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atazanavir sulfate 200 mg cap generic reyataz

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Uses

Treatment of HIV Infection

Atazanavir with low-dose ritonavir (ritonavir-boosted atazanavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults, adolescents, and children 3 months of age or older. 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.

Atazanavir with cobicistat (cobicistat-boosted atazanavir) is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naive or treatment-experienced adults. When cobicistat-boosted atazanavir is included in an antiretroviral regimen, the fixed-combination preparation containing both drugs (atazanavir/cobicistat) can be used or, alternatively, single-entity atazanavir and single-entity cobicistat can be administered at the same time. The manufacturer of atazanavir/cobicistat states that use of the fixed combination in antiretroviral-experienced patients should be guided by the number of baseline primary HIV PI resistance substitutions. Estimated creatinine clearance should be assessed in all patients prior to initiation of cobicistat-boosted atazanavir (administered as fixed combination atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat).(See Renal Effects under Cautions: Warnings/Precautions.)

Although unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) has been used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naive adults and adolescents 13 years of age or older who cannot tolerate ritonavir, unboosted atazanavir is not included in preferred or alternative regimens recommended for initial treatment in antiretroviral-naive patients because it is less potent than boosted atazanavir. In addition, unboosted atazanavir should not be used in antiretroviral-experienced patients with prior virologic failure.

Atazanavir usually is used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). A pharmacokinetic enhancer (pharmacokinetic booster) is necessary to improve the pharmacokinetic profile of atazanavir. Although concomitant use of low-dose ritonavir or cobicistat with atazanavir increases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the HIV PI, these pharmacokinetic enhancers are not interchangeable in antiretroviral regimens since low-dose ritonavir and cobicistat have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions. In addition, although ritonavir-boosted atazanavir may be used in adults, adolescents, and children 3 months of age or older, efficacy and safety of cobicistat-boosted atazanavir (administered as fixed-combination atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat) have been established only in adults.

Ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir should always be used in conjunction with one or more antiretroviral agents and should not be used alone for treatment of HIV-1 infection.Ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir usually is used in an HIV PI-based regimen that includes 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

For initial treatment in HIV-infected adults and adolescents who are antiretroviral-naive, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that ritonavir-boosted atazanavir in conjunction with tenofovir alafenamide fumarate (TAF) and emtricitabine or ritonavir-boosted atazanavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are considered alternative PI-based regimens. These experts state that cobicistat-boosted atazanavir in conjunction with TAF and emtricitabine or cobicistat-boosted atazanavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative PI-based regimens for initial treatment in antiretroviral-naive adults and adolescents. In addition, these experts also state that ritonavir-boosted atazanavir or cobicistat-boosted atazanavir in conjunction with abacavir and lamivudine are other regimen options for initial treatment in antiretroviral-naive patients when recommended or alternative regimens cannot be used, but should be used only in patients with baseline plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.

The HHS panel states that unboosted atazanavir (i.e., atazanavir without low-dose ritonavir or cobicistat) is not recommended for initial treatment because it is less potent than boosted atazanavir.

Clinical Experience

In an open-label, noninferiority study in antiretroviral-naive 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. 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. 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.

Safety and efficacy of cobicistat-boosted atazanavir have been evaluated in a randomized, double-blind, active-controlled study in 692 treatment-naive HIV-infected adults (mean age 37 years, 83% male, 60% white, mean baseline plasma HIV-1 RNA level 4.8 log10 copies/mL, mean baseline CD4 T-cell count 352 cells/mm). All patients had a baseline estimated creatinine clearance greater than 70 mL/minute and were randomized in a 1:1 ratio to receive cobicistat-boosted atazanavir (single-entity atazanavir 300 mg once daily administered with single-entity cobicistat 150 mg once daily) or ritonavir-boosted atazanavir (single-entity atazanavir 300 mg once daily administered with single-entity ritonavir 100 mg once daily). All patients also received concomitant treatment with tenofovir DF and emtricitabine (administered as fixed-combination tablets containing tenofovir DF 300 mg and emtricitabine 200 mg once daily). At week 48, 85% of patients receiving the regimen that included cobicistat-boosted atazanavir and 87% of those receiving the regimen that included ritonavir-boosted atazanavir had plasma HIV-1 RNA levels less than 50 copies/mL. In addition, the mean increase from baseline in CD4 T-cell counts at week 48 was 213 cells/mm in those receiving cobicistat-boosted atazanavir and 219 cells/mm in those receiving ritonavir-boosted atazanavir.

Safety and efficacy of unboosted atazanavir used in conjunction with other antiretroviral agents have been evaluated in 2 randomized multicenter studies in antiretroviral-naive adults (study AI424-034 and AI424-008). 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/mm) 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). 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. 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. 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. At week 48, increases in CD4 T-cell counts were greater in patients receiving the regimen that included atazanavir (increase of 176 cells/mm) than in those receiving the regimen that included efavirenz (increase of 160 cells/mm).

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/mm) 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). In this study, an initial regimen of atazanavir, lamivudine, and stavudine was as effective as an initial regimen of nelfinavir, lamivudine, and stavudine. 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. 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/mm, respectively). 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.

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. Use of these regimens in antiretroviral-experienced patients should be guided by the number of baseline primary PI resistance substitutions. Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is not recommended in antiretroviral-experienced patients with prior virologic failure.

Clinical Experience

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. 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. 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. 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. 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. 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.(See Saquinavir under Antiretroviral Agents: HIV Protease Inhibitors, in Drug Interactions.) 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. This was similar to 46 or 36%, respectively, of patient receiving a regimen containing lopinavir/ritonavir.

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. 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. 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. 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. 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.

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.

For initial treatment in HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or integrase strand transfer inhibitor (INSTI) in conjunction with 2 NRTIs (dual NRTIs). These experts state that ritonavir-boosted atazanavir in conjunction with 2 NRTIs is a preferred regimen for initial treatment in children 3 years of age or older and an alternative regimen for initial treatment in children 3 months to less than 3 years of age weighing 5-25 kg. The panel states that unboosted atazanavir (i.e., without low-dose ritonavir) is not recommended for initial treatment in pediatric patients.

Efficacy and safety of cobicistat-boosted atazanavir (administered as atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat) have not been established in patients younger than 18 years of age.

For further information on treatment of HIV infection in pediatric patients,

Clinical Experience

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 18 years of age (PACTG 1020A). At week 96, 51 or 47% of antiretroviral-naive children and 34 or 24% of antiretroviral-experienced children had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively. At week 96, the median increase in absolute CD4 T-cell count from baseline was 335 cells/mm in antiretroviral-naive children and 220 cells/mm in antiretroviral-experienced children.

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). 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); those weighing 10 kg to less than 15 kg received 200 mg of atazanavir (oral powder) and 80 mg of ritonavir (oral solution); those weighing 15 kg to less than 25 kg received 250 mg of atazanavir (oral powder) and 80 mg of ritonavir (oral solution); and those weighing 25 kg to less than 35 kg received 300 mg of atazanavir (oral powder) and 100 of ritonavir. At 48 weeks, 79 or 54% of antiretroviral-naive children and 62 or 50% of antiretroviral-experienced children had achieved plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively. The median increase in absolute CD4 T-cell count from baseline was 215 cells/mm in antiretroviral-naive children and 133 cells/mm in antiretroviral-experienced children; the median increase in T-cell percentage from baseline was 6 and 4%, respectively.

Postexposure Prophylaxis following Occupational Exposure to HIV

Ritonavir-boosted atazanavir is used in conjunction with 2 NRTIs 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.

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).Ritonavir-boosted atazanavir and 2 NRTIs is one of several alternative regimens recommended when the preferred regimen cannot be used. The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

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. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Ritonavir-boosted atazanavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals who have had exposure to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

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

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 if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

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

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

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

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

Ritonavir-boostedAtazanavir or Unboosted Atazanavir

When ritonavir-boosted atazanavir is used, single-entity atazanavir is administered as capsules or oral powder with single-entity ritonavir capsules, tablets, or oral solution.

Capsules

Atazanavir capsules should be swallowed whole and should not be opened.

Capsules are used in adults, adolescents, and pediatric patients 6 years of age or older.

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 or older weighing 40 kg or more who are unable to tolerate ritonavir.

Atazanavir capsules should be stored at 25°C, but may be exposed to 15-30°C.

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.

The oral powder can be used in pediatric patients 3 months of age or older weighing 5 kg or more.

Atazanavir oral powder must be administered with low-dose ritonavir (ritonavir-boosted atazanavir). The dose of low-dose ritonavir should be administered immediately following the atazanavir dose.

The oral powder should be stored in the original packet at less than 30°C and should not be opened until ready to use. The oral powder preferably should be mixed with food (e.g., applesauce, yogurt), but may be mixed with a beverage (e.g., milk, infant formula, water) for infants who are able to drink from a cup. For infants younger than 6 months of age who cannot eat solid food or drink from a cup, the oral powder may be mixed with infant formula and administered using an oral dosing syringe. Administration using an infant bottle is not recommended because the full atazanavir dose may not be delivered.

The entire dose should be administered within 1 hour after the powder has been mixed with food or beverage; the mixture may be left at room temperature for up to 1 hour after preparation.

If mixing with food, packets containing atazanavir oral powder should be tapped to settle the powder and a clean pair of scissors used to cut along the dotted line. Using a spoon, the contents of the recommended number of packets should be mixed with at least 1 tablespoon of food (e.g., applesauce, yogurt) in a small container (e.g., cup, bowl). The mixture should be fed to the patient. Then, an additional 1 tablespoon of food should be added to the small container and mixed; the residual mixture should be fed to the patient.

If mixing with a beverage, packets containing atazanavir oral powder should be tapped to settle the powder and a clean pair of scissors used to cut along the dotted line. Using a spoon, the contents of the recommended number of packets should be mixed in a drinking cup with at least 30 mL of beverage. The patient should drink the mixture. Then, an additional 15 mL of beverage should be added to the drinking cup and mixed; the patient should drink the residual mixture. If water is used as the beverage, the patient also should eat food at the time of administration.

If mixing with liquid infant formula, packets containing atazanavir oral powder should be tapped to the settle powder and a clean pair of scissors used to cut along the dotted line. Using a spoon, the contents of the recommended number of packets should be mixed in a small medicine cup with 10 mL of prepared liquid infant formula. The entire mixture should be drawn into an oral dosing syringe and administered into the infant's right or left inner cheek. Then, an additional 10 mL of infant formula should be poured into the medicine cup to rinse off any remaining atazanavir oral powder. The residual mixture should be drawn into the oral dosing syringe and administered into the infant's right or left inner cheek.

Cobicistat-boosted Atazanavir

When cobicistat-boosted atazanavir is used, fixed-combination tablets containing both drugs are commercially available (atazanavir/cobicistat). Alternatively, single-entity atazanavir is administered as capsules at the same time as single-entity cobicistat tablets.

Dosage

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

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

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naive Adults

The recommended dosage of ritonavir-boosted atazanavir for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive adults is 300 mg of single-entity atazanavir once daily given in conjunction with single-entity ritonavir 100 mg once daily.

The recommended dosage of cobicistat-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-naive adults is 300 mg of atazanavir once daily with 150 mg of cobicistat once daily. When fixed-combination atazanavir/cobicistat is used, adults should receive 1 tablet (300 mg of atazanavir and 150 mg of cobicistat) once daily. Alternatively, adults can receive 300 mg of single-entity atazanavir (one 300-mg capsule) once daily given in conjunction with single-entity cobicistat 150 mg once daily.

If unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used for the treatment of HIV-1 infection in antiretroviral-naive adults unable to tolerate ritonavir, the recommended dosage is 400 mg of single-entity atazanavir once daily.

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 single-entity atazanavir once daily given in conjunction with single-entity ritonavir 100 mg once daily.

The recommended dosage of cobicistat-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-experienced adults is 300 mg of atazanavir once daily with 150 mg of cobicistat once daily. When fixed-combination atazanavir/cobicistat is used, adults should receive 1 tablet (300 mg of atazanavir and 150 mg of cobicistat) once daily. Alternatively, adults can receive 300 mg of single-entity atazanavir (one 300-mg capsule) once daily given in conjunction with single-entity cobicistat 150 mg once daily.

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.Ritonavir-boosted atazanavir is used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

The PEP regimen should be initiated as soon as possible following occupational exposure (preferably within hours) and continued for 4 weeks, if tolerated.

Pediatric Dosage

Treatment of HIV Infection

Dosage of atazanavir oral powder for the treatment of HIV-1 infection in pediatric patients 3 months of age or older weighing 5 kg or more is based on weight.(See Table 1.) Atazanavir oral powder must be used with low-dose ritonavir (ritonavir-boosted atazanavir).

Table 1: Dosage of Ritonavir-boosted Atazanavir for Pediatric Patients 3 Months of Age or Older Weighing 5 kg or More[1 ]
Body Weight Atazanavir Dosage (Oral Powder) Ritonavir Dosage (Oral Solution)
5 to less than 15 kg 200 mg (4 packets) once daily 80 mg once daily
15 to less than 25 kg 250 mg (5 packets) once daily 80 mg once daily
25 kg or more and not able to swallow capsules 300 mg (6 packets) once daily 100 mg once daily

In patients weighing 5 to less than 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 years to less than 18 years of age is based on weight.(See Table 2.) Atazanavir capsules usually are used with low-dose ritonavir (ritonavir-boosted atazanavir).

Table 2: Dosage of Ritonavir-boosted Atazanavir for Pediatric Patients 6 Years to Less than 18 Years of Age[1 ]
Body Weight Atazanavir Dosage (Capsules) Ritonavir Dosage
Less than 15 kg Capsules not recommended
15 to less than 20 kg 150 mg once daily 100 mg once daily
20 to less than 40 kg 200 mg once daily 100 mg once daily
40 kg or more 300 mg once daily 100 mg once daily

If unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used for the treatment of HIV-1 infection in antiretroviral-naive adolescents 13 years of age or older who weigh at least 40 kg and are unable to tolerate ritonavir, the recommended dosage is 400 mg of single-entity atazanavir once daily. Unboosted atazanavir should not be used in antiretroviral-experienced adolescents.

Special Populations

Hepatic Impairment

If unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used in treatment-naive patients with hepatic impairment, a dosage of 400 mg once daily should be used in those with mild hepatic impairment (Child-Pugh class A) and a dosage of 300 mg once daily should be used in those with moderate hepatic impairment (Child-Pugh class B). Unboosted atazanavir should not be used in patients with severe hepatic impairment (Child-Pugh class C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Ritonavir-boosted atazanavir and cobicistat-boosted atazanavir should not be used in patients with any degree of hepatic impairment.

Renal Impairment

Dosage of ritonavir-boosted atazanavir or unboosted atazanavir does not need to be adjusted in patients with renal impairment who are not undergoing hemodialysis.

If ritonavir-boosted atazanavir is used in antiretroviral-naive patients with end-stage renal disease undergoing hemodialysis, the recommended dosage is 300 mg of single-entity atazanavir once daily given in conjunction with single-entity ritonavir 100 mg once daily.

Prior to initiation of cobicistat-boosted atazanavir (administered as fixed-combination atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat), estimated creatinine clearance should be assessed. Some experts state that dosage adjustments are not necessary when cobicistat-boosted atazanavir is used in patients with renal impairment who do not require hemodialysis. However, these experts and the manufacturer state that cobicistat-boosted atazanavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearances less than 70 mL/minute.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir should not be used in antiretroviral-experienced patients with end-stage renal disease undergoing hemodialysis.

Pregnant and Postpartum Women

If atazanavir is used during pregnancy or the postpartum period, it should be administered as ritonavir-boosted atazanavir.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

For the treatment of HIV-1 infection in pregnant or postpartum women, the manufacturer states that the usually recommended adult dosage of ritonavir-boosted atazanavir should be used during pregnancy or the postpartum period unless certain drugs are used concomitantly.

Some experts recommend that an increased dosage of ritonavir-boosted atazanavir (i.e., 400 mg of single-entity atazanavir once daily with single-entity ritonavir 100 mg once daily) should be used for treatment of HIV-1 infection in pregnant women during the second and third trimesters.

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 manufacturer recommends a dosage of 400 mg of single-entity atazanavir once daily with single-entity ritonavir 100 mg once daily.Ritonavir-boosted atazanavir is not recommended in antiretroviral-experienced pregnant women receiving both a histamine H2-receptor antagonist and tenofovir DF.

Cobicistat-boosted atazanavir should not be used in treatment-experienced pregnant women receiving a histamine H2-receptor antagonist and/or tenofovir DF during the second or third trimester.

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.

Concomitant use of ritonavir-boosted atazanavir, cobicistat-boosted atazanavir (administered as fixed-combination atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat), or unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) with drugs 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 (e.g., alfuzosin, cisapride, ergot alkaloids, indinavir, irinotecan, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam). In addition, concomitant use of cobicistat-boosted atazanavir and colchicine, dronedarone, lurasidone, or ranolazine is contraindicated.(See Drug Interactions.)

Concomitant use of ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir with drugs that are strong inducers of CYP3A when such use may lead to decreased atazanavir exposures resulting in possible loss of virologic response (e.g., nevirapine, rifampin, St. John's wort [Hypericum perforatum]).(See Drug Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Rash (generally mild to moderate maculopapular eruptions) occurred in 20% of patients receiving atazanavir in clinical studies. 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. Atazanavir generally was continued without interruption in these patients. If severe rash develops, atazanavir should to discontinued.

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.

Cardiovascular Effects

Abnormalities in atrioventricular (AV) conduction, including prolongation of the PR interval, have occurred in individuals receiving atazanavir. Cardiac conduction abnormalities generally are limited to first-degree AV block; prolongation of the corrected QT (QTc) interval observed in HIV-infected patients receiving atazanavir has not been directly attributed to the drug. 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; second- or third-degree block was not observed.

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), ECG monitoring should be considered in such patients.

Caution is advised if atazanavir is used with other drugs that prolong the PR interval (e.g., some β-adrenergic blocking agents, some calcium-channel blocking agents, digoxin, verapamil, lopinavir/ritonavir).(See Drug Interactions.)

Renal Effects

Because cobicistat decreases estimated creatinine clearance by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function, this effect should be considered when interpreting changes in estimated creatinine clearance in patients receiving cobicistat-boosted atazanavir. This is particularly important in those needing creatinine clearance monitoring because of a medical condition or other concomitant drugs.

Estimated creatinine clearance should be assessed prior to initiating cobicistat-boosted atazanavir. Although cobicistat may cause only modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, the patient should be closely monitored for renal safety if there is an increase in serum creatinine of more than 0.4 mg/dL from baseline during cobicistat-boosted atazanavir therapy.

The manufacturer states that dosage recommendations are not available for drugs that require dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted atazanavir. Therefore, alternative drugs that do not require dosage adjustments based on renal impairment should be considered in patients receiving cobicistat-boosted atazanavir.

New-onset or worsening renal impairment, including acute renal failure and Fanconi syndrome, has been reported in patients receiving cobicistat in an antiretroviral regimen that also included tenofovir disoproxil fumarate (tenofovir DF). In clinical trials, 1.5% of patients receiving cobicistat-boosted atazanavir concomitantly with tenofovir DF discontinued the drug because of adverse renal effects. None of these patients had renal impairment at baseline; laboratory findings showed evidence of proximal tubulopathy which improved following discontinuance of the drugs, but did not completely resolve in all patients.

Concomitant use of cobicistat-boosted atazanavir and tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute. Whenever cobicistat-boosted atazanavir and tenofovir DF are used concomitantly, urine glucose and urine protein should be documented at baseline and estimated creatinine clearance, urine glucose, and urine protein should be routinely monitored throughout concomitant therapy. In addition, serum phosphorus should be monitored in those with or at risk for renal impairment. Concomitant use of a nephrotoxic agent is not recommended in patients receiving an antiretroviral regimen that includes cobicistat-boosted atazanavir and tenofovir DF.

Hyperbilirubinemia

Because atazanavir is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin), reversible asymptomatic elevations in indirect (unconjugated) bilirubin occur in most patients receiving the drug. Total bilirubin concentrations at least 2.6 times the upper limit of normal (ULN) have been reported in 35-49% of patients receiving the drug in clinical trials; long-term safety data are not available for patients experiencing persistent elevations in total bilirubin exceeding 5 times the ULN. Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations that occur with hyperbilirubinemia should be evaluated for etiologies other than hyperbilirubinemia.

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).

Hyperbilirubinemia has been observed in pregnant women receiving atazanavir, and neonates exposed to the drug in utero also are at risk of hyperbilirubinemia.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be advised that atazanavir oral powder contains aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine.

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

Hepatic Effects

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.

If atazanavir is used in patients with underlying hepatic disease (e.g., HBV or HCV coinfection), appropriate laboratory tests should be performed to evaluate hepatic function prior to and during atazanavir treatment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Nephrolithiasis and Cholelithiasis

There have been postmarketing reports of nephrolithiasis and cholelithiasis in patients receiving atazanavir. Some patients required hospitalization for additional management or experienced complications.

If signs or symptoms of nephrolithiasis or cholelithiasis occur, temporary interruption or discontinuance of atazanavir therapy may be considered.

Interactions

Atazanavir usually is used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat) to improve the pharmacokinetic profile of atazanavir. When ritonavir-boosted atazanavir or cobicistat-boosted atazanavir is used, the cautions, precautions, contraindications, and drug interactions associated with atazanavir and the pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat) should be considered.

Concomitant use of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir with certain drugs is contraindicated or requires particular caution. Concomitant use with some drugs may result in clinically important adverse effects due to higher exposures of the concomitant drug or higher exposures of atazanavir and/or the pharmacokinetic enhancer (i.e., ritonavir or cobicistat). Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir and possible development of resistance. Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern. However, concomitant use of cobicistat-boosted atazanavir with other drugs may result in different drug interactions than those observed or expected with ritonavir-boosted atazanavir because of complex or unknown mechanisms of drug interactions.

Concomitant use of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir with other drugs that are administered in conjunction with a pharmacokinetic enhancer (e.g., ritonavir-boosted HIV protease inhibitors [PIs], ritonavir-boosted paritaprevir, elvitegravir) is not recommended. Dosage recommendations for such regimens have not been established and concomitant use of more than one pharmacokinetic enhancer may result in complex drug interactions, including decreased plasma concentrations of the antiretroviral agents leading to loss of therapeutic effect and development of resistance.

Potential drug interactions should be considered prior to and during use of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir. Patients should be monitored for adverse reactions associated with other drugs used concomitantly with ritonavir-boosted atazanavir or cobicistat-boosted atazanavir.(See Drug Interactions.)

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 can occur. Initiation of antidiabetic therapy (e.g., insulin, oral antidiabetic agents) or dosage adjustment of existing antidiabetic therapy may be required.

Immune Reconstitution Syndrome

Patients receiving potent antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy. Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) 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.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance noted in patients receiving antiretroviral therapy.

The mechanism and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.

Hemophilia A and B

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in hemophilia A or B patients receiving HIV PIs; a causal relationship has not been established.

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

HIV Resistance

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

Specific Populations

Pregnancy

Atazanavir has been evaluated in a limited number of women during pregnancy and the postpartum period. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. 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).

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that ritonavir-boosted atazanavir in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs) is a preferred PI-based regimen for initial treatment in antiretroviral-naive pregnant women. Dosage adjustments may be necessary in certain pregnant women.(See Pregnant and Postpartum Women under Dosage and Administration: Special Populations.)

The manufacturer states that cobicistat-boosted atazanavir should be used during pregnancy only if potential benefits to the woman justify potential risks to the fetus.Cobicistat-boosted atazanavir should not be used in treatment-experienced pregnant women receiving a histamine H2-receptor antagonist and/or tenofovir DF. The HHS panel states that data are insufficient to date to recommend routine use of cobicistat-boosted atazanavir for initial treatment in antiretroviral-naive pregnant women.

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) should not be used in pregnant or postpartum women.

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

Hyperbilirubinemia has occurred in pregnant women receiving atazanavir. In a clinical trial evaluating ritonavir-boosted atazanavir in conjunction with 2 NRTIs, 30-62% of pregnant women in the study developed hyperbilirubinemia (total bilirubin at least 2.6 times higher than the ULN). Although severe hyperbilirubinemia (bilirubin concentrations exceeding 20 mg/dL) was not observed in neonates born to women in the study, elevated bilirubin concentrations (4 mg/dL or greater) occurred in 28% of neonates within the first 24 hours of life. All neonates exposed to atazanavir in utero should be monitored for development of severe hyperbilirubinemia during the first few days of life.

Postpartum women should be monitored closely 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.

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.apregistry.com.

Based on prospective reports from the Antiretroviral Pregnancy Registry 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).

Lactation

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

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Because of the risk of kernicterus, atazanavir should not be used in neonates and infants younger than 3 months of age. In addition, any infant exposed to the drug in utero should be monitored closely.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.) Safety, efficacy, and pharmacokinetic profile of atazanavir have not been established in infants younger than 3 months of age.

Safety, efficacy, and pharmacokinetic profile of ritonavir-boosted atazanavir and unboosted atazanavir have been evaluated in pediatric patients 3 months of age or older weighing 5 kg or more. Adverse effects reported in pediatric patients 6 years to less than 18 years of age receiving atazanavir capsules were generally similar to those reported in adults. Adverse effects reported in pediatric patients weighing 5 kg or more receiving atazanavir oral powder were generally similar to those reported in pediatric patients receiving the capsules.

Safety and efficacy of cobicistat-boosted atazanavir (administered as atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat) have not been established in patients younger than 18 years of age.

Geriatric Use

Experience in those 65 years of age or older is insufficient to determine whether they respond differently to ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir than younger adults. Caution should be exercised 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.

Hepatic Impairment

Atazanavir is principally metabolized and eliminated by the liver and increased plasma concentrations of atazanavir are expected in patients with moderate to severe hepatic impairment. Dosage adjustments are recommended when unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).(See Hepatic Impairment under Dosage and Administration: Special Populations.) Unboosted atazanavir should not be used in patients with severe hepatic impairment (Child-Pugh class C).

Ritonavir-boosted atazanavir and cobicistat-boosted atazanavir are not recommended in patients with any degree of hepatic impairment.

HIV-infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection and those with markedly increased AST (SGOT) or ALT (SGPT) concentrations prior to atazanavir therapy may be at increased risk for further elevations in hepatic enzyme concentrations or hepatic decompensation. Liver function should be evaluated prior to and periodically during atazanavir therapy in such patients.

Renal Impairment

Plasma concentrations of atazanavir are not markedly altered in individuals with severe renal impairment who are not undergoing hemodialysis. Although atazanavir is not appreciably removed by hemodialysis, plasma concentrations of the drug are lower in individuals undergoing dialysis.

Ritonavir-boosted atazanavir can be used in antiretroviral-naive patients with end-stage renal disease who are undergoing hemodialysis.(See Renal Impairment under Dosage and Administration: Special Populations.)

Ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, and unboosted atazanavir should not be used in antiretroviral-experienced patients with end-stage renal disease who are undergoing hemodialysis.

Cobicistat has been shown to decrease estimated creatinine clearance without affecting renal glomerular function. Prior to initiation of cobicistat-boosted atazanavir (administered as fixed-combination atazanavir/cobicistat or, alternatively, as single-entity atazanavir and single-entity cobicistat), estimated creatinine clearance should be assessed.Cobicistat-boosted atazanavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearances less than 70 mL/minute.(See Renal Effects under Cautions: Warnings/Precautions.)

Common Adverse Effects

The most common adverse effects in adults receiving ritonavir-boosted atazanavir or unboosted atazanavir in conjunction with other antiretrovirals are headache, nausea, jaundice/scleral icterus, abdominal pain, rash, vomiting, diarrhea, insomnia, peripheral neurologic symptoms, dizziness, myalgia, depression, and fever.

The most common adverse effects in adults receiving cobicistat-boosted atazanavir are jaundice, ocular icterus, and nausea.

The most common adverse effects in pediatric patients 6 years to less than 18 years of age receiving ritonavir-boosted atazanavir or unboosted atazanavir are elevated total bilirubin, cough, fever, jaundice/scleral icterus, rash, vomiting, diarrhea, neutropenia, headache, peripheral edema, extremity pain, nasal congestion, oropharyngeal pain, wheezing, rhinorrhea, and hypoglycemia.

The most common adverse effects in pediatric patients 3 months to 10 years of age receiving ritonavir-boosted atazanavir are neutropenia and elevated amylase, ALT, total bilirubin, and lipase concentrations.

Drug Interactions

When atazanavir is used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat), drug interactions associated with both atazanavir and the pharmacokinetic enhancer should be considered. Because low-dose ritonavir and cobicistat are associated with different drug interactions, interactions reported or expected with ritonavir-boosted atazanavir may differ from those reported or expected with cobicistat-boosted atazanavir.

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Atazanavir, ritonavir, and cobicistat are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Atazanavir inhibits CYP3A and 2C8. Ritonavir and cobicistat inhibit CYP3A and 2D6.

Pharmacokinetic interactions are likely if ritonavir-boosted, cobicistat-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. Concomitant use of ritonavir-boosted atazanavir or cobicistat-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 cobicistat-boosted atazanavir, or loss of therapeutic effect and possible development of resistance to atazanavir.

Concomitant use of cobicistat-boosted atazanavir with drugs primarily metabolized by CYP2D6 may result in increased plasma concentration of such drugs, increase or prolong therapeutic effects and adverse reactions of such drugs, and may require dosage adjustments or additional monitoring. Use of cobicistat-boosted atazanavir with drugs that are highly dependent on CYP2C8 for clearance and have narrow therapeutic ranges (e.g., paclitaxel, repaglinide) is not recommended.

Pharmacokinetic interactions also are possible when unboosted atazanavir is used with CYP2C8 substrates. Atazanavir is not expected to interact with CYP2C19, 2C9, 2D6, 2B6, 2A6, 1A2, or 2E1 substrates.

Cobicistat is metabolized by CYP2D6 to a minor extent. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or 2B6; based on in vivo data, cobicistat is not expected to induce CYP3A to a clinically important extent. It is not known whether cobicistat induces CYP2C9 or 2C19, but any effect is expected to be minimal based on in vitro CYP3A induction data.

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). It is not known whether cobicistat induces UGT 1A1, but any effect is expected to be minimal based on CYP3A induction data.

Drugs Affected by P-glycoprotein Transport

Cobicistat is a P-gp inhibitor. Potential pharmacokinetic interactions if cobicistat-boosted atazanavir is used with drugs transported by P-gp (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).

Drugs Affecting or Affected by Other Membrane Transporters

Cobicistat inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3. Potential pharmacokinetic interactions if cobicistat-boosted atazanavir is used concomitantly with drugs that are substrates of BCRP, OATP1B1, or OATP1B3 (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).

Based on in vitro data, cobicistat is not expected to induce multidrug-resistance gene (MDR) 1 to a clinically important extent.

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.(See Drug Interactions: GI Drugs.)

Acetaminophen

Pharmacokinetic interactions between acetaminophen and atazanavir are unlikely.

Alfuzosin

Potential pharmacokinetic interactions with alfuzosin (increased alfuzosin plasma concentrations).

Concomitant use of alfuzosin and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated because increased alfuzosin concentrations may result in hypotension.

Antiarrhythmic Agents

Possible pharmacokinetic interactions if certain antiarrhythmic agents (e.g., amiodarone, dofetilide, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine) are used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased plasma concentrations of the antiarrhythmic, which may increase the potential for serious and/or life-threatening adverse effects). In addition, possible pharmacokinetic interactions if disopyramide or mexiletine is used concomitantly with cobicistat-boosted atazanavir (increased concentrations of the antiarrhythmic).

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and antiarrhythmic agents should be used concomitantly with caution; plasma concentration monitoring of the antiarrhythmic agents, if available, should be considered.

Amiodarone

Some experts state that if amiodarone is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir, the patient should be monitored for amiodarone toxicity and consideration given to ECG and amiodarone plasma concentration monitoring.

Dronedarone

Concomitant use of dronedarone and cobicistat-boosted atazanavir is contraindicated.

Some experts state that concomitant use of dronedarone and ritonavir-boosted or unboosted atazanavir also is contraindicated.

Anticoagulants

Apixaban

Possible pharmacokinetic interactions if apixaban is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased apixaban concentrations).

Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with apixaban is not recommended.

Dabigatran

Possible pharmacokinetic interactions if dabigatran is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir (increased dabigatran concentrations).

Concomitant use of ritonavir-boosted or cobicistat-boosted atazanavir with dabigatran is not recommended in certain patients with renal impairment. Some experts state that concomitant use should be avoided in those with creatinine clearances less than 50 mL/minute.

Edoxaban

Possible pharmacokinetic interactions if edoxaban is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased edoxaban concentrations).

Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and edoxaban should be avoided.

Rivaroxaban

Possible pharmacokinetic interactions if rivaroxaban is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased concentrations of rivaroxaban) and increased risk of bleeding.

Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir should be avoided.

Warfarin

Potential pharmacokinetic interactions if warfarin is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased or decreased plasma concentrations of warfarin) and potential for serious and/or life-threatening bleeding. The effect of cobicistat-boosted atazanavir on warfarin concentrations is not known.

If warfarin is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, the international normalized ratio (INR) should be monitored, especially when initiating or discontinuing atazanavir; warfarin dosage should be adjusted as needed.

Some experts state that if ritonavir-boosted atazanavir is switched to cobicistat-boosted atazanavir, the effect of cobicistat on warfarin concentrations is not expected to be equivalent to the effect of ritonavir on warfarin concentrations.

Anticonvulsants

Carbamazepine

Concomitant use of unboosted atazanavir and carbamazepine may decrease plasma concentrations of atazanavir and is not recommended.

Concomitant use of ritonavir-boosted atazanavir and carbamazepine may decrease plasma concentrations of atazanavir and increase plasma concentrations of the anticonvulsant. If ritonavir-boosted atazanavir is initiated in a patient already receiving a stable carbamazepine dosage, reduction of the anticonvulsant dosage may be needed. Some experts recommend that alternatives to carbamazepine should be considered in patients receiving ritonavir-boosted atazanavir or plasma concentrations of both drugs should be monitored and antiretroviral response assessed.

Concomitant use of cobicistat-boosted atazanavir and carbamazepine may decrease plasma concentrations of atazanavir and cobicistat and may result in loss of therapeutic effect and development of resistance. Concomitant use of cobicistat-boosted atazanavir and carbamazepine is contraindicated.

Eslicarbazepine

Concomitant use of cobicistat-boosted atazanavir and eslicarbazepine may decrease atazanavir and cobicistat plasma concentrations. An alternative anticonvulsant or alternative antiretroviral therapy should be considered; if concomitant use of eslicarbazepine and cobicistat-boosted atazanavir is necessary, the patient should be monitored for lack or loss of virologic response.

Ethosuximide

Possible pharmacokinetic interactions if ethosuximide is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased ethosuximide concentrations). If ethosuximide is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, the patient should be clinically monitored for ethosuximide toxicities.

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.

Concomitant use of ritonavir-boosted atazanavir and lamotrigine decreases lamotrigine plasma concentrations and decreases the area under the plasma concentration-time curve (AUC) by 32%. An alternative anticonvulsant should be considered in patients receiving ritonavir-boosted atazanavir. If lamotrigine is used concomitantly with ritonavir-boosted atazanavir, increased lamotrigine dosage may be needed and lamotrigine plasma concentration monitoring should be considered.

Data are not available regarding concomitant use of cobicistat-boosted atazanavir and lamotrigine. In patients receiving cobicistat-boosted atazanavir, an alternative anticonvulsant should be considered or lamotrigine plasma concentrations should be monitored.

Oxcarbazepine

Concomitant use of cobicistat-boosted atazanavir and oxcarbazepine may decrease atazanavir and cobicistat plasma concentrations. An alternative anticonvulsant or alternative antiretroviral should be considered; if concomitant use of oxcarbazepine and cobicistat-boosted atazanavir is necessary, the patient should be monitored for lack or loss of antiretroviral response.

Phenobarbital and Phenytoin

Concomitant use of unboosted atazanavir and phenobarbital or phenytoin may decrease plasma concentrations of atazanavir and is not recommended.

Concomitant use of ritonavir-boosted atazanavir and phenobarbital or phenytoin may decrease plasma concentrations or atazanavir and the anticonvulsant. If ritonavir-boosted atazanavir is used concomitantly with phenobarbital or phenytoin, adjustment of the anticonvulsant dosage may be needed. Some experts recommend that alternatives to phenobarbital and phenytoin should be considered in patients receiving ritonavir-boosted atazanavir or plasma concentrations of both drugs should be monitored and antiretroviral response assessed.

Concomitant use of cobicistat-boosted atazanavir and phenobarbital or phenytoin may decrease plasma concentrations of atazanavir and cobicistat and may result in loss of therapeutic effect and development of resistance. Concomitant use of cobicistat-boosted atazanavir and phenobarbital or phenytoin is contraindicated.

Antifungal Agents

Fluconazole

Pharmacokinetic interactions unlikely if ritonavir-boosted or cobicistat-boosted atazanavir is used with fluconazole (no clinically important changes in plasma concentrations of atazanavir or fluconazole).

Dosage adjustments are not necessary if ritonavir-boosted or cobicistat-boosted atazanavir is used with fluconazole.

Isavuconazonium

Concomitant use of isavuconazonium sulfate (prodrug of isavuconazole) and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir may result in increased isavuconazole concentrations and altered atazanavir concentrations.

If isavuconazonium sulfate and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir are used concomitantly, the patient should be monitored for atazanavir-associated adverse effects and virologic efficacy and isavuconazole concentration monitoring should be considered.

Itraconazole

Possible pharmacokinetic interactions if ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is used with itraconazole (increased plasma concentrations of itraconazole, atazanavir, and cobicistat).

If itraconazole is used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, consideration should be given to monitoring itraconazole plasma concentrations and adjusting itraconazole dosage accordingly. Caution is advised if high itraconazole dosage (more than 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir. Specific dosage recommendations are not available for concomitant use of cobicistat-boosted atazanavir and itraconazole. Some experts state that itraconazole dosages exceeding 200 mg daily are not recommended in patients receiving ritonavir-boosted or cobicistat-boosted atazanavir, unless plasma itraconazole concentrations are used to guide dosage of the antifungal.

Ketoconazole

Pharmacokinetic interactions unlikely if unboosted atazanavir is used with ketoconazole (no clinically important changes in atazanavir plasma concentrations).

Possible pharmacokinetic interactions if ketoconazole is used with ritonavir-boosted or cobicistat-boosted atazanavir (increased plasma concentrations of ketoconazole, atazanavir, and cobicistat). Caution is advised if high ketoconazole dosage (more than 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir. Specific dosage recommendations are not available for concomitant use of cobicistat-boosted atazanavir and ketoconazole.

Posaconazole

Pharmacokinetic interactions if posaconazole is used with ritonavir-boosted or unboosted atazanavir (increased plasma concentration and AUC of atazanavir); possible pharmacokinetic interactions if used concomitantly with cobicistat-boosted atazanavir (increased atazanavir concentrations).

If posaconazole is used with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, the patient should be monitored for atazanavir-associated adverse effects.

Voriconazole

Pharmacokinetic interactions 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). Possible pharmacokinetic interactions if voriconazole is used with unboosted atazanavir (altered voriconazole and atazanavir plasma concentrations). Data are not available regarding concomitant use of voriconazole and cobicistat-boosted atazanavir.

Concomitant use of voriconazole and ritonavir-boosted or cobicistat-boosted atazanavir is not recommended unless potential benefits outweigh risks. If voriconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir, patients should be monitored for voriconazole-associated adverse effects and loss of voriconazole or atazanavir efficacy; consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

If voriconazole is used concomitantly with unboosted atazanavir, the patient should be monitored for toxicities.

Antimalarial Agents

Atovaquone and Proguanil

Pharmacokinetic interactions if the fixed combination of atovaquone and proguanil (atovaquone/proguanil) is used concomitantly with ritonavir-boosted atazanavir (decreased atovaquone and proguanil plasma concentrations). Some experts state that an alternative antimalarial should be considered, if possible, in patients receiving ritonavir-boosted atazanavir.

Antimycobacterial Agents

Bedaquiline

Possible pharmacokinetic interactions if bedaquiline is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir (increased bedaquiline concentrations); clinical importance is unknown.

Some experts state that bedaquiline may be used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir if potential benefits outweigh risks, but caution is advised and patients should be monitored for corrected QT (QTc) interval prolongation and liver dysfunction.

Rifabutin

Pharmacokinetic interactions if rifabutin is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased peak plasma concentration and AUC of rifabutin and its metabolite). Possible pharmacokinetic interactions if rifabutin is used concomitantly with cobicistat-boosted atazanavir (increased rifabutin concentrations expected; effects on atazanavir and cobicistat concentrations unknown).

If rifabutin is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, dosage of the antimycobacterial agent should be reduced (e.g., 150 mg once every other day or 3 times weekly) and increased monitoring for rifabutin-associated adverse effects (e.g., neutropenia, uveitis) is warranted. Some experts recommend a rifabutin dosage of 150 mg once daily or 300 mg 3 times weekly and state that patients should be monitored for antimycobacterial response and therapeutic drug concentration monitoring should be considered.

Rifampin

Pharmacokinetic interactions if rifampin is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (substantially decreased plasma concentrations of atazanavir) with possible loss of therapeutic effect of the antiretroviral agent and development of resistance.

Concomitant use of rifampin and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated. If a rifamycin is indicated in a patient receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, some experts state that rifabutin should be considered as an alternative to rifampin.

Rifapentine

Possible pharmacokinetic interactions if rifapentine is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (decreased atazanavir plasma concentrations). Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and rifapentine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV-infected patients.

Antineoplastic Agents

Dasatinib or Nilotinib

Possible pharmacokinetic interactions if dasatinib or nilotinib is used concomitantly with cobicistat-boosted atazanavir (increased antineoplastic agent concentrations).

If dasatinib or nilotinib is used concomitantly with cobicistat-boosted atazanavir, decreased dosage of the antineoplastic agent may be necessary.

Irinotecan

Pharmacokinetic interactions if irinotecan is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir. Atazanavir inhibits UGT 1A1 and may interfere with the metabolism of irinotecan leading to an increase in irinotecan toxicity.

Concomitant use of irinotecan with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated.

Paclitaxel

Possible pharmacokinetic interactions if paclitaxel is used concomitantly with unboosted atazanavir (increased plasma concentrations of paclitaxel); caution is advised.

Clinically important interactions are not expected if paclitaxel is used concomitantly with ritonavir-boosted atazanavir.

Concomitant use of paclitaxel and cobicistat-boosted atazanavir is not recommended.

Vinblastine or Vincristine

Possible pharmacokinetic interactions if vinblastine or vincristine is used concomitantly with cobicistat-boosted atazanavir (increased antineoplastic agent concentrations).

If vincristine or vinblastine is used concomitantly with cobicistat-boosted atazanavir, the patient should be monitored for adverse hematologic or GI effects.

Antipsychotic Agents

Lurasidone

Possible pharmacokinetic interactions if lurasidone is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased lurasidone concentrations). Potential for serious and/or life-threatening adverse effects if lurasidone is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir.

Concomitant use of ritonavir-boosted or cobicistat-boosted atazanavir and lurasidone is contraindicated.

The manufacturer of atazanavir states that if concomitant use of unboosted atazanavir and lurasidone is necessary, lurasidone dosage should be reduced. Some experts state that unboosted atazanavir should not be used concomitantly with lurasidone.

Perphenazine, Risperidone, Thioridazine

Possible pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted atazanavir is used concomitantly with perphenazine, risperidone, or thioridazine (increased plasma concentrations of the antipsychotic agent).

If perphenazine, risperidone, or thioridazine is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir, a reduced dosage of the antipsychotic may be needed. Some experts state that the antipsychotic should be initiated using the lowest dosage, maintenance dosage should be adjusted as needed, and the patient should be monitored for toxicities associated with the antipsychotic.

Pimozide

Concomitant use of pimozide and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated because of the potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).

Quetiapine

Pharmacokinetic interactions expected if quetiapine is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased quetiapine concentrations).

Alternative antiretroviral therapy should be considered. If ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is necessary in a patient receiving a stable dosage of quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage and the patient should be monitored for quetiapine efficacy and adverse effects. If quetiapine is necessary in a patient receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, some experts recommend that quetiapine should be initiated using the lowest dosage and titrated as needed.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects between atazanavir and enfuvirtide.

Maraviroc

Concomitant use of maraviroc and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir results in increased maraviroc plasma concentrations and AUC. If maraviroc is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, the recommended maraviroc dosage is 150 mg twice daily.

No in vitro evidence of antagonistic antiretroviral effects between atazanavir and maraviroc.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of dolutegravir and ritonavir-boosted or unboosted atazanavir results in increased dolutegravir AUC. Data are not available regarding concomitant use of dolutegravir and cobicistat-boosted atazanavir.

Some experts state that dosage adjustments are not necessary if dolutegravir is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Elvitegravir

Concomitant use of single-entity elvitegravir and ritonavir-boosted atazanavir results in increased trough plasma concentrations of elvitegravir but the AUC of elvitegravir and AUC of atazanavir are unaffected. If ritonavir-boosted atazanavir and single-entity elvitegravir are used concomitantly, some experts recommend that single-entity atazanavir 300 mg, single-entity ritonavir 100 mg, and single-entity elvitegravir 85 mg be given once daily. Data are not available regarding concomitant use of single-entity elvitegravir and cobicistat-boosted atazanavir and some experts state that cobicistat-boosted atazanavir should not be used concomitantly with single-entity elvitegravir.

Possible pharmacokinetic interactions if the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF) is used concomitantly with ritonavir-boosted or unboosted atazanavir (altered concentrations of elvitegravir, cobicistat, and/or atazanavir). EVG/c/FTC/TDF should not be used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Raltegravir

Concomitant use of raltegravir and ritonavir-boosted or unboosted atazanavir results in increased raltegravir plasma concentrations and AUC. Data are not available regarding concomitant use of raltegravir and cobicistat-boosted atazanavir.

Dosage adjustments are not necessary if raltegravir is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

The antiretroviral effects of raltegravir and atazanavir are additive to synergistic against HIV-1 in vitro.

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, etravirine, nevirapine, rilpivirine). The antiretroviral effects of atazanavir and nevirapine may be additive to synergistic against HIV-1 in vitro.

Efavirenz

Concomitant use of efavirenz and unboosted atazanavir results in substantially decreased plasma concentrations and AUC of atazanavir, but no clinically important effects on efavirenz plasma concentrations. Depending on the specific regimen used, concomitant use of ritonavir-boosted atazanavir and efavirenz may increase atazanavir plasma concentrations and AUC. Concomitant use of efavirenz with cobicistat-boosted atazanavir may result in decreased plasma concentrations of atazanavir and cobicistat, but no change in efavirenz concentrations.

Unboosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-naive or antiretroviral-experienced patients.

If ritonavir-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naive 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.Ritonavir-boosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-experienced patients.

If cobicistat-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naive adults, a regimen of single-entity atazanavir 400 mg and single-entity cobicistat 150 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime) is recommended.Cobicistat-boosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-experienced patients.

Etravirine

Pharmacokinetic interactions if etravirine is used concomitantly with ritonavir-boosted or unboosted atazanavir (increased etravirine plasma concentrations and AUC; decreased atazanavir plasma concentrations and AUC) with possible decreased antiretroviral efficacy. Pharmacokinetic interactions if etravirine is used concomitantly with cobicistat-boosted atazanavir (decreased atazanavir and cobicistat concentrations).

Concomitant use of etravirine and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is not recommended.

If ritonavir-boosted atazanavir is used concomitantly with etravirine, some experts recommend a regimen of atazanavir 300 mg once daily and ritonavir 100 mg once daily in conjunction with usual etravirine dosage.

Nevirapine

Pharmacokinetic interactions 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). Pharmacokinetic interactions if nevirapine is used concomitantly with cobicistat-boosted atazanavir (decreased cobicistat concentrations).

Concomitant use of nevirapine and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated.

Rilpivirine

Concomitant use of rilpivirine and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir may result in increased rilpivirine plasma concentrations, but is not expected to affect atazanavir plasma concentrations.

Some experts state that dosage adjustments are not needed if rilpivirine and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir are used concomitantly.

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, stavudine, tenofovir, zidovudine).

Didanosine

Administration of buffered didanosine and atazanavir at the same time results in substantially decreased plasma concentrations and AUC of atazanavir and decreased plasma concentrations and AUC of didanosine. Administration of didanosine delayed-release capsules and atazanavir at the same time and with food results in decreased plasma concentrations and AUC of didanosine, but does not affect atazanavir plasma concentrations.

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir should be administered (with food) at least 2 hours before or 1 hour after buffered or delayed-release didanosine preparations (without food).

Lamivudine and Zidovudine

No clinically important pharmacokinetic interactions reported when unboosted atazanavir (400 mg once daily) is used concomitantly with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily).

Tenofovir Alafenamide Fumarate

Concomitant use of ritonavir-boosted atazanavir and tenofovir alafenamide fumarate results in a 91% increase in the AUC of tenofovir.

Some experts state that dosage adjustments for tenofovir alafenamide are not necessary if the drug is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Tenofovir Disoproxil Fumarate

Pharmacokinetic interactions between tenofovir disoproxil fumarate (tenofovir DF) and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (decreased atazanavir plasma concentrations and AUC; increased tenofovir plasma concentrations and AUC and possible increased risk of tenofovir-associated adverse effects, including renal disorders).

Unboosted atazanavir should not be used concomitantly with tenofovir DF.

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. Patients should be monitored for tenofovir toxicity; tenofovir should be discontinued if tenofovir-associated adverse effects occur.

If tenofovir DF and cobicistat-boosted atazanavir are used concomitantly, a regimen of atazanavir 300 mg, cobicistat 150 mg, and tenofovir DF 300 mg once daily with food is recommended. Baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed and patients should be monitored for tenofovir toxicity. Serum phosphorus concentrations should be monitored in patients with or at risk for renal impairment. Concomitant use of cobicistat-boosted atazanavir and tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute.

If ritonavir-boosted atazanavir is used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, the recommended dosage is atazanavir 400 mg, ritonavir 100 mg, and tenofovir DF 300 mg given once daily with food. Patients should be monitored for tenofovir toxicity.

If cobicistat-boosted atazanavir is used concomitantly with tenofovir DF and a histamine H2-receptor antagonist in antiretroviral-experienced adults, some experts recommend single-entity atazanavir 400 mg and single-entity cobicistat 150 mg once daily with food. Patients should be monitored for tenofovir toxicity.

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. Dosage recommendations are not available for pregnant women receiving both a histamine H2-receptor antagonist and tenofovir in conjunction with ritonavir-boosted atazanavir.

HIV Protease Inhibitors (PIs)

In vitro studies indicate that the antiretroviral effects of atazanavir and amprenavir (active metabolite of fosamprenavir) or saquinavir are synergistic, the antiretroviral effects of atazanavir and lopinavir are additive to synergistic, and the antiretroviral effects of atazanavir and tipranavir are additive to antagonistic. There is no in vitro evidence of antagonism between atazanavir and other HIV PIs (amprenavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir).

Darunavir

Concomitant use of atazanavir 300 mg once daily with ritonavir-boosted darunavir (darunavir 400 mg and ritonavir 100 mg twice daily [dosage differs from usually recommended dosage]) results in plasma concentrations of atazanavir that are similar to those attained with ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily) and plasma concentrations of darunavir similar to those attained without atazanavir.

The manufacturer of darunavir states that concomitant use of darunavir and ritonavir-boosted atazanavir is not recommended.

Fosamprenavir

Pharmacokinetic interactions between atazanavir and ritonavir-boosted fosamprenavir (decreased plasma concentrations and AUC of atazanavir; no change in plasma concentrations or AUC of amprenavir [active metabolite of fosamprenavir]); data not available regarding concomitant use of fosamprenavir (without low-dose ritonavir) and atazanavir.

Appropriate dosages for concomitant use of atazanavir and fosamprenavir (with or without low-dose ritonavir) with respect to safety and efficacy have not been established.

Indinavir

Both indinavir and atazanavir are associated with hyperbilirubinemia and additive adverse effects are possible.

Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir and indinavir is contraindicated.

Lopinavir

Because prolonged PR interval has been reported with both lopinavir and atazanavir, the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and atazanavir should be used concomitantly with caution and clinical monitoring.

Ritonavir

Pharmacokinetic interactions if ritonavir is used concomitantly with atazanavir (increased plasma concentration and AUC of atazanavir). 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). Additional pharmacokinetic interactions are possible if ritonavir-boosted atazanavir is used concomitantly with other HIV PIs and such use is not recommended.

Safety and efficacy of concomitant use of atazanavir and ritonavir dosages exceeding 100 mg once daily have not been established and such concomitant use is not recommended.

Concomitant use of cobicistat-boosted atazanavir with ritonavir or ritonavir-containing preparations is not recommended since cobicistat and ritonavir have similar effects on CYP3A.

Saquinavir

Concomitant use of atazanavir (300 mg once daily) and saquinavir (1.6 g once daily as Invirase) and ritonavir (100 mg once daily) results in increased plasma concentrations and AUC of saquinavir (42 and 60%, respectively) and no change in plasma atazanavir concentrations. In a clinical study, a regimen of atazanavir, saquinavir, tenofovir, and a NRTI did not provide adequate efficacy.(See Clinical Experience under Treatment of HIV Infection: Antiretroviral-Experienced Adults and Adolescents, in Uses.)

Prolonged PR interval has been reported with both saquinavir and atazanavir and additive effects on the PR interval could occur.

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. Atazanavir and ritonavir-boosted saquinavir should be used concomitantly with caution and clinical monitoring.

Tipranavir

Pharmacokinetic interactions between ritonavir-boosted atazanavir and ritonavir-boosted tipranavir (decreased atazanavir plasma concentrations and AUC and increased tipranavir plasma concentrations and AUC).

Concomitant use of atazanavir (with or without low-dose ritonavir) and tipranavir is not recommended.

Atovaquone

Concomitant use of ritonavir-boosted atazanavir and atovaquone does not affect atovaquone concentrations. Dosage adjustments are not needed if ritonavir-boosted atazanavir and atovaquone are used concomitantly.

Benzodiazepines

Alprazolam

Potential pharmacokinetic interactions if alprazolam is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased benzodiazepine plasma concentrations).

Although pharmacokinetic studies evaluating concomitant use are lacking, some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of alprazolam in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Clonazepam

Potential pharmacokinetic interactions if clonazepam is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased clonazepam concentrations).

If clonazepam is used concomitantly with cobicistat-boosted atazanavir, clinical monitoring is recommended. Although pharmacokinetic studies evaluating concomitant use are lacking, some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of clonazepam in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Diazepam

If diazepam is used concomitantly with cobicistat-boosted atazanavir, reduction of the diazepam dosage may be needed and the patient should be monitored for adverse effects. Some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of diazepam in patients receiving ritonavir-boosted or cobicistat-boosted atazanavir.

Midazolam or Triazolam

Pharmacokinetic interactions if midazolam or triazolam is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased benzodiazepine plasma concentrations) and potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).

Concomitant use of oral midazolam or triazolam and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated.

Concomitant use of parenteral midazolam and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir should be undertaken with caution and in a monitored setting where respiratory depression and/or prolonged sedation can be managed. In addition, a reduced dosage of midazolam should be considered, especially if more than a single dose of midazolam is given. Some experts state that parenteral midazolam can be given in a single dose with caution in a monitored situation for procedural sedation in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

β-Adrenergic Blocking Agents

Possible pharmacokinetic interactions if certain β-adrenergic blocking agents metabolized by CYP2D6 (e.g., carvedilol, metoprolol, timolol) are used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased concentrations of the β-adrenergic blocking agent).

If carvedilol, metoprolol, or timolol is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, clinical monitoring of the patient is recommended and reduction of the dosage of the β-adrenergic blocking agent may be needed. Alternatively, some experts state that use of β-adrenergic blocking agents that are not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol) should be considered.

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. Pharmacokinetic interactions are not expected if cobicistat-boosted atazanavir and atenolol are used concomitantly.

Bosentan

Possible pharmacokinetic interactions if bosentan is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased bosentan plasma concentrations, decreased atazanavir and cobicistat plasma concentrations).

Unboosted atazanavir should not be used concomitantly with bosentan.

In patients who have been receiving ritonavir-boosted or cobicistat-boosted atazanavir for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir-boosted or cobicistat-boosted atazanavir; after at least 10 days of ritonavir-boosted or cobicistat-boosted atazanavir therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

In patients switching from ritonavir-boosted atazanavir to cobicistat-boosted atazanavir, the current bosentan dosage should be maintained.

Buspirone

Possible pharmacokinetic interactions if buspirone is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased buspirone concentrations).

If buspirone is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, buspirone dosage should be titrated, a lower buspirone dosage should be considered, and the patient should be monitored for prolonged or adverse effects.

Calcium-channel Blocking Agents

Possible pharmacokinetic interactions if certain calcium-channel blocking agents (e.g., amlodipine, felodipine, nicardipine, nifedipine, verapamil) are used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased concentrations of the calcium-channel blocking agent). These calcium-channel blocking agents should be used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with caution; dosage titration and clinical and ECG monitoring are recommended.

Pharmacokinetic interactions if diltiazem is used concomitantly with unboosted atazanavir (increased diltiazem plasma concentrations and AUC). Concomitant use of diltiazem with ritonavir-boosted or cobicistat-boosted atazanavir is expected to result in greater increases in diltiazem concentrations. Diltiazem and atazanavir should be used concomitantly with caution. If diltiazem is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, a 50% reduction in diltiazem dosage should be considered and ECG monitoring is recommended.

Cobicistat

Pharmacokinetic interactions if cobicistat is used concomitantly with atazanavir (increased plasma concentrations and AUC of atazanavir). Cobicistat is a pharmacokinetic enhancer (pharmacokinetic booster) and is used in conjunction with atazanavir for therapeutic advantage (cobicistat-boosted atazanavir).

Colchicine

Potential pharmacokinetic interactions if colchicine is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir (increased colchicine plasma concentrations).

Concomitant use of colchicine and ritonavir-boosted or unboosted atazanavir is not recommended in patients with renal or hepatic impairment. Concomitant use of colchicine and cobicistat-boosted atazanavir is contraindicated in patients with renal or hepatic impairment.

When colchicine is used for treatment of gout flares in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, an initial colchicine dose of 0.6 mg should be given followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.

When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.

Corticosteroids

Orally Inhaled or Intranasal Corticosteroids

Possible pharmacokinetic interactions if fluticasone (orally inhaled or intranasal) is used concomitantly with unboosted atazanavir (increased fluticasone concentrations). Concomitant use of budesonide (orally inhaled or intranasal), fluticasone (orally inhaled or intranasal), or mometasone (orally inhaled or intranasal) with ritonavir-boosted or cobicistat-boosted atazanavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.

Fluticasone (orally inhaled or intranasal) and unboosted atazanavir should be used concomitantly with caution. Budesonide (orally inhaled or intranasal), fluticasone (orally inhaled or intranasal), and mometasone (orally inhaled or intranasal) should not be used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir unless potential benefits of the inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects. An alternative corticosteroid (e.g., beclomethasone) should be considered, especially when long-term use of the corticosteroid is anticipated.

Local Injections of Corticosteroids

Concomitant use of intra-articular or other local injections of methylprednisolone, prednisolone, or triamcinolone with ritonavir-boosted or cobicistat-boosted atazanavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.

Ritonavir-boosted or cobicistat-boosted atazanavir should not be used concomitantly with local injections of methylprednisolone, prednisolone, or triamcinolone; other nonsteroidal therapies should be considered. If intra-articular corticosteroid therapy is required, an alternative antiretroviral that does not alter CYP3A4 activity should be considered (e.g., dolutegravir, raltegravir).

Systemic Corticosteroids

Concomitant use of systemic budesonide or prednisone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir may result in increased corticosteroid concentrations and may result in adrenal insufficiency or Cushing's syndrome. Systemic budesonide or prednisone should not be used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir unless potential benefits outweigh the risks of systemic corticosteroid adverse effects.

Concomitant use of systemic dexamethasone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir may result in decreased atazanavir concentrations and possible decreased antiretroviral efficacy and development of atazanavir resistance. Systemic dexamethasone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir should be used concomitantly with caution; alternative corticosteroids should be considered for long-term use.

Co-trimoxazole

Clinically important interactions between co-trimoxazole and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir are unlikely.

Dapsone

Clinically important interactions between dapsone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir are unlikely.

Digoxin

Pharmacokinetic interactions if digoxin is used concomitantly with ritonavir-boosted or cobicistat-boosted atazanavir (increased digoxin concentrations). Digoxin and ritonavir-boosted or cobicistat-boosted atazanavir should be used concomitantly with caution; the digoxin dosage should be titrated and digoxin plasma concentrations monitored.

Eplerenone

Concomitant use of eplerenone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is expected to result in increased eplerenone concentrations.

Some experts state that concomitant use of eplerenone and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated.

Ergot Alkaloids

Concomitant use of ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine) and ritonavir-boosted, cobicistat-boosted, or unboosted 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).

If a woman receiving atazanavir or any other PI as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine) should be used for treatment of the hemorrhage only if alternative treatments (e.g., carboprost, misoprostol, oxytocin, dinoprostone) cannot be used and the potential benefits of the ergot alkaloid outweigh the risks. In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.

Estrogens and Progestins

Pharmacokinetic interactions if oral contraceptives containing ethinyl estradiol and norgestimate or norethindrone are used concomitantly with ritonavir-boosted or unboosted atazanavir (increased or decreased plasma concentrations of ethinyl estradiol; increased plasma concentrations of the progestin). Data are not available regarding concomitant use of oral contraceptives and cobicistat-boosted atazanavir and possible effects on estrogen and progestin concentrations.

If ritonavir-boosted atazanavir is used with an oral contraceptive, caution is advised and use of an oral contraceptive preparation containing at least 35 mcg of ethinyl estradiol is recommended. If unboosted atazanavir is used with an oral contraceptive, caution is advised and use of an oral contraceptive preparation containing no more than 30 mcg of ethinyl estradiol is recommended.

Additional or alternative nonhormonal forms of contraception should be considered in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Data are not available regarding use of etonogestrel-releasing subdermal implant contraceptives in patients receiving ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir; some experts recommend use of alternative or additional methods of contraception or use of alternative antiretrovirals.

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. Alternative methods of contraception are recommended.

Flibanserin

Concomitant use of flibanserin and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is expected to increase flibanserin concentrations.

Some experts state that concomitant use of flibanserin and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated.

GI Drugs

Antacids

Potential pharmacokinetic interactions if antacids or buffered medications are given concomitantly with atazanavir (decreased oral absorption of atazanavir).Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir should be administered at least 2 hours before or 1-2 hours after antacids or buffered medications.

Cisapride

Concomitant use of cisapride and ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir is contraindicated because of possible increased cisapride plasma concentrations and potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).

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. Concomitant use of ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir with famotidine (20 or 40 mg) may result in changes in the pharmacokinetics of atazanavir.

If ritonavir-boosted atazanavir is used in adults receiving a histamine H2-receptor antagonist, a regimen of 300 mg of single-entity atazanavir once daily with single-entity ritonavir 100 mg once daily with food is recommended. Atazanavir and ritonavir should be given simultaneously with and/or at least 10 hours after the histamine H2-receptor antagonist. For antiretroviral-naive patients, dosage of the histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent). In antiretroviral-experienced patients, dosage of the histamine H2-receptor antagonist should not exceed famotidine 20 mg twice daily (or equivalent).

If cobicistat-boosted atazanavir is used in adults receiving a histamine H2-receptor antagonist, a regimen of 300 mg of atazanavir once daily with cobicistat 150 mg once daily (administered as fixed-combination atazanavir/cobicistat or as single-entity atazanavir with single-entity cobicistat) with food is recommended.Cobicistat-boosted atazanavir should be given simultaneously with and/or at least 10 hours after the histamine H2-receptor antagonist. In antiretroviral-naive patients, dosage of the histamine H2-receptor antagonist should not exceed famotidine 40 mg twice daily (or equivalent). In antiretroviral-experienced patients, dosage of the histamine H2-receptor antagonist should not exceed famotidine 20 mg twice daily (or equivalent).

If unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used in antiretroviral-naive 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 at least 2 hours before and at least 10 hours after a dose of the histamine H2-receptor antagonist. 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.

If ritonavir-boosted atazanavir is used in an ant

Pharmacokinetics

Absorption

Bioavailability

Atazanavir usually is administered with low-dose ritonavir (ritonavir-boosted atazanavir) or cobicistat (cobicistat-boosted atazanavir). Ritonavir and cobicistat are pharmacokinetic enhancers (pharmacokinetic boosters) that decrease metabolism of atazanavir, resulting in increased atazanavir plasma concentrations and area under the plasma concentration-time curve (AUC).

Pharmacokinetic parameters reported with a once-daily regimen of ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg) are similar to those reported with a once-daily regimen of cobicistat-boosted atazanavir (fixed-combination tablet of atazanavir and cobicistat [atazanavir/cobicistat] containing atazanavir 300 mg and cobicistat 150 mg).

Atazanavir is rapidly absorbed following oral administration. Steady-state peak plasma concentrations of atazanavir are attained approximately 2- 2.5, 2.7-3, or approximately 3.5 hours after a dose of unboosted atazanavir, ritonavir-boosted atazanavir, or cobicistat-boosted atazanavir, respectively.

Food

Food increases bioavailability and reduces pharmacokinetic variability of oral atazanavir.

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.

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.

Administration of a single dose of cobicistat-boosted atazanavir (administered as the fixed-combination tablet of atazanavir/cobicistat containing 300 mg of atazanavir and 150 mg of cobicistat) with a light meal increases atazanavir AUC by 28% and increases peak plasma concentrations by 42% compared with fasting; administration with a high-fat meal does not affect atazanavir AUC, but decreases peak plasma concentrations by 14%.

Plasma Concentrations

When unboosted atazanavir is used, the drug demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in plasma concentrations and AUC. Steady-state atazanavir concentrations following administration of unboosted atazanavir are attained between days 4-8, with an accumulation of approximately 2.3-fold.

Data from HIV-infected pregnant women receiving ritonavir-boosted atazanavir indicate that steady-state peak plasma concentrations and AUC of atazanavir are approximately 28-43% higher during the postpartum period (4-12 weeks) compared with historical data in HIV-infected, nonpregnant patients.

Distribution

Extent

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

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

Atazanavir is distributed into milk in rats. In a limited number of women, concentrations of atazanavir in breast milk were approximately 13% of plasma concentrations.

Plasma Protein Binding

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

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

Elimination

Metabolism

Atazanavir is extensively metabolized and eliminated in the liver. CYP3A is involved in metabolism of the drug.

Elimination Route

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.

Half-life

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.

Following administration of ritonavir-boosted atazanavir, the mean half-life of atazanavir at steady state is 8.6-18.1 hours.

Following administration of cobicistat-boosted atazanavir, the mean half-life of atazanavir at steady state is approximately 7.5 hours.

Special Populations

No clinically important differences in pharmacokinetics of atazanavir have been reported in those older than 65 years of age compared with younger adults.

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. The half-life of the drug is 12.1 hours in those with moderate to severe hepatic impairment.

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