REYATAZ ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. Limitations of Use:
REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4) ] .
Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4) ] . REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1)
Contraindications
REYATAZ is contraindicated:
in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2) ] .
when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA ® for erectile dysfunction. Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Antimycobacterials Rifampin Antineoplastics Apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics Lurasidone (with ritonavir), pimozide Benzodiazepines Orally administered midazolam a , triazolam Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility Agent Cisapride Hepatitis C Direct-Acting Antivirals Elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum ) Lipid-Modifying Agents: Lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil b when dosed as REVATIO ® for the treatment of pulmonary arterial hypertension Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine
In patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ. (4)
Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. ( 4 )
Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. ( 4 )
Warnings and precautions
Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.1 , 7.3 , 12.2 , 17)
Severe Skin Reactions: Discontinue if severe rash develops. (5.2 , 17)
Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.8)
Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3)
Hepatotoxicity: Patients with hepatitis B or C virus are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.8 , 5.4 , 8.8)
Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of REYATAZ in patients with progressive renal disease. (5.5)
Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6)
The concomitant use of REYATAZ with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.7 , 7.3)
Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.9) , immune reconstitution syndrome (5.10) , and redistribution/accumulation of body fat. (5.11)
Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.12)
5.1Cardiac Conduction Abnormalities
REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10) ] .
In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants who had on-study electrocardiogram measurements.
Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2) ] .
5.2Severe Skin Reactions
In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1) ] .
Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ [see Contraindications (4) and Adverse Reactions (6.1) ] . REYATAZ should be discontinued if severe rash develops.
5.3Patients with Phenylketonuria
Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.
5.4Hepatotoxicity Patients
with underlying hepatitis B or C virus or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , and Use in Specific Populations (8.8) ] .
5.5Chronic Kidney Disease
Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease.
Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7 ) and Adverse Reactions (6.2) ] .
5.6Nephrolithiasis and Cholelithiasis Cases
of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 receiving REYATAZ therapy. Some patients required hospitalization for additional management, and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2) ] .
5.7Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of
REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead to:
clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir.
loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance. See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7) ] .
5.8Hyperbilirubinemia
Most patients taking REYATAZ experience asymptomat
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Interactions
Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4 , 7 , 12.3)
7.1Potential for
REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide).
When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3) ] . The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
7.2Potential for Other Drugs to Affect
REYATAZ Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect ( see Table 16 ). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with REYATAZ [see Dosage and Administration ( 2.3 , 2.4 , 2.5 and 2.6) ] .
7.3Established and Other Potentially Significant Drug Interactions Table
16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders.
Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6) . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) ] . Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established.
In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ] . indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ] . ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults.
See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ] . glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4) ] . voxilaprevir/sofosbuvir/velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended.
Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ] . Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] .
Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied.
It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban REYATAZ with ritonavir ↑ rivaroxaban Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an incr
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Pregnancy and breastfeeding
8.1Pregnancy 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
REYATAZ must be administered with ritonavir in pregnant patients.
For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H 2 -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 H 2 -receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.
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) ] . Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8) ] , including those who are pregnant [see Data ] . Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to REYATAZ in utero , should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data ] . Data Human Data In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
cardiac conduction abnormalities [see Warnings and Precautions (5.1) ]
rash [see Warnings and Precautions (5.2) ]
hyperbilirubinemia [see Warnings and Precautions (5.8) ]
chronic kidney disease [see Warnings and Precautions (5.5) ]
nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Treatment-Naive Adult Participants The safety profile of REYATAZ in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants 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 participants 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. Table 7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424-138 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. 96 weeks c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d 400 mg / 100 mg (twice daily) and tenofovir DF/emtricitabine e (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.
Study AI424-034 Studies AI424-007, -008 64 weeks c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 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 participants receiving REYATAZ with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, b Study AI424-045 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. 48 weeks c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 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.
Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424-138 a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. 96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d Variable Limit e (n=441) (n=437) Chemistry High SGOT/AST ≥5.1 × ULN 3% 1% SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily.
Study AI424-034 Studies AI424-007, -008 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limit d (n=404) (n=401) (n=279) (n=191) Chemistry High SGOT/AST ≥5.1 × ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.
Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the
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ATAZANAVIR SULFATE EQ 300MG BASE
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