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F1-b0001_reyataz full pi 06_05

REYATAZ®
Pharmacokinetics
The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of REYATAZ
(atazanavir sulfate) Capsules
(atazanavir sulfate) 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 3).
Table 3: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or HIV-Infected Patients in the Fed State
(Patient Information Leaflet Included)
300 mg with ritonavir
DESCRIPTION
400 mg once daily
________________
100 mg once daily
_________________
REYATAZ® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.
HIV-Infected
HIV-Infected
The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)- Subjects
Patients
Subjects
Patients
6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is Parameter (n=14)
C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9.
Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.
REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, or 200 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, and titanium dioxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and Figure 1 displays the mean plasma concentrations of atazanavir at steady-state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light CLINICAL PHARMACOLOGY
meal in HIV-infected adult patients.
Microbiology
Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10)
for HIV-Infected Adult Patients
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viralGag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
Antiviral Activity In VitroAtazanavir exhibits anti-HIV-1 activity with a mean 50% inhibitory concentration (IC50) 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-2cells. Two-drug combination studies with ATV showed additive to antagonistic antiviral activity in vitro with abacavir and the NNRTIs(delavirdine, efavirenz, and nevirapine) and additive antiviral activity in vitro with the PIs (amprenavir, indinavir, lopinavir, nelfinavir, riton-avir, and saquinavir), NRTIs (didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusioninhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.
ResistanceIn vitro: HIV-1 isolates with a decreased susceptibility to ATV have been selected in vitro and obtained from patients treated with ATVor atazanavir/ritonavir (ATV/RTV). HIV-1 isolates that were 93- to 183-fold resistant to ATV from three different viral strains were selectedin vitro by 5 months. The mutations in these HIV-1 viruses that contributed to ATV resistance included I50L, N88S, I84V, A71V, and M46I.
Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50Lmutation were growth impaired and displayed increased in vitro susceptibility 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 notappear to be cross-resistant.
Clinical Studies of Treatment-Naive Patients: ATV-resistant clinical isolates from treatment-naive patients who experienced virologicfailure developed an I50L mutation (after an average of 50 weeks of ATV therapy), often in combination with an A71V mutation. Intreatment-naive patients, viral isolates that developed the I50L mutation showed phenotypic resistance to ATV but retained in vitrosusceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical dataavailable to demonstrate the effect of the I50L mutation on the efficacy of subsequently administered PIs.
Clinical Studies of Treatment-Experienced Patients: In contrast, from studies of treatment-experienced patients treated with ATV or ATV/RTV, Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater most ATV-resistant isolates from patients who experienced virologic failure developed mutations that were associated with resistance than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease mutations to develop in the viral isolates Days 4 and 8, with an accumulation of approximately 2.3-fold.
of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) includedV32I, 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 mutations that devel- oped on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single if multiple PI resistance mutations were present in the HIV-1 of the patient at baseline, ATV resistance developed through mutations 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 associated with resistance to other PIs and could include the development of the I50L mutation.
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 Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of theisolates with mutations 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 mutation in addition to other changes Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates patients dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and that developed the I50L mutation in addition to other PI-resistance-associated mutations were also cross-resistant to other PIs.
semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI-resistance-associated muta- tions detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of twice daily in Study AI424-045 is shown in Table 1.
monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuroni- Overall, both the number and type of baseline PI mutations affected response rates in treatment-experienced patients. In the ATV/RTV dation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been group, patients had lower response rates when 3 or more baseline PI mutations including a mutation at position 36, 71, 77, 82 or 90 characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that were present compared to patients with 1-2 PI mutations including one of these mutations.
Table 1: HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in
Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respec- Study AI424-045, As-Treated Analysis
tively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The Number and Type of
Virologic Response = HIV RNA <400 copies/mLb
mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours Baseline PI Mutationsa
ATV/RTV (n=110)
LPV/RTV (n=113)
at steady-state following a dose of 400 mg daily with a light meal.
3 or more primary PI mutations includingc:
Effects on Electrocardiogram
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.
(See WARNINGS.)
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 had a QTc interval >500 msec.
Special Populations
Number of baseline primary PI mutationsa
A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; ≥65 years) healthy subjects.
There were no clinically important pharmacokinetic differences observed due to age or gender.
There are insufficient data to determine whether there are any effects of race on the pharmacokinetics of atazanavir.
Primary mutations include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.
b Results should be interpreted with caution because the subgroups were small.
c There were insufficient data (n<3) for PI mutations V32I, I47V, G48V, I50V, and F53L.
The pharmacokinetics of atazanavir in pediatric patients are under investigation. There are insufficient data at this time to recommenda dose.
The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in in vitro susceptibility relative to reference, Table 2). The analyses are based on a select patient population with 62% of patients receiving an In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine There are no pharmacokinetic data available on patients with impaired renal function.
clinically relevant break points for REYATAZ.
Impaired Hepatic FunctionAtazanavir is metabolized and eliminated primarily by the liver. REYATAZ has been studied in adult subjects with moderate to severe Table 2: Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis
hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC (0-∞) was 42% greater Virologic Response = HIV RNA <400 copies/mLb
in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects Baseline Phenotypea
ATV/RTV (n=111)
LPV/RTV (n=111)
was 12.1 hours compared to 6.4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moder- ately or severely impaired hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). The pharmacokinetics of REYATAZ
in combination with ritonavir have not been studied in subjects with hepatic impairment.
Drug-Drug Interactions (see also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions)
Atazanavir is metabolized in the liver by CYP3A. Atazanavir inhibits CYP3A and UGT1A1 at clinically relevant concentrations with Ki of 2.35 µM (CYP3A4 isoform) and 1.9 µM, respectively. REYATAZ should not be administered concurrently with medications with narrow Fold change in in vitro susceptibility relative to the wild-type reference.
therapeutic windows that are substrates of CYP3A or UGT1A1 (see CONTRAINDICATIONS).
Results should be interpreted with caution because the subgroups were small.
Atazanavir competitively inhibits CYP1A2 and CYP2C9 with Ki values of 12 µM and a Cmax/Ki ratio of ~0.25. There is a potential drug- INDICATIONS AND USAGE
drug interaction between atazanavir and CYP1A2 or CYP2C9 substrates. Atazanavir does not inhibit CYP2C19 or CYP2E1 at clinically REYATAZ (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 48 weeks Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs duration in antiretroviral-naive and antiretroviral-treatment-experienced patients.
metabolized by CYP3A. In a multiple-dose study, REYATAZ (atazanavir sulfate) decreased the urinary ratio of endogenous 6β-OH cortisol The following points should be considered when initiating therapy with REYATAZ: to cortisol versus baseline, indicating that CYP3A production was not induced.
In antiretroviral-experienced patients with prior virologic failure, coadministration of REYATAZ/ritonavir is recommended.
Drugs that induce CYP3A activity may increase the clearance of atazanavir, resulting in lowered plasma • In Study AI424-045 REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of concentrations. Coadministration of REYATAZ and other drugs that inhibit CYP3A may increase atazanavir plasma concentrations.
time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of propor- as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized tions below the HIV RNA lower limit of detection (see Description of Clinical Studies).
in Tables 4 and 5. For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions, Tables 10 and 11.
The number of baseline primary protease inhibitor mutations affects the virologic response to REYATAZ/ritonavir
(see CLINICAL PHARMACOLOGY: Microbiology).
There are no data regarding the use of REYATAZ/ritonavir in therapy-naive patients.
Table 4: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs a
Description of Clinical Studies
Ratio (90% Confidence Interval)
Patients Without Prior Antiretroviral Therapy of Atazanavir Pharmacokinetic
Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + Parameters with/without
Coadministered Drug;
zidovudine twice daily. Study AI424-034 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) Coadministered
Coadministered Drug
No Effect = 1.00
to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) Dose/Schedule
Dose/Schedule
(300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL).
Treatment response and outcomes through Week 48 are presented in Table 6.
Table 6: Outcomes of Randomized Treatment Through Week 48 (Study AI424-034)
REYATAZ efavirenz
400 mg once daily
600 mg once daily
+ lamivudine
+ lamivudine
+ zidovudine d
+ zidovudine d
Outcome (n=405)
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor® HIV-1 MonitorTM Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes confirmed viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
d As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm.
Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients.
a Data provided are under fed conditions unless otherwise noted.
Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log All drugs were given under fasted conditions.
10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 7.
One subject did not receive REYATAZ.
d Compared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the atazanavir geometric Table 7: Outcomes of Randomized Treatment Through Week 48 (Study AI424-008)
mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively.
REYATAZ 400 mg once daily
nelfinavir 1250 mg twice daily
+ lamivudine + stavudine
+ lamivudine + stavudine
f Ratio of atazanavir plus ritonavir plus tenofovir to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir Outcome (n=181)
exposure than atazanavir 400 mg (see footnote d). The geometric mean values of atazanavir pharmacokinetic parameters when coadministeredwith ritonavir and tenofovir were: C max = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL.
Table 5: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ a
Ratio (90% Confidence Interval) of
Coadministered Drug Pharmacokinetic
Coadministered
Parameters with/without REYATAZ;
Coadministered
Drug Dose/
No Effect = 1.00
Schedule
Dose/Schedule
a Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor® HIV-1 MonitorTM Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes confirmed viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.
c Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.
Patients With Prior Antiretroviral Therapy Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 is an ongoing, randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimenscontaining PIs, NRTIs, and NNRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 283 weeks for NRTIs, and 85 weeks for NNRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL desacetyl-diltiazem: desacetyl-diltiazem: desacetyl-diltiazem: (range: 2.6 to 5.88 log10 copies/mL).
Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 8.
REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference
in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that
REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the
HIV RNA lower limit of detection. See also Tables 1 and 2 in CLINICAL PHARMACOLOGY: Microbiology.
Table 8: Outcomes of Treatment Through Week 48 in Study AI424-045 (Patients with Prior Antiretroviral
Experience)
REYATAZ 300 mg
Iopinavir/ritonavir
Differencea
+ ritonavir 100 mg
(400/100 mg)
(REYATAZ-
once daily +
twice daily+
lopinavir/
tenofovir + 1 NRTI
tenofovir + 1 NRTI
ritonavir)
Outcome (n=119)
a Time-averaged difference through Week 48 for HIV RNA; Week 48 difference in HIV RNA percentages and CD4+ mean changes, a Data provided are under fed conditions unless otherwise noted.
REYATAZ/ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV RNA; 95% confidence interval otherwise.
b All drugs were given under fasted conditions.
b Roche Amplicor® HIV-1 MonitorTM Assay, test version 1.5.
c One subject did not receive REYATAZ.
c Protocol-defined primary efficacy outcome measure.
d Not the recommended therapeutic dose of atazanavir.
d Based on patients with baseline and Week 48 CD4+ cell count measurements (REYATAZ/ritonavir, n=85; lopinavir/ritonavir, n=93).
e The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard e Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48.
therapeutic dosing of saquinavir at 1200 mg TID. However, the Cmax is about 79% higher than that for the standard dosing of saquinavir (soft No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.
In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ (atazanavir sulfate) 400 mg with saquinavir (n=115) was -1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ (atazanavir The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of patients sulfate). During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis saquinavir did not provide adequate efficacy (see PRECAUTIONS: Drug Interactions, Table 11).
carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Study AI424-045 also compared changes from baseline in lipid values (see ADVERSE REACTIONS, Table 17).
Information for Patients
Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about
lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to medicines that should NOT be taken with REYATAZ. A Patient Package Insert (PPI) for REYATAZ is available for patient information.
only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The progression to AIDS and death. Patients should remain under the care of a physician while using REYATAZ. Patients should be mean change from baseline was -1.59 log10 copies/mL in the REYATAZ treatment arm and -2.02 log10 copies/mL in the lopinavir/ advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always ritonavir arm. Based on the results of this study, REYATAZ without ritonavir is inferior to lopinavir/ritonavir in PI-experienced patients be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with with prior virologic failure and is not recommended for such patients.
their doctor. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule.
CONTRAINDICATIONS
However, if a dose is skipped, the patient should not double the next dose.
REYATAZ is contraindicated in patients with known hypersensitivity to any of its ingredients, including atazanavir.
Patients should be informed that REYATAZ is not a cure for HIV infection and that they may continue to develop Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 9.
demonstrating that therapy with REYATAZ can reduce the risk of transmitting HIV to others through sexual contact.
REYATAZ may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescrip- tion, nonprescription medication, or herbal products, particularly St. John’s wort.
Table 9: Drugs That Are Contraindicated with REYATAZ Due to Potential CYP450-Mediated Interactions*
Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 Drug class
Drugs within class that are contraindicated with REYATAZ
inhibitor-associated adverse events including hypotension, visual changes, and prolonged penile erection, and should promptly report dihydroergotamine, ergotamine, ergonovine, methylergonovine Patients should be informed that atazanavir may produce changes in the electrocardiogram (PR prolongation). Patients should consult their physician if they are experiencing symptoms such as dizziness or lightheadedness.
REYATAZ should be taken with food to enhance absorption.
Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This * Please see Table 10 for additional drugs that should not be coadministered with REYATAZ.
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.
WARNINGS
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including ALERT: Find out about medicines that should NOT be taken with REYATAZ. This statement is included on the product’s bottle
protease inhibitors, and that the cause and long-term health effects of these conditions are not known at this time. It is unknown whether label. (See CONTRAINDICATIONS, WARNINGS: Drug Interactions, and PRECAUTIONS: Drug Interactions.)
long-term use of REYATAZ will result in a lower incidence of lipodystrophy than with other protease inhibitors.
Drug Interactions
Drug Interactions
Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A (eg, calcium Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase (PDE5) inhibitors) or UGT1A1 (eg, irinotecan) channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) or UGT1A1 (eg, irinotecan) may result in may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. (Also increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects (see Tables see PRECAUTIONS: Drug Interactions, Tables 10 and 11.)
10 and 11). Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Coadministration of REYATAZ and drugs Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction (eg, sildenafil, tadalafil, or vardenafil) that induce CYP3A, such as rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration for patients receiving protease inhibitors, including REYATAZ. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected of REYATAZ and drugs that inhibit CYP3A may increase atazanavir plasma concentrations.
to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, The potential for drug interactions with REYATAZ changes when REYATAZ is coadministered with the potent CYP3A inhibitor including hypotension, visual changes, and priapism. (See PRECAUTIONS: Drug Interactions and Information for Patients, and the
ritonavir. The magnitude of CYP3A-mediated drug interactions (effect on atazanavir or effect on coadministered drug) may change when complete prescribing information for the PDE5 inhibitor.) REYATAZ is coadministered with ritonavir. See the complete prescribing information for Norvir® (ritonavir) for information on drug Concomitant use of REYATAZ with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including REYATAZ, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A pathway Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if antacids, buffered (eg, atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, medications, H2-receptor antagonists, and proton-pump inhibitors are administered with atazanavir.
are used in combination with these drugs.
Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate expo- coadministering REYATAZ with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem [see Table 11]).
sures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of REYATAZ with ritonavir and fluticasone Drugs that are contraindicated or not recommended for coadministration with REYATAZ are included in Table 10. These recommendations propionate is expected to produce the same effects. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluti- casone propionate. Therefore, coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the
potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS: Drug Interactions).
Table 10: Drugs That Should Not Be Administered with REYATAZ
Concomitant use of REYATAZ and St. John's wort (Hypericum perforatum), or products containing St. John's wort, is not recom- Drug Class: Specific Drugs
Clinical Comment
mended. Coadministration of protease inhibitors, including REYATAZ, with St. John's wort is expected to substantially decreaseconcentrations of the protease inhibitor and may result in suboptimal levels of atazanavir and lead to loss of virologic response and possible Decreases plasma concentrations and AUC of most protease inhibitors by about resistance to atazanavir or to the class of protease inhibitors.
90%. This may result in loss of therapeutic effect and development of resistance.
Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, PR Interval Prolongation
resulting in increased irinotecan toxicities.
Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, CONTRAINDICATED due to potential for serious and/or life-threatening events abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been such as prolonged or increased sedation or respiratory depression.
rare reports of second-degree AV block and other conduction abnormalities and no reports of third-degree AV block (see OVERDOSAGE).
CONTRAINDICATED due to potential for serious and/or life-threatening events In clinical trials, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of such as acute ergot toxicity characterized by peripheral vasospasm and lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients ischemia of the extremities and other tissues.
(n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patientsand 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical CONTRAINDICATED due to potential for serious and/or life-threatening reactions experience, atazanavir should be used with caution in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). (See CLINICAL PHARMACOLOGY: Effects on Electrocardiogram.)
Potential for serious reactions such as myopathy including rhabdomyolysis.
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. When used in combination with atazanavir, CONTRAINDICATED due to potential for serious and/or life-threatening reactions 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, there was no substantial additive effect of atazanavir and atenolol on the Both REYATAZ and indinavir are associated with indirect (unconjugated) PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol. (See PRECAUTIONS: Drug Interactions.)
hyperbilirubinemia. Combinations of these drugs have not been studied and Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers (other than atenolol), coadministration of REYATAZ and indinavir is not recommended.
verapamil, and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, Concomitant use of REYATAZ and proton-pump inhibitors is not recommended. caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A Coadministration of REYATAZ with proton-pump inhibitors is expected to substantially (eg, verapamil). (See PRECAUTIONS: Drug Interactions.)
decrease REYATAZ plasma concentrations and reduce its therapeutic effect.
Diabetes Mellitus/Hyperglycemia
Patients taking REYATAZ should not use products containing St. John’s wort New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmar- (Hypericum perforatum) because coadministration may be expected to reduce keting surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose plasma concentrations of atazanavir. This may result in loss of therapeutic adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.
effect and development of resistance.
In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have beenreported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor Table 11: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be
therapy and these events has not been established.
Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table
applies to REYATAZ with or without ritonavir, unless otherwise indicated)

PRECAUTIONS
General

Concomitant
Effect on Concentration
Drug Class:
of Atazanavir or
Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl Specific Drugs
Concomitant Drug
Clinical Comment
transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur HIV Antiviral Agents
with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing Coadministration of REYATAZ with didanosine buffered tablets persistent elevations in total bilirubin >5 times ULN. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral did not alter exposure to didanosine; however, exposure to atazanavir icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended was markedly decreased (presumably due to the increase in since long-term efficacy of reduced doses has not been established. (See ADVERSE REACTIONS: Laboratory Abnormalities, Tables
gastric pH caused by buffers in the didanosine tablets). In addition, it is recommended that didanosine be administered on an empty stomach; therefore, REYATAZ should be given (with food) 2 h before In controlled clinical trials (n=1597), rash (all grades, regardless of causality) occurred in 21% of patients treated with REYATAZ. The or 1 h after didanosine buffered formulations (see CLINICAL
median time to onset of rash was 8 weeks after initiation of REYATAZ and the median duration of rash was 1.3 weeks. Rashes were PHARMACOLOGY: Drug-Drug Interactions). Because didanosine
generally mild-to-moderate maculopapular skin eruptions. Dosing with REYATAZ was often continued without interruption in patients EC capsules are to be given on an empty stomach and REYATAZ who developed rash. The discontinuation rate for rash in clinical trials was 0.4%. REYATAZ should be discontinued if severe rash develops.
is to be given with food, they should be administered at different times.
Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving REYATAZ.
coadministered with tenofovir, it is recommended that REYATAZ Atazanavir is principally metabolized by the liver; caution should be exercised when administering this drug to patients with hepatic 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as impairment because atazanavir concentrations may be increased (see DOSAGE AND ADMINISTRATION). Patients with underlying hepatitis
a single daily dose with food). REYATAZ without ritonavir should
B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transam- not be coadministered with tenofovir. REYATAZ increases tenofovir
inase elevations or hepatic decompensation. There are no clinical trial data on the use of REYATAZ/ritonavir in patients with any degree concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subse- tenofovir should be monitored for tenofovir-associated adverse events.
quent use of other protease inhibitors. (See CLINICAL PHARMACOLOGY: Microbiology.)
In treatment-naive patients who receive efavirenz and REYATAZ, the recommended dose is REYATAZ 300 mg with ritonavir 100 mg and There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia efavirenz 600 mg (all once daily), as this combination results in atazanavir type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, exposure that approximates the mean exposure to atazanavir produced by treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these 400 mg of REYATAZ alone. Dosing recommendations for efavirenz and REYATAZ in treatment-experienced patients have not been established.
REYATAZ/ritonavir: The effects of coadministration have not been
studied. Nevirapine, an inducer of CYP3A, is expected to decrease Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, atazanavir exposure. In the absence of data, coadministration is not 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.
a For magnitude of interactions, see CLINICAL PHARMACOLOGY: Tables 4 and 5.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Table 11:
Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May
Two-year carcinogenicity studies in mice and rats were conducted with atazanavir. At the high dose in female mice, the incidence of (continued) Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the
benign hepatocellular adenomas was increased at systemic exposures 7.2–fold higher than those in humans at the table applies to REYATAZ (atazanavir sulfate) with or without ritonavir, unless otherwise indicated)
recommended 400–mg clinical dose. There were no increases in the incidence of tumors in male mice at any dose in the study. In rats, Concomitant
Effect on Concentration
no significant positive trends in the incidence of neoplasms occurred at systemic exposures up to 5.7-fold higher than those in humans Drug Class:
of Atazanavir or
at the recommended 400–mg clinical dose. The clinical relevance of the carcinogenic findings in female mice is unknown. Specific Drugs
Concomitant Drug
Clinical Comment
Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of meta- bolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in HIV Antiviral Agents
rats, and in vivo DNA damage test in rat duodenum (comet assay). Appropriate dosing recommendations for this combination, with or At the systemic drug exposure levels (AUC) equal to (in male rats) or two times (in female rats) those at the human clinical dose without ritonavir, with respect to efficacy and safety, have not been (400 mg once daily), atazanavir did not produce significant effects on mating, fertility, or early embryonic development.
established. In a clinical study, saquinavir 1200 mg coadministeredwith REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus Pregnancy
nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy (see Description of Clinical Studies).
At maternal doses producing the systemic drug exposure levels equal to (in rabbits) or two times (in rats) those at the human clinicaldose (400 mg once daily), atazanavir did not produce teratogenic effects. In the pre- and post-natal development assessment in rats, If REYATAZ is coadministered with ritonavir, it is recommended that atazanavir, at maternally toxic drug exposure levels two times those at the human clinical dose, caused body weight loss or weight REYATAZ 300 mg once daily be given with ritonavir 100 mg oncedaily with food. See the complete prescribing information for gain suppression in the offspring. Offspring were unaffected at a lower dose that produced maternal exposure equivalent to that observed Norvir® (ritonavir) for information on drug interactions with ritonavir.
Hyperbilirubinemia occurred frequently during treatment with REYATAZ (atazanavir sulfate). It is not known whether REYATAZ admin- REYATAZ/ritonavir: Although not studied, the coadministration of
istered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young REYATAZ/ritonavir and other protease inhibitors would be expected to infants. In the prepartum period, additional monitoring and alternative therapy to REYATAZ should be considered. increase exposure to the other protease inhibitor. Such coadministration There are no adequate and well-controlled studies in pregnant women. Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients (including pregnant women) receiving REYATAZ in combination with Other Agents
nucleoside analogues, which are known to be associated with increased risk of lactic acidosis syndrome. REYATAZ should be used during Reduced plasma concentrations of atazanavir are expected if pregnancy only if the potential benefit justifies the potential risk to the fetus. antacids, including buffered medications, are administered with Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral
REYATAZ. REYATAZ should be administered 2 h before or 1 h after Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
Coadministration with REYATAZ has the potential to produce serious The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid
and/or life-threatening adverse events and has not been studied. Caution risking postnatal transmission of HIV. It is not known whether atazanavir is secreted in human milk. A study in lactating rats has
is warranted and therapeutic concentration monitoring of these drugs demonstrated that atazanavir is secreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse is recommended if they are used concomitantly with REYATAZ.
reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving REYATAZ.
Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is Pediatric Use
recommended that INR (International Normalized Ratio) be monitored.
The optimal dosing regimen for use of REYATAZ in pediatric patients has not been established. REYATAZ should not be administeredto pediatric patients below the age of 3 months due to the risk of kernicterus.
Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been Geriatric Use
studied. Concentration monitoring of these drugs is recommended Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond if they are used concomitantly with REYATAZ.
differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjust- ment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring Concomitant use of trazodone and REYATAZ with or without ritonavir of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observedfollowing coadministration of trazodone and ritonavir. If trazodone is ADVERSE REACTIONS
used with a CYP3A4 inhibitor such as REYATAZ, the combination Adult Patients
should be used with caution and a lower dose of trazodone should be Treatment-Emergent Adverse Events in Treatment-Naive Patients Selected drug-related clinical adverse events of moderate or severe intensity reported in ≥2% of treatment-naive patients receivingcombination therapy including REYATAZ are presented in Table 12. For other information regarding observed or potentially serious adverse REYATAZ/ritonavir
Coadministration of ketoconazole has only been studied with REYATAZ events, see WARNINGS and PRECAUTIONS.
without ritonavir (negligible increase in atazanavir AUC and Cmax).
Due to the effect of ritonavir on ketoconazole, high doses of ketoconazoleand itraconazole (>200 mg/day) should be used cautiously with Table 12: Selected Treatment-Emergent Adverse Eventsa of Moderate or Severe Intensity Reported in 2% of
Adult Treatment-Naive Patientsb
Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. However, administration of Phase III Study AI424-034
Phase II Studies AI424-007, -008
voriconazole with ritonavir 400 mg every 12 hours decreased 120 weeks c,d
73 weeks c,d
voriconazole steady-state AUC by an average of 82%. The effect of 64 weeks c
64 weeks c
REYATAZ 400 mg
nelfinavir 750 mg TID
lower ritonavir doses on voriconazole is not known at this time. Until REYATAZ 400 mg efavirenz 600 mg
once daily +
or 1250 mg BID +
data are available, voriconazole should not be administered to patients once daily +
once daily +
stavudine +
stavudine +
receiving REYATAZ/ritonavir. Coadministration of voriconazole with lamivudine +
lamivudine +
lamivudine or
lamivudine or
REYATAZ (without ritonavir) may increase atazanavir concentrations; zidovudine e
zidovudine e
didanosine
didanosine
(n=404) (n=401)
A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended.
Body as a Whole
Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of Digestive System
REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, ↑ calcium channel Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including REYATAZ, are used in combination with atorvastatin. Caution should be exercised.
Nervous System
Reduced plasma concentrations of atazanavir are expected ifH 2-receptor antagonists are administered with REYATAZ. This may result in loss of therapeutic effect and development of resistance.
To lessen the effect of H2-receptor antagonists on atazanavir exposure, Skin and Appendages
it is recommended that an H2-receptor antagonist and REYATAZ be administered as far apart as possible, preferably 12 hours apart.
* None reported in this treatment arm.
Therapeutic concentration monitoring is recommended for a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
immunosuppressant agents when coadministered with b Based on regimens containing REYATAZ.
Concomitant use of fluticasone and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate.
e As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Use with caution. Consider alternatives to fluticasone propionate,particularly for long-term use.
Treatment-Emergent Adverse Events in Treatment-Experienced Patients REYATAZ/ritonavir
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may Selected drug-related clinical adverse events of moderate-severe intensity in ≥2% of treatment-experienced patients receiving increase plasma concentrations of fluticasone propionate, resulting in REYATAZ/ritonavir are presented in Table 13. For other information regarding observed or potentially serious adverse events, see significantly reduced serum cortisol concentrations. Coadministration WARNINGS and PRECAUTIONS.
of fluticasone propionate and REYATAZ/ritonavir is not recommended
unless the potential benefit to the patient outweighs the risk of
systemic corticosteroid side effects (see WARNINGS).
Table 13: Selected Treatment-Emergent Adverse Eventsa of Moderate or Severe Intensity Reported in 2% of Adult
Treatment-Experienced Patientsb, Study AI424-045
Increased concentrations of clarithromycin may cause QTc prolongations; ↓ 14-OH clarithromycin therefore, a dose reduction of clarithromycin by 50% should be 48 weeksc
48 weeksc
considered when it is coadministered with REYATAZ. In addition, REYATAZ/ritonavir lopinavir/ritonavir
concentrations of the active metabolite 14-OH clarithromycin are 300/100 mg once daily
400/100 mg twice dailyd
significantly reduced; consider alternative therapy for indications + tenofovir + NRTI
+ tenofovir + NRTI
other than infections due to Mycobacterium avium complex.
(n=119) (n=118)
Coadministration of REYATAZ/ritonavir with clarithromycin has not Body as a Whole
Hormonal contraceptives: ↑ ethinyl estradiol Coadministration of REYATAZ/ritonavir with hormonal contraceptives has Digestive System
not been studied. However, higher doses of ritonavir, without REYATAZ, decrease contraceptive steroid concentrations. Because contraceptive steroid concentrations may be altered when REYATAZ or REYATAZ/ritonavir is coadministered with oral contraceptives or with the contraceptive Nervous System
patch, alternate methods of nonhormonal contraception are recommended.
Coadministration with REYATAZ has not been studied but may Musculoskeletal System
result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. Use sildenafil * None reported in this treatment arm.
with caution at reduced doses of 25 mg every 48 hours with a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
increased monitoring for adverse events. Use tadalafil with caution b Based on the regimen containing REYATAZ (atazanavir sulfate).
at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
Laboratory Abnormalities
For magnitude of interactions, see CLINICAL PHARMACOLOGY: Tables 4 and 5.
The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ with Grade 3-4 laboratoryabnormalities are presented in Table 14.
Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole. REYATAZ does not interact with substratesof CYP2D6 (eg, nortriptyline, desipramine, metoprolol).
In study AI424-045, 20 patients treated with REYATAZ (atazanavir sulfate)/ritonavir 300 mg/100 mg once daily and 18 patients treated Table 14: Grade 3-4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Naive Patientsa
with lopinavir/ritonavir 400 mg/100 mg twice daily were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN Phase III Study AI424-034
Phase II Studies AI424-007, -008
developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels 64 weeks b
120 weeks b,c
73 weeks b,c
>5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients 64 weeks b
nelfinavir 750 mg
(see PRECAUTIONS: General).
(atazanavir sulfate)
efavirenz
400 mg once
TID or 1250 mg BID
OVERDOSAGE
daily + stavudine +
+ stavudine +
Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg have been taken by healthy volunteers without once daily +
once daily +
lamivudine or +
lamivudine or +
symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the lamivudine +
lamivudine +
stavudine +
stavudine +
400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events zidovudine e
zidovudine e
didanosine didanosine
resolved spontaneously. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without Variable Limit d
(n=404) (n=401)
associated liver function test changes) or PR interval prolongation may be observed. (See WARNINGS, PRECAUTIONS, and CLINICAL
PHARMACOLOGY: Effects on Electrocardiogram.)
Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote foroverdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
DOSAGE AND ADMINISTRATION
REYATAZ Capsules must be taken with food.
The recommended oral dose of REYATAZ is as follows: • REYATAZ 400 mg (two 200-mg capsules) once daily taken with food.
* None reported in this treatment arm.
There are no data regarding the use of REYATAZ/ritonavir in therapy-naive patients.
a Based on regimen(s) containing REYATAZ.
• REYATAZ 300 mg (two 150-mg capsules) once daily plus ritonavir 100 mg once daily taken with food.
REYATAZ without ritonavir is not recommended for treatment-experienced patients with prior virologic failure (see Description
of Clinical Studies).
e As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Efficacy and safety of REYATAZ 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.
For Study AI424-034, changes from baseline in fasting LDL-cholesterol, HDL-cholesterol, total cholesterol, and fasting triglycerides Efavirenz. In treatment-naive patients who receive efavirenz and REYATAZ, the recommended dose is REYATAZ 300 mg withritonavir 100 mg and efavirenz 600 mg (all once daily). Dosing recommendations for efavirenz and REYATAZ in treatment-expe- Table 15: Lipid Values, Mean Change from Baseline, Study AI424-034
rienced patients have not been established.
REYATAZ a,b
efavirenz b,c
Didanosine. When coadministered with didanosine buffered formulations, REYATAZ should be given (with food) 2 hours Baseline
Baseline
____________ _____
____________
Tenofovir disoproxil fumarate. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be
(n=383 e)
(n=283 e)
(n=272 e)
(n=378 e)
(n=264 e)
(n=253 e)
coadministered with tenofovir.
For these drugs and other antiretroviral agents for which dosing modification may be appropriate, see CLINICAL PHARMACOLOGY:
Drug-Drug Interactions and PRECAUTIONS, Table 11.
Patients with Renal Impairment
There are insufficient data to recommend a dosage adjustment for patients with renal impairment (see CLINICAL PHARMACOLOGY:
Special Populations, Impaired Renal Function).
a REYATAZ 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Patients with Hepatic Impairment
b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. Use of serum lipid-reducing REYATAZ should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impair- agents was more common in the efavirenz treatment arm (3%) than in the REYATAZ arm (1%).
ment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be consid- c Efavirenz 600 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
ered. REYATAZ should not be used in patients with severe hepatic impairment (Child-Pugh Class C). REYATAZ/ritonavir has not been d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and studied in subjects with hepatic impairment and is not recommended. (See PRECAUTIONS and CLINICAL PHARMACOLOGY: Special
Week 48 values, and is not a simple difference of the baseline and Week 48 mean values.
Populations, Impaired Hepatic Function.)
e Number of patients with LDL-cholesterol measured.
HOW SUPPLIED
REYATAZ® (atazanavir sulfate) Capsules are available in the following strengths and configurations of plastic bottles with child-
The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3- Capsule Shell
Markings on Capsule
Capsules
4 laboratory abnormalities are presented in Table 16.
Strength*
Color (cap/body)
(ink color)
per Bottle
NDC Number
Table 16: Grade 3-4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Experienced Patients,
Study AI424-045a
48 weeksb
48 weeksb
REYATAZ/ritonavir
lopinavir/ritonavir
300/100 mg once daily
400/100 mg twice dailyd
+ tenofovir + NRTI
+ tenofovir + NRTI
Variable Limit c
(n=119) (n=118)
* atazanavir equivalent as atazanavir sulfate.
REYATAZ (atazanavir sulfate) Capsules should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP US Patent Nos: 5,849,911 and 6,087,383.
a Based on regimen(s) containing REYATAZ.
b Median time on therapy.
c ULN = upper limit of normal.
d As a fixed-dose combination.
Lipids, Change from Baseline For Study AI424-045, changes from baseline in fasting LDL-cholesterol, HDL-cholesterol, total cholesterol, and fasting triglycerides are shown in Table 17. The observed magnitude of dyslipidemia was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.
Table 17: Lipid Values, Mean Change from Baseline, Study AI424-045
REYATAZ/ritonavira,b
lopinavir/ritonavir b,c
Baseline
____________
Baseline
_____________
(n=111e)
(n=108e)
a REYATAZ 300 mg once daily + ritonavir + tenofovir + 1 NRTI.
b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. Use of serum lipid- reducing agents was more common in the lopinavir/ritonavir treatment arm (19%) than in the REYATAZ/ritonavir arm (8%).
c Lopinavir/ritonavir (400/100 mg) BID + tenofovir + 1 NRTI.
d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.
e Number of patients with LDL-cholesterol measured.
f Fasting.
Patients Co-infected With Hepatitis B and/or Hepatitis C VirusLiver function tests should be monitored in patients with a history of hepatitis B or C. In studies AI424-008 and AI424-034, 74 patientstreated with 400 mg of REYATAZ once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitisB and/or C at study entry. ALT levels >5 times the upper limit of normal (ULN) developed in 15% of the REYATAZ-treated patients, 14%of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of theREYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and controlregimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients.
What important information should I know about taking REYATAZ (atazanavir sulfate) with other medicines*?
PATIENT INFORMATION
Do not take REYATAZ if you take the following medicines (not all brands may be listed; tell your healthcare provider about
all the medicines you take). REYATAZ may cause serious, life-threatening side effects or death when used with these

REYATAZ® (RAY-ah-taz)
medicines.
• Ergot medicines: dihydroergotamine, ergonovine, ergotamine, and methylergonovine such as CAFERGOT®, MIGRANAL®,
D.H.E. 45®, ergotrate maleate, METHERGINE®, and others (used for migraine headaches).
(generic name = atazanavir sulfate) Capsules
• HALCION® (triazolam, used for insomnia).
ALERT: Find out about medicines that should NOT be taken with REYATAZ. Read the section “What important information
• VERSED® (midazolam, used for sedation).
should I know about taking REYATAZ with other medicines?” • ORAP® (pimozide, used for Tourette’s disorder).
Read the Patient Information that comes with REYATAZ before you start using it and each time you get a refill. There may be new • PROPULSID® (cisapride, used for certain stomach problems).
information. This leaflet provides a summary about REYATAZ and does not include everything there is to know about your medi- Do not take the following medicines with REYATAZ because of possible serious side effects:
cine. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.
• CAMPTOSAR® (irinotecan, used for cancer).
What is REYATAZ?
• CRIXIVAN® (indinavir, used for HIV infection). Both REYATAZ and CRIXIVAN sometimes cause increased levels of bilirubin in REYATAZ is a prescription medicine used with other anti-HIV medicines to treat people who are infected with the human immuno- deficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). REYATAZ is a type of anti-HIV • Cholesterol-lowering medicines MEVACOR® (lovastatin) or ZOCOR® (simvastatin).
medicine called a protease inhibitor. HIV infection destroys CD4+ (T) cells, which are important to the immune system. The immunesystem helps fight infection. After a large number of T cells are destroyed, AIDS develops. REYATAZ helps to block HIV protease, Do not take the following medicines with REYATAZ because they may lower the amount of REYATAZ in your blood.
an enzyme that is needed for the HIV virus to multiply. REYATAZ may lower the amount of HIV in your blood, help your body keep This may lead to an increased HIV viral load. Resistance to REYATAZ or cross-resistance to other HIV medicines may develop: its supply of CD4+ (T) cells, and reduce the risk of death and illness associated with HIV.
• Rifampin (also known as RIMACTANE®, RIFADIN®, RIFATER®, or RIFAMATE®, used for tuberculosis).
Does REYATAZ cure HIV or AIDS?
• St. John’s wort (Hypericum perforatum), an herbal product sold as a dietary supplement, or products containing St. John’s REYATAZ does not cure HIV infection or AIDS. At present there is no cure for HIV infection. People taking REYATAZ may still
get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop • “Proton-pump inhibitors” used for indigestion, heartburn, or ulcers such as AcipHex® (rabeprazole), NEXIUM® (esomeprazole), because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium PREVACID® (lansoprazole), PRILOSEC® (omeprazole), or PROTONIX® (pantoprazole).
complex (MAC) infections. It is very important that you see your healthcare provider regularly while taking REYATAZ.
REYATAZ does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or
Do not take the following medicine if you are taking REYATAZ and NORVIR together.
being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using a
latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood.
The following medicines may require your healthcare provider to monitor your therapy more closely:
• CIALIS® (tadalafil), LEVITRA® (vardenafil), or VIAGRA® (sildenafil). REYATAZ may increase the chances of serious side effects Who should not take REYATAZ?
that can happen with CIALIS, LEVITRA, or VIAGRA. Do not use CIALIS, LEVITRA, or VIAGRA while you are taking REYATAZ unless Do not take REYATAZ if you:
your healthcare provider tells you it is okay.
• are taking certain medicines. (See “What important information should I know about taking REYATAZ with other
• LIPITOR® (atorvastatin). There is an increased chance of serious side effects if you take REYATAZ with this cholesterol- medicines?”) Serious life-threatening side effects or death may happen. Before you take REYATAZ, tell your healthcare provider about all medicines you are taking or planning to take. These include other prescription and nonprescription medicines,vitamins, and herbal supplements.
• Medicines for abnormal heart rhythm: CORDARONE® (amiodarone), lidocaine, quinidine (also known as CARDIOQUIN®, • are allergic to REYATAZ or to any of its ingredients. The active ingredient is atazanavir sulfate. See the end of this leaflet
for a complete list of ingredients in REYATAZ. Tell your healthcare provider if you think you have had an allergic reaction to • VASCOR® (bepridil, used for chest pain).
What should I tell my healthcare provider before I take REYATAZ?
• Tricyclic antidepressants such as ELAVIL® (amitriptyline), NORPRAMIN® (desipramine), SINEQUAN® (doxepin), SURMONTIL® Tell your healthcare provider:
(trimipramine), TOFRANIL® (imipramine), or VIVACTIL® (protriptyline).
If you are pregnant or planning to become pregnant. It is not known if REYATAZ can harm your unborn baby. Pregnant
• Medicines to prevent organ transplant rejection: SANDIMMUNE® or NEORAL® (cyclosporin), RAPAMUNE® (sirolimus), or women have experienced serious side effects when taking REYATAZ with other HIV medicines called nucleoside analogues.
You and your healthcare provider will need to decide if REYATAZ is right for you. If you use REYATAZ while you are pregnant, • The antidepressant trazodone (DESYREL® and others).
talk to your healthcare provider about the Antiretroviral Pregnancy Registry.
• Fluticasone propionate (ADVAIR®, FLONASE®, FLOVENT®), given by nose or inhaled to treat allergic symptoms or • If you are breast-feeding. You should not breast-feed if you are HIV-positive because of the chance of passing HIV to your
asthma.Your doctor may choose not to keep you on fluticasone, especially if you are also taking NORVIR®.
baby. Also, it is not known if REYATAZ can pass into your breast milk and if it can harm your baby. If you are a woman whohas or will have a baby, talk with your healthcare provider about the best way to feed your baby.
The following medicines may require a change in the dose or dose schedule of either REYATAZ or the other
If you have liver problems or are infected with the hepatitis B or C virus. See “What are the possible side effects of REYATAZ?”
medicine:
If you have diabetes. See “What are the possible side effects of REYATAZ?”
• FORTOVASE®, INVIRASE® (saquinavir).
If you have hemophilia. See “What are the possible side effects of REYATAZ?”
About all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Keep a list of your medicines with you to show your healthcare provider. For more information, see “What important information should I know about taking REYATAZ with other medicines?” and “Who should not take REYATAZ?” Some • VIDEX® (didanosine) or antacids.
medicines can cause serious side effects if taken with REYATAZ.
• VIREAD® (tenofovir disoproxil fumarate).
How should I take REYATAZ?
Take REYATAZ once every day exactly as instructed by your healthcare provider. Your healthcare provider will prescribe
• Calcium channel blockers such as CARDIZEM® or TIAZAC® (diltiazem), COVERA-HS® or ISOPTIN SR® (verapamil), and the amount of REYATAZ that is right for you. • For adults who have never taken anti-HIV medicines before, the usual dose is 400 mg (two 200-mg capsules) once daily taken • Medicines for indigestion, heartburn, or ulcers such as AXID® (nizatidine), PEPCID AC® (famotidine), TAGAMET® (cimetidine), • For adults who have taken anti-HIV medicines in the past, the usual dose is 300 mg (two 150-mg capsules) plus 100 mg of NORVIR® (ritonavir) once daily taken with food. Your dose will depend on your liver function and on the other anti-HIV medicines that you are taking. REYATAZ is always Women who use birth control pills or “the patch” should choose a different kind of contraception. REYATAZ may
used with other anti-HIV medicines. If you are taking REYATAZ with SUSTIVA® (efavirenz) or with VIREAD® (tenofovir disoproxil affect the safety and effectiveness of birth control pills or the patch. Talk to your healthcare provider about choosing an effective fumarate), you should also be taking NORVIR® (ritonavir).
Always take REYATAZ with food (a meal or snack) to help it work better. Swallow the capsules whole. Do not open the
Remember:
capsules. Take REYATAZ at the same time each day.
If you are taking antacids or VIDEX® (didanosine) Chewable/Dispersible Buffered Tablets, take REYATAZ 2 hours before
1. Know all the medicines you take.
2. Tell your healthcare provider about all the medicines you take.
Do not change your dose or stop taking REYATAZ without first talking with your healthcare provider. It is important
3. Do not start a new medicine without talking to your healthcare provider.
to stay under a healthcare provider’s care while taking REYATAZ.
When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not
How should I store REYATAZ?
to run out of REYATAZ. The amount of HIV in your blood may increase if the medicine is stopped for even a short time.
• Store REYATAZ Capsules at room temperature, 59° to 86° F (15° to 30° C). Do not store this medicine in a damp place such
If you miss a dose of REYATAZ, take it as soon as possible and then take your next scheduled dose at its regular time. If,
as a bathroom medicine cabinet or near the kitchen sink.
however, it is within 6 hours of your next dose, do not take the missed dose. Wait and take the next dose at the regular • Keep your medicine in a tightly closed container.
time. Do not double the next dose. It is important that you do not miss any doses of REYATAZ or your other anti-HIV
• Throw away REYATAZ when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
medicines.
If you take more than the prescribed dose of REYATAZ, call your healthcare provider or poison control center right away.
General information about REYATAZ
Can children take REYATAZ?
This medicine was prescribed for your particular condition. Do not use REYATAZ for another condition. Do not give REYATAZ to REYATAZ has not been fully studied in children under 16 years of age. REYATAZ should not be used in babies under the age of other people, even if they have the same symptoms you have. It may harm them. Keep REYATAZ and all medicines out of the
reach of children and pets.
This summary does not include everything there is to know about REYATAZ. Medicines are sometimes prescribed for condi- What are the possible side effects of REYATAZ?
tions that are not mentioned in patient information leaflets. Remember, no written summary can replace careful discussion with The following list of side effects is not complete. Report any new or continuing symptoms to your healthcare provider. If you have
your healthcare provider. If you would like more information, talk with your healthcare provider or you can call 1-800-321-1335.
questions about side effects, ask your healthcare provider. Your healthcare provider may be able to help you manage these sideeffects.
What are the ingredients in REYATAZ?
The following side effects have been reported with REYATAZ:
Active Ingredient: atazanavir sulfate
rash (redness and itching) sometimes occurs in patients taking REYATAZ, most often in the first few weeks after the medi-
Inactive Ingredients: Crospovidone, lactose monohydrate (milk sugar), magnesium stearate, gelatin, FD&C Blue #2, and
cine is started. Rashes usually go away within 2 weeks with no change in treatment. Tell your healthcare provider if rash occurs.
yellowing of the skin or eyes. These effects may be due to increases in bilirubin levels in the blood (bilirubin is made by
* VIDEX® is a registered trademark of Bristol-Myers Squibb Company. COUMADIN® and SUSTIVA® are registered trademarks the liver). Call your healthcare provider if your skin or the white part of your eyes turn yellow. Although these effects may not of Bristol-Myers Squibb Pharma Company. DESYREL® is a registered trademark of Mead Johnson and Company. Other brands be damaging to your liver, skin, or eyes, it is important to tell your healthcare provider promptly if they occur.
listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.
a change in the way your heart beats (heart rhythm change). Call your healthcare provider right away if you get dizzy or
lightheaded. These could be symptoms of a heart problem.
diabetes and high blood sugar (hyperglycemia) sometimes happen in patients taking protease inhibitor medicines like REYATAZ.
Some patients had diabetes before taking protease inhibitors while others did not. Some patients may need changes in theirdiabetes medicine.
if you have liver disease including hepatitis B or C, your liver disease may get worse when you take anti-HIV medicines like
some patients with hemophilia have increased bleeding problems with protease inhibitors like REYATAZ.
changes in body fat. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”),
breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
of these conditions are not known at this time.
Other common side effects of REYATAZ taken with other anti-HIV medicines include nausea; headache; stomach pain; vomiting; diarrhea; depression; fever; dizziness; trouble sleeping; numbness, tingling, or burning of hands or feet; and muscle pain.

Source: http://www.hiv.ch/rubriken/therapie/medikamente/usprescinfo.pdf

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