FDA label 58d54d18-76cb-4ac1-beb3-da8db45c28b1

5 WARNINGS AND PRECAUTIONS Review the Full Prescribing Information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR in combination with trametinib. • New primary malignancies, cutaneous and non-cutaneous : Can occur when TAFINLAR is administered as a single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. ( 5.1 , 2.3 ) • Tumor promotion in BRAF wild-type melanoma : Increased cell proliferation can occur with BRAF inhibitors. ( 5.2 ) • Hemorrhage : Major hemorrhagic events can occur in patients receiving TAFINLAR with trametinib. Monitor for signs and symptoms of bleeding. ( 5.3 , 2.3 ) • Cardiomyopathy : Assess LVEF before treatment with TAFINLAR and trametinib, after one month of treatment, then every 2 to 3 months thereafter. ( 5.4 , 2.3 ) • Uveitis : Perform ophthalmologic evaluation for any visual disturbances. ( 5.5 , 2.3 ) • Serious febrile reactions : Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. ( 5.6 , 2.3 ) • Serious skin toxicity : Monitor for skin toxicities. Discontinue for intolerable Grade 2, 3, or 4 rash not improving within 3 weeks despite interruption of TAFINLAR. ( 5.7 , 2.3 ) • Hyperglycemia : Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. ( 5.8 ) • Glucose-6-phosphate dehydrogenase deficiency : Closely monitor for hemolytic anemia. ( 5.9 ) • Embryo-fetal toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used with trametinib. Cutaneous Malignancies TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients receiving TAFINLAR and in none of the patients receiving dacarbazine. Across clinical trials of TAFINLAR (N = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 2.1 months (range: 7 days to 12.2 months). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks. In Trial 2, the incidence of basal cell carcinoma in patients receiving TAFINLAR in combination with trametinib was 3.3% (7/209) compared with 6% (13/211) of patients receiving single-agent TAFINLAR. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the TAFINLAR plus trametinib arm and was 4.4 months (range: 29 days to 16.5 months) in the single-agent TAFINLAR arm. Among the 7 patients receiving TAFINLAR with trametinib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3). Cutaneous squamous cell carcinoma and keratoacanthoma occurred in 3% of patients receiving TAFINLAR with trametinib and 10% of patients receiving single-agent TAFINLAR. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the Tafinlar plus trametinib arm and was 2 months (range: 9 days to 20.9 months) in the single-agent TAFINLAR arm. New primary melanoma occurred in 0.5% (1/209) of patients receiving TAFINLAR with trametinib and in 1.9% (4/211) of patients receiving single-agent TAFINLAR. Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR are required in patients who develop new primary cutaneous malignancies [see Dosage and Administration (2.3)] . Non-cutaneous Malignancies Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)] . In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving TAFINLAR with trametinib and in 2.8% (6/211) of patients receiving single-agent TAFINLAR. Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.3)] . 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or in combination with trametinib [see Indications and Usage (1), Dosage and Administration (2.1)] . 5.3 Hemorrhage Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is administered with trametinib. In Trial 2, the incidence of hemorrhagic events in patients receiving TAFINLAR with trametinib was 19% (40/209) compared with 15% (32/211) of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving TAFINLAR with trametinib compared with 3% (6/211) of patients receiving single-agent TAFINLAR. Intracranial hemorrhage was fatal in 1.4% (3/209) of patients receiving TAFINLAR with trametinib compared with none of the patients receiving single-agent TAFINLAR. Permanently discontinue TAFINLAR for all Grade 4 hemorrhagic events and for any persistent Grade 3 hemorrhagic events. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level. 5.4 Cardiomyopathy Cardiomyopathy can occur with TAFINLAR. In Trial 2, all patients were required to have an echocardiogram at baseline to document normal left ventricular ejection fraction (LVEF) and serial echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. Cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional lower limit of normal, occurred in 6% (12/206) of patients receiving TAFINLAR with trametinib and 2.9% (6/207) of patients receiving single-agent TAFINLAR. The median time to onset of cardiomyopathy on the TAFINLAR plus trametinib arm was 8.2 months (range: 28 days to 24.9 months), and was 4.4 months (range: 28 days to 19.1 months) on the TAFINLAR arm. In Trial 2, cardiomyopathy was identified within the first month of initiation of TAFINLAR with trametinib in 2 of 12 patients, and in 2 of 6 patients receiving single-agent TAFINLAR. Development of cardiomyopathy in patients receiving TAFINLAR and trametinib resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%). In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption (2.4%), dose reduction (0.5%), or discontinuation (1.0%). Cardiomyopathy resolved in 10 of 12 patients receiving TAFINLAR with trametinib, and in 3 of 6 patients receiving single-agent TAFINLAR. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR with trametinib, one month after initiation of TAFINLAR, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal (LLN). Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared to baseline [see Dosage and Administration (2.3)] . 5.5 Uveitis Uveitis (including iritis and iridocyclitis) can occur with TAFINLAR. Uveitis occurred in 1% (6/586) of patients receiving TAFINLAR across multiple clinical trials and in 2% (9/559) of patients receiving TAFINLAR with trametinib across Trials 2 and 3. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification; for severe uveitis or iridocyclitis, interrupt TAFINLAR and treat as clinically indicated. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of >6 weeks duration [see Dosage and Administration (2.3)] . 5.6 Serious Febrile Reactions Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR. The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)] . In Trial 1, the incidence of fever (serious and non-serious) was 28% in patients receiving TAFINLAR and 10% in patients receiving dacarbazine. In patients receiving TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 day to 6.6 months) and the median duration of fever was 3 days (range: 1 day to 4.2 months). Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 3.7% (7/187) of patients receiving TAFINLAR and in none of the 59 patients receiving dacarbazine. In Trials 2 and 3, fever occurred in 54% (303/559) of patients receiving TAFINLAR with trametinib; the median time to onset of first occurrence of fever was 1 month (range: 1 day to 23.5 months) and the median duration of fever was 3 days (range: 1 day to 11.3 months). Approximately one-half of the patients who received TAFINLAR with trametinib and experienced pyrexia had 3 or more discrete episodes. 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 TAFINLAR with trametinib. 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 TAFINLAR for fever of 101.3ºF or higher. Withhold TAFINLAR for any serious febrile reaction or fever complicated 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 TAFINLAR 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. 5.7 Serious Skin Toxicity Serious skin toxicity can occur with TAFINLAR. Across clinical trials of TAFINLAR administered with trametinib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients. Withhold TAFINLAR for intolerable or severe skin toxicity. TAFINLAR may be resumed at the next lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)] . 5.8 Hyperglycemia Hyperglycemia can occur with TAFINLAR. In Trial 1, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy receiving TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients receiving TAFINLAR compared with none of the dacarbazine-treated patients. In Trial 2, 27% (4/15) of patients with a history of diabetes receiving TAFINLAR with trametinib and 13% (2/16) of patients with a history of diabetes receiving single-agent TAFINLAR 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, respectively, receiving TAFINLAR with trametinib compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent TAFINLAR. Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with pre-existing diabetes or hyperglycemia. 5.9 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR. 5.10 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. If TAFINLAR is used during pregnancy or if the patient becomes pregnant while taking TAFINLAR, 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 an effective non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of TAFINLAR. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (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)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Cardiomyopathy [see Warnings and Precautions (5.4)] • Uveitis [see Warnings and Precautions (5.5)] • Serious Febrile Reactions [see Warnings and Precautions (5.6)] • Serious Skin Toxicity [see Warnings and Precautions (5.7)] • Hyperglycemia [see Warnings and Precautions (5.8)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.9)] • Most common adverse reactions (≥20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. ( 6.1 ) • Most common adverse reactions (≥20%) for TAFINLAR, in combination with trametinib, are pyrexia, rash, chills, headache, arthralgia, and cough. ( 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 TAFINLAR as a single agent and in combination with trametinib. TAFINLAR Administered as a Single Agent The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg). Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14.1)]. Trial 1, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m 2 intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (≥Grade 2), corrected QT interval greater than or equal to 480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% White, and had a median age of 53 years. The most commonly occurring adverse reactions (≥20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES). The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). Table 3. Select Common Adverse Reactions Occurring in ≥10% (All Grades) or ≥2% (Grades 3 or 4) of Patients Treated with TAFINLAR a Primary System Organ Class Preferred Term TAFINLAR N = 187 Dacarbazine N = 59 All Grades (%) Grades 3 and 4 b (%) All Grades (%) Grades 3 and 4 (%) Skin and subcutaneous tissue disorders Hyperkeratosis 37 1 0 0 Alopecia 22 NA f 2 NA f Palmar-plantar erythrodysesthesia syndrome 20 2 2 0 Rash 17 0 0 0 Nervous system disorders Headache 32 0 8 0 General disorders and administration site conditions Pyrexia 28 3 10 0 Musculoskeletal and connective tissue disorders Arthralgia 27 1 2 0 Back pain 12 3 7 0 Myalgia 11 0 0 0 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Papilloma c 27 0 2 0 cuSCC d, e 7 4 0 0 Respiratory, thoracic, and mediastinal disorders Cough 12 0 5 0 Gastrointestinal disorders Constipation 11 2 14 0 Infections and infestations Nasopharyngitis 10 0 3 0 a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). c Includes skin papilloma and papilloma. d cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma. e Cases of cuSCC were required to be reported as Grade 3 per protocol. f NA = not applicable. Table 4. Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in Trial 1 [Between-Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4)] a Test TAFINLAR N = 187 DTIC N = 59 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hyperglycemia 50 6 43 0 Hypophosphatemia 37 6 b 14 2 Increased alkaline phosphatase 19 0 14 2 Hyponatremia 8 2 3 0 a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1). Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were: Gastrointestinal Disorders: Pancreatitis. Immune System Disorders: Hypersensitivity manifesting as bullous rash. Renal and Urinary Disorders: Interstitial nephritis. TAFINLAR Administered with Trametinib The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, Trial 2 (n = 209) a 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 Trials 2 and 3, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both 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, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies (14.2)] . Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 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 TAFINLAR in patients receiving TAFINLAR plus trametinib in Trials 2 and 3 were: pyrexia, rash, chills, headache, arthralgia, and cough. Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, observed in Trial 2. The demographics and baseline tumor characteristics of patients enrolled in Trial 2 are summarized in Clinical Studies [see Clinical Studies (14.2)] . Patients receiving TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients receiving TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for >6 months to 12 months while 46% were exposed to TAFINLAR for >1 year. In Trial 2, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients receiving TAFINLAR plus trametinib; the most common was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of Tafinlar occurred in 56% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). Table 5. Select Adverse Reactions Occurring in ≥10% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Trial 2 a Trial 2 Pooled TAFINLAR plus Trametinib N = 559 TAFINLAR plus Trametinib N =209 TAFINLAR N = 211 Adverse Reactions All Grades (%) Grades 3 and 4 b (%) 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 Gastrointestinal disorders Constipation 13 0.2 13 0.5 10 0 Nervous system disorders Headache 30 0.9 33 0.5 30 1.4 Dizziness 11 0.2 14 0 7 0 Musculoskeletal, connective tissue, and bone disorders Arthralgia 25 0.9 26 0.9 31 0 Myalgia 15 0.2 13 0.5 13 0 Skin and subcutaneous tissue disorders Rash c 32 1.1 42 0 27 1.4 Dry skin 10 0 12 0 16 0 Respiratory, thoracic, and mediastinal disorders Cough 20 0 21 0 21 0 Infections and infestations Nasopharyngitis 12 0 12 0 10 0 a NCI CTCAE version 4 b Grade 4 adverse reactions limited to headache (n = 1). c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis. Other clinically important adverse reactions for TAFINLAR across Trials 2 and 3 (N = 559) observed in less than 10% of patients receiving TAFINLAR in combination with trametinib were: Gastrointestinal Disorders: pancreatitis Subcutaneous Tissue Disorders: panniculitis Table 6. Select Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Trial 2 Trial 2 Pooled TAFINLAR plus Trametinib N = 559 a TAFINLAR plus Trametinib N = 209 b TAFINLAR N = 211 b Test All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Liver Function Tests Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Chemistry Hyperglycemia 60 4.7 65 6 57 4.3 Hypophosphatemia 38 6 38 3.8 35 7 Hyponatremia 25 8 24 6 14 2.9 a For these laboratory tests the denominator is 556. b For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm. c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the Trial 2 combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.

<table width="100%"> <col width="41%"/> <col width="32%"/> <col width="9%"/> <col width="9%"/> <col width="9%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Primary System Organ Class</content> </paragraph> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">TAFINLAR</content> <content styleCode="bold">N = 187</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Dacarbazine </content> <content styleCode="bold">N = 59</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">All</content> </paragraph> <paragraph> <content styleCode="bold">Grades (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Grades</content> </paragraph> <paragraph> <content styleCode="bold">3 and 4^b </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> </td> <td align="center" styleCode="Rrule 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 styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Hyperkeratosis</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Alopecia</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>NA^f </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>NA^f </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Palmar-plantar erythrodysesthesia syndrome</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule 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 Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Rash</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule 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 Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Nervous system disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Headache</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">General disorders and administration site conditions</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Pyrexia</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Arthralgia</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Back pain</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Myalgia</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule 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 Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Neoplasms benign, malignant, and unspecified (including cysts and polyps)</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Papilloma^c </item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> cuSCC^{d, e} </item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Cough</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Constipation</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Infections and infestations</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> <td styleCode="Rrule Lrule Botrule " valign="bottom"/> <td styleCode="Rrule Botrule " valign="bottom"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="bottom"> <list listType="ordered"> <item> <caption> </caption> Nasopharyngitis</item> </list> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="34%"/> <col width="32%"/> <col width="11%"/> <col width="11%"/> <col width="11%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Test</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">TAFINLAR</content> </paragraph> <paragraph> <content styleCode="bold">N = 187</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">DTIC</content> </paragraph> <paragraph> <content styleCode="bold">N = 59</content> </paragraph> </td> </tr> <tr> <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 styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hyperglycemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>50</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>43</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>Hypophosphatemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>6^b </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</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increased alkaline phosphatase</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>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</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Hyponatremia</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>8</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>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table width="100%"> <col width="30%"/> <col width="12%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="9%"/> <col width="9%"/> <tbody> <tr> <td styleCode="Rrule Lrule Toprule " valign="bottom"/> <td styleCode="Lrule Toprule " valign="bottom"/> <td styleCode="Rrule Toprule " valign="bottom"/> <td align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"> <paragraph> <content styleCode="bold">Trial 2</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule " valign="bottom"/> <td align="center" colspan="2" valign="bottom"> <paragraph> <content styleCode="bold">Pooled TAFINLAR plus Trametinib</content> </paragraph> <paragraph> <content styleCode="bold">N = 559</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">TAFINLAR plus Trametinib N =209</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">TAFINLAR</content> </paragraph> <paragraph> <content styleCode="bold">N = 211</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"> <paragraph> <content styleCode="bold">Adverse Reactions</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^b </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 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> Constipation</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>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>13</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>10</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">Nervous system disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Headache</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>30</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>33</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>30</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> 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">Musculoskeletal, connective tissue, and bone disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Arthralgia</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>25</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>0.9</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> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Myalgia</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>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>13</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>13</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">Skin and subcutaneous tissue disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Rash^c </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>1.1</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>0</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> Dry skin</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>12</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>0</paragraph> </td> </tr> <tr> <td colspan="7" 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"> <list listType="ordered"> <item> <caption> </caption> Cough</item> </list> </td> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>20</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>21</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>21</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">Infections and infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> Nasopharyngitis</item> </list> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>12</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>12</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>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>