MEKTOVI

5 WARNINGS AND PRECAUTIONS • New Primary Malignancies, Cutaneous and Non-cutaneous: Can occur when MEKTOVI is used in combination with encorafenib. Monitor patients for new malignancies prior to initiation of treatment, during treatment, and after discontinuation of treatment. ( 5.1 ) • Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every 2 to 3 months thereafter. The safety of MEKTOVI has not been established in patients with LVEF below 50%. ( 5.2 ) • Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur. ( 5.3 ) • Ocular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. ( 5.4 ) • Interstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. ( 5.5 ) • Hepatotoxicity: Monitor liver function tests before and during treatment with MEKTOVI and encorafenib and as clinically indicated. ( 5.6 ) • Rhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. ( 5.7 ) • Hemorrhage: Major hemorrhagic events can occur in patients receiving MEKTOVI and encorafenib. ( 5.8 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when MEKTOVI is used in combination with encorafenib. In PHAROS, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients who received MEKTOVI in combination with encorafenib. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment [see Dosage and Administration (2.3) ] . 5.2 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. In PHAROS, 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 11% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% 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) ] . 5.3 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. In PHAROS, VTE occurred in 7% of patients receiving MEKTOVI in combination with encorafenib, including 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) ] . 5.4 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). In PHAROS, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness treated with MEKTOVI in combination with encorafenib. No patient permanently discontinued MEKTOVI due to serous retinopathy; 1% of patients required dose interruptions. 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%. In PHAROS, uveitis occurred in 1% of patients receiving MEKTOVI in combination with encorafenib. 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) ] . 5.5 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. In PHAROS, 1 patient (1%) receiving MEKTOVI with encorafenib developed 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) ] . 5.6 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. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase. 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) ] . 5.7 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%). In PHAROS, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients treated with MEKTOVI in combination with encorafenib. No patient experienced rhabdomyolysis. 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) ] . 5.8 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. In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each). Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3) , Adverse Reactions (6.1) ] . 5.9 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 pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the last dose [see Use in Specific Populations (8.1 , 8.3 )]. 5.10 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: • New Primary Malignancies [see Warnings and Precautions (5.1) ] • Cardiomyopathy [see Warnings and Precautions (5.2) ] • Venous Thromboembolism [see Warnings and Precautions (5.3) ] • Ocular Toxicities [see Warnings and Precautions (5.4) ] • Interstitial Lung Disease [see Warnings and Precautions (5.5) ] • Hepatotoxicity [see Warnings and Precautions (5.6) ] • Rhabdomyolysis [see Warnings and Precautions (5.7) ] • Hemorrhage [see Warnings and Precautions (5.8) ] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.9) ] • Risks Associated with Combination Treatment [see Warnings and Precautions (5.10) ] Melanoma: Most common adverse reactions (≥25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, vomiting, and abdominal pain. ( 6.1 ) NSCLC: Most common adverse reactions (≥25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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) [see Clinical Studies (14.1) ] or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib once daily across multiple clinical trials (NCT03915951, NCT01909453). The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure of 98 patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer to MEKTOVI 45 mg twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity in PHAROS [see Clinical Studies (14.2) ] . BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma 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 (14.1) ] 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 COLUMBUS Grades per National Cancer Institute CTCAE v4.03. Adverse Reaction MEKTOVI with encorafenib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 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. (%) All Grades (%) Grades 3 and 4 (%) General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms. 43 3 46 6 Pyrexia 18 4 30 0 Peripheral edema 13 1 15 1 Gastrointestinal Disorders Nausea 41 2 34 2 Diarrhea 36 3 34 2 Vomiting 30 2 16 1 Abdominal pain 28 4 16 1 Constipation 22 0 6 1 Skin and Subcutaneous Tissue Disorders Rash 22 1 53 13 Nervous System Disorders Dizziness 15 3 4 0 Visual Disorders Visual impairment 20 0 4 0 Serous retinopathy/RPED 20 3 2 0 Vascular Disorders Hemorrhage 19 3 9 2 Hypertension 11 6 11 3 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, Photosensitivity Immune system disorders: Drug hypersensitivity Table 4: Laboratory Abnormalities Occurring in ≥10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS Grades per National Cancer Institute CTCAE v4.03. Laboratory Abnormality MEKTOVI with encorafenib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 (%) All Grades (%) 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 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) The safety of MEKTOVI in combination with encorafenib is described in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in an open-label, single-arm trial (PHAROS). The PHAROS trial [see Clinical Studies (14.2) ] excluded patients with abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for MEKTOVI and encorafenib was 8.4 and 9.2 months respectively. The most common (≥25%) adverse reactions in patients receiving MEKTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. Adverse reactions leading to dose interruptions of MEKTOVI occurred in 62% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (17%); nausea (15%); fatigue (9%); AST increased (7%); ALT increased, anemia, musculoskeletal pain, vomiting (6% each); and acute kidney injury, hemorrhage, and LV dysfunction/cardiomyopathy (5% each). Adverse reactions leading to dose reductions of MEKTOVI occurred in 33% of patients receiving MEKTOVI; the most common (≥5%) were diarrhea (8%), nausea (6%), and AST increased (5%). A total of 17% of patients receiving MEKTOVI experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI; the most common (≥2%) were diarrhea (3.1%); musculoskeletal pain, LV dysfunction/cardiomyopathy, fatigue, nausea, rash, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of MEKTOVI occurred in more than 1 patient. Serious adverse reactions occurred in 38% of patients who received MEKTOVI in combination with encorafenib. Serious adverse reactions in ≥2% of patients included hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received MEKTOVI (45 mg twice-daily) in combination with encorafenib, including intracranial hemorrhage and myocardial infarction (1% each). Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS. Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving MEKTOVI in Combination with Encorafenib in PHAROS Grades per National Cancer Institute CTCAE v4.03. Adverse Reaction MEKTOVI with encorafenib N=98 All Grades (%) Grade 3 and 4 One Grade 5 adverse reaction of hemorrhage occurred. (%) General Disorders and Administration Site Conditions Fatigue Fatigue includes fatigue, asthenia. 61 8 Edema Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema. 23 1 Pyrexia 22 0 Gastrointestinal Disorders Nausea 58 3.1 Diarrhea Diarrhea includes diarrhea, colitis. 52 7 Vomiting 37 1 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. 32 1 Constipation 27 0 Eye Disorders Visual impairment Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. 29 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, non-cardiac chest pain, neck pain. 48 4.1 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular,dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. 27 3.1 Pruritis Pruritis includes pruritus, pruritus genital. 16 0 Dry skin 13 0 Alopecia 12 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional. 27 8 Cough Cough includes cough, productive cough. 26 0 Nervous System Disorders Dizziness Dizziness includes dizziness, balance disorder. 17 1 Headache 11 0 Metabolism and Nutrition Disorders Decreased appetite 14 1 Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. 12 4.1 Hypertension 10 5 Cardiac Disorders Left ventricular dysfunction/cardiomyopathy Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. 11 1 Investigations Weight increased 11 1 Psychiatric Disorders Insomnia 10 0 Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were: Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity Immune system disorders: Drug hypersensitivity Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving MEKTOVI with Encorafenib in PHAROS Grades per National Cancer Institute CTCAE v4.03. Laboratory Abnormality Based on the number of patients with available baseline and at least one on-treatment laboratory test. MEKTOVI with encorafenib All Grades (%) Grades 3 and 4 (%) Hematology Anemia 47 11 Lymphopenia 24 6 Thrombocytopenia 20 1.1 Leukopenia 12 0 Neutropenia 12 1.1 Chemistry Increased creatinine 91 3.2 Hyperglycemia 48 6 Increased creatine kinase 41 3.3 Lipase increased 40 14 Increased ALT 34 9 Hypoalbuminemia 32 0 Increased AST 31 10 Increased alkaline phosphatase 31 3.2 Hyperkalemia 31 2.1 Hyponatremia 26 11 Serum amylase increased 22 1.1 Hypocalcemia 12 2.1

<table width="90%"><caption>Table 3: Adverse Reactions Occurring in &#x2265;10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS<footnote ID="_Ref145348429">Grades per National Cancer Institute CTCAE v4.03.</footnote></caption><col width="30%"/><col width="20%"/><col width="20%"/><col width="15%"/><col width="15%"/><thead><tr><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Adverse Reaction</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">MEKTOVI with </content> <content styleCode="bold">encorafenib </content> <content styleCode="bold">N=192</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Vemurafenib</content> <content styleCode="bold">N=186</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">All </content> <content styleCode="bold">Grades</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grades </content> <content styleCode="bold">3 and 4</content><footnote ID="_Ref145341138">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.</footnote> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">All </content> <content styleCode="bold">Grades</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grades </content> <content styleCode="bold">3 and 4</content><footnoteRef IDREF="_Ref145341138"/> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders and Administration Site Conditions</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fatigue<footnote ID="_Ref145341153">Represents a composite of multiple, related preferred terms.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>46</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pyrexia<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Peripheral edema<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal pain<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>53</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Visual Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Visual impairment<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Serous retinopathy/RPED<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hemorrhage<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Hypertension<footnoteRef IDREF="_Ref145341153"/></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 4: Laboratory Abnormalities Occurring in &#x2265;10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS<footnote ID="_RefID0EOJAG">Grades per National Cancer Institute CTCAE v4.03.</footnote></caption><col width="29%"/><col width="21%"/><col width="20%"/><col width="15%"/><col width="15%"/><thead><tr><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><content styleCode="bold">Laboratory Abnormality</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">MEKTOVI </content> <content styleCode="bold">with encorafenib </content> <content styleCode="bold">N=192</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="middle"><content styleCode="bold">Vemurafenib</content> <content styleCode="bold">N=186</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="middle"><content styleCode="bold">All </content> <content styleCode="bold">Grades</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grades </content> <content styleCode="bold">3 and 4 </content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">All </content> <content styleCode="bold">Grades</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Rrule Botrule " valign="middle"><content styleCode="bold">Grades </content> <content styleCode="bold">3 and 4 </content> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Hematology</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lymphopenia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>30</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Neutropenia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.5</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Chemistry</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased Creatinine</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>93</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>92</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased Creatine Phosphokinase </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>58</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased Gamma Glutamyl Transferase </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>34</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased ALT </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased AST </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>1.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased Alkaline Phosphatase </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2.2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Hyponatremia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>0.5</paragraph></td></tr></tbody></table>

<table styleCode="Noautorules" width="100%"><caption>Table 5: Adverse Reactions Occurring in &#x2265;10% of Patients Receiving MEKTOVI in Combination with Encorafenib in PHAROS<footnote ID="_Ref145348505">Grades per National Cancer Institute CTCAE v4.03.</footnote></caption><col width="34%"/><col width="33%"/><col width="33%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold"> </content></paragraph><paragraph><content styleCode="bold"> </content></paragraph><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">MEKTOVI</content></paragraph><paragraph><content styleCode="bold">with encorafenib</content></paragraph><paragraph><content styleCode="bold">N=98</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">All</content></paragraph><paragraph><content styleCode="bold">Grades</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Grade 3 and 4</content><footnote ID="_Ref145348813">One Grade 5 adverse reaction of hemorrhage occurred.</footnote></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders and Administration Site Conditions</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fatigue<footnote ID="_Ref145348822">Fatigue includes fatigue, asthenia.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>61</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema<footnote ID="_Ref145348828">Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>58</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea<footnote ID="_Ref145348839">Diarrhea includes diarrhea, colitis.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal pain<footnote ID="_Ref145348845">Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Visual impairment<footnote ID="_Ref145348851">Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Musculoskeletal pain<footnote ID="_Ref145348861">Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, non-cardiac chest pain, neck pain.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.1</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash<footnote ID="_Ref145348870">Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular,dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritis<footnote ID="_Ref145348877">Pruritis includes pruritus, pruritus genital.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dry skin</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Alopecia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea<footnote ID="_Ref145348888">Dyspnea includes dyspnea, dyspnea exertional.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough<footnote ID="_Ref145348893">Cough includes cough, productive cough.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dizziness<footnote ID="_Ref145348904">Dizziness includes dizziness, balance disorder.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hemorrhage<footnoteRef IDREF="_Ref145348813"/><footnote ID="_Ref145348914">Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Left ventricular dysfunction/cardiomyopathy<footnote ID="_Ref145348923">Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Weight increased</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>