Reyataz (Atazanavir Sulfate) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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 [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 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 Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,^b Study AI424-138

	48 weeksc	48 weeksc
	REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined	lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined
	(n=441)	(n=437)
* 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.
Digestive System
Nausea	4%	8%
Jaundice/scleral icterus	4%	*
Diarrhea	2%	11%
Skin and Appendages
Rash	3%	2%

Table 5: Selected Treatment-Emergent Adverse Reactions^a 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	64 weeksc efavirenz 600 mg once daily + lamivudine + zidovudinee	120 weeksc,d REYATAZ 400 mg once daily + stavudine + lamivudine or didanosine	73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or didanosine
	(n=404)	(n=401)	(n=279)	(n=191)
* 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.
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%

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 Reactions^a 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	48 weeksc lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + NRTI
	(n=119)	(n=118)
* 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.
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 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

a Based 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.
Variable	Limitc	48 weeksb	48 weeksb
		REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined	lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined
		(n=441)	(n=437)
Chemistry	High
SGOT/AST	≥5.1 x ULN	2%	<1%
Total Bilirubin	≥2.6 x ULN	34%	<1%
Creatinine Kinase	≥5.1 x ULN	5%	5%
Total Cholesterol	≥240 mg/dL	7%	18%
Hematology	Low
Neutrophils	<750 cells/mm3	3%	<1%

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	64 weeksb	120 weeksb,c	73 weeksb,c
		REYATAZ 400 mg once daily + lamivudine + zidovudinee	efavirenz 600 mg once daily + lamivudine + zidovudinee	REYATAZ 400 mg once daily + stavudine + lamivudine or + stavudine + didanosine	nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or + stavudine + didanosine
		(n=404)	(n=401)	(n=279)	(n=191)
* 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.
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%

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 AI424-045^a

Variable	Limitc	48 weeksb	48 weeksb
		REYATAZ/ritonavir 300/100 mg once daily + tenofovir + NRTI	lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + NRTI
		(n=119)	(n=118)
a Based on regimen(s) containing REYATAZ.
b Median time on therapy.
c ULN = upper limit of normal.
d As a fixed-dose combination.
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%

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 48	Baseline	Week 48	Week 48
	mg/dL	mg/dL	Changed	mg/dL	mg/dL	Changed
	(n=428e)	(n=372e)	(n=372e)	(n=424e)	(n=335e)	(n=335e)
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.
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 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.
LDL-Cholesterolf	92	105	+14%	93	111	+19%
HDL-Cholesterolf	37	46	+29%	36	48	+37%
Total Cholesterolf	149	169	+13%	150	187	+25%
Triglyceridesf	126	145	+15%	129	194	+52%

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

	REYATAZa,b			efavirenzb,c
	Baseline	Week 48	Week 48	Baseline	Week 48	Week 48
	mg/dL	mg/dL	Changed	mg/dL	mg/dL	Changed
	(n=383e)	(n=283e)	(n=272e)	(n=378e)	(n=264e)	(n=253e)
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.
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%

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	Week 48	Week 48	Baseline	Week 48	Week 48
	mg/dL	mg/dL	Changed	mg/dL	mg/dL	Changed
	(n=111e)	(n=75e)	(n=74e)	(n=108e)	(n=76e)	(n=73e)
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. 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.
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%

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 comparable 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 (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in 2% of patients. The most common Grade 3–4 laboratory abnormality was elevation of total bilirubin (≥3.2 mg/dL) which occurred in 49% of pediatric patients. 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 8% (5/60) of the REYATAZ/ritonavir-treated patients and 6% (3/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 8% (5/60) 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, cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions ]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see Warnings and Precautions ]

Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions ], pruritus

REPORTS OF SUSPECTED REYATAZ SIDE EFFECTS / ADVERSE REACTIONS

Possible Reyataz side effects / adverse reactions in 38 year old female

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-04

Patient: 38 year old female

Reactions: in Vitro Fertilisation, Abortion Spontaneous, Generalised Oedema

Suspect drug(s):
Reyataz
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2007-12-21
    End date: 2011-01-01

Norvir
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2007-12-21
    End date: 2011-01-01

Tenofovir Disoproxil Fumarate
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2007-12-21
    End date: 2011-07-01

Possible Reyataz side effects / adverse reactions in 39 year old male

Reported by a consumer/non-health professional from United Kingdom on 2011-10-04

Patient: 39 year old male

Reactions: Viral Load Increased, Glomerular Filtration Rate Decreased

Suspect drug(s):
Ritonavir

Truvada

Reyataz
    Start date: 2009-01-01

Possible Reyataz side effects / adverse reactions in 39 year old female

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-05

Patient: 39 year old female

Reactions: Intra-Uterine Death, Hypertension

Adverse event resulted in: hospitalization

Suspect drug(s):
Norvir
    Dosage: not taken at conception
    Administration route: Oral
    Start date: 2011-07-01

Norvir
    Dosage: taken at conception
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2010-07-01
    End date: 2011-05-20

Reyataz
    Dosage: taken at conception
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2010-07-01
    End date: 2011-05-20

Truvada
    Dosage: 1 tab/caps not taken at conception
    Administration route: Oral
    Start date: 2011-07-01

Truvada
    Dosage: 1 tab/caps taken at conception
    Administration route: Oral
    Indication: Antiretroviral Therapy
    Start date: 2010-07-01
    End date: 2011-05-20

Reyataz
    Dosage: not taken at conception
    Administration route: Oral
    Start date: 2011-07-01

Other drugs received by patient: Aldomet; Labetalol HCL