FDA label 05df8902-e7e4-4ac2-acac-c390d97be948

5 WARNINGS AND PRECAUTIONS Review the Full Prescribing Information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib. • New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy while on therapy, and following discontinuation of treatment. ( 5.1 , 2.3 ) • Hemorrhage : Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding ( 5.2 , 2.3 ) • Venous thromboembolism : Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST. ( 5.3 , 2.3 ). • Cardiomyopathy : Assess LVEF before treatment, after one month of treatment, then every 2 to 3 months thereafter. ( 5.4 , 2.3 ) • Ocular toxicities : Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. ( 5.5 , 2.3 ). • Interstitial lung disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. ( 5.6 , 2.3 ) • Serious febrile reactions: Can occur when MEKINIST is used with dabrafenib. ( 5.7 , 2.3 ) • Serious skin toxicity: Monitor for skin toxicities and for secondary infections. Discontinue MEKINIST for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. ( 5.8 , 2.3 ) • Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. ( 5.9 , 2.3 ) • Embryo-fetal toxicity: MEKINIST can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is administered with dabrafenib. Cutaneous Malignancies In Trial 2, the incidence of basal cell carcinoma in patients receiving MEKINIST and dabrafenib was 3.3% (7/209) compared with 6% (13/211) in patients receiving single-agent dabrafenib. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the MEKINIST plus dabrafenib arm and was 4.4 months (range: 29 days to 16.5 months) in the dabrafenib arm. Among the 7 patients receiving MEKINIST with dabrafenib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3). Cutaneous squamous cell carcinomas (cuSCC) and keratoacanthoma occurred in 3% of patients receiving MEKINIST and dabrafenib and 10% of patients receiving single-agent dabrafenib. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the MEKINIST plus dabrafenib arm and was 2 months (range: 9 days to 20.9 months) in the dabrafenib arm. New primary melanoma occurred in 0.5% (1/209) of patients receiving MEKINIST and dabrafenib and in 1.9% (4/211) of patients receiving dabrafenib alone. Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST are recommended in patients who develop new primary cutaneous malignancies. Non-Cutaneous Malignancies Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving MEKINIST plus dabrafenib and in 2.8% (6/211) of patients receiving single-agent dabrafenib. Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies [see Dosage and Administration (2.3)]. 5.2 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. In Trial 2, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib was 19% (40/209) compared with 15% (32/211) of patients receiving dabrafenib alone. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving MEKINIST in combination with dabrafenib compared with 2.8% (6/211) of patients receiving single-agent dabrafenib. In Trial 2, 1.4% (3/209) of patients receiving MEKINIST and dabrafenib developed fatal intracranial hemorrhage compared with none of the patients receiving single-agent dabrafenib alone. Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level. 5.3 Venous Thromboembolism Venous thromboembolism can occur with MEKINIST. In Trial 2, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% (6/209) of patients receiving MEKINIST and dabrafenib compared with 0.9% (2/211) of patients receiving single-agent dabrafenib. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level [see Dosage and Administration (2.3)] . 5.4 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST. In clinical trials of MEKINIST, all patients were required to have an echocardiogram at baseline to document normal LVEF and repeat echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. In Trial 1, cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/211) of patients receiving MEKINIST; no chemotherapy-treated patient in Trial 1 developed cardiomyopathy. The median time to onset of cardiomyopathy in patients receiving MEKINIST was 2.1 months (range: 16 days to 5.1 months); cardiomyopathy was identified within the first month of receiving MEKINIST in five of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/211) and/or dose reduction (7/211) of MEKINIST. Cardiomyopathy resolved in 10 of these 14 (71%) patients. Across clinical trials of MEKINIST as a single agent (N = 329), 11% of patients developed evidence of cardiomyopathy [decrease in LVEF below institutional lower limits of normal (LLN) with an absolute decrease in LVEF ≥10% below baseline] and 5% demonstrated a decrease in LVEF below institutional LLN with an absolute decrease in LVEF of ≥20% below baseline. In Trial 2, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline) occurred in 6% (12/206) of patients receiving MEKINIST and dabrafenib and in 2.9% (6/207) of patients receiving single-agent dabrafenib. The median time to onset of cardiomyopathy in patients receiving MEKINIST and dabrafenib was 8.2 months (range: 28 days to 24.9 months); cardiomyopathy was identified within the first month of receiving MEKINIST and dabrafenib in 2 of these 12 patients. In patients receiving MEKINIST and dabrafenib, cardiomyopathy resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Cardiomyopathy resolved in 10 of 12 patients receiving MEKINIST and dabrafenib. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold MEKINIST for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction of >20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST [see Dosage and Administration (2.3)] . 5.5 Ocular Toxicities Retinal Vein Occlusion (RVO) Across all clinical trials with MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO [see Dosage and Administration (2.3)] . Retinal Pigment Epithelial Detachment (RPED) Retinal pigment epithelial detachment (RPED) can occur with MEKINIST administration. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In Trial 1 and Trial 2, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown. Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks [see Dosage and Administration (2.3)] . 5.6 Interstitial Lung Disease I n clinical trials of single-agent MEKINIST (N = 329), ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2.4% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 5.3 months (range: 2 to 5.7 months). In Trial 2, 1.0% (2/209) of patients receiving MEKINIST and dabrafenib developed pneumonitis compared with none of the patients receiving single-agent dabrafenib. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis [see Dosage and Administration (2.3)]. 5.7 Serious Febrile Reactions Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib. Fever (serious and non-serious) occurred in 57% (119/209) of patients receiving MEKINIST and dabrafenib and in 33% (69/211) of patients receiving dabrafenib alone. The median time to initial onset of fever was 1.2 months (range: 1 day to 23.5 months) with a median duration of fever of 3 days (range: 1 day to 1.7 months) on the MEKINIST plus dabrafenib arm compared with a median time to initial onset of fever of 20 days (range: 1 day to 22.9 months) and median duration of fever of 3 days (range: 1 day to 1.9 months) on the dabrafenib arm. Approximately one-half of the patients who received MEKINIST and dabrafenib and experienced pyrexia had three or more discrete episodes. Across clinical trials of MEKINIST administered with dabrafenib, serious febrile reactions or fever of any severity complicated by severe rigors/chills hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving MEKINIST and dabrafenib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients. Withhold MEKINIST for fever higher than 104ºF or for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)] . Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension renal failure, or severe chills/rigors, and there is no evidence of active infection. 5.8 Serious Skin Toxicity Serious skin toxicity can occur with MEKINIST. In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients receiving MEKINIST and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with MEKINIST. Skin toxicity requiring hospitalization occurred in 6% of patients treated with MEKINIST, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to initial onset of skin toxicity in patients treated with MEKINIST was 15 days (range: 1 day to 7.3 months) and median time to resolution of skin toxicity was 1.6 months (range: 1 day to 9.3 months). Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was required in 1% of patients with skin toxicity . In Trial 2, the overall incidence of any skin toxicity was 55% for patients receiving MEKINIST and dabrafenib compared with 55% for patients receiving single-agent dabrafenib. No serious or severe cases of skin toxicity occurred in patients treated with MEKINIST and dabrafenib. The median time to initial onset of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.9 months (range: 1 day to 22.1 months) and median time to resolution of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.2 months (range: 1 day to 24.4 months). Reductions in the dose of MEKINIST were required in 5% of patients receiving MEKINIST and dabrafenib and no patients required permanent discontinuation of MEKINIST for skin toxicity. Across clinical trials of MEKINIST administered with dabrafenib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients. Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)] . 5.9 Hyperglycemia Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy can occur when MEKINIST is administered with dabrafenib. In Trial 2, 27% (4/15) of patients with a history of diabetes who received MEKINIST and dabrafenib and 13% (2/16) of patients with a history of diabetes who received single-agent dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients receiving MEKINIST and dabrafenib, respectively, compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent dabrafenib. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia. 5.10 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)] . Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1, 8.3)] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Hemorrhage [see Warnings and Precautions (5.2)] • Venous Thromboembolism [see Warnings and Precautions (5.3)] • Cardiomyopathy [see Warnings and Precautions (5.4)] • Ocular Toxicities [see Warnings and Precautions (5.5)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Most common adverse reactions (≥20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema. ( 6.1 ) • Most common adverse reactions (≥20%) for MEKINIST with dabrafenib include pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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 the Warnings and Precautions section and below reflect exposure to MEKINIST as a single agent and in combination with dabrafenib. MEKINIST Administered as a Single Agent MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, >99% were White, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST. Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 every 3 weeks) [see Clinical Studies (14.1)] . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with MEKINIST was 4.3 months. In Trial 1, 9% of patients receiving MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of MEKINIST were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most common reasons cited for dose reductions of MEKINIST. Table 3. Selected Adverse Reactions Occurring in ≥10% of Patients Receiving MEKINIST and at a Higher Incidence (≥5%) than in the Chemotherapy Arm or ≥2% (Grades 3 or 4) Adverse Reactions Adverse Reactions MEKINIST Chemotherapy N = 211 N = 99 All Grades a Grades 3 and 4 b All Grades a Grades 3 and 4 b Skin and subcutaneous tissue disorders Rash 57 8 10 0 Acneiform dermatitis 19 <1 1 0 Dry skin 11 0 0 0 Pruritus 10 2 1 0 Paronychia 10 0 1 0 Gastrointestinal disorders Diarrhea 43 0 16 2 Stomatitis c 15 2 2 0 Abdominal pain d 13 1 5 1 Vascular disorders Lymphedema e 32 1 4 0 Hypertension 15 12 7 3 Hemorrhage f 13 <1 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. e Includes lymphedema, edema, and peripheral edema. f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage. Other clinically important adverse reactions observed in less than or equal to 10% of patients (N = 329) treated with MEKINIST were: Cardiac Disorders: Bradycardia Gastrointestinal Disorders: Dry mouth. Infections and Infestations: Folliculitis, rash pustular, cellulitis. Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis. Nervous System Disorders: Dizziness, dysgeusia. Ocular Disorders: Blurred vision, dry eye. Table 4. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in Patients Treated with MEKINIST in Trial 1 [Between-arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4) a ] Test MEKINIST Chemotherapy N = 211 N = 99 All Grades Grades 3 and 4 All Grades Grades 3 and 4 Increased aspartate aminotransferase (AST) 60 2 16 1 Hypoalbuminemia 42 2 23 1 Increased alanine aminotransferase (ALT) 39 3 20 3 Anemia 38 2 26 3 Increased alkaline phosphatase 24 2 18 3 a No Grade 4 events were reported in either treatment arm. MEKINIST Administered with Dabrafenib The safety of MEKINIST, administered with dabrafenib, was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received Mekinist in two trials, Trial 2 (n = 209) multicenter, double-blind, randomized (1:1), active-controlled trial and Trial 3 (n = 350) a multicenter, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of G6PD deficiency. Among these 559 patients, 197 (35%) were exposed to MEKINIST for >6 months to 12 months while 185 (33%) were exposed to MEKINIST for >1 year. The median age was 55 years (range: 18 to 91), 57% were male, and 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline, and 0.5% had a history of brain metastases. The most commonly occurring adverse reactions (≥20%) for MEKINIST in patients receiving MEKINIST plus dabrafenib were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. The demographics and baseline tumor characteristics of patients enrolled in Trial 2 are summarized in Clinical Studies [see Clinical Studies (14.1)] . Patients receiving MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients receiving MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for >6 months to 12 months while 46% were exposed to MEKINIST for >1 year. In Trial 2, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (18%), chills (7%), vomiting (6%) and decreased ejection fraction (4.8%). Table 5 and Table 6 present selected adverse drug reactions and laboratory abnormalities, respectively, of MEKINIST observed in Trial 2. Table 5. Incidence of Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in Trial 2 a Adverse Reactions Pooled MEKINIST plus Dabrafenib N = 559 Trial 2 MEKINIST plus Dabrafenib N =209 Dabrafenib N = 211 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General disorders and administrative site conditions Pyrexia 54 5 57 7 33 1.9 Chills 31 0.5 31 0 17 0.5 Edema peripheral b 21 0.7 25 1.4 11 0.5 Gastrointestinal disorders Nausea 35 0.4 34 0.5 27 1.4 Diarrhea 31 1.3 30 1.4 16 0.9 Vomiting 27 1.1 25 1.0 14 0.5 Abdominal pain c 18 0.9 26 1.0 14 2.4 Nervous system disorders Dizziness 11 0.2 14 0 7 0 Vascular disorders Hypertension 26 11 25 6 16 6 Hemorrhage d 18 2.0 19 1.9 15 1.9 Skin and subcutaneous tissue disorders Rash e 32 1.1 42 0 27 1.4 * ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. b Includes peripheral edema, edema, lymphedema, localized edema , and generalized edema. c Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Most common events (≥1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm). e Includes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients receiving MEKINIST in combination with dabrafenib (N = 559) were: Cardiac Disorders: bradycardia Musculoskeletal Disorders: rhabdomyolysis Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence * than in Patients Receiving Single-Agent Dabrafenib in Trial 2 Test Pooled MEKINIST plus Dabrafenib N = 559 a Trial 2 MEKINIST plus Dabrafenib N = 209 b Dabrafenib N = 211 b All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Hematology Neutropenia 46 7 50 6 16 1.9 Anemia 43 2.3 43 2.4 38 4.3 Lymphopenia 32 8 38 9 28 7 Thrombocytopenia 21 0.7 19 0.5 10 0.5 Liver Function Tests Increased AST 59 4.1 60 4.3 21 1.0 Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Increased ALT 48 4.5 44 3.8 28 1.0 Chemistry Hyperglycemia 60 4.7 65 6 57 4.3 Hypoalbuminemia 48 1.1 53 1.4 27 0 Hyponatremia 25 8 24 6 14 2.9 * ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving MEKINIST with dabrafenib compared with patients receiving dabrafenib as a single agent AST = Aspartate aminotransferase; ALT = Alanine aminotransferase. a For these laboratory tests the denominator is 556. b For these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, hyperglycemia (each n = 1) in the Trial 2 combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm.

<table ID="_RefID0E1EAG" width="100%"> <caption>Table 3. Selected Adverse Reactions Occurring in &#x2265;10% of Patients Receiving MEKINIST and at a Higher Incidence (&#x2265;5%) than in the Chemotherapy Arm or &#x2265;2% (Grades 3 or 4) Adverse Reactions</caption> <col width="41%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <col width="10%"/> <tbody> <tr> <td align="center" rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Adverse Reactions</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">MEKINIST</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> </td> </tr> <tr> <td align="center" colspan="2" valign="middle"> <paragraph> <content styleCode="bold">N = 211</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">N = 99</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">All</content> </paragraph> <paragraph> <content styleCode="bold">Grades^a </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4^b </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">All</content> </paragraph> <paragraph> <content styleCode="bold">Grades^a </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4^b </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Rash</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>57</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Acneiform dermatitis</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Dry skin</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Pruritus</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Paronychia</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Diarrhea</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>43</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Stomatitis^c </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Abdominal pain^d </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Vascular disorders</content> </paragraph> </td> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Lymphedema^e </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Hypertension</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <list listType="unordered"> <item> <caption> </caption>Hemorrhage^f </item> </list> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="43%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Test</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">MEKINIST</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> </td> </tr> <tr> <td rowspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"/> <td align="center" colspan="2" styleCode="Rrule Lrule " valign="middle"> <paragraph> <content styleCode="bold">N = 211</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule " valign="middle"> <paragraph> <content styleCode="bold">N = 99</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">All</content> </paragraph> <paragraph> <content styleCode="bold">Grades</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">All</content> </paragraph> <paragraph> <content styleCode="bold">Grades</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increased aspartate aminotransferase (AST)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypoalbuminemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increased alanine aminotransferase (ALT)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>38</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Increased alkaline phosphatase</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>3</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="23%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="8%"/> <col width="8%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Adverse Reactions</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Pooled MEKINIST plus Dabrafenib</content> </paragraph> <paragraph> <content styleCode="bold">N = 559</content> </paragraph> </td> <td align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Trial 2</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">MEKINIST plus Dabrafenib N =209</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Dabrafenib</content> </paragraph> <paragraph> <content styleCode="bold">N = 211</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" styleCode="Rrule Lrule 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 Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <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 Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <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 Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="7" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General disorders and administrative site conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Pyrexia</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>54</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>57</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>33</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Chills</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Edema peripheral^b </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> </tr> <tr> <td colspan="7" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Nausea</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Diarrhea</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Vomiting</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Abdominal pain^c </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> </tr> <tr> <td colspan="7" 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"> <list listType="ordered"> <item> <caption> </caption> Dizziness</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="7" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Vascular disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Hypertension</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Hemorrhage^d </item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> </tr> <tr> <td colspan="7" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Rash^e </item> </list> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>1.1</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>1.4</paragraph> </td> </tr> </tbody> </table>