combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®).1,10 Refer to the full prescribing information for specific uses of the combination product.10 Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.10
Other General Considerations
- Atazanavir is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1, and atazanavir prescribing is guided by UGT1A1 genotype testing and interpretation.12 In patients who are poor metabolizers of UGT1A1, consider an alternative agent to ritonavir-boosted atazanavir particularly if there are concerns of jaundice.12 Refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for recommendations for atazanavir prescribing in patients with known poor metabolizer UGT1A1 genotypes.12
Administration
Atazanavir is used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.1 Atazanavir is administered orally in conjunction with low-dose ritonavir ( ritonavir-boosted atazanavir) or unboosted (i.e., without low-dose ritonavir) once daily with food.1
If atazanavir is used concomitantly with certain drugs (e.g., antacids, didanosine, histamine H2-receptor antagonists), dosage adjustments may be needed and/or doses of atazanavir and the other drug may need to be given at separate times.1
Oral Administration
Atazanavir is available as capsules or oral powder.1
Capsules
Atazanavir capsules should be swallowed whole; do not open the capsules.1
Capsules are used in adults, adolescents, and pediatric patients ≥6 years of age.1
Atazanavir capsules usually are administered with low-dose ritonavir ( ritonavir-boosted atazanavir), but may be used without low-dose ritonavir in adults and adolescents ≥13 years of age weighing ≥40 kg who are unable to tolerate ritonavir.1
Store atazanavir capsules at 25°C (excursions permitted between 15-30°C); keep in a tightly closed container1
Oral Powder
Atazanavir oral powder is provided in single-use packets containing 50 mg of atazanavir; the oral powder must be mixed with food or beverage prior to administration.1
The oral powder can be used in pediatric patients ≥3 months of age weighing ≥5 kg.1
Atazanavir oral powder must be administered with low-dose ritonavir ( ritonavir-boosted atazanavir).1 Administer the dose of low-dose ritonavir immediately following the atazanavir dose.1
Store the oral powder in the original packet at 20-30°C and do not open until ready to use.1
Prior to mixing the oral powder, determine the number of packets (3, 4, 5, or 6 packets) that are needed and tap the packet to settle the powder.1 Use a clean pair of scissors to cut along the dotted line.1 Mix the oral powder preferably with food (e.g., applesauce, yogurt); the oral powder may be mixed with a beverage (e.g., milk, infant formula, water) for infants who are able to drink from a cup.1 For infants <6 months of age who cannot eat solid food or drink from a cup, mix the oral powder with infant formula and administer using an oral dosing syringe.1 Administration using an infant bottle is not recommended because the full atazanavir dose may not be delivered.1
If administering with food, mix the contents of the recommended number of packets with at least 1 tablespoon of food (e.g., applesauce, yogurt) in a small container (e.g., cup, bowl) using a spoon.1 Feed the mixture to the patient.1 Then, add an additional 1 tablespoon of food to the small container; mix and feed the residual mixture to the patient.1
If administering with a beverage, mix the contents of the recommended number of packets with ≥30 mL of beverage using a spoon.1 Instruct the child to drink the mixture.1 Then, add an additional 15 mL of beverage to the drinking cup, mix, and have the child drink the residual mixture.1 If water is used as the beverage, have the child eat food at the time of administration.1
If administering with liquid infant formula, mix the contents of the recommended number of packets in a small medicine cup with 10 mL of prepared liquid infant formula using a spoon.1 Draw the entire mixture into an oral dosing syringe and administer into the infant's right or left inner cheek.1 Then, pour an additional 10 mL of infant formula into the medicine cup to rinse off any remaining atazanavir oral powder.1 Draw the residual mixture into the oral dosing syringe and administer into the infant's right or left inner cheek.1
Administer the entire dosage of the oral powder within 1 hour after the powder has been mixed with food or bevera the mixture may be left at a temperature of 20-30°C for up to 1 hour after preparation.1 For additional information on mixing and administering the oral powder, refer to the full instructions for use provided by the manufacturer.1
Fixed Combinations Containing Atazanavir
Atazanavir is also commercially available in a fixed-combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®).10 Refer to the full prescribing information for administration of the combination product.10
Dosage
Atazanavir is commercially available as capsules or oral powder containing atazanavir sulfate; dosage is expressed in terms of atazanavir.1
Adult Dosage
For adults who cannot swallow the capsules, administer atazanavir oral powder once daily with food at the same recommended adult dosage as the capsules along with ritonavir.1
Treatment of HIV Infection in Antiretroviral-naïve Adults
The recommended dosage of ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-naïve adults is 300 mg of atazanavir once daily given in conjunction with ritonavir 100 mg once daily.1
If unboosted atazanavir (i.e., without low-dose ritonavir) is used for the treatment of HIV-1 infection in antiretroviral-naïve adults unable to tolerate ritonavir, the recommended dosage of atazanavir is 400 mg once daily.1
The recommended dosage of ritonavir-boosted atazanavir in combination with efavirenz is 400 mg of atazanavir once daily given in conjunction with ritonavir 100 mg once daily.1
The fixed-combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®) is also used for the treatment of HIV-1 infection in antiretroviral-naïve adults; refer to the full prescribing information for dosage of atazanavir/cobicistat in adults.10
Treatment of HIV Infection in Antiretroviral-experienced Adults
The recommended dosage of ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-experienced adults is 300 mg of atazanavir once daily given in conjunction with ritonavir 100 mg once daily.1
The recommended dosage of ritonavir-boosted atazanavir in combination with a histamine H2-receptor antagonist and tenofovir disoproxil fumarate (tenofovir DF) is 400 mg of atazanavir once daily given in conjunction with ritonavir 100 mg once daily.1
Do not use atazanavir without ritonavir in treatment-experienced adult patients.1
The fixed-combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®) is also used for the treatment of HIV-1 infection in antiretroviral-experienced adults; refer to the full prescribing information for dosage of atazanavir/cobicistat in adults.10
Postexposure Prophylaxis following Occupational Exposure to HIV
For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of ritonavir-boosted atazanavir is 300 mg of atazanavir once daily with ritonavir 100 mg once daily.199 Alternatively, atazanavir 400 mg once daily can be used without ritonavir, but not in combination with tenofovir DF.199
Initiate the PEP regimen as soon as possible following occupational exposure (preferably within hours) and continue for 4 weeks, if tolerated.199
Pediatric Dosage
A change in the dosage may be required when transitioning between formulations; refer to the dosage table for the specific formulation.1
Treatment of HIV Infection
Dosage of atazanavir oral powder for the treatment of HIV-1 infection in pediatric patients ≥3 months of age weighing ≥5 kg is based on weight.1 (See Table 1.) Atazanavir oral powder must be used with low-dose ritonavir ( ritonavir-boosted atazanavir); administer ritonavir immediately after atazanavir powder.1
Table 1: Dosage of Ritonavir-boosted Atazanavir Oral Powder for Pediatric Patients ≥3 Months of Age Weighing ≥5 kga1
Body Weight | Atazanavir Dosage (Oral Powder) | Ritonavir Dosage (Oral Solution) |
|---|
5 to <15 kg | 200 mg (4 packets) once dailyb | 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 |
aRecommendations regarding the timing and maximum doses of concomitant proton pump inhibitors and histamine H2-receptor antagonists in adults also apply to pediatric patients.
bIn 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 protease inhibitor (PI), atazanavir oral powder in a dosage of 150 mg (3 packets) once daily may be used with close HIV viral load monitoring.
Dosage of atazanavir capsules for the treatment of HIV-1 infection in pediatric patients 6 to <18 years of age is based on weight.1 (See Table 2.) Atazanavir capsules usually are used with low-dose ritonavir ( ritonavir-boosted atazanavir); administer atazanavir capsules and ritonavir simultaneously with food.1
Table 2: Dosage of Ritonavir-boosted Atazanavir Capsules for Antiretroviral-Naive and Antiretroviral-Experienced Pediatric Patients 6 to <18 Years of Agea , b1
Body Weight | Atazanavir Dosage (Capsules) | Ritonavir Dosage |
|---|
<15 kg | Capsules not recommended | |
≥15 to <35 kg | 200 mg once daily | 100 mg once daily |
≥35 kg | 300 mg once daily | 100 mg once daily |
aRecommendations regarding the timing and maximum doses of concomitant proton pump inhibitors and histamine H2-receptor antagonists in adults also apply to pediatric patients.
bIn antiretroviral-experienced patients, administer atazanavir capsules with ritonavir.
For the treatment of HIV-1 infection in antiretroviral-naïve adolescents ≥13 years of age who weigh ≥40 kg and are unable to tolerate ritonavir, the recommended dosage of atazanavir is 400 mg once daily.1
The fixed-combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®) is also used for the treatment of HIV-1 infection in pediatric patients; refer to the full prescribing information for dosage of the atazanavir/cobicistat in pediatric patients.10
Special Populations
Consult the product labeling of the combination preparation containing atazanavir and cobicistat (atazanavir/cobicistat; Evotaz®) for specific dosage recommendations in patients with renal or hepatic impairment, during pregnancy, or geriatric use.10
Hepatic Impairment
Do not use ritonavir-boosted atazanavir in patients with any degree of hepatic impairment.1
If unboosted atazanavir (i.e., without low-dose ritonavir) is used in treatment-naïve patients with hepatic impairment, the recommended dosage of atazanavir is 400 mg once daily in those with mild hepatic impairment (Child-Pugh class A) and 300 mg once daily in those with moderate hepatic impairment (Child-Pugh class B).1 Do not use unboosted atazanavir in patients with severe hepatic impairment (Child-Pugh class C).1
Renal Impairment
Dosage of atazanavir does not need to be adjusted in patients with renal impairment who are not undergoing hemodialysis.1
If ritonavir-boosted atazanavir is used in antiretroviral-naïve patients with end-stage renal disease undergoing hemodialysis, the recommended atazanavir dosage is 300 mg once daily given in conjunction with ritonavir 100 mg once daily.1
Use of atazanavir is not recommended in antiretroviral-experienced patients with HIV-1 infection who have end-stage renal disease and are undergoing hemodialysis.1
Pregnant and Postpartum Patients
Administer atazanavir with ritonavir if used during pregnancy.1 No dosage adjustments are necessary for postpartum patients; however, closely monitor patients for adverse events because atazanavir exposures could be increased during the first 2 months after delivery.1
For the treatment of HIV-1 infection in antiretroviral-naïve or antiretroviral-experienced pregnant patients, the recommended dosage of atazanavir is 300 mg once daily given in conjunction with ritonavir 100 mg once daily.1
If ritonavir-boosted atazanavir is used during the second or third trimester in antiretroviral-experienced pregnant women who are also receiving either a histamine H2-receptor antagonist or tenofovir DF, the recommended dosage of atazanavir is 400 mg once daily with ritonavir 100 mg once daily.1 Atazanavir is not recommended in antiretroviral-experienced pregnant patients during the second and third trimester who are taking receiving both a histamine H2-receptor antagonist and tenofovir DF.1
Geriatric Use
The manufacturer makes no specific dosage recommendations for geriatric patients.1 Exercise caution in administration and monitoring because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1
Cautions ⬆ ⬇
Contraindications
- History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to atazanavir sulfate or any ingredient in the formulation.1
- Concomitant use with drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A (CYP3A) or uridine diphosphate-glucuronosyltransferase (UGT) 1A1 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (see list below).1
- Concomitant use with drugs that are strong inducers of CYP3A when such use may lead to decreased atazanavir exposures resulting in possible loss of virologic response (see list below).1
- The following drugs are contraindicated with atazanavir (with or without ritonavir, unless otherwise noted): alfuzosin, amiodarone (with ritonavir), quinidine (with ritonavir), carbamazepine, phenobarbital, phenytoin, rifampin, apalutamide, encorafenib, irinotecan, ivosidenib, lurasidone (with ritonavir), pimozide, oral triazolam, oral midazolam, dihydroergotamine, ergotamine, ergonovine, methylergonovine, cisapride, elbasvir/grazoprevir, glecaprevir/pibrentasvir, St. John's wort ( Hypericum perforatum ), lovastatin, simvastatin, lomitapide, sildenafil for the treatment of pulmonary arterial hypertension (Revatio®), indinavir, and nevirapine.1
Warnings/Precautions
Severe Dermatologic Reactions
Rash (all grades, regardless of causality) occurred in 20% of patients receiving atazanavir in clinical studies.1 The median time to onset of rash was 7.3 weeks following initiation of atazanavir therapy and the median duration of rash was 1.4 weeks.1 The rashes were generally mild-to-moderate maculopapular skin eruptions, and atazanavir generally was continued without interruption in these patients.1
Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir.1 Discontinue atazanavir if severe rash develops.1
Cardiac Conduction Abnormalities
Abnormalities in atrioventricular (AV) conduction, including prolongation of the PR interval, have occurred in individuals receiving atazanavir.1 Cardiac conduction abnormalities generally are limited to first-degree AV block, but second-degree AV block and other conduction abnormalities have also been reported.1 Asymptomatic first-degree AV block was observed in 5.9 or 3-10.4% of patients in clinical trials receiving regimens that included atazanavir or comparator antiretrovirals (fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], nelfinavir, efavirenz), respectively.1
Because of limited clinical experience in patients with preexisting cardiac conduction abnormalities (e.g., marked first-degree AV block, second- or third-degree AV block), consider ECG monitoring in such patients.1
Chronic Kidney Disease
Chronic kidney disease has been reported in postmarketing experience in patients with HIV-1 infection treated with atazanavir (with or without ritonavir).1 Reports included granulomatous interstitial nephritis (proven by biopsy) associated with the deposition of atazanavir drug crystals in the renal parenchyma.1
Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease.1 Perform renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) in all patients prior to and during atazanavir treatment.1 Expert consultation is advised for patients who have confirmed renal laboratory abnormalities during atazanavir therapy.1 Consider discontinuation of atazanavir in patients with progressive kidney disease.1
Hyperbilirubinemia
Because atazanavir is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin), asymptomatic elevations in indirect (unconjugated) bilirubin occur in most patients receiving the drug.1 The hyperbilirubinemia is reversible upon atazanavir discontinuation.1 Assess hepatic transaminase elevations that occur with hyperbilirubinemia for alternative etiologies.1
Long-term safety data are not available for patients who experience persistent elevations in total bilirubin >5 times the upper limit of normal.1 If jaundice or scleral icterus that results from bilirubin elevations cause cosmetic concerns, alternative antiretroviral therapy can be considered; reduction of atazanavir dosage is not recommended (efficacy data not available for reduced dosages).1
Phenylketonuria
Advise individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) that atazanavir oral powder contains phenylalanine, a component of aspartame.1 Each packet of atazanavir oral powder (50 mg of atazanavir) contains 35 mg of phenylalanine.1 Atazanavir capsules do not contain phenylalanine.1
Hepatotoxicity
HIV-infected patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection or elevated serum transaminase concentrations prior to initiating atazanavir may be at increased risk for further transaminase elevations or hepatic decompensation.1
If atazanavir is used in patients with underlying hepatic disease (e.g., HBV or HCV coinfection), perform appropriate laboratory tests to evaluate hepatic function prior to and during atazanavir treatment.1
Nephrolithiasis and Cholelithiasis
There have been postmarketing reports of nephrolithiasis and cholelithiasis in patients with HIV-1 infection receiving atazanavir.1 Some patients required hospitalization for additional management or experienced complications.1
If signs or symptoms of nephrolithiasis or cholelithiasis occur, consider temporary interruption or discontinuance of atazanavir therapy.1
Drug Interactions
When ritonavir-boosted atazanavir is used, consider the cautions, precautions, contraindications, and drug interactions associated with atazanavir and ritonavir.1,10
Since ritonavir is a CYP3A inhibitor, initiation of ritonavir-boosted atazanavir in patients receiving drugs metabolized by CYP3A or initiation of drugs metabolized by CYP3A in patients already receiving ritonavir-boosted atazanavir, may increase plasma concentrations of the drugs metabolized by CYP3A.1,10 Initiation of drugs that inhibit CYP3A may increase concentrations of ritonavir-boosted atazanavir, and initiation of drugs that induce CYP3A may decrease concentrations of ritonavir-boosted atazanavir.1,10
Interactions with ritonavir-boosted atazanavir resulting in greater exposures of concomitant medications may lead to clinically important adverse effects (including severe, life-threatening, or fatal events).1 Some interactions may result in clinically important adverse effects due to greater exposures to ritonavir-boosted atazanavir, or loss of therapeutic effect of ritonavir-boosted atazanavir and development of resistance.1,10
Consider potential drug interactions prior to and during use of ritonavir-boosted atazanavir.1,10 Monitor patients for adverse reactions associated with other drugs used concomitantly with ritonavir-boosted atazanavir.1,10
Additional drug interactions may exist for the fixed-dose combination of atazanavir and cobicistat (Evotaz®).10 See the full prescribing information for drug interactions of this combination product.10
Hyperglycemic and Diabetogenic Effects
Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV protease inhibitors (PIs); diabetic ketoacidosis has also occurred.1 Initiation of antidiabetic therapy (e.g., insulin, oral antidiabetic agents) or dosage adjustment of existing antidiabetic therapy was required in some cases.1 A causal relationship between these events and PI therapy has not been established.1
Immune Reconstitution Syndrome
Patients receiving potent antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex, M. tuberculosis , cytomegalovirus, Pneumocystis jirovecii ); this may necessitate further evaluation and treatment.1
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is variable and can occur many months after initiation of antiretroviral therapy.1
Fat Redistribution
Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance was noted in patients receiving antiretroviral therapy.1
The mechanism and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1
Hemophilia A and B
Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in hemophilia A or B patients receiving HIV PIs.1 Increased hemostatic (e.g., antihemophilic factor) therapy was needed in some patients.1 In >50% of the reported cases, PI therapy was continued or reintroduced.1 A causal relationship has not been established.1
HIV Resistance
HIV-1 strains resistant to atazanavir may occur.1,9,11 Varying degrees of cross-resistance occur among the various HIV PIs.1 Resistance to atazanavir may not necessarily preclude subsequent use of other HIV PIs.1
Pharmacogenomics
In patients who are poor metabolizers of UGT1A1, consider an alternative agent to ritonavir-boosted atazanavir particularly if there are concerns of jaundice.12
Specific Populations
Pregnancy
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to atazanavir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1,202
Atazanavir has been evaluated in a limited number of women during pregnancy.1 Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate.1 No treatment-related malformations were observed in rats and rabbits using dosages that resulted in atazanavir exposures 0.7-1.2 times those reported with the usual human dosage of ritonavir-boosted atazanavir (300 mg of atazanavir once daily with ritonavir 100 mg once daily).1
Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing antiretroviral regimens during pregnancy (including 1037 first-trimester exposures), there was no difference in the rate of overall birth defects in those exposed to atazanavir-containing regimens compared with the estimated background risk of major birth defects (2-4% in the US population).1
Dosage adjustments may be necessary in certain pregnant women.1 Lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant patients receiving atazanavir in conjunction with NRTIs.1 Hyperbilirubinemia has occurred in pregnant patients receiving atazanavir.1 Advise pregnant patients of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.1
Closely monitor postpartum women for adverse effects during the first 2 months after delivery since atazanavir concentrations and areas under the concentration-time curve (AUC) may be increased approximately 28-43% during the postpartum period (4-12 weeks).1
Lactation
Atazanavir is distributed into human milk.1 It is not known whether atazanavir affects human milk production.1 Atazanavir is distributed into milk in rats and was associated with neonatal growth retardation that reversed after weaning.1
Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.1
Pediatric Use
Because of the risk of kernicterus, do not use atazanavir in neonates and infants <3 months of age.1 Safety, efficacy, and pharmacokinetic profile of atazanavir have not been established in infants <3 months of age.1 All contraindications, warnings, and precautions of atazanavir apply to pediatric patients.1
Safety, efficacy, and pharmacokinetic profile of atazanavir have been evaluated in pediatric patients ≥3 months of age weighing ≥5 kg.1 Adverse effects reported in pediatric patients 6 to <18 years of age receiving atazanavir capsules were generally similar to those reported in adults.1 Adverse effects reported in pediatric patients weighing ≥5 kg receiving atazanavir oral powder were generally similar to those reported in pediatric patients receiving the capsules.1
Geriatric Use
Experience in patients ≥65 years of age is insufficient to determine whether they respond differently to atazanavir than younger adults.1 Exercise caution in administration and monitoring because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease or drug therapy in geriatric patients.1
No clinically important differences in pharmacokinetics of atazanavir have been reported in those >65 years of age compared with younger adults.1
Hepatic Impairment
Dosage adjustments are necessary when atazanavir without ritonavir is used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Do not use unboosted atazanavir in patients with severe hepatic impairment (Child-Pugh class C).1
Do not use ritonavir-boosted atazanavir in patients with any degree of hepatic impairment.1
HIV-infected patients with chronic HBV or HCV coinfection and those with markedly increased transaminase concentrations prior to atazanavir therapy may be at increased risk for further elevations in hepatic enzyme concentrations or hepatic decompensation.1 Perform hepatic laboratory testing prior to and periodically during atazanavir therapy in such patients.1
Renal Impairment
Plasma concentrations of atazanavir are not markedly altered in individuals with severe renal impairment who are not undergoing hemodialysis.1 In patients with severe renal impairment on hemodialysis, 2.1% of the administered dose of atazanavir was removed in a 4-hour dialysis session.1
Ritonavir-boosted atazanavir can be used in antiretroviral-naïve patients with end-stage renal disease who are undergoing hemodialysis.1
Use of atazanavir is not recommended in antiretroviral-experienced patients with HIV-1 infection who have end-stage renal disease and are undergoing hemodialysis.1
Common Adverse Effects
The most common adverse effects (incidence ≥2%) are headache, nausea, jaundice/scleral icterus, abdominal pain, rash, vomiting, diarrhea, insomnia, peripheral neurologic symptoms, dizziness, myalgia, depression, and fever.1
Drug Interactions ⬆ ⬇
When atazanavir is used with ritonavir, consider the drug interactions associated with both atazanavir and ritonavir.1,209 The following drug interactions are based on studies using ritonavir-boosted atazanavir or unboosted atazanavir.1
Additional drug interactions may exist for the fixed-dose combination of atazanavir and cobicistat (Evotaz®).10 See the full prescribing information for drug interactions of this combination product.10
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Atazanavir is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 Atazanavir inhibits CYP3A and 2C8.1 Ritonavir inhibits CYP3A.1
Pharmacokinetic interactions are likely if ritonavir-boosted or unboosted atazanavir is used concomitantly with drugs that are inducers or substrates of CYP3A with possible alteration in metabolism and concentrations of atazanavir and/or the other drug.1 Concomitant use of ritonavir-boosted atazanavir with such drugs may lead to severe, life-threatening, or fatal events due to increased exposures of certain drugs; adverse effects due to increased exposures to ritonavir-boosted atazanavir; or loss of therapeutic effect and possible development of resistance to atazanavir.1
Pharmacokinetic interactions also are possible when unboosted atazanavir is used with CYP2C8 substrates.1 Use of atazanavir without ritonavir is not recommended when coadministered with drugs that are highly dependent on CYP2C8 metabolism and have narrow therapeutic indices (e.g., paclitaxel, repaglinide).1 When ritonavir-boosted atazanavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.1 Atazanavir is not expected to interact with CYP2C19, 2C9, 2D6, 2B6, 2A6, 1A2, or 2E1 substrates.1
Drugs Metabolized by Uridine diphosphate-glucuronosyltransferase 1A1
Atazanavir inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1; pharmacokinetic interactions are possible with drugs that are UGT 1A1 substrates (altered metabolism of the other drug).1
Drugs Affecting Gastric pH
Atazanavir solubility decreases as pH increases; reduced plasma concentrations of atazanavir are expected if drugs that affect gastric pH (e.g., antacids, buffered medications, histamine H2-receptor antagonists, proton-pump inhibitors) are used concomitantly.1
Acetaminophen
Pharmacokinetic interactions between acetaminophen and atazanavir are unlikely.1
Alfuzosin
Potential pharmacokinetic interactions exist with alfuzosin (increased alfuzosin plasma concentrations).1
Concomitant use of alfuzosin and atazanavir is contraindicated because increased alfuzosin concentrations may result in hypotension.1
Antiarrhythmic Agents
Amiodarone, Quinidine
Pharmacokinetic interaction exists if ritonavir-boosted atazanavir is used concomitantly with amiodarone or quinidine (increased plasma concentrations and systemic exposure of the antiarrhythmic agent).1 Concomitant use of ritonavir-boosted atazanavir with amiodarone or quinidine is contraindicated due to potential for serious or life-threatening adverse effects (e.g., cardiac arrhythmias).1
Bepridil, Systemic Lidocaine
Concomitant use of atazanavir with bepridil or systemic lidocaine may result in increased concentrations of the antiarrhythmic agent and serious and/or life-threatening adverse events, although, the interaction has not been studied.1 Exercise caution and monitor concentrations of the antiarrhythmic drugs if they are used concomitantly with atazanavir.1
Anticoagulants
Apixaban
Concomitant use of atazanavir with ritonavir (a strong CYP3A4 and P-glycoprotein [P-gp] inhibitor) and apixaban may result in increased exposure of apixaban and thus an increased risk of bleeding.1 Refer to the full prescribing information of apixaban for specific dosing recommendations.1
Concomitant use of atazanavir (without ritonavir) and apixaban may result in increased exposure of apixaban and thus an increased risk of bleeding.1 Monitor patients closely when apixaban is used concomitantly with atazanavir (without ritonavir).1
Dabigatran, Edoxaban
Concomitant use of atazanavir with ritonavir and dabigatran or edoxaban may result in increased exposure of the anticoagulant and thus an increased risk of bleeding.1 Refer to the full prescribing information of the anticoagulant for specific dosing recommendations.1
Rivaroxaban
Concomitant use of atazanavir with ritonavir (a strong CYP3A4 and P-gp inhibitor) and rivaroxaban is may result in increased exposure of the rivaroxaban and thus an increased risk of bleeding.1 Concomitant use of atazanavir with ritonavir and rivaroxaban is not recommended.1
Concomitant use of atazanavir (without ritonavir) and rivaroxaban may result in increased exposure of the rivaroxaban and thus an increased risk of bleeding.1 Monitor patients closely when rivaroxaban is used concomitantly with atazanavir (without ritonavir).1
Warfarin
Concomitant use of warfarin and atazanavir may result in increased plasma concentrations of warfarin and potential for serious and/or life- threatening bleeding, although, the interaction has not been studied.1
Monitor the international normalized ratio (INR).1
Anticonvulsants
Carbamazepine
Concomitant use of unboosted atazanavir and carbamazepine may decrease plasma concentrations of atazanavir and is not recommended.1
Concomitant use of ritonavir-boosted atazanavir and carbamazepine may decrease plasma concentrations of atazanavir and increase plasma concentrations of the anticonvulsant.1 If ritonavir-boosted atazanavir is initiated in a patient already receiving a stable carbamazepine dosage, reduction of the anticonvulsant dosage may be needed.1
Lamotrigine
Concomitant use of unboosted atazanavir and lamotrigine is not expected to affect lamotrigine concentrations; dosage adjustments are not needed if lamotrigine is used concomitantly with unboosted atazanavir.1
Concomitant use of ritonavir-boosted atazanavir and lamotrigine decreases lamotrigine plasma concentrations and may require dosage adjustments of lamotrigine.1
Phenobarbital, Phenytoin
Concomitant use of unboosted atazanavir and phenobarbital or phenytoin may decrease plasma concentrations of atazanavir and is not recommended.1
Concomitant use of ritonavir-boosted atazanavir and phenobarbital or phenytoin may decrease plasma concentrations of atazanavir and the anticonvulsant.1 If ritonavir-boosted atazanavir is used concomitantly with phenobarbital or phenytoin, adjustment of the anticonvulsant dosage may be needed.1
Antifungal Agents
Fluconazole
Pharmacokinetic interactions unlikely if atazanavir is used with fluconazole (no clinically important changes in plasma concentrations of atazanavir or fluconazole).1
Itraconazole
Possible pharmacokinetic interactions are possible if ritonavir-boosted atazanavir is used with itraconazole (increased plasma concentrations of itraconazole).1 Caution is advised if high itraconazole dosage (more than 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir.1
Ketoconazole
Pharmacokinetic interactions unlikely if unboosted atazanavir is used with ketoconazole (no clinically important changes in atazanavir plasma concentrations).1
Possible pharmacokinetic interaction if ketoconazole is used with ritonavir-boosted atazanavir (increased plasma concentrations of ketoconazole).1 Caution is advised if high ketoconazole dosage (more than 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir.1
Voriconazole
Pharmacokinetic interactions exist if voriconazole is used with ritonavir-boosted atazanavir (decreased atazanavir and voriconazole plasma concentrations in patients with a functional CYP2C19 allele; decreased atazanavir concentrations and increased voriconazole concentrations in patients without a functional CYP2C19 allele).1
Concomitant use of voriconazole and ritonavir-boosted atazanavir is not recommended unless potential benefits outweigh risks.1 If voriconazole is used concomitantly with ritonavir-boosted atazanavir, monitor patients for voriconazole-associated adverse effects and loss of voriconazole or atazanavir efficacy.1
Coadministration of voriconazole and atazanavir without ritonavir may affect atazanavir concentrations; however, no data are available.1
Antimycobacterial Agents
Rifabutin
Pharmacokinetic interactions exist if rifabutin is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased peak plasma concentration of rifabutin).1
If rifabutin is used concomitantly with atazanavir, a reduction in the dosage of the antimycobacterial agent of up to 75% (e.g., 150 mg once every other day or 3 times weekly) is recommended; increased monitoring for rifabutin-associated adverse effects (e.g., neutropenia) is warranted.1
Rifampin
Pharmacokinetic interactions exist if rifampin is used concomitantly with atazanavir (substantially decreased plasma concentrations of atazanavir) with possible loss of therapeutic effect of the antiretroviral agent and development of resistance.1
Concomitant use of rifampin and atazanavir is contraindicated.1
Antineoplastic Agents
Apalutamide
Coadministration of atazanavir (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors.1
Irinotecan
Pharmacokinetic interactions occur if irinotecan is used concomitantly with atazanavir.1 Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan leading to an increase in irinotecan toxicity.1
Concomitant use of irinotecan with atazanavir is contraindicated.1
Ivosidenib
Coadministration of ivosidenib (with or without ritonavir) is contraindicated due to the potential loss of virologic response and risk of serious adverse events such as QT interval prolongation.1
Paclitaxel
Possible pharmacokinetic interactions are possible if paclitaxel is used concomitantly with unboosted atazanavir (increased plasma concentrations of paclitaxel); concomitant use is not recommended.1
Clinically important interactions are not expected if paclitaxel is used concomitantly with ritonavir-boosted atazanavir.1
Antiplatelet Agents
Clopidogrel
Coadministration of atazanavir (with or without ritonavir) and clopidogrel is not recommended due to the potential reduction of antiplatelet activity of clopidogrel.1
Ticagrelor
Coadministration with ticagrelor is not recommended due to the potential increase in the risk of dyspnea, bleeding, and other adverse events associated with ticagrelor.1
Antipsychotic Agents
Lurasidone
Pharmacokinetic interactions may occur if lurasidone is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased lurasidone concentrations).1 There is potential for serious and/or life-threatening adverse effects if lurasidone is used concomitantly with ritonavir-boosted atazanavir.1
Concomitant use of ritonavir-boosted atazanavir and lurasidone is contraindicated.1
If concomitant use of unboosted atazanavir and lurasidone is necessary, reduce lurasidone dosa refer to the lurasidone prescribing information for specific information.1
Pimozide
Concomitant use of pimozide and atazanavir is contraindicated because of the potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1
Quetiapine
Pharmacokinetic interactions are expected if quetiapine is used concomitantly with atazanavir (increased quetiapine concentrations).1
In patients taking quetiapine, consider alternative antiretroviral therapy.1 If ritonavir-boosted atazanavir therapy is necessary in a patient receiving a stable dosage of quetiapine, reduce the quetiapine dosage to one-sixth of the original dosage and monitor the patient for quetiapine-associated adverse effects.1
If quetiapine therapy is necessary in a patient receiving ritonavir-boosted atazanavir, refer to the quetiapine prescribing information for initial dosage and titration of quetiapine.1
Antiretroviral Agents
HIV Entry and Fusion Inhibitors
Enfuvirtide
No in vitro evidence of antagonistic antiretroviral effects between atazanavir and enfuvirtide.1
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
There is no in vitro evidence of antagonistic antiretroviral effects between atazanavir and HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz, nevirapine).1
Efavirenz
Concomitant use of efavirenz and atazanavir results in substantially decreased plasma concentrations and AUC of atazanavir.1
If ritonavir-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naïve adults, a regimen of atazanavir 400 mg and ritonavir 100 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime) is recommended.1 Do not use ritonavir-boosted atazanavir concomitantly with efavirenz in antiretroviral-experienced patients.1
Nevirapine
Pharmacokinetic interaction exists if nevirapine is used concomitantly with ritonavir-boosted or unboosted atazanavir (substantially decreased atazanavir plasma concentrations and AUC with possible loss of therapeutic effect and development of resistance; increased nevirapine plasma concentrations and AUC and increased risk of nevirapine-associated adverse effects).1
Concomitant use of nevirapine and atazanavir is contraindicated.1
HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
In vitro studies indicate that antagonism does not occur between atazanavir and HIV-nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, lamivudine, tenofovir, zidovudine).1
Didanosine
Administration of buffered didanosine and atazanavir at the same time results in substantially decreased plasma concentrations and AUC of atazanavir.1 Administration of didanosine delayed-release capsules and atazanavir at the same time and with food results in decreased plasma concentrations and AUC of didanosine,1
Administer atazanavir (with food) at least 2 hours before or 1 hour after buffered didanosine; administer atazanavir and delayed-release didanosine preparations at different times.1
Lamivudine
No clinically important pharmacokinetic interactions were reported when atazanavir was used concomitantly with lamivudine.1
Tenofovir Disoproxil Fumarate
Concomitant use of tenofovir DF and atazanavir may decrease atazanavir plasma concentrations and AUC, and increase tenofovir plasma concentrations leading to possible increased risk of tenofovir-associated adverse effects, including renal disorders.1
Unboosted atazanavir should not be used concomitantly with tenofovir DF.1
If tenofovir DF and ritonavir-boosted atazanavir are used concomitantly, a regimen of atazanavir 300 mg, ritonavir 100 mg, and tenofovir DF 300 mg once daily with food is recommended.1 Monitor patients for tenofovir toxicity.1
If ritonavir-boosted atazanavir is used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, the recommended dosage of atazanavir is 400 mg in conjunction with ritonavir 100 mg given once daily.1
If an antiretroviral-experienced pregnant woman in the second or third trimester is receiving ritonavir-boosted atazanavir and either a histamine H2-receptor antagonist or tenofovir DF, the recommended dosage is atazanavir 400 mg and ritonavir 100 mg once daily with food.1 Dosage recommendations are not available for antiretroviral-experienced pregnant women receiving ritonavir-boosted atazanavir and both tenofovir DF and a histamine H2-receptor antagonist during the second and third trimesters.1
Zidovudine
No clinically important pharmacokinetic interactions were reported when atazanavir was used concomitantly with zidovudine.1
HIV Protease Inhibitors (PIs)
There is no in vitro evidence of antagonism between atazanavir and other HIV PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir).1
Indinavir
Both indinavir and atazanavir are associated with indirect (unconjugated) hyperbilirubinemia.1
Concomitant use of atazanavir and indinavir is contraindicated.1
Ritonavir
Pharmacokinetic interactions are possible if ritonavir is used concomitantly with atazanavir (increased plasma concentration and AUC of atazanavir).1 Low-dose ritonavir (100 mg once daily) is a pharmacokinetic enhancer (pharmacokinetic booster), and is used in conjunction with atazanavir for therapeutic advantage ( ritonavir- boosted atazanavir).1,200
If atazanavir is used in combination with ritonavir in adults, it is recommended that atazanavir 300 once daily is given with ritonavir 100 mg once daily with food.1
Refer to the full prescribing for ritonavir for drug interactions reported with ritonavir.209
Saquinavir
Pharmacokinetic interactions are possible if saquinavir is used concomitantly with atazanavir (increased plasma concentrations of saquinavir).1 In a clinical study, a regimen of atazanavir, saquinavir, tenofovir DF, and NRTIs did not provide adequate efficacy.1
Appropriate dosages for concomitant use of atazanavir and saquinavir (with or without low-dose ritonavir) with respect to safety and efficacy have not been established.1
Other PIs
Coadministration of atazanavir with ritonavir and an additional PI is expected to increase exposure to the other PI, although, no studies have been conducted.1 Such coadministration is not recommended.1
Atenolol
In a pharmacokinetic study evaluating concomitant use of atazanavir 400 mg once daily with atenolol 50 mg once daily, no clinically important pharmacokinetic interactions were observed.1
Benzodiazepines
Midazolam or Triazolam
Pharmacokinetic interactions may occur if midazolam or triazolam is used concomitantly with atazanavir (increased benzodiazepine plasma concentrations) and there is potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1
Concomitant use of oral midazolam or triazolam and atazanavir is contraindicated.1
Concomitant use of parenteral midazolam and atazanavir should be undertaken with caution and in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1 In addition, consider a reduced dosage of midazolam, especially if more than a single dose of midazolam is given.1
Bosentan
Possible pharmacokinetic interactions may occur if bosentan is used concomitantly with unboosted atazanavir (decreased atazanavir plasma concentrations).1 Do not use unboosted atazanavir concomitantly with bosentan.1
In adults who have been receiving ritonavir-boosted atazanavir for at least 10 days, initiate bosentan at a dosage of 62.5 mg once daily or every other day based on individual tolerability.1
In patients who have been receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted atazanavir; after at least 10 days of ritonavir-boosted atazanavir therapy, resume bosentan at a dosage of 62.5 mg once daily or every other day based on individual tolerability.1
Calcium-channel Blocking Agents
Possible pharmacokinetic interactions may occur if certain calcium-channel blocking agents (felodipine, nicardipine, nifedipine, verapamil) are used concomitantly with atazanavir (increased concentrations of the calcium-channel blocking agent).1 Use with caution; dosage titration of the calcium-channel blocking agent should be considered and ECG monitoring is recommended.1
Pharmacokinetic interactions may occur if diltiazem is used concomitantly with atazanavir (increased diltiazem plasma concentrations).1 Use with caution.1 If diltiazem is used concomitantly with atazanavir, consider a 50% reduction in diltiazem dosa ECG monitoring is recommended.1 Concomitant use of diltiazem and atazanavir with ritonavir has not been studied.1
Colchicine
Pharmacokinetic interactions may occur if colchicine is used concomitantly with atazanavir (increased colchicine plasma concentrations).1
Concomitant use of colchicine and atazanavir is not recommended in patients with renal or hepatic impairment.1
When colchicine is used for treatment of gout flares in patients receiving atazanavir, administer an initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.1
When colchicine is used for prophylaxis of gout flares in patients receiving atazanavir, reduce colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily, or reduce to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1
When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving atazanavir, use a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily).1
Corticosteroids
Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of atazanavir and development of resistance.1 Alternative corticosteroids should be considered.1 Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particluarly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.1 Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects.1
Co-trimoxazole
Clinically important interactions between co-trimoxazole and atazanavir are unlikely.1
Dapsone
Clinically important interactions between dapsone and atazanavir are unlikely.1
Ergot Alkaloids
Concomitant use of ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine) and atazanavir is contraindicated because of possible increased concentrations of the ergot alkaloids and potential for serious adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues).1
Estrogens and Progestins
Pharmacokinetic interactions may occur if oral contraceptives containing ethinyl estradiol and norgestimate or norethindrone are used concomitantly with atazanavir (increased or decreased plasma concentrations of ethinyl estradiol; increased plasma concentrations of the progestin).1 Use caution if considering concomitant use of these oral contraceptives with atazanavir (with or without ritonavir).1
If ritonavir-boosted atazanavir is used with an oral contraceptive, use of an oral contraceptive preparation containing at least 35 mcg of ethinyl estradiol is recommended.1 If unboosted atazanavir is used with an oral contraceptive, use of an oral contraceptive preparation containing no more than 30 mcg of ethinyl estradiol is recommended.1
Data are not available regarding use of other hormonal contraceptives (e.g., transdermal contraceptive preparations, contraceptive vaginal ring, injectable contraceptive preparations, oral contraceptive preparations containing progestins other than norgestimate or norethindrone, or oral contraceptive preparations containing less than 25 mcg of ethinyl estradiol) in patients receiving ritonavir-boosted or unboosted atazanavir.1 Alternative methods of contraception are recommended.1
Fluticasone
Pharmacokinetic interactions may occur if fluticasone (orally inhaled or intranasal) is used concomitantly with unboosted atazanavir (increased fluticasone concentrations).1 Use with caution; consider alternatives, especially when long-term use of the corticosteroid is anticipated.1
Concomitant use of fluticasone (orally inhaled or intranasal) and ritonavir-boosted atazanavir may increase fluticasone concentrations and cause significantly reduced serum cortisol concentrations; adrenal insufficiency and Cushing's syndrome have been reported in postmarketing experience.1 Coadministration of fluticasone and ritonavir-boosted atazanavir is not recommended unless the potential benefits outweigh the risks of systemic corticosteroid adverse effects.1
GI Drugs
Antacids
Potential pharmacokinetic interactions exist if antacids or buffered medications are given concomitantly with atazanavir (decreased plasma concentrations of atazanavir).1 Administer atazanavir 2 hours before or 1 hour after antacids or buffered medications.1
Cisapride
Concomitant use of cisapride and atazanavir is contraindicated because of possible increased cisapride plasma concentrations and potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1
Histamine H2-receptor Antagonists
Atazanavir 400 mg once daily administered simultaneously with famotidine 40 mg twice daily results in a substantial decrease in plasma concentrations of atazanavir and possible loss of the therapeutic effect of the antiretroviral agent and development of resistance.1
If ritonavir-boosted atazanavir is used in antiretroviral-naïve adults receiving a histamine H2-receptor antagonist, a regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily with food is recommended.1 Atazanavir and ritonavir should be given simultaneously with and/or ≥10 hours after the histamine H2-receptor antagonist.1 Dosage of the histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent).1 In antiretroviral-experienced patients, dosage of the histamine H2-receptor antagonist should not exceed famotidine 20 mg twice daily (or equivalent).1
If unboosted atazanavir (i.e., without low-dose ritonavir) is used in antiretroviral-naïve adults receiving a histamine H2-receptor antagonist, a regimen of 400 mg of atazanavir once daily with food should be used and the dose given ≥2 hours before and ≥10 hours after a dose of the histamine H2-receptor antagonist.1 Dosage of the histamine H2-receptor antagonist should not exceed famotidine 40 mg daily (or equivalent) and a single dose of the histamine H2-receptor antagonist should not exceed famotidine 20 mg (or equivalent) in these patients.1
If ritonavir-boosted atazanavir is used in antiretroviral-experienced adults receiving a histamine H2-receptor antagonist, a regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily (all as a single dose with food) is recommended.1 Atazanavir and ritonavir should be given simultaneously with and/or ≥10 hours after the histamine H2-receptor antagonist.1 Dosage of the histamine H2-receptor antagonist should not exceed famotidine 20 mg twice daily (or equivalent).1
If ritonavir-boosted atazanavir is used in an antiretroviral regimen that includes tenofovir DF and a histamine H2-receptor antagonist used concomitantly, the recommended dosage for antiretroviral-experienced adults is atazanavir 400 mg and ritonavir 100 mg once daily (all as a single dose with food).1
If ritonavir-boosted atazanavir is used in an antiretroviral-experienced pregnant woman in the second or third trimester of pregnancy who is receiving a histamine H2-receptor antagonist, the dosage is 400 mg of atazanavir once daily with ritonavir 100 mg once daily.1 Atazanavir is not recommended in pregnant women during the second and third trimester receiving both a histamine H2-receptor antagonist and tenofovir in conjunction with atazanavir.1
Proton-pump Inhibitors
Concomitant use of omeprazole 40 mg once daily and ritonavir-boosted or unboosted atazanavir results in substantially decreased plasma concentrations of atazanavir and may result in loss of the therapeutic effect of the antiretroviral agent and development of resistance.1
If ritonavir-boosted atazanavir is used in antiretroviral-naïve adults receiving a proton-pump inhibitor, a regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily with food is recommended.1 Administer the proton-pump inhibitor approximately 12 hours before ritonavir-boosted atazanavir; dosage of the proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent).1
Do not use proton-pump inhibitors in antiretroviral-experienced patients receiving atazanavir.1
Gonadotropin-releasing Hormone Receptor (GnRH) Antagonists
Elagolix
Coadministration of elagolix and atazanavir (with or without ritonavir) is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix.1
In the event coadministration is necessary, limit concomitant use of elagolix 200 mg twice daily with atazanavir (with or without ritonavir) for up to 1 month or limit concomitant use of elagolix 150 mg once daily with atazanavir (with or without ritonavir) for up to 6 months and monitor virologic response.1
Hepatitis C Virus (HCV) Antivirals
Elbasvir and Grazoprevir
Concomitant use of atazanavir and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) results in increased grazoprevir concentrations.1 Increased grazoprevir concentrations may increase the risk of ALT elevations.1
Concomitant use of elbasvir/grazoprevir and atazanavir is contraindicated.1
Glecaprevir and Pibrentasvir
Concomitant use of atazanavir and the fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) results in increased glecaprevir and pibrentasvir concentrations and may increase the risk of ALT elevations.1
Concomitant use of glecaprevir/pibrentasvir and atazanavir is contraindicated.1
Voxilaprevir, Sofosbuvir, and Velpatasvir
Concomitant use of atazanavir and the fixed combination of voxilaprevir, sofosbuvir, and velpatasvir (voxilaprevir/sofosbuvir/velpatasvir) results in increased voxilaprevir concentrations.1
Concomitant use of voxilaprevir/sofosbuvir/velpatasvir and atazanavir is not recommended.1
HMG-CoA Reductase Inhibitors (Statins)
Concomitant use of atazanavir and certain statins (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin) may increase plasma concentrations of statins and increase the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.1
Atorvastatin
If atorvastatin is used concomitantly with atazanavir, titrate atorvastatin dosage carefully and use the lowest necessary dosage.1
Lovastatin
Concomitant use of lovastatin with atazanavir is contraindicated.1
Rosuvastatin
If rosuvastatin is used concomitantly with atazanavir, rosuvastatin dosage should not exceed 10 mg daily.1 Titrate rosuvastatin dosage carefully and use the lowest necessary dosage.1
Simvastatin
Concomitant use of simvastatin with atazanavir is contraindicated.1
Immunosuppressive Agents
Pharmacokinetic interactions may occur with certain immunosuppressive agents (cyclosporine, sirolimus, tacrolimus); increased plasma concentrations of the immunosuppressive agent expected.1
If cyclosporine, sirolimus, or tacrolimus is used concomitantly with atazanavir, monitor plasma concentrations of the immunosuppressive agent.1
Kinase Inhibitors
Fostamatinib
When coadministering fostamatinib with atazanavir (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia.1 Fostamatinib dose reduction may be required.1
Lomitapide
Concomitant use of atazanavir and lomitapide increases plasma lomitapide concentrations via CYP3A4 inhibition.1
Concomitant use is contraindicated due to potential for hepatotoxicity and significantly increased transaminases.1
Macrolides
Azithromycin
Clinically important interactions between azithromycin and atazanavir are unlikely.1
Clarithromycin
Pharmacokinetic interactions may occur if clarithromycin is used concomitantly with atazanavir (increased plasma concentrations of clarithromycin, decreased plasma concentrations of 14-hydroxyclarithromycin, increased plasma concentrations of atazanavir).1 Because increased clarithromycin concentrations may result in prolongation of the corrected QT (QTc) interval, consider a 50% reduction in clarithromycin dosage in patients receiving atazanavir.1 Consider alternative anti-infective therapy for indications other than infections due to Mycobacterium avium complex .1 Concomitant use of atazanavir with ritonavir and clarithromycin has not been studied.1
Erythromycin
Clinically important interactions between atazanavir and erythromycin are unlikely.1
Opioids
Buprenorphine
Pharmacokinetic interactions may occur if buprenorphine is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased buprenorphine and norbuprenorphine concentrations).1
Because of the potential for decreased atazanavir plasma concentrations, do not use buprenorphine concomitantly with unboosted atazanavir.1
If buprenorphine is used concomitantly with ritonavir-boosted atazanavir, monitor the patient for sedation and adverse cognitive effects and consider a reduced dosage of buprenorphine.1
Methadone
Clinically significant pharmacokinetic interactions between methadone and unboosted atazanavir are unlikely.1
Phosphodiesterase Type 5 Inhibitors
Concomitant use of atazanavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) is expected to result in substantially increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects associated with these agents (e.g., hypotension, syncope, visual disturbances, priapism).1
Sildenafil
Concomitant use of sildenafil (Revatio®) for treatment of pulmonary arterial hypertension (PAH) is contraindicated in patients receiving atazanavir.1 Safe and effective dosages for concomitant use have not been established.1
If sildenafil is used for treatment of erectile dysfunction in patients receiving atazanavir, use a reduced sildenafil dosage of 25 mg once every 48 hours and monitor the patient closely for sildenafil-related adverse effects.1
Tadalafil
If tadalafil is indicated for treatment of PAH in patients who have been receiving atazanavir (with or without ritonavir)for at least 1 week, initiate tadalafil at a dosage of 20 mg once daily and, if tolerated, increase dosage to 40 mg once daily.1 Do not initiate atazanavir in patients receiving tadalafil for treatment of PAH; discontinue tadalafil for at least 24 hours prior to initiating atazanavir (with or without ritonavir).1 After at least 1 week, resume tadalafil at a dosage of 20 mg once daily, and if tolerated, increase dosage to 40 mg once daily.1
If tadalafil is used for treatment of erectile dysfunction in patients receiving atazanavir, tadalafil dosage should not exceed 10 mg once every 72 hours; closely monitor the patient for tadalafil-related adverse effects.1
Vardenafil
If vardenafil is used for treatment of erectile dysfunction in patients receiving unboosted atazanavir, vardenafil dosage should not exceed 2.5 mg once every 24 hours.1 Use the drugs concomitantly with caution and monitor the patient for vardenafil-related adverse effects.1
If vardenafil is used for treatment of erectile dysfunction in patients receiving ritonavir-boosted atazanavir, vardenafil dosage should not exceed 2.5 mg once every 72 hours.1 Use the drugs concomitantly with caution and monitor the patient for vardenafil-related adverse effects.1
Repaglinide
Possible pharmacokinetic interactions if repaglinide is used concomitantly with unboosted atazanavir (increased concentrations of repaglinide); concomitant use is not recommended.1 Clinically important interactions are not expected if repaglinide is used with ritonavir-boosted atazanavir.1
Salmeterol
Pharmacokinetic interactions may occur if salmeterol is used concomitantly with atazanavir (increased salmeterol concentrations) resulting in increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1
Concomitant use of salmeterol and atazanavir is not recommended.1
St. John's Wort
Concomitant use of atazanavir and St. John's wort ( Hypericum perforatum ) may result in decreased atazanavir plasma concentrations leading to potential loss of therapeutic effect and development of resistance.1 Concomitant use of St. John's wort and atazanavir is contraindicated.1
Trazodone
Possible pharmacokinetic interactions if trazodone is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased plasma concentrations of trazodone);1 nausea, dizziness, hypotension, and syncope have been reported when trazodone was used with ritonavir.1 Caution is advised; consider a lower dosage of trazodone in patients receiving concomitant atazanavir.1
Tricyclic Antidepressants
Potential pharmacokinetic interactions may occur if a tricyclic antidepressant is used concomitantly with atazanavir (increased plasma concentration of the tricyclic antidepressant), resulting in potentially serious and/or life-threatening adverse effects.1 Monitor plasma concentrations of the tricyclic antidepressants if used concomitantly with atazanavir.1
Other Information ⬆ ⬇
Description
Atazanavir, a synthetic azapeptide, inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with HIV protease.1 During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes.1,2 By interfering with the formation of these essential proteins and enzymes, atazanavir blocks maturation of the virus and causes formation of nonfunctional, immature noninfectious virions.1,2 Atazanavir has some activity in vitro against HIV-2.1
HIV-1 strains with reduced susceptibility to atazanavir can be produced in vitro and strains with reduced susceptibility to atazanavir have emerged during therapy with the drug.1,11 Varying degrees of cross-resistance occur among HIV protease inhibitors (PIs).1 Some HIV-1 isolates resistant to atazanavir may be cross-resistant to other HIV PIs (e.g., amprenavir [active metabolite of fosamprenavir], indinavir, lopinavir, nelfinavir, ritonavir, saquinavir).1
Atazanavir is extensively metabolized by the hepatic cytochrome P-450 (CYP) enzyme system, principally CYP3A, and usually is administered with a pharmacokinetic enhancer (pharmacokinetic booster) to improve the pharmacokinetic profile of the drug.1 10 200 Atazanavir may be administered with low-dose ritonavir ( ritonavir-boosted atazanavir) or with cobicistat ( cobicistat-boosted atazanavir).1 10 200 Because ritonavir and cobicistat are potent inhibitors of CYP3A, concomitant administration with atazanavir results in increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the HIV PI.1 10 200 The antiretroviral activity of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir is due to atazanavir.1 10
Atazanavir is rapidly absorbed following oral administration.1 Peak plasma concentrations of atazanavir are attained in approximately 2.5 hours.1 When unboosted atazanavir is used, the drug demonstrates nonlinear pharmacokinetics with greater than dose- proportional increases in plasma concentrations and AUC.1 Steady-state atazanavir concentrations following administration of unboosted atazanavir are attained between days 4-8, with an accumulation of approximately 2.3-fold.1
Food increases bioavailability and reduces pharmacokinetic variability of oral atazanavir.1 Administration of a single 400-mg dose of unboosted atazanavir with a light meal increases the AUC by 70% and increases peak plasma concentrations by 57% compared with fasting; administration with a high-fat meal increases the AUC by 35%, but does not increase peak plasma concentrations.1 Administration of a single dose of ritonavir-boosted atazanavir (300 mg of atazanavir with 100 mg of ritonavir) with a light meal increases atazanavir AUC by 33% and increases peak plasma concentrations by 40% compared with fasting; administration with a high-fat meal does not affect atazanavir AUC.1
Atazanavir is 86% bound to serum proteins; binding is independent of concentration.1 Atazanavir binds to both α-1-acid glycoprotein (89%) and albumin (86%).1 Low concentrations of atazanavir are attained in CSF and semen after oral administration.1 Atazanavir is distributed into fetal umbilical cord blood in low concentrations.1 When ritonavir-boosted atazanavir was used in pregnant women, atazanavir concentrations in cord blood were approximately 12-19% of maternal plasma concentrations at delivery.1
Atazanavir is extensively metabolized and eliminated in the liver.1 CYP3A is involved in metabolism of the drug.1 Following administration of unboosted atazanavir, approximately 79% of a dose is eliminated in feces and 13% is eliminated in urine as metabolites and unchanged drug.1 The mean half-life of atazanavir is 6.5-7.9 hours at steady state in individuals receiving unboosted atazanavir (400 mg of atazanavir once daily) given with a light meal.1 Following administration of ritonavir-boosted atazanavir, the mean half-life of atazanavir at steady state is 8.6-18.1 hours.1
Following administration of unboosted atazanavir, the AUC of the drug is increased 42% in adults with moderate to severe hepatic impairment (Child-Pugh class B and C) compared with healthy adults.1 The half-life of the drug is 12.1 hours in those with moderate to severe hepatic impairment.1
Advice to Patients
- Inform patients of the importance of compliance with human immunodeficiency virus (HIV) therapy and remaining under the care of a clinician.1 Advise patients to take the antiretroviral regimen as prescribed and not alter or discontinue the regimen without consulting a clinician.1
- Inform patients that atazanavir is used in conjunction with other antiretrovirals for the treatment of HIV infection.1
- Advise patients to take atazanavir with food daily and take other concomitant antiretroviral therapy as prescribed.1
- If a dose of atazanavir is missed, advise patients to take the dose as soon as it is remembered and take the next dose at the regularly scheduled time; if a dose is skipped, advise patients to not double the next dose.1
- If atazanavir oral powder is used, advise caregivers to carefully follow mixing and administration instructions provided by the manufacturer.1
- If atazanavir oral powder is used, advise caregivers of patients with phenylketonuria that atazanavir oral powder contains phenylalanine.1
- Advise patients that ECG changes (PR prolongation) have occurred during atazanavir therapy and to consult a clinician if dizziness or lightheadedness occurs.1
- Inform patients that asymptomatic increases in indirect bilirubin that may be accompanied by yellowing of the skin or whites of the eyes have occurred in patients receiving atazanavir; inform patients that alternative antiretroviral therapy can be considered after discussion with a clinician.1
- Inform patients that atazanavir therapy may lead to the development of chronic kidney disease, and to maintain adequate hydration during treatment.1
- Advise patients to inform their clinician immediately of any signs or symptoms of infection, because in some patients with advanced HIV infection, signs and symptoms of inflammation may occur soon after starting antiretroviral therapy.1
- Inform patients that redistribution/accumulation of body fat may occur with antiretroviral therapy, although, long-term health effects are unknown.1
- Advise patients that mild rash and severe skin reactions, including Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, have occurred during atazanavir therapy.1 Inform patients to immediately discontinue atazanavir and contact a clinician if manifestations of severe skin reactions or hypersensitivity occur (e.g., severe rash or rash accompanied by shortness of breath, fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema).1
- Advise patients that kidney stones and/or gallstones have been reported and some patients required hospitalization or experienced complications, and that discontinuance of the drug may be necessary.1
- Advise women to inform their clinician if they are or plan to become pregnant.1 Advise women that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to atazanavir during pregnancy.1
- Advise women to inform their clinician if they plan to breast-feed.1 Advise HIV-infected women not to breast-feed because of the risk of HIV transmission to the baby.1
- Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), and any concomitant illnesses.1
- Advise patients of other important precautionary information.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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 |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions December 11, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
1. Bristol-Myers Squibb. Reyataz® (atazanavir sulfate) capsules and oral powder prescribing information. Princeton, NJ; 2023 Nov.
2. Sanne I, Piliero P, Squires K et al. Results of a phase 2 clinical trial at 48 weeks (A1424-007); a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr . 2003; 32:18-29. [PubMed 12514410]
3. Haas DW, Zala C, Schrader S et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS . 2003; 17:1339-49. [PubMed 12799555]
4. Piliero PJ. Atazanavir: a novel HIV-1 protease inhibitor. Expert Opin Investig Drugs . 2002; 11:1295-1301 [PubMed 12225250]
7. Squires K, Lazzarin A, Gatell JM et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr . 2004; 36:1011-9. [PubMed 15247553]
8. Wood R, Phanuphak P, Cahn P et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr . 2004; 36:684-92. [PubMed 15167287]
9. Murphy RL. Reviving protease inhibitors: new data and more options. J Acquir Immune Defic Syndr . 2003; 33(suppl 1):S43-52. [PubMed 12946064]
10. Bristol-Myers Squibb, Evotaz® (atazanavir and cobicistat) tablet prescribing information. Princeton, NJ; 2020 July.
11. Colonno RJ, Thiry A, Limoli K et al. Activities of atazanavir 9BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother . 2003; 47:1324-3. [PubMed 12654666]
12. Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin Pharmacol Ther. 2016;99(4):363-369.
14. Goldsmith DR, Perry CM. Atazanavir. Drugs . 2003; 63:1679-93. [PubMed 12904086]
28. Molina JM, Andrade-Villanueva J, Echevarria J et al. Once-daily atazanavir/ritonavir versus twice daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1 infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet . 2008; 372:646-55. [PubMed 18722869]
29. Molina JM, Andrade-Villanueva J, Echevarria J et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr . 2010; 53:323-32. [PubMed 20032785]
30. Johnson M, Grinsztejn B, Rodriguez C et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS . 2005; 19:685-94. [PubMed 15821394]
31. Johnson M, Grinsztejn B, Rodriguez C et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS . 2006; 20:711-8. [PubMed 16514301]
35. Murphy RL, Sanne I, Cahn P et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS . 2003; 17:2603-14. [PubMed 14685054]
198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From HHS AIDS Information (AIDSinfo) website. [Web]
199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]
200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
203. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the United States - 2021 update: a clinical practice guideline (Accessed August 15, 2022). Centers for Disease Control and Prevention website.
209. Abbvie, Inc. Norvir® (ritonavir) tablets, oral powder, and oral solution prescribing information. North Chicago, IL; 2021 Dec.