Adverse reactions : תופעות לוואי

6        ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
•     Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]
•     Severe Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
•     Cardiovascular Events [see Warnings and Precautions (5.3)]
•     Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)] 6.1      Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Adult Subjects
Treatment-Experienced Subjects: The safety profile of CELSENTRI is primarily based on 840 HIV-1–infected subjects who received at least 1 dose of CELSENTRI during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.


Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with CELSENTRI for subjects in these trials was 48 weeks, with the total exposure on CELSENTRI twice daily at 309 patient-years versus 111 patient-years on placebo each administered with optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with twice-daily therapy with CELSENTRI with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of SELZENTRY.
The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with 2 subjects (0.5%) on SELZENTRY permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 3. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on placebo are not displayed.


Table 3 Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on CELSENTRI (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
Body System/              CELSENTRI
Adverse Event              Twice Dailya                Placebo
Exposure-
Adjusted                 Exposure-
Rate                Adjusted Rate
(per 100 pt- (n = 209    (per 100 pt-
(n = 426)       yrs)         )           yrs)
%        PYE = 309  b    %        PYE = 111b
Eye Disorders
Conjunctivitis                    2             3          1             3 Ocular infections,                2             3          1             2 inflammations, and associated manifestations
Gastrointestinal Disorders
Constipation                      6             9          3             6 General Disorders and
Administration Site
Conditions
Pyrexia                          13            20          9            17 Pain and discomfort               4             5          3             5 Infections and Infestations
Upper respiratory tract          23            37         13            27 infection
Herpes infection                  8            11          4             8 Sinusitis                         7            10          3             6 Bronchitis                        7             9          5             9 Folliculitis                      4             5          2             4 Anogenital warts                  2             3          1             3 Influenza                         2             3         0.5            1 Otitis media                      2             3         0.5            1 Metabolism and Nutrition
Disorders
Appetite disorders                8            11          7            13 Musculoskeletal and
Connective Tissue Disorders
Joint-related signs and           7            10          3             5 symptoms
Muscle pains                     3        4    0.5   1
Neoplasms Benign,
Malignant, and Unspecified
Skin neoplasms benign            3        4    1     3
Nervous System Disorders
Dizziness/postural dizziness     9        13   8     17
Paresthesias and dysesthesias    5         7   3      6
Sensory abnormalities            4         6   1      3
Disturbances in consciousness    4         5   3      6
Peripheral neuropathies          4         5   3      6
Psychiatric Disorders
Disturbances in initiating and   8        11   5     10 maintaining sleep
Depressive disorders             4        6    3     5
Anxiety symptoms                 4        5    3     7
Renal and Urinary
Disorders
Bladder and urethral             5        7    1     3 symptoms
Urinary tract signs and          3        4    1     3 symptoms
Respiratory, Thoracic, and
Mediastinal Disorders
Coughing and associated          14       21   5     10 symptoms
Upper respiratory tract signs    6        9    3     6 and symptoms
Nasal congestion and             4        6    3     5 inflammations
Breathing abnormalities          4        5     2    5
Paranasal sinus disorders        3        4    0.5   1
Skin and Subcutaneous
Tissue Disorders
Rash                             11       16   5     11
Apocrine and eccrine gland        5        7   4     7.5 disorders
Pruritus                         4        5     2    4
Lipodystrophies                  3        5    0.5   1
Erythema                         2        3     1    2
Vascular Disorders
Vascular hypertensive               3             4            2             4 disorders a
300-mg dose equivalent.
b
PYE = Patient-years of exposure.
Laboratory Abnormalities: Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving CELSENTRI.

Table 4. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
CELSENTRI
Twice Daily + OBT         Placebo + OBT
Laboratory Parameter                                  (n = 421)a             (n = 207)a Preferred Term                Limit                   %                      % Aspartate aminotransferase        >5.0 x ULN                 4.8                    2.9 Alanine aminotransferase          >5.0 x ULN                 2.6                    3.4 Total bilirubin                   >2.5 x ULN                 5.5                    5.3 Amylase                           >2.0 x ULN                 5.7                    5.8 Lipase                            >2.0 x ULN                 4.9                    6.3 3
Absolute neutrophil count          <750/mm                   4.3                    2.4 ULN = Upper limit of normal.
a
Percentages based on total subjects evaluated for each laboratory parameter.
Treatment-Naive Subjects: Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received CELSENTRI 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 5. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on efavirenz are not displayed.


Table 5 Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on CELSENTRI (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)
CELSENTRI                     Efavirenz
300 mg Twice Daily +         600 mg Once Daily +
Lamivudine/Zidovudine        Lamivudine/Zidovudine
Body System/                    (n = 360)                    (n = 361) Adverse Event                       %                             %
Blood and Lymphatic System
Disorders
Anemias NEC                                    8                          5 Neutropenias                                   4                          3 Ear and Labyrinth Disorders
Ear disorders NEC                              3                          2 Gastrointestinal Disorders
Flatulence, bloating, and distention          10                          7 Gastrointestinal atonic and                    9                          5 hypomotility disorders NEC
Gastrointestinal signs and                     3                          2 symptoms NEC
General Disorders and
Administration Site Conditions
Body temperature perception                    3                          1 Infections and Infestations
Upper respiratory tract infection             32                         30 Bronchitis                                    13                          9 Herpes infection                               7                          6 Bacterial infections NEC                       6                          3 Herpes zoster/varicella                        5                          4 Tinea infections                               4                          3 Lower respiratory tract and lung               3                          2 infections
Neisseria infections                           3                          0 Viral infections NEC                           3                          2 Musculoskeletal and Connective
Tissue Disorders
Joint-related signs and symptoms               6                          5 Nervous System Disorders
Paresthesias and dysesthesias                  4                          3 
Memory loss (excluding dementia)                3                           1 Renal and Urinary Disorders
Bladder and urethral symptoms                   4                           3 Reproductive System and Breast
Disorders
Erection and ejaculation conditions             3                           2 and disorders
Respiratory, Thoracic, and
Mediastinal Disorders
Upper respiratory tract signs and               9                           5 symptoms
Skin and Subcutaneous Disorders
Nail and nail bed conditions                    6                           2 (excluding infections and infestations)
Lipodystrophies                                 4                           3 Acnes                                           3                           2 Alopecias                                       2                           1 
Laboratory Abnormalities:

Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks) CELSENTRI 300 mg                 Efavirenz
Twice Daily +           600 mg Once Daily+
Laboratory                         Lamivudine/Zidovudine Lamivudine/Zidovudine Parameter                                 (n = 353)a                 (n = 350)a Preferred Term          Limit                    %                          % Aspartate              >5.0 x ULN                  4.0                        4.0 aminotransferase
Alanine                >5.0 x ULN                  3.9                        4.0 aminotransferase
Creatine kinase       >10.0 x ULN                  3.9                        4.8 Amylase                >2.0 x ULN                  4.3                        6.0 3
Absolute neutrophil     <750/mm                    5.7                        4.9 count
Hemoglobin              <7.0 g/dL                  2.9                        2.3 ULN = Upper limit of normal.
a n = Total number of subjects evaluable for laboratory abnormalities.

Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.
Less Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with CELSENTRI or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on CELSENTRI or are potential risks due to the mechanism of action. Events attributed to the subjects’ underlying HIV-1 infection are not listed.
Blood and Lymphatic System: Marrow depression and hypoplastic anemia.
Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.
Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice.
Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.
Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.
Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.
Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.
6.2    Postmarketing Experience
The following adverse events have been identified during post-approval use of CELSENTRI Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).
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

Additionally, you should also report to GSK Israel (il.safety@gsk.com)