Drug Description

Atazanavir (ATV), also known as Reyataz, is an azapeptide inhibitor of HIV-1 protease.

HIV/AIDS-Related Uses

Atazanavir sulfate was approved by the U.S. Food and Drug Administration (FDA) on June 20, 2003. Currently, atazanavir sulfate is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled studies of 96 weeks duration in antiretroviral-naïve and 48 weeks duration in antiretroviral-treatment-experienced adult and pediatric patients at least 6 years of age.

Dosing Information

Mode of Delivery

Oral.

Dosage Form

Capsules containing atazanavir 100, 150, 200, or 300 mg.

The following points should be considered when initiating therapy with atazanavir sulfate:

• In Study AI424-045, atazanavir sulfate/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that atazanavir sulfate/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection.
• The number of baseline primary protease inhibitor mutations affects the virologic response to atazanavir sulfate/ritonavir.

Dosage and Administration

General Dosing Recommendations

• Atazanavir sulfate capsules must be taken with food.
• The recommended oral dosage of atazanavir sulfate depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H₂-receptor antagonists or proton-pump inhibitors, dose separation may be required.
• When coadministered with didanosine buffered or enteric-coated formulations, atazanavir sulfate should be given (with food) 2 hours before or 1 hour after didanosine.
• Atazanavir sulfate without ritonavir is not recommended for treatment-experienced patients with prior virologic failure.
• Efficacy and safety of atazanavir sulfate with ritonavir in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for Norvir (ritonavir) when using this agent.

Recommended Adult Dosage
All atazanavir sulfate dosing regimens are to be administered as a single dose with food.

Treatment-Naïve Adult Patients:

• Atazanavir sulfate 300 mg with ritonavir 100 mg once daily.
• If unable to tolerate ritonavir: Atazanavir sulfate 400 mg once daily.
• When combined with tenofovir, H₂-receptor antagonist, or a proton pump inhibitor: Atazanavir sulfate 300 mg with ritonavir 100 mg once daily.
  -The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 40 mg twice daily. Administer atazanavir sulfate and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist.
  - If unable to tolerate ritonavir, administer atazanavir sulfate 400 mg once daily at least 2 hours before and at least 10 hours after the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg and the total daily dose should not exceed a dose comparable to famotidine 40 mg.
  -The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg daily and must be taken approximately 12 hours prior to atazanavir sulfate and ritonavir.
   
• When combined with efavirenz: Atazanavir sulfate 400 mg with ritonavir 100 mg once daily.
  -Efavirenz should be administered on an empty stomach, preferably at bedtime.

Treatment-Experienced Adult Patients:

• Atazanavir sulfate 300 mg with ritonavir 100 mg once daily.
• Do not coadminister with proton-pump inhibitors or efavirenz in treatment-experienced patients.
• When given with an H₂-receptor antagonist: Atazanavir sulfate 300 mg with ritonavir 100 mg once daily.
  - The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily. Administer atazanavir sulfate and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist.

• When given with both tenofovir and an H₂-receptor antagonist: Atazanavir sulfate 400 mg with ritonavir 100 mg once daily.
  - The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily. Administer atazanavir sulfate and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist.
   

Recommended Pediatric Dosage
The recommended dosage of atazanavir sulfate for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage. Atazanavir sulfate capsules must be taken with food. The data are insufficient to recommend dosing of atazanavir sulfate for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.

Treatment-Naïve Pediatric Patients:

The recommended dosage of atazanavir sulfate with ritonavir in treatment-naïve patients at least 6 years of age is shown below.
For treatment-naïve patients at least 13 years of age and at least 39 kg, who are unable to tolerate ritonavir, the recommended dose is atazanavir sulfate 400 mg (without ritonavir) once daily with food. 

Dosage for Treatment-Naïve Pediatric Patients (6 to less than 18 years of age) for Atazanavir Sulfate Capsules with Ritonavir:

• 15 to less than 25 kg (33 to less than 55 lbs): atazanavir sulfate 150 mg plus ritonavir 80 mg
• 25 to less than 32 kg (55 to less than 70 lbs): atazanavir sulfate 200 mg plus ritonavir 100 mg
• 32 to less than 39 kg (70 to less than 86 lbs): atazanavir sulfate 250 mg plus ritonavir 100 mg at least 39 kg  (86 lbs): atazanavir sulfate 300 mg plus ritonavir 100 mg

The recommended dosage of atazanavir sulfate can be achieved using a combination of commercially available capsule strengths.
The dosage of atazanavir sulfate and ritonavir was calculated as follows:
-15 kg to less than 20 kg: atazanavir sulfate 8.5 mg/kg with ritonavir 4 mg/kg once daily with food.
-at least 20 kg: atazanavir sulfate 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed atazanavir sulfate 300 mg and ritonavir 100 mg.

Treatment-Experienced Pediatric Patients:

The recommended dosage of atazanavir sulfate with ritonavir in treatment-experienced patients at least 6 years of age is shown below.

Dosage for Treatment-Experienced Pediatric Patients (6 to less than 18 years of age) for Atazanavir Sulfate Capsules with Ritonavir:

• 25 to less than 32 kg (55 to less than 70 lbs): atazanavir sulfate 200 mg plus ritonavir 100 mg
• 32 to less than 39 kg (70 to less than 86 lbs): atazanavir sulfate 250 mg plus ritonavir 100 mg
• at least 39 kg  (86 lbs): atazanavir sulfate 300 mg plus ritonavir 100 mg

The recommended dosage of atazanavir sulfate can be achieved using a combination of commercially available capsule strengths.
The dosage was calculated as atazanavir sulfate 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed atazanavir sulfate 300 mg and ritonavir 100 mg.

Dosing During Pregnancy and the Postpartum Period

• Atazanavir sulfate should not be administered without ritonavir.
• Atazanavir sulfate should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
• For pregnant patients, no dose adjustment is required for atazanavir sulfate with the following exceptions:

For treatment-experienced pregnant women during the second or third trimester, when atazanavir sulfate is coadministered with either an H₂-receptor antagonist or tenofovir, atazanavir sulfate 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a atazanavir sulfate dose for use with both an H₂-receptor antagonist and tenofovir in treatment-experienced pregnant women.

• No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.

 Renal Impairment

• For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for atazanavir sulfate. Treatment-naïve patients with end stage renal disease managed with hemodialysis should receive atazanavir sulfate 300 mg with ritonavir 100 mg. Atazanavir sulfate should not be administered to HIV-treatment experienced patients with end stage renal disease managed with hemodialysis.

Hepatic Impairment

• Atazanavir sulfate should be used with caution in patients with mild-to-moderate hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. Atazanavir sulfate should not be used in patients with severe hepatic impairment (Child-Pugh Class C). Atazanavir/ritonavir has not been studied in subjects with hepatic impairment and is not recommended.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Pharmacology

Atazanavir is an azapeptide protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, preventing formation of mature virions. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC₅₀) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9 to 32 nM), with EC₅₀ values above the EC₅₀ values of failure isolates.Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, efavirenz, and nevirapine, the PIs amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec. In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval.

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of atazanavir sulfate 400 mg once daily and after administration of atazanavir sulfate 300 mg with ritonavir 100 mg once daily. Atazanavir is rapidly absorbed with a T_max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in area under the plasma concentration-time curve (AUC) and mean maximum plasma concentration (C_max) values over the dose range of 200–800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.

Administration of atazanavir sulfate with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single dose of 400 mg atazanavir sulfate with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and a 57% increase in C_max relative to the fasting state. Administration of a single 400-mg dose of atazanavir sulfate with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% and no change in C_max relative to the fasting state. Administration of atazanavir sulfate with either a light or high fat meal decreases the coefficient of variation of AUC and C_max by approximately one-half, compared to the fasting state.

Coadministration of a single 300-mg dose of atazanavir sulfate and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C_max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C_max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T_max increased from 2.0 to 5.0 hours. Coadministration of atazanavir sulfate with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state.

Atazanavir is 86% bound to human serum proteins; protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients taking atazanavir sulfate 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid (CSF) and semen. The CSF/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226; the seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir consist of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites include glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized, neither of which demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Following a single 400-mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K_inact value of 0.05 to 0.06 min^-1 and K_i value of 0.84 to 1.0 μM. Atazanavir is also a direct inhibitor for UGT1A1 (K_i=1.9 μM) and CYP2C8 (K_i=2.1 μM). Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir sulfate decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Drug interaction studies were performed with atazanavir sulfate and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. For additional information on the effects of coadministration of atazanavir sulfate on the AUC, C_max, and C_min, consult the complete prescribing information for Reyataz (atazanavir sulfate).

Atazanavir is in FDA Pregnancy Category B. Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. Nevertheless, because the studies in humans cannot rule out the possibility of harm, atazanavir sulfate should be used during pregnancy only if clearly needed. Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women receiving atazanavir sulfate in combination with nucleoside analogs. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir sulfate, including pregnant women. All infants, including neonates exposed to atazanavir sulfate in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.

An Antiretroviral Pregnancy Registry (APR) has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents. Physicians may register their patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. As of January 2010, the APR has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.

In clinical trial AI424-182, atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir/ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times the upper limit of normal). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12–19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. [9] In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and post-natal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level. 

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether atazanavir is secreted in human breast milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in the nursing infant, mothers should be instructed not to breastfeed if they are receiving atazanavir sulfate.

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

Clinical Studies of Treatment-Naïve Patients: Comparison of Ritonavir-Boosted Atazanavir Sulfate vs. Unboosted Atazanavir Sulfate: Study AI424-089 compared atazanavir sulfate 300 mg once daily with ritonavir 100 mg vs. Atazanavir sulfate 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm can be found in the complete prescribing information for Reyataz (atazanavir sulfate).

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir Sulfate 300 mg With Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naïve Patients Receiving Atazanavir Sulfate 400 mg Without Ritonavir:
ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on atazanavir sulfate 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.

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

Adverse Events/Toxicity

Cardiac Conduction Abnormalities: Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been rare reports of second-degree AV block and other conduction abnormalities. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), atazanavir should be used with caution in these patients.

Atazanavir in combination with diltiazem increased diltiazem plasma concentration by 2-fold with an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one-half should be considered and ECG monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, no clinically significant additive effect of atazanavir and atenolol on the PR interval was observed. Dose adjustment of atenolol is not required when used in combination with atazanavir. Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers [other than atenolol, see Drug Interactions], verapamil, and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A (eg, verapamil).

Rash: In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with atazanavir sulfate. The median time to onset of rash in clinical studies was
7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies. Dosing with atazanavir sulfate was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Atazanavir sulfate should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported in patients receiving atazanavir sulfate.

Hyperbilirubinemia: Most patients taking atazanavir sulfate experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir sulfate. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times ULN. Alternative antiretroviral therapy to atazanavir sulfate may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established.

Hepatotoxicity: Caution should be exercised when administering atazanavir sulfate to patients with hepatic impairment because atazanavir concentrations may be increased. Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, appropriate laboratory testing should be conducted prior to initiating therapy with atazanavir sulfate and these patients should be monitored during treatment.

Nephrolithiasis: Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving atazanavir sulfate therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

Diabetes Mellitus/Hyperglycemia: New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in some patients treated with combination antiretroviral therapy, including atazanavir sulfate. During the initial phase of combination antiretroviral therapy, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Hemophilia: There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-Resistance: Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.

The most common treatment-emergent adverse reactions (≥2%) in treatment-naïve and treatment-experienced adults are nausea, jaundice/scleral icterus, rash, and myalgia.

The safety profile of atazanavir sulfate in pediatric patients (6 to less than 18 years of age) was comparable to that observed in clinical studies of atazanavir sulfate in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric patients were cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in 2% of patients. The most common Grade 3–4 laboratory abnormality was elevation of total bilirubin (≥3.2 mg/dL) which occurred in 49% of pediatric patients. All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Drug and Food Interactions

Atazanavir sulfate capsules must be taken with food. Administration of atazanavir sulfate with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single dose of 400 mg atazanavir sulfate with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and a 57% increase in C_max relative to the fasting state. Administration of a single 400-mg dose of atazanavir sulfate with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% and no change in C_max relative to the fasting state. Administration of atazanavir sulfate with either a light or high fat meal decreases the coefficient of variation of AUC and C_max by approximately one-half, compared to the fasting state.

Coadministration of a single 300-mg dose of atazanavir sulfate and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C_max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C_max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of atazanavir sulfate with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state.

Atazanavir sulfate is contraindicated when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

Drugs That Are Contraindicated with Reyataz (atazanavir sulfate) (Information below applies to atazanavir sulfate with or without ritonavir, unless otherwise indicated):

• Alpha 1Adrenoreceptor Antagonist: Alfuzosin. Potential for increased alfuzosin concentrations, which can result in hypotension.
• Antimycobacterials: Rifampin. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
• Antineoplastics: Irinotecan. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
• Benzodiazepines: Triazolam, orally administered midazolam. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with atazanavir sulfate may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
• Ergot Derivatives: Dihydroergotamine, ergotamine, ergonovine, methylergonovine. Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
• GI Motility Agent: Cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Herbal Products: St. John’s wort (Hypericum perforatum). Patients taking atazanavir sulfate should not use products containing St. John’s wort because coadministration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.
• HMG-CoA Reductase Inhibitors: Lovastatin, simvastatin. Potential for serious reactions such as myopathy including rhabdomyolysis.
• Neuroleptic: Pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• PDE5 Inhibitor: Sildenafil when dosed as Revatio for the treatment of pulmonary arterial hypertension. A safe and effective dose in combination with atazanavir sulfate has not been established for sildenafil (Revatio) when used for the treatment of pulmonary hypertension. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
• Protease Inhibitors: Indinavir. Both atazanavir sulfate and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

Potential for Reyataz (atazanavir sulfate) to Affect Other Drugs:
Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir sulfate and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Caution should be used when atazanavir sulfate without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir sulfate with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir sulfate is coadministered with ritonavir. See the complete prescribing information for Norvir (ritonavir) for information on drug interactions with ritonavir.

Potential for Other Drugs to Affect Atazanavir:
Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir sulfate’s therapeutic effect. Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H₂-receptor antagonists are administered with atazanavir.

Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information below applies to Reyataz [atazanavir sulfate] with or without ritonavir, unless otherwise indicated)

• Didanosine buffered formulations enteric-coated (EC) capsules: Coadministration of atazanavir sulfate with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that atazanavir sulfate be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir sulfate with food results in a decrease in didanosine exposure. Thus, atazanavir sulfate and didanosine EC should be administered at different times.

• Tenofovir disoproxil fumarate: Tenofovir may decrease the AUC and C_min of atazanavir. When coadministered with tenofovir, it is recommended that atazanavir sulfate 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). Atazanavir sulfate without ritonavir should not be coadministered with tenofovir. Atazanavir sulfate increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving atazanavir sulfate and tenofovir should be monitored for tenofovirassociated adverse events. For pregnant women taking atazanavir sulfate with ritonavir and tenofovir, see Dosage and Administration.

• Efavirenz: Efavirenz decreases atazanavir exposure. In treatment-naive patients: If atazanavir sulfate is combined with efavirenz, atazanavir sulfate 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Do not coadminister atazanavir sulfate with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.

• Nevirapine: Do not coadminister atazanavir sulfate with nevirapine because 1) nevirapine substantially decreases atazanavir exposure and 2) potential risk for nevirapine associated toxicity due to increased nevirapine exposures.

• Saquinavir (soft gelatin capsules): Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with atazanavir sulfate 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy.

• Ritonavir: If atazanavir sulfate is coadministered with ritonavir, it is recommended that atazanavir sulfate 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for Norvir (ritonavir) for information on drug interactions with ritonavir.

• Other Protease Inhibitors: Atazanavir/ritonavir: Although not studied, the coadministration of atazanavir/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.

• Antacids and buffered medications: Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with atazanavir sulfate. Atazanavir sulfate should be administered 2 hours before or 1 hour after these medications.

• Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine. Coadministration with atazanavir sulfate has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with Reyataz (atazanavir sulfate).

• Warfarin: Coadministration with atazanavir sulfate has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.

• Tricyclic antidepressants: Coadministration with atazanavir sulfate has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir sulfate.

• Trazodone: Concomitant use of trazodone and atazanavir sulfate with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as atazanavir sulfate, the combination should be used with caution and a lower dose of trazodone should be considered.

• Antifungals: ketoconazole, itraconazole. Coadministration of ketoconazole has only been studied with atazanavir sulfate without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with atazanavir/ritonavir.
 
• Antifungals: voriconazole. Coadministration of voriconazole with atazanavir sulfate, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving atazanavir/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with atazanavir sulfate (without ritonavir) may increase atazanavir concentrations; however, no data are available.

• Colchicine: Atazanavir sulfate should not be coadministered with colchicine to patients with renal or hepatic impairment.

Recommended dosage of colchicine when administered with atazanavir sulfate:

Treatment of gout flares:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.
Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

• Rifabutin: A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.

• Parenterally administered midazolam: Concomitant use of parenteral midazolam with atazanavir sulfate may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with atazanavir sulfate is CONTRAINDICATED.

• Calcium channel blockers: diltiazem. Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of atazanavir/ritonavir with diltiazem has not been studied.

• Calcium channel blockers (eg, felodipine, nifedipine, nicardipine, and verapamil). Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.

• Bosentan: Plasma concentrations of atazanavir may be decreased when bosentan is administered with atazanavir sulfate without ritonavir. Coadministration of bosentan and atazanavir sulfate without ritonavir is not recommended.

Coadministration of bosentan in patients on atazanavir/ritonavir:
For patients who have been receiving atazanavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

Coadministration of atazanavir/ritonavir in patients on bosentan:
Discontinue bosentan at least 36 hours before starting atazanavir/ritonavir. At least 10 days after starting atazanavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.

• HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin. Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.

• H₂-Receptor antagonists: Plasma concentrations of atazanavir were substantially decreased when atazanavir sulfate 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.

In treatment-naïve patients:
Atazanavir sulfate 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. An H₂-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with atazanavir sulfate 300 mg with ritonavir 100 mg in treatment-naïve patients.
OR
For patients unable to tolerate ritonavir, atazanavir sulfate 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, atazanavir sulfate should not be used without ritonavir in pregnant women.

In treatment-experienced patients:
Whenever an H₂-receptor antagonist is given to a patient receiving atazanavir sulfate with ritonavir, the H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the atazanavir sulfate and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H₂-receptor antagonist.

• Atazanavir sulfate 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H₂-receptor antagonist. For pregnant women taking atazanavir sulfate with ritonavir and an H₂-receptor antagonist, see Dosage and Administration.
• Atazanavir sulfate 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H₂-receptor antagonist. For pregnant women taking atazanavir sulfate with ritonavir and both tenofovir and an H₂-receptor antagonist, see Dosage and Administration.

• Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone. Use with caution if coadministration of atazanavir sulfate or atazanavir/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with atazanavir plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If atazanavir sulfate is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.

Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.

Coadministration of atazanavir sulfate or atazanavir/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.

• Immunosuppressants: cyclosporin, sirolimus, tacrolimus. Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with Reyataz (atazanavir sulfate).

• Inhaled beta agonist: salmeterol. Coadministration of salmeterol with atazanavir sulfate is not recommended. Concomitant use of salmeterol and atazanavir sulfate may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

• Inhaled/nasal steroid: fluticasone. Concomitant use of fluticasone propionate and atazanavir sulfate (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.

Concomitant use of fluticasone propionate and atazanavir/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and atazanavir/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

• Clarithromycin: Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir sulfate. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of atazanavir/ritonavir with clarithromycin has not been studied.

• Buprenorphine: Coadministration of buprenorphine and atazanavir sulfate with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of atazanavir sulfate plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and atazanavir sulfate with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and atazanavir sulfate without ritonavir may decrease atazanavir plasma concentrations. Atazanavir sulfate without ritonavir should not be coadministered with buprenorphine.

• PDE5 inhibitors: sildenafil, tadalafil, vardenafil. Coadministration with atazanavir sulfate has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Use of Revatio (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with atazanavir sulfate.

The following dose adjustments are recommended for the use of Adcirca (tadalafil) with atazanavir sulfate:

• Coadministration of Adcirca in patients on atazanavir sulfate (with or without ritonavir): For patients receiving atazanavir sulfate (with or without ritonavir) for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
• Coadministration of atazanavir sulfate (with or without ritonavir) in patients on Adcirca: Avoid the use of Adcirca when starting atazanavir sulfate (with or without ritonavir). Stop Adcirca at least 24 hours before starting atazanavir sulfate (with or without ritonavir). At least one week after starting atazanavir sulfate (with or without ritonavir), resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

• Use Viagra (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
• Use Cialis (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
• Atazanavir/ritonavir: Use Levitra (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
• Atazanavir sulfate: Use Levitra (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.

• Proton-pump inhibitors: omeprazole.  Plasma concentrations of atazanavir were substantially decreased when omeprazole atazanavir sulfate 400 mg or atazanavir 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.

In treatment-naïve patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the atazanavir sulfate 300 mg with ritonavir 100 mg dose.

In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatment-experienced patients receiving atazanavir sulfate.

Drugs with No Observed or Predicted Interactions with Atazanavir Sulfate
Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for Norvir for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between Reyataz (atazanavir sulfate) and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir sulfate does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interactions were observed when atazanavir sulfate was coadministered with methadone, fluconazole, acetaminophen, or atenolol.

For additional drug interaction data, consult the complete prescribing information for Reyataz (atazanavir sulfate).

Contraindications

Reyataz (atazanavir sulfate) is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

Drugs That Are Contraindicated with Reyataz (atazanavir sulfate) (Information below applies to atazanavir sulfate with or without ritonavir, unless otherwise indicated):

• Alpha 1Adrenoreceptor Antagonist: Alfuzosin. Potential for increased alfuzosin concentrations, which can result in hypotension.
• Antimycobacterials: Rifampin. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
• Antineoplastics: Irinotecan. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
• Benzodiazepines: Triazolam, orally administered midazolam. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with atazanavir sulfate may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
• Ergot Derivatives: Dihydroergotamine, ergotamine, ergonovine, methylergonovine. Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
• GI Motility Agent: Cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Herbal Products: St. John’s wort (Hypericum perforatum). Patients taking atazanavir sulfate should not use products containing St. John’s wort because coadministration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.
• HMG-CoA Reductase Inhibitors: Lovastatin, simvastatin. Potential for serious reactions such as myopathy including rhabdomyolysis.
• Neuroleptic: Pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• PDE5 Inhibitor: Sildenafil when dosed as Revatio for the treatment of pulmonary arterial hypertension. A safe and effective dose in combination with atazanavir sulfate has not been established for sildenafil (Revatio) when used for the treatment of pulmonary hypertension. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
• Protease Inhibitors: Indinavir. Both atazanavir sulfate and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. [1]  [2]

References

[1] FDA Reyataz Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed 09/01/2011.

[2] FDA Reyataz Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021567s027lbl.pdf. Accessed 03/04/2012.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Atazanavir.

Chemistry

CAS Name

2,5,6,10,13-Pentaazatetradecanedioic acid, 3,12-bis(1,1-dimethylethyl)-8-hydroxy- 4,11-dioxo-9-(phenylmethyl)-6-((4-(2- pyridinyl)phenyl)methyl)-, dimethyl ester, (3S,8S,9S,12S)-, sulfate (1:1) (salt) (atazanazir sulfate) [1]

CAS Number

229975-97-7 (atazanavir sulfate) [2]

Molecular Formula

C38-H52-N6-O7.H2-SO4 (atazanavir sulfate) [3]

Molecular Weight

802.93 (atazanavir sulfate) [4]

Physical Description

White to pale yellow crystalline powder. [5]

Solubility

Slightly soluble in water (4 to 5 mg/mL, free base equivalent), with the pH of a saturated solution in water of about 1.9 at 24 +/- 3°C. [6]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 09/01/2011.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 09/01/2011.

[3] FDA Reyataz Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed 09/01/2011.

[4] FDA Reyataz Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed 09/01/2011.

[5] FDA Reyataz Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed 09/01/2011.

[6] FDA Reyataz Prescribing Information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed 09/01/2011.

Further Reading

Reyataz Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Barreiro P, Rendon A, Rodriguez-Novoa S, Soriano V. Atazanavir: the advent of a new generation of more convenient protease inhibitors. HIV Clin Trials. 2005 Jan-Feb;6(1):50-61. Review.
Feldt T, Oette M, Kroidl A, Gobels K, Leidel R, Sagir A, Kuschak D, Haussinger D. Atazanavir for treatment of HIV infection in clinical routine: efficacy, pharmacokinetics and safety. Eur J Med Res. 2005 Jan 28;10(1):7-10.
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Manufacturer Information

Atazanavir

Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335

Reyataz

Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335