Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]

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Determine the number of packets (3, 4, 5 or 6 packets) that are needed.

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Prior to mixing, tap the packet to settle the powder.

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It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.

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Use a clean pair of scissors to cut each packet along the dotted line.

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Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.

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Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.

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Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.

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Administer ritonavir immediately following REYATAZ powder administration.

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Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.

Adverse Reactions in Treatment-Naive Adult Subjects

The safety profile of REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive subjects receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Adverse Reactions in Treatment-Experienced Adult Subjects

The safety profile of REYATAZ in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced subjects receiving REYATAZ with ritonavir are presented in Table 9.

Laboratory Abnormalities in Treatment-Naive Subjects

The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection

The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14.

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Capsules

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of REYATAZ in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric subjects were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of subjects. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Oral Powder

The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least 5 kg to less than 35 kg, including 134 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All subjects received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.

In Study AI424-045, 20 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir-treated. AST levels >5 times ULN developed in 10% (2/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.

In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the subjects treated with REYATAZ, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions (5.8)].

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data].

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

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REYATAZ must be administered with ritonavir in pregnant patients.

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For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:

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

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No dosage 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 [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Data

Risk Summary

The Centers for Disease Control and Prevention recommend that patients with HIV-1 infection, not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed.

Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In 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 [see Warnings and Precautions (5.1)].

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

Absorption

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.

Food Effect

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

Coadministration of a single 300-mg dose of REYATAZ 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 Cmax 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 Cmax 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 REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Distribution

Atazanavir is 86% bound to human serum proteins and 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 subjects with HIV-1 infection dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Metabolism

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

Elimination

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 subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Specific Populations

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=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, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

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 ritonavir for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).

Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).

Mechanism of Action

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Antiviral Activity in Cell Culture

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 (1.9-32 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 PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir 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 atazanavir and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Subjects: Comparison of Ritonavir-Boosted REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in treatment-naive subjects with HIV-1 infection. A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23.

Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from subjects who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir 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 atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir 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 atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir 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 lopinavir/ritonavir arm, one of the virologic failure subject isolates had a 69-fold decrease in lopinavir 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 lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive subjects who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir 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 subjects, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir 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 Subjects: In studies of treatment-experienced subjects treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from subjects 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 subjects who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF 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 atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of subject isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the subject at baseline, atazanavir 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 subjects experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment but their presence did not correlate with the level of atazanavir resistance.

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one subject among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold-change of 3.5, with a ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one subject each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two subjects who failed treatment with atazanavir with ritonavir. Viruses from nine subjects in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1).

Cross-Resistance

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

Baseline Genotype/Phenotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced subjects receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced subjects. In the atazanavir with ritonavir group, subjects had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to subjects with 1–2 PI substitutions, including one of these substitutions.

The response rates of antiretroviral-experienced subjects in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of subjects receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Mutagenesis

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Impairment of Fertility

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.

Pediatric Trials with REYATAZ Capsules

Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from this open-label, multicenter clinical trial which included subjects from 6 years to 21 years of age. In this study, 105 subjects (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) subjects (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and experienced subjects with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive subjects and 220 cells/mm3 in antiretroviral-experienced subjects.

Pediatric Trials with REYATAZ Oral Powder

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.

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AI424-397 (PRINCE I; NCT01099579): In pediatric subjects from 3 months to less than 6 years of age

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AI424-451 (PRINCE II; NCT01335698): In pediatric subjects from 3 months to less than 11 years of age

In these studies 155 subjects (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder with ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive subjects had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced subjects had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Subjects exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Subjects who received REYATAZ or REYATAZ with ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.

One hundred thirty-four (134) subjects from both studies weighing 5 kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated. Subjects 5 kg to less than 10 kg received either 150 mg or 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution; and subjects 25 kg to less than 35 kg received 300 mg REYATAZ and 100 mg ritonavir.

Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced subjects with HIV-1 RNA <400 copies/mL at Week 48 were 79% (41/52) and 62% (51/82), respectively in subjects who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced subjects with HIV-1 RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively, in subjects who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy (last observation carried forward) was 215 cells/mm3 (6%) in antiretroviral-naive subjects and 133 cells/mm3 (4%) in antiretroviral-experienced subjects who received REYATAZ oral powder with ritonavir.

REYATAZ Capsules

REYATAZ® (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.

Keep capsules in a tightly closed container.

Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

REYATAZ Oral Powder

REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See Dosage and Administration (2.5)].

Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). Store REYATAZ oral powder in the original packet. Do not open until ready to use. After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid.

Cardiac Conduction Abnormalities

Inform patients that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Tell patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)].

Severe Skin Reaction

Inform patients that there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue REYATAZ and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Hyperbilirubinemia

Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8)].

Patients with Phenylketonuria

Advise caregivers of patients with phenylketonuria that REYATAZ oral powder contains phenylalanine [see Warnings and Precautions (5.3)].

Chronic Kidney Disease

Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ [see Warnings and Precautions (5.5)].

Nephrolithiasis and Cholelithiasis

Inform patients that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6)].

Drug Interactions

REYATAZ may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort, to their healthcare provider prior to use [see Contraindications (4), Warnings and Precautions (5.7)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.10)].

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11)].

Dosing Instructions

Advise patients to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if a dose of REYATAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped the patient should not double the next dose.

Pregnancy

Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. REYATAZ can also be passed to the baby in breast milk and it is not known whether it could harm the baby [see Use in Specific Populations (8.2)].