Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 Cardiomyopathy
Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range 0 to 21 months).
Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
5.2 Venous Thromboembolism
In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
5.3 Ocular Toxicities
Serous Retinopathy
In COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months).
Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, 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 (2.3), Adverse Reactions (6.1)].
Retinal Vein Occlusion
RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 1 patient experienced RVO (0.1%).
The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.
Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO [see Dosage and
Administration (2.3), Adverse Reactions (6.1)].
Uveitis
Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib 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 (2.3), Adverse Reactions (6.1)].
5.4 Interstitial Lung Disease
In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis.
Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
5.5 Hepatotoxicity
Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation.
Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
5.6 Rhabdomyolysis
Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%).
Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
5.7 Hemorrhage
Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. 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.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.8 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily.
Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose [see Use in Specific Populations (8.1, 8.3)].
5.9 Risks Associated with Combination Treatment
MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment.
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

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