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 (5.8)]
•   chronic kidney disease [see Warnings and Precautions (5.5)]
•   nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)] 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 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 Adverse Reactionsa of Moderate or Severe Intensity Reported in 2% of Adult Treatment-Naive Patients,b Study AI424-
138

96 weeksc                                96 weeksc
REYATAZ 300 mg with ritonavir            lopinavir 400 mg with ritonavir 100 mg (once daily) and tenofovir      100 mg (twice daily) and tenofovir DF with emtricitabined                 DF with emtricitabined
(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 REYATAZ.
c
Median time on therapy.
d
As a fixed-dose combination: 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 Patients,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 REYATAZ              efavirenz           REYATAZ                  nelfinavir 400 mg once daily + 600 mg once daily    400 mg once daily +       750 mg TID or lamivudine +       + lamivudine +         stavudine +           1250 mg BID + zidovudine e        zidovudinee        lamivudine or             stavudine + didanosine            lamivudine or 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 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.

Adverse Reactions in Treatment-Experienced Adult 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 Adverse Reactionsa of Moderate or Severe Intensity Reported in 2% of Adult Treatment-Experienced Patients,b Study
AI424-045

48 weeksc
48 weeksc                     lopinavir/ritonavir 400/100 mg
REYATAZ/ritonavir 300/100 mg               twice dailyd + tenofovir DF + once daily + tenofovir DF + NRTI                       NRTI
(n=119)                                 (n=118)
Body as a Whole
Fever                                             2%                                        * Digestive System
Jaundice/scleral icterus                          9%                                        * Diarrhea                                          3%                                      11% Nausea                                            3%                                       2% Nervous System
Table 9:                  Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in 2% of Adult Treatment-Experienced Patients,b Study
AI424-045

48 weeksc
48  weeksc                    lopinavir/ritonavir 400/100 mg
REYATAZ/ritonavir 300/100 mg               twice dailyd + tenofovir DF + once daily + tenofovir DF + NRTI                       NRTI
(n=119)                                 (n=118)
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 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

96 weeksb                       96 weeksb
REYATAZ 300 mg                    lopinavir 400 mg with ritonavir 100 mg           with ritonavir 100 mg
(once daily) and tenofovir DF     (twice daily) and tenofovir with emtricitabinec                      DF with emtricitabinec

Variable                             Limitd                    (n=441)                            (n=437) Chemistry                             High
SGOT/AST                         5.1  ULN                    3%                                 1% SGPT/ALT                         5.1  ULN                    3%                                 2% Total Bilirubin                  2.6  ULN                    44%                               <1% Lipase                           2.1  ULN                    2%                                 2% Creatine Kinase                  5.1  ULN                    8%                                 7% Total Cholesterol               240 mg/dL                     11%                               25% Hematology                            Low
Table 10:                      Grade 3–4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Naive Patients,a Study AI424-138

96 weeksb                        96 weeksb
REYATAZ 300 mg                    lopinavir 400 mg with ritonavir 100 mg           with ritonavir 100 mg
(once daily) and tenofovir DF     (twice daily) and tenofovir with emtricitabinec                      DF with emtricitabinec

Variable                                   Limitd                     (n=441)                            (n=437) Neutrophils                        <750 cells/mm3                   5%                                 2% a
Based on the regimen containing REYATAZ.
b
Median time on therapy.
c
As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.
d
ULN = upper limit of normal.

Table 11:                      Grade 3–4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Naive Patients,a Studies AI424-034, AI424-007, and AI424-
008
Study AI424-034                   Studies AI424-007, -008
64 weeksb         64 weeksb           120 weeksb,c          73 weeksb,c REYATAZ               efavirenz             REYATAZ            nelfinavir 400 mg               600 mg                400 mg         750 mg TID or once daily           once daily            once daily       1250 mg BID + lamivudine         + lamivudine           + stavudine        + stavudine + zidovudinee        + zidovudinee        + lamivudine or    + lamivudine or + stavudine        + stavudine
+ didanosine       + didanosine
Variable                        Limitd               (n=404)           (n=401)              (n=279)                (n=191) Chemistry                        High
SGOT/AST                  5.1  ULN               2%                 2%                   7%                    5% SGPT/ALT                  5.1  ULN               4%                 3%                   9%                    7% Total Bilirubin           2.6  ULN              35%                <1%                  47%                    3% Amylase                   2.1  ULN                *                  *                  14%                   10% Lipase                    2.1  ULN              <1%                 1%                   4%                    5% Creatine                  5.1  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% Table 11:                       Grade 3–4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Naive Patients,a Studies AI424-034, AI424-007, and AI424-
008
Study AI424-034                       Studies AI424-007, -008
64   weeksb         64    weeksb        120 weeksb,c               73 weeksb,c REYATAZ              efavirenz             REYATAZ               nelfinavir 400 mg              600 mg                400 mg            750 mg TID or once daily          once daily            once daily          1250 mg BID + lamivudine        + lamivudine           + stavudine           + stavudine + zidovudinee       + zidovudinee        + lamivudine or       + lamivudine or + stavudine           + stavudine
+ didanosine          + didanosine
Variable                        Limitd               (n=404)          (n=401)                 (n=279)                (n=191) 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.

Change in Lipids 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 12 and 13, respectively.

Table 12:                       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       mg/dL   Changed       mg/dL   Changed      mg/dL      mg/dL   Changed       mg/dL   Changed (n=428e)    (n=372 ) (n=372e) e
(n=342 ) (n=342e) e
(n=424e)   (n=335 ) (n=335e) e
(n=291 ) (n=291e) e


LDL-Cholesterolf       92         105      +14%         105      +14%           93      111       +19%          110       +17% f
HDL-Cholesterol        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 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 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 DF, 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 13:                   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) 
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.

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 14.
Table 14:               Grade 3–4 Laboratory Abnormalities Reported in 2% of Adult Treatment-Experienced Patients, Study AI424-045a

48 weeksb                        48 weeksb

REYATAZ/ritonavir                lopinavir/ritonavir
300/100 mg once daily +        400/100 mg twice dailyd + tenofovir DF + NRTI             tenofovir DF+ NRTI
Variable                     Limitc                      (n=119)                          (n=118) Chemistry                     High
SGOT/AST               5.1  ULN                      3%                                 3% SGPT/ALT               5.1  ULN                      4%                                 3% Total Bilirubin        2.6  ULN                      49%                              <1% Lipase                 2.1  ULN                      5%                                 6% Creatine Kinase        5.1  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.
b
Median time on therapy.
c
ULN = upper limit of normal.
d
As a fixed-dose combination.

Change in Lipids 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       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% Triglyceridesf                  215            161            −4%              196            224          +30% a
REYATAZ 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 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 DF + 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.

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 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 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 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 efavirenz- treated 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 (5.8)].
6.2         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 (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 (5.5)]
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 http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m oh.gov.il