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

  • cardiac conduction abnormalities [see WARNINGS AND PRECAUTIONS]
  • rash [see WARNINGS AND PRECAUTIONS]
  • hyperbilirubinemia [see WARNINGS AND PRECAUTIONS]
  • nephrolithiasis and cholelithiasis [see WARNINGS AND PRECAUTIONS]

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 were 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 7 and 8, respectively.

Table 7: Selected Treatment-Emergent Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive 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.
bBased on the regimen containing REYATAZ.
c Median time on therapy.
dAs a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.

Table 8: 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% * 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 andAppendages
  Rash 7% 10% 5% 1%
* None reported in this treatment arm.
a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
bBased on regimens containing REYATAZ.
c Median time on therapy.
dIncludes 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 9.

Table 9: 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 weeks c 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.
bBased 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 300 mg with ritonavir 100 mg and 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 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%
a Based on the regimen containing REYATAZ.
bMedian time on therapy.
c ULN = upper limit of normal.
dAs a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.

Table 11: 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.
bMedian time on therapy.
c Includes long-term follow-up.
dULN = 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 12.

Table 12: Grade 3–4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Experienced Patients, Study AI424-045a

Variable Limitc 48 weeksbREYATAZ/ ritonavir 300/100 mg once daily + tenofovir + NRTI(n=119) 48 weeksblopinavir/ 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%
a Based on regimen(s) containing REYATAZ.
bMedian 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 13 and 14, respectively.

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-138

REYATAZ/ritonavira,b lopinavir/ritonavirb,c
Baselinemg/dL (n=428e) Week 48 Week 96 Baseline mg/dL (n=424e) Week 48 Week 96
mg/dL (n=372e) Changed (n=372e) mg/dL (n=342e) Changed (n=342e) mg/dL (n=335e) Changed (n=335e) mg/dL (n=291e) Changed (n=291e)
f LDL-Cholesterolf 92 105 +14% 105 +14% 93 111 +19% 110 +17%
HDL-Cholesterolf 37 46 +29% 44 +21% 36 48 +37% 46 +29%
Total Cholesterolf 149 169 +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.
bValues 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.
dThe 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.
fFasting.

Table 14: 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.
bValues 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.
dThe 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.
fFasting.

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 15. 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 15: 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 % - 196 224 +30%
a REYATAZ 300 mg once daily + ritonavir + tenofovir + 1 NRTI.
bValues 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.
dThe 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.
fFasting.

Clinical Trial Experience In Pediatric Patients

Adverse Reactions in Pediatric Patients: REYATAZ Capsules

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.

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events ( ≥ 5%, regardless of causality) reported in pediatric 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 taking the capsule formulation were elevation of total bilirubin ( ≥ 3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Pediatric Patients: REYATAZ Oral Powder

The data described below reflect exposure to REYATAZ oral powder in 89 subjects weighing from 10 kg to less than 25 kg, including 65 patients exposed for 48 weeks. These data are from two pooled open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric patients (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 15 months to less than 7.5 years of age. In these studies 53% were female and 47% were male. All patients received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric patients taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients weighing 10 kg to less than 25 kg taking REYATAZ oral powder were increased amylase (19%), neutropenia (12%), increased SGPT/ALT (5%), elevation of total bilirubin ( ≥ 2.6 times ULN, 12%), increased lipase (5%), and decreased hemoglobin (3%). 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

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 once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 15% of the 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 efavirenztreated patients, and 17% of the nelfinavir-treated patients. Within REYATAZ 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, angioedema