Adverse reactions : תופעות לוואי

6. 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 (5.7)]
•   chronic kidney disease [see Warnings and Precautions (5.4)]
•   nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.5)] 

6.1. Clinical 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 subjects
The safety profile of atazanavir in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received atazanavir 300 mg with ritonavir 100 mg and 1089 subjects received atazanavir 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 subjects receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive subjects with HIV-1 infection,b Study AI424- 138

96 weeksc                          96 weeksc atazanavir 300 mg with ritonavir Lopinavir/ ritonavird 400 mg / 100
100 mg (once daily) and tenofovir mg (twice daily) and tenofovir DF / DF / emtricitabined                   emtricitabinee
(n=441)                            (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 atazanavir.
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.

Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive subjects with HIV-1 infection,b Studies AI424-034, AI424-007, and AI424-008 
Study AI424-034               Studies AI424-007, -008
64 weeksc        64 weeksc     120 weeksc,d          73 weeksc,d atazanavir        efavirenz      atazanavir       nelfinavir 750 mg
400 mg once 600 mg once daily 400 mg once daily + TID or 1250 mg BID daily +            +          stavudine /         + stavudine / lamivudine / lamivudine/zidovu  lamivudine or        lamivudine or zidovudinee          dinee        didanosine           didanosine
(n=404)          (n=401)         (n=279)              (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           <1%                  1%               4%                       3% symptoms
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 atazanavir.
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.

Adverse Reactions in Treatment-Experienced Adult Subjects
The safety profile of atazanavir in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection 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 subjects receiving atazanavir with ritonavir are presented in Table 9.


Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced subjects with HIV-1 infection,b Study AI424- 045 48 weeksc                             48 weeksc
Atazanavir with ritonavir           lopinavir/ritonavir 400/100 mg
300/100 mg                  (twice dailyd) and tenofovir DF
(once daily) and tenofovir DF and                  and NRTI
NRTI                                 (n=118)
(n=119)
Body as a Whole
Fever                                    2%                                     * Digestive System
Jaundice/scleral                                                                  * 9% icterus
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 atazanavir.
c
Median time on therapy.
d
As a fixed-dose product.
Laboratory Abnormalities in Treatment-Naive subjects
The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, 
including atazanavir 300 mg with ritonavir 100 mg or atazanavir 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 Subjects with HIV-1 infection,a Study AI424-138

96 weeksb                    96 weeksb atazanavir 300 mg with         lopinavir 400 mg / ritonavir 100 mg (once daily) ritonavir 100 mgc (twice and tenofovir DF /       daily) and tenofovir DF emtricitabinec               /emtricitabined
Variable                   Limite                    (n=441)                      (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 atazanavir.
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.

Table 11: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 infection,a Studies AI424-034, AI424-007, and AI424- 008 Study AI424-034               Studies AI424-007, -008
120 weeksb,c      73 weeksb,c
64 weeksb        64 weeksb atazanavir       nelfinavir
Atazanavir         efavirenz
400 mg       750 mg TID or
400 mg            600 mg once daily      1250 mg BID once daily        once daily with stavudine with stavudine
+ lamivudine     + lamivudine
+ lamivudine or + lamivudine or
/zidovudinee     / zidovudinee with stavudine with stavudine
+ didanosine      + didanosine
(n=404)            (n=401)
Variable                   Limitd                                             (n=279)          (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                 ≥5.1 x ULN          6%                 6%                11%                  9% Kinase
Total                    ≥240 mg/dL          6%                 24%               19%                 48% Cholesterol
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 atazanavir.
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.

Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 infection 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

Atazanavir/ritonavira,b                             Iopinavir/ritonavirb,c Baseline         Week 48             Week 96         Baseline     Week 48             Week 96 mg/dL mg/dL Change mg/dL Change mg/dL mg/dL Change mg/dL Changed d                    d                             d

(n=428e) (n=372e) (n=372e) (n=342e) (n=342e) (n=424e) (n=335e) (n=335e) (n=291e) (n=291e) LDL-                   92        105     +14%           105   +14%         93       111     +19%        110    +17% HDL-                   37        46      +29%           44    +21%         36       48      +37%         46    +29% Total                 149        169     +13%           169   +13%         150      187     +25%        186    +25% f
Triglycerides         126        145     +15%           140   +13%         129      194     +52%        184    +50% a. atazanavir 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 atazanavir /ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir /ritonavir arm. Through Week 96, serum lipid- reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir /ritonavir arm.
c. Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose product 300 mg tenofovir DF, 200 mg emtricitabine once daily.

d. The change from baseline is the mean of within-subject changes from baseline for subjects 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 subjects with LDL-cholesterol measured.
f. Fasting.

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 atazanavir a,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) LDL-Cholesterolf              98               98             +1%         98         114          +18% HDL-Cholesterol                39              43            +13%        38           46          +24% Total Cholesterol             164              168            +2%        162          195         +21% f
Triglycerides               138             124           -9%          129           168          +23% a. Atazanavir 400 mg once daily with the fixed-dose product: 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 atazanavir arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the atazanavir arm.
c. Efavirenz 600 mg once daily with the fixed-dose product: 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 subjects with LDL-cholesterol measured.
f. Fasting.

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy including atazanavir /ritonavir having Grade 3-4 laboratory abnormalities are presented in Table 14.


Table 14: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045a
48 weeksb                  48 weeksb atazanavir /ritonavir   lopinavir/ritonavir 400/100
300/100 mg (once daily) + mg (twice dailyd) + tenofovir tenofovir DF + NRTI             DF+ NRTI
Variable              Limitc
(n=119)                    (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% 3
Neutrophils              <750 cells/mm                       7%                           8% a Based on regimen(s) containing atazanavir.
b Median time on therapy.
c ULN = upper limit of normal.
d As a fixed-dose product.

Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection 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 atazanavir /ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.


Table 15: Lipid Values, Means Chande from Basline, Study AI424-045 atazanavir /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) LDL-Cholesterolf              108             98             -10%          104            103       +1% HDL-Cholesterol                40                39          -7%           39           41          +2% Total Cholesterol             188                170         -8%          181          187          +6% f
Triglycerides                 215                161         -4%          196          224          +30% a. atazanavir 300 mg once daily + ritonavir + tenofovir DF + 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 atazanavir /ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir /ritonavir arm.
c. Lopinavir/ritonavir (400/100 mg) as a fixed dose regiment, BID + tenofovir DF + 1 NRTI.
d. The change from baseline is the mean of within-subjects changes from baseline for subjects with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.
e. Number of subjects with LDL-cholesterol measured.
f. Fasting.
Adverse Reactions in Pediatric Subjects with HIV-1 Infection: atazanavir Capsules The safety and tolerability of atazanavir Capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.
The safety profile of atazanavir in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade 2-4 adverse events (≥5%, regardless of causality) reported in pediatric subjects 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 subjects. The most common Grade 3-4 laboratory abnormalities occurring in pediatric subjects 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 subjects with HIV-1 Infection Co-Infected with Hepatitis B and/or Hepatitis C Virus
In Study AI424-138, 60 subjects administered Atazanavir /ritonavir 300 mg/100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed dose tenofovir DF-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir /ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir /ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.
In Study AI424-045, 20 subjects administered atazanavir /ritonavir 300 mg/100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the subjects administered atazanavir /ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir-treated. AST levels >5 times ULN developed in 10% (2/20) of the subjects administered atazanavir /ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.
In Studies AI424-008 and AI424-034, 74 subjects treated with Atazanavir 400 mg 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 subjects treated with atazanavir -, 14% of the subjects treated with efavirenz-, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with atazanavir , 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions (5.7)].


6.2. Postmarketing Experience
The following events have been identified during postmarketing use of Atazanavir. 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 (5.1)]
Gastrointestinal System: pancreatitis
Hepatic System: hepatic function abnormalities
Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6)], cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9)]
Musculoskeletal System: arthralgia
Renal System: nephrolithiasis [see Warnings and Precautions (5.6)], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.4)] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il