Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 New Primary Malignancies
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI.
Cutaneous Malignancies
In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) [see Adverse Reactions (6.1)].
For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients.
In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab.
Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.
Non-Cutaneous Malignancies
Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.5)].
5.2 Tumor Promotion in BRAF Wild-Type Tumors
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Therapeutic indications (1), Dosage and Administration (2.1)].
5.3 Hemorrhage
In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%) and rectal hemorrhage (2.3%).
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
5.4 Uveitis
Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%.
Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
5.5 QT Prolongation
BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology (11.2)]. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib.
Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
5.6 Embryo-Fetal Toxicity
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses.
Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the final dose of BRAFTOVI [see Use in Specific Populations (8.1, 8.3)].
5.7 Risks Associated with BRAFTOVI as a Single Agent
BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended [see Dosage and Administration (2.5)].
5.8 Risks Associated with Combination Treatment
BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib or cetuximab. Refer to the prescribing information for binimetinib and cetuximab for additional risk information.

6 ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
•    New Primary Malignancies [see Warnings and Precautions (5.1)]
•    Hemorrhage [see Warnings and Precautions (5.3)]
•    Uveitis [see Warnings and Precautions (5.45.4)]
•    QT Prolongation [see Warnings and Precautions (5.5)] 
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.
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS).
The COLUMBUS trial [see Clinical Studies (13.1)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib.
The most common (> 25%) adverse reactions in patients receiving BRAFTOVI in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%), and pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%), and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common were hemorrhage in 2% and headache in 1% of patients.
Table 5 and Table 6 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 BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 5.
Table 5:   Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination With Binimetinib in COLUMBUSa
BRAFTOVI
Vemurafenib with binimetinib
N=186
N=192
Adverse Reaction                    All               Grades          All           Grades Grades             3 and 4b       Grades          3 and 4
(%)                 (%)           (%)              (%)
General Disorders and Administration Site Conditions
Fatiguec                                  43                    3                46                 6 Pyrexiac                                  18                    4                30                 0 Table 5:   Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination With Binimetinib in COLUMBUSa
BRAFTOVI
Vemurafenib with binimetinib
N=186
N=192
Adverse Reaction                   All               Grades          All           Grades Grades              3 and 4b       Grades          3 and 4
(%)                 (%)           (%)              (%)
Gastrointestinal Disorders
Nausea                                                41                         2                     34                2 Vomitingc                                             30                         2                     16                1 Abdominal painc                                       28                         4                     16                1 Constipation                                          22                         0                      6                1 Musculoskeletal and Connective Tissue Disorders
Arthralgiac                                           26                         1                     46                6 Myopathyc                                             23                         0                     22                1 Pain in extremity                                     11                         1                     13                1 Skin and Subcutaneous Tissue Disorders
Hyperkeratosisc                                       23                         1                     49                1 Rashc                                                 22                         1                     53                13 Dry skinc                                             16                         0                     26                0 Alopeciac                                             14                         0                     38                0 c
Pruritus                                              13                         1                     21                1 Nervous System Disorders
Headachec                                             22                         2                     20                1 Dizzinessc                                            15                         3                      4                0 Peripheral neuropathyc                                12                         1                     13                2 Vascular Disorders
Hemorrhagec                                           19                         3                      9                2 a    Grades per National Cancer Institute CTCAE v4.03.
b    Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1) and rash (n=1) in the BRAFTOVI with binimetinib arm.
c    Represents a composite of multiple, related preferred terms.

BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs.
23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:
Nervous system disorders: Facial paresis
Gastrointestinal disorders: Pancreatitis
Skin and subcutaneous tissue disorders: Panniculitis
Immune system disorders: Drug hypersensitivity
Table 6:        Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination With Binimetinib in COLUMBUSa
BRAFTOVI
Vemurafeniba with binimetiniba
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 Gamma Glutamyl Transferase                 45              11        34            4.8 Increased ALT                                        29              6         27            2.2 Increased AST                                        27              2.6       24            1.6 Hyperglycemia                                        28              5         20            2.7 Increased Alkaline Phosphatase                       21              0.5       35            2.2 Hyponatremia                                         18              3.6       15            0.5 Hypermagnesemia                                      10              1.0       26            0.5 a    Grades per National Cancer Institute CTCAE v4.03.

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (13.2)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.
The most common (≥ 25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9% of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in combination with cetuximab experienced an adverse reaction that resulted in permanent 

discontinuation of BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than one patient (>0.5%).
Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.

Table 7:   Adverse Reactions Occurring in ≥ 10% of Patients Receiving BRAFTOVI in Combination With Cetuximab in BEACON CRCa
BRAFTOVI               Irinotecan with cetuximab or with cetuximab             FOLFIRI with cetuximab
N=216                           N=193
Adverse Reaction                      All                              All ≥ Grade 3b                     ≥ Grade 3
Grades                          Grades
(%)                           (%)
(%)                              (%)
General Disorders and Administration Site Conditions
Fatiguec                                       51                 7               50               8 Pyrexiac                                       17                 1               15               1 Gastrointestinal Disorders
Nausea                                         34                 1               41               1 c
Diarrhea                                       33                 2               48              10 c
Abdominal pain                                 30                 4               32               5 Vomiting                                       21                 1               29               3 Constipation                                   15                 0               18               1 Metabolism and Nutrition Disorders
Decreased appetite                             27                 1               27               3 Musculoskeletal and Connective Tissue Disorders
Arthralgiac                                    27                 1                3               0 Myopathyc                                      15                 1                4               0 Pain in extremity                              10                 0                1               0 Skin and Subcutaneous Tissue Disorders
Dermatitis acneiformc                          32                 1               43               3 Rashc                                          26                 0               26               2 Pruritusc                                      14                 0                6               0 Melanocytic nevus                              14                 0                0               0 c
Dry skin                                       13                 0               12               1 Nervous System Disorders
Headachec                                      20                 0                3               0 Peripheral neuropathyc                         12                 1                6               0 Vascular Disorders
Hemorrhagec                                    19                 2                9               0 Psychiatric Disorders


Table 7:   Adverse Reactions Occurring in ≥ 10% of Patients Receiving BRAFTOVI in Combination With Cetuximab in BEACON CRCa
BRAFTOVI               Irinotecan with cetuximab or with cetuximab             FOLFIRI with cetuximab
N=216                           N=193
Adverse Reaction                     All                              All ≥ Grade 3b                     ≥ Grade 3
Grades                          Grades
(%)                           (%)
(%)                              (%)
Insomniac                                    13                 0             6               0 a    Grades per National Cancer Institute CTCAE v4.03.
b    Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1).
c    Represents a composite of multiple, related preferred terms.

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were:
Gastrointestinal disorders: Pancreatitis
Table 8: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination With Cetuximab in BEACON CRCa
BRAFTOVI                  Irinotecan with cetuximab or with cetuximab               FOLFIRI with cetuximab
Laboratory Abnormalityb               All             Grades              All          Grades Grades             3 and 4          Grades          3 and 4
(%)                (%)              (%)             (%)
Hematology
Anemia                                                      34                        4                   48   5 Lymphopenia                                                 24                        7                   35   5 Increased Activated Partial
13                        1                   7    1
Thromboplastin Time
Chemistry
Hypomagnesemia                                              19                        0                   22   1 Increased Alkaline Phosphatase                              18                        4                   30   7 Increased ALT                                               17                        0                   29   3 Increased AST                                               15                        1                   22   2 Hypokalemia                                                 12                        3                   32   5 Hyponatremia                                                11                        2                   13   2 a      Grades per National Cancer Institute CTCAE v4.03.
b      Based on the number of patients with available baseline and at least one on-treatment laboratory test.


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

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