Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
•   Cardiomyopathy [see Warnings and Precautions (5.1)]
•   Venous Thromboembolism [see Warnings and Precautions (5.2)]
•   Ocular Toxicities [see Warnings and Precautions (5.3)]
•   Interstitial Lung Disease [see Warnings and Precautions (5.4)]
•   Hepatotoxicity [see Warnings and Precautions (5.5)]
•   Rhabdomyolysis [see Warnings and Precautions (5.6)]
•   Hemorrhage [see Warnings and Precautions (5.7)] 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in Warnings and Precautions [see Warnings and Precautions (5)] reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active- controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation- positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials.
The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS.
The COLUMBUS trial [see Clinical Studies (14)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib.
The most common (≥ 25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain.
Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients.
Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3.
Table 3:            Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUSa
MEKTOVI
Vemurafenib with encorafenib
N=186
N=192
Adverse Reaction                             All                  Grades                  All                 Grades Grades                 3 and 4b              Grades                3 and 4b (%)                     (%)                  (%)                    (%) General Disorders and Administration Site Conditions
Fatiguec                                               43                      3                    46                     6 c
Pyrexia                                                18                      4                    30                     0 Peripheral edemac                                      13                      1                    15                     1 Gastrointestinal Disorders
Nausea                                                 41                      2                    34                     2 Diarrhea                                               36                      3                    34                     2 c
Vomiting                                               30                      2                    16                     1 Abdominal painc                                        28                      4                    16                     1 Constipation                                           22                      0                     6                     1 Skin and Subcutaneous Tissue Disorders
Rashc                                                  22                      1                    53                     13 Nervous System Disorders
Dizzinessc                                             15                      3                     4                     0 Visual Disorders
Visual impairmentc                                     20                      0                     4                     0 Serous retinopathy/RPEDc                               20                      3                     2                     0 Vascular Disorders
Hemorrhagec                                            19                      3                     9                     2 Hypertensionc                                          11                      6                    11                     3 a    Grades per National Cancer Institute CTCAE v4.03.
b    Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm.
c    Represents a composite of multiple, related preferred terms.

Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were:
Gastrointestinal disorders: Colitis
Skin and subcutaneous tissue disorders: Panniculitis
Immune system disorders: Drug hypersensitivity
Table 4:        Laboratory Abnormalities Occurring in ≥ 10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUSa
MEKTOVI
Vemurafenib with encorafenib
N=186
N=192
Laboratory Abnormality                        All          Grades      All           Grades Grades         3 and 4   Grades          3 and 4
(%)             (%)      (%)              (%)
Hematology
Anemia                                               36             3.6       34                 2.2 Leukopenia                                           13              0        10                 0.5 Lymphopenia                                          13             2.1       30                 7 Neutropenia                                          13             3.1      4.8                 0.5 Chemistry
Increased Creatinine                                 93             3.6       92                 1.1 Increased Creatine Phosphokinase                     58              5       3.8                 0 Increased Gamma Glutamyl Transferase                 45             11        34                 4.8 Increased ALT                                        29              6        27                 2.2 Increased AST                                        27             2.6       24                 1.6 Increased Alkaline Phosphatase                       21             0.5       35                 2.2 Hyponatremia                                         18             3.6       15                 0.5 a    Grades per National Cancer Institute CTCAE v4.03.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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