Adverse reactions : תופעות לוואי

6   ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling: 
•   Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)].
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/
 and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com 

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 pooled safety population in the WARNINGS AND PRECAUTIONS section reflect exposure to Rubraca at 600 mg BID in 1146 patients treated on clinical trials including ARIEL3, and TRITON2.


Maintenance Treatment of Recurrent Ovarian Cancer
The safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, a randomized (2:1), double-blind, placebo-controlled study in which 561 patients received either Rubraca 600 mg BID (n=372) or placebo (n=189) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.3 months (range: < 1 month to 35 months) for patients who received Rubraca and 5.5 months for patients who received placebo.

Dose interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving Rubraca and 10% of those receiving placebo; dose reductions due to an adverse reaction occurred in 55% of Rubraca patients and 4% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of
Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and fatigue/asthenia (13%).
Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 2% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were anemia (3%), thrombocytopenia (3%) and nausea (3%). Table 2 describes the adverse reactions occurring in ≥20% of patients; while Table 3 describes the laboratory abnormalities occurring in ≥25% of patients occurring in ARIEL3.
Table 2. Adverse Reactions in ARIEL3 Occurring in ≥ 20% of Patients 
Rubraca                                Placebo
N=372                                  N=189 a                                      a
Grades 1-4      Grades 3-4             Grades 1-4     Grades 3-4
Adverse reactions                               %               %                      %              % Gastrointestinal Disorders
Nausea                                        76                       4                 36           0.5 b
Abdominal pain/distention                     46                       3                 39           0.5 Constipation                                  37                       2                 24            1 Vomiting                                      37                       4                 15            1 Diarrhea                                      32                      0.5                22            1 b
Stomatitis                                    28                       1                 14           0.5 General Disorders and Administration Site Conditions
Fatigue/asthenia                              73                       7                 46            3 Skin and Subcutaneous Tissue Disorders
Rashb                                         43                       1                 23            0 Nervous System Disorders
Dysgeusia                                     40                       0                  7            0 Investigations
AST/ALT elevation                             38                      11                  4            0 Blood and Lymphatic System Disorders
Anemia                                        39                      21                  5           0.5 Thrombocytopenia                              29                       5                  3            0 Neutropenia                                   20                       8                  5            1 Respiratory, Thoracic, and Mediastinal Disorders
Nasopharyngitis/Upper respiratory tract
29                      0.3                18            1 infectionb
Metabolism and Nutrition Disorders
Decreased appetite                            23                       1                 14            0 a
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) b
Consists of grouped related terms that reflect the medical concept of the adverse reaction 
Adverse reactions occurring < 20% of patients treated with Rubraca include headache (18%), dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%), peripheral edema (11%), and depression (11%).
Table 3. Laboratory Abnormalities in ARIEL3 Occurring in ≥ 25% of Patients 
Rubraca                                      Placebo
N=372                                       N=189
Grade 1-4            Grade 3-4           Grade 1-4              Grade 3-4 Laboratory Parametera                      %                     %                 %                      % Chemistry
Increase in creatinine                     98                   0.3                90                     0 Increase in cholesterol                    84                    4                 78                     0 Increase in ALT                            73                    7                  4                     0 Increase in AST                            61                    1                  4                     0 Increase in Alkaline                       37                   0.3                10                     0 Phosphatase
Hematology
Decrease in hemoglobin                     88                    13                56                     1 Decrease in platelets                      44                    2                  9                     0 Decrease in leukocytes                     44                    3                 29                     0 Decrease in neutrophils                    38                    6                 22                     3 Decrease in lymphocytes                    29                    5                 20                     3 a
Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

6.2 Postmarketing Experience

Immune System Disorders: Hypersensitivity including swelling/oedema of the face and eyes.