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Reyataz

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Reyataz

Reyataz

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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.

Clinical Trial Experience in Adults

Treatment-Emergent Adverse Reactions in Treatment-Naive Patients

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

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

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 4 and 5, respectively.

Table 4: Selected Treatment-Emergent Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Na´ve Patients,b Study AI424-138

  96 weeksc REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined
(n=441)
96 weeksc lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined
(n=437)
Digestive System
  Nausea 4% 8%
  Jaundice/scleral icterus  5% *
  Diarrhea 2% 12%
Skin and Appendages
  Rash 3% 2%
* 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 combination: 300 mg tenofovir, 200 mg emtricitabine once daily.

Table 5: Selected Treatment-Emergent Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive Patients,b Studies AI424-034, AI424-007, and AI424-008

  Study AI424-034 Studies AI424-007, -008
64 weeksc
REYATAZ 400 mg once daily+ lamivudine+ zidovudinee
(n=404)
64 weeksc
efavirenz 600 mg once daily + lamivudine + zidovudinee
(n=401)
120 weeksc,d
REYATAZ 400 mg once daily + stavudine + lamivudine or didanosine
(n=279)
73 weeksc,d
nelfinavir 750 mg TID or 1250 mg BID + stavudine + 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% :k 7% :k
  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%
* 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 combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Treatment-Emergent Adverse Reactions in Treatment-Experienced Patients

The safety profile of REYATAZ in treatment-experienced adults is based on 119 HIV-1 infected patients 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 patients receiving REYATAZ/ritonavir are presented in Table 6.

Table 6: Selected Treatment-Emergent Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Experienced Patients,b Study AI424-045

  48 weeksc REYATAZ/ritonavir 300/100 mg once daily + tenofovir + NRTI
(n=119)
48 weeksc lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + 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% *
* 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 combination.

Laboratory Abnormalities in Treatment-Naive Patients

The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ (atazanavir sulfate) 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities are presented in Tables 7 and 8, respectively.

Table 7: Grade 3–4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Naive Patients,a Study AI424-138

Variable Limitc 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined
(n=441)
96 weeksb lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined
(n=437)
Chemistry High    
  SGOT/AST   ≥ 5.1 x ULN 3% 1%
  SGPT/ALT   ≥ 5.1 x ULN 3% 2%
  Total Bilirubin ≥ 2.6 x ULN 44% < 1%
  Lipase ≥ 2.1 x ULN 2% 2%
  Creatine Kinase ≥ 5.1 x ULN 8% 7%
   Total Cholesterol ≥ 240 mg/dL 11% 25%
Hematology Low
  Neutrophils < 750 cells/mm³ 5% 2%
aBased on the regimen containing REYATAZ.
b Median time on therapy.
c ULN = upper limit of normal.
d As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.

Table 8: Grade 3–4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment- Naive Patients,a Studies AI424-034, AI424-007, and AI424-008

Variable Limitd Study AI424-034 Studies AI424-007, -008
64 weeksb REYATAZ 400 mg once daily + lamivudine + zidovudinee
(n=404)
64 weeksb efavirenz 600 mg once daily + lamivudine + zidovudinee
(n=401)
120 weeksb,c REYATAZ 400 mg once daily + stavudine + lamivudine or + stavudine + didanosine
(n=279)
73 weeksb,c nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or + stavudine + didanosine
(n=191)
Chemistry High        
SGOT/AST ≥ 5.1 x ULN 2% 2% 7% 5%
SGPT/ALT ≥ 5.1 x ULN 4% 3% 9% 7%
Total Bilirubin ≥ 2.6 x ULN 35% < 1% 47% 3%
Amylase ≥ 2.1 x ULN * * 14% 10%
Lipase ≥ 2.1 x ULN <1% 1% 4% 5%
Creatine Kinase ≥ 5.1 x 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/mm³ 7% 9% 3% 7%
* 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 combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Laboratory Abnormalities in Treatment-Experienced Patients

The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3–4 laboratory abnormalities are presented in Table 9.

Table 9: Grade 3–4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Experienced Patients, Study AI424-045a

Variable Limitc 48 weeksb REYATAZ/ritonavir 300/100 mg once daily + tenofovir + NRTI
(n=119)
48 weeksb lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + NRTI
(n=118)
Chemistry High    
SGOT/AST ≥ 5.1 x ULN 3% 3%
SGPT/ALT ≥ 5.1 x ULN 4% 3%
Total Bilirubin ≥ 2.6 x ULN 49% < 1%
Lipase ≥ 2.1 x ULN 5% 6%
Creatine Kinase ≥ 5.1 x ULN 8% 8%
Total Cholesterol ≥ 240 mg/dL 25% 26%
Triglycerides ≥ 751 mg/dL 8% 12%
Glucose ≥ 251 mg/dL 5% < 1%
Hematology Low
Platelets < 50,000 cells/mm³ 2% 3%
Neutrophils < 750 cells/mm³ 7% 8%
aBased 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 in Treatment-Naive Patients

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 10 and 11, respectively.

Table 10: Lipid Values, Mean Change from Baseline, Study AI424-138

REYATAZ/ritonavira,b lopinavir/ritonavirb,c
Baseline Week 48 Week 96 Baseline Week 48 Week 96
mg/dL
(n=428e)
mg/dL
(n=372e)
Change4
(n=372e)
mg/dL
(n=342e)
Changed
(n=342e)
mg/dL
(n=424e)
mg/dL
(n=335e)
Changed
(n=335e)
mg/dL
(n=291e)
Changed
(n=291e)
LDL- 92 Cholesterolf 105 +14% 105 +14% 93 111 +19% 110 +17%
HDL- 37 Cholesterolf 46 +29% 44 +21% 36 48 +37% 46 +29%
Total 149 Cholesterolf 169 +13% 169 +13% 150 187 +25% 186 +25%
Triglyceridesf 126 145 +15% 140 +13% 129 194 +52% 184 +50%
a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose combination: 300 mg tenofovir, 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 REYATAZ/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ/ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ/ritonavir arm.
c Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir, 200 mg emtricitabine once daily.
d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively.
e Number of patients with LDL-cholesterol measured.
f Fasting.

Table 11: Lipid Values, Mean Change from Baseline, Study AI424-034

  REYATAZa,b efavirenzb,c
Baseline mg/dL
(n=383e)
Week 48 mg/dL
(n=283e)
Week 48 Changed
(n=272e)
Baseline mg/dL
(n=378e)
Week 48 mg/dL
(n=264e)
Week 48 Changed
(n=253e)
LDL-Cholesterolf 98 98 +1% 98 114 +18%
HDL-Cholesterol 39 43 +13% 38 46 +24%
Total Cholesterol 164 168 +2% 162 195 +21%
Triglyceridesf 138 124 -9% 129 168 +23%
a REYATAZ 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice 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 0% in the efavirenz treatment arm and < 1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm.
c Efavirenz 600 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
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.

Lipids, Change from Baseline in Treatment-Experienced Patients

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 12. 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 12: Lipid Values, Mean Change from Baseline, Study AI424-045

  REYATAZ/ritonavira,b lopinavir/ritonavirb,c
Baseline mg/dL
(n=111e)
Week 48 mg/dL
(n=75e)
Week 48 Changed
(n=74e)
Baseline mg/dL
(n=108e)
Week 48 mg/dL
(n=76e)
Week 48 Changed
(n=73e)
LDL-Cholesterolf 108 98 -10% 104 103 +1%
HDL-Cholesterol 40 39 -7% 39 41 +2%
Total Cholesterol 188 170 -8% 181 187 +6%
Triglyceridesf 215 161 -4% 196 224 +30%
aREYATAZ 300 mg once daily + ritonavir + tenofovir + 1 NRTI.
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 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ/ritonavir arm.
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.

Clinical Trial Experience in Pediatric Patients

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. Use of REYATAZ in pediatric patients less than 6 years of age is under investigation.

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

Patients Co-infected With Hepatitis B and/or Hepatitis C Virus

Liver function tests should be monitored in patients with a history of hepatitis B or C.

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

In study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 18 patients treated 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 developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ ritonavir-treated patients. AST levels > 5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.

In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ (atazanavir sulfate) once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times 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 the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients. [See WARNINGS AND PRECAUTIONS]

Postmarketing Experience

The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see WARNINGS AND PRECAUTIONS]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis [see WARNINGS AND PRECAUTIONS], cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see WARNINGS AND PRECAUTIONS]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see WARNINGS AND PRECAUTIONS], interstitial nephritis

Skin and Appendages: alopecia, maculopapular rash [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS], pruritus

Read the Reyataz (atazanavir sulfate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

See also CONTRAINDICATIONS and CLINICAL PHARMACOLOGY.

Potential 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. Caution should be used when REYATAZ without ritonavir is 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 14]

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

Potential for Other Drugs to Affect Atazanavir

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ's therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with atazanavir.

Established and Other Potentially Significant Drug Interactions

Table 13 provides dosing recommendations 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 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesaor 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
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules ↓ atazanavir
↓ didanosine
 
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate ↓atazanavir
↑tenofovir
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. 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.
Tenofovir may decrease the AUC and Cmin of atazanavir. 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 coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see DOSAGE AND ADMINISTRATION
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir Efavirenz decreases atazanavir exposure.
In treatment-naive patients:
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients:
Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure. Do not coadminister REYATAZ with nevirapine because:
  • Nevirapine substantially decreases atazanavir exposure.
  • Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
nevirapine ↓atazanavir
↑nevirapine
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 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies].
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. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir.
others ↑ other protease inhibitor REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors: boceprevir ↓atazanavir
↓ritonavir
Concomitant administration of boceprevir and atazanavir/ ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ ritonavir and boceprevir is not recommended.
telaprevir ↓ telaprevir
↑ atazanavir
Concomitant administration of telaprevir and atazanavir/ ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
Other Agents
Antacids and buffered medications ↓ atazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
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 INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone ↑ trazodone Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics: carbamazepine ↓atazanavir
↑carbamazepine
Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital ↓ atazanavir
↓phenytoin
↓ phenobarbital
Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole REYATAZ/ ritonavir:
↑ ketoconazole
↑itraconazole
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole ( > 200 mg/day) should be used cautiously with REYATAZ/ritonavir.
voriconazole REYATAZ/ ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole
↓atazanavir
REYATAZ/ ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole
↓ atazanavir
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the co-administration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine ↑ colchicine REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment.
Recommended dosage of colchicine when administered with REYATAZ:
Treatment of gout flares:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.
Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifabutin ↑rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolamb ↑midazolam Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem felodipine, nifedipine, nicardipine, and verapamil ↑diltiazem and desacetyl-diltiazem
↑calcium channel blocker
Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended.
Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan ↓ atazanavir
↑bosentan
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in patients on REYATAZ/ ritonavir:
For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Coadministration of REYATAZ/ritonavir in patients on bosentan:
Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑rosuvastatin
Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H2-Receptor
antagonists
↓ atazanavir

Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
In treatment-experienced patients:
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.

  • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H2-receptor antagonist, see DOSAGE AND ADMINISTRATION.
  • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H2-receptor antagonist, see DOSAGE AND ADMINISTRATION.
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol
↑ norgestimatec
↑ ethinyl estradiol
↑ norethindroned
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone REYATAZ ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
  REYATAZ/ritonavir ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ/ ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients< receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see WARNINGS AND PRECAUTIONS].
Macrolide antibiotics: clarithromycin ↑ clarithromycin
↓ 14-OH clarithromycin
↑ atazanavir
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine ↑ buprenorphine
↑ norbuprenorphine
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil
↑ tadalafil
↑ vardenafil
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see CONTRAINDICATIONS].
The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ:
Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
  • For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
  • Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
REYATAZ/ritonavir: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
REYATAZ: Use LEVITRA® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole ↓ atazanavir Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive patients:
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
In treatment-experienced patients:
Proton-pump inhibitors should not be used in treatmentexperienced patients receiving REYATAZ.
aFor magnitude of interactions see CLINICAL PHARMACOLOGY, Tables 17 and 18.
b See CONTRAINDICATIONS, Table 3 for orally administered midazolam. c In combination with atazanavir 300 mg and ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily.

Drugs with No Observed or Predicted Interactions with REYATAZ

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for NORVIR® for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ (atazanavir sulfate) and dapsone, trimethoprim/ sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol. [See CLINICAL PHARMACOLOGY, Tables 17 and 18]

Read the Reyataz Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/26/2013
This monograph has been modified to include the generic and brand name in many instances.

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