ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:New Primary Malignancies [see Warnings and Precautions (5.1)] Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)] Hemorrhage [see Warnings and Precautions (5.3)] Cardiomyopathy [see Warnings and Precautions (5. )] Uveitis [see Warnings and Precautions (5. )] Serious Febrile Reactions [see Warnings and Precautions (5. )] Serious Skin Toxicities [see Warnings and Precautions (5. )] Hyperglycemia [see Warnings and Precautions (5. )] Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5. )] There are additional adverse reactions associated with trametinib. Refer to the trametinib prescribing information for additional information.. New Primary Malignancies [see Warnings and Precautions (5.1)] Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)] Hemorrhage [see Warnings and Precautions (5.3)] Cardiomyopathy [see Warnings and Precautions (5. )] Uveitis [see Warnings and Precautions (5. )] Serious Febrile Reactions [see Warnings and Precautions (5. )] Serious Skin Toxicities [see Warnings and Precautions (5. )] Hyperglycemia [see Warnings and Precautions (5. )] Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5. )] Most common adverse reactions (>= 20%) for TAFINLAR as 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, include:Unresectable or metastatic melanoma: pyrexia, rash, chills, headache, arthralgia, and cough. (6.1) Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. (6.1) NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Unresectable or metastatic melanoma: pyrexia, rash, chills, headache, arthralgia, and cough. (6.1) Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. (6.1) NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety populations described in the WARNINGS AND PRECAUTIONS reflect exposure to TAFINLAR as single agent in 586 patients with various solid tumors, including BRAF V600 mutation-positive unresectable or metastatic melanoma, enrolled in BREAK-2, BREAK-3, BREAK-MB, BRF113220, and BRF112680 and that to TAFINLAR administered with trametinib in 1087 patients enrolled in METRIC, MEK113583, MEK111504, COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among these 586 patients who received TAFINLAR as single agent, 46% were exposed for months or longer and 15% were exposed for greater than one year. Among the 1087 patients who received TAFINLAR administered with trametinib, 70% were exposed for months or longer and 21% were exposed for greater than one year.Metastatic or Unresectable BRAF V600E or V600K Mutation-Positive MelanomaTAFINLAR as Single AgentThe safety of TAFINLAR was evaluated in BREAK-3, 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 1000 mg/m2 intravenously every weeks (n 63) [see Clinical Studies (14.1)]. The trial excluded patients with abnormal LVEF or cardiac valve morphology (>= Grade 2), corrected QT interval >= 480 milliseconds on electrocardiogram, or known history of G6PD 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 median age of 53 years.The most common 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 the BREAK-3 study 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 and Table present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as single agent in the BREAK-3 study.Table 3. Select Adverse Reactions Occurring in >= 10% (All Grades) or >= 2% (Grades or 4) of Patients Treated With TAFINLAR in the BREAK-3 Studya Abbreviations: cuSCC, cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma; NULL, not applicable. aAdverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. bGrade adverse reactions limited to hyperkeratosis (n 1) and constipation (n 1). cIncludes skin papilloma and papilloma. dCases of cuSCC were required to be reported as Grade per protocol.TAFINLARN 187Dacarbazine = 59Adverse ReactionsAllGrades(%)Grades3 and 4b(%)AllGrades(%)Grades3 and 4(%)Skin and subcutaneous tissue Hyperkeratosis37100 Alopecia22NA2NA Palmar-plantar erythrodysesthesia syndrome20220 Rash17000Nervous system Headache32080General Pyrexia283100Musculoskeletal Arthralgia27120 Back pain12370 Myalgia11000Neoplasms Papillomac 27020 cuSCCd 7400Respiratory Cough12050Gastrointestinal Constipation112140Infections Nasopharyngitis10030Table 4. Laboratory Abnormalities Worsening from Baseline Occurring at Higher Incidence in Patients Treated With TAFINLAR in the BREAK-3 Study [Between-Arm Difference of >= 5% (All Grades) or >= 2% (Grades or 4)]a aAdverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. bGrade laboratory abnormality limited to hypophosphatemia (n 1).TAFINLARN 187Dacarbazine = 59Laboratory AbnormalityAllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Hyperglycemia506430Hypophosphatemia376b 142Increased alkaline phosphatase190142Hyponatremia8230Other clinically important adverse reactions observed in less than 10% of patients (N 586) treated with TAFINLAR were:Gastrointestinal: PancreatitisImmune System: Hypersensitivity manifesting as bullous rashRenal and Urinary: Interstitial nephritisTAFINLAR with TrametinibThe 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, the COMBI-d study (n 209) multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n 350) multicenter, open-label, randomized (1:1), active controlled trial. In the COMBI-d and COMBI-v studies, patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within months, history of Class II or greater congestive heart failure (New York Heart Association), history of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED), QTcB interval >= 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or 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 >= year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were white, 72% had baseline ECOG performance status and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline and 0.5% had history of brain metastases.The most common adverse reactions (>= 20%) for TAFINLAR in patients who received TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.2)]. Patients who received TAFINLAR plus trametinib had median duration of exposure of 11 months (range: days to 30 months) to TAFINLAR. Among the 209 patients who received TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for 6 months to 12 months while 46% were exposed to TAFINLAR for 1 year.In the COMBI-d study, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients who received TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients who received TAFINLAR plus trametinib; the most frequent 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 who received TAFINLAR plus trametinib; the most frequent were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). Table and Table present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.Table 5. Select Adverse Reactions Occurring in >= 10% (All Grades) of Patients Treated With TAFINLAR Administered With Trametinib in the COMBI-d Studya aNCI CTCAE version 4.0.bGrade adverse reactions limited to headache (n 1).cIncludes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.Pooled TAFINLAR plus TrametinibN 559COMBI-d StudyTAFINLAR plus Trametinib = 209TAFINLARN 211Adverse ReactionsAllGrades(%)Grades3 and 4b(%)AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexia545577331.9 Chills310.5310170.5Skin Rashc 321.1420271.4 Dry skin100120160Nervous system Headache300.9330.5301.4 Dizziness110.214070Musculoskeletal Arthralgia250.9260.9310 Myalgia150.2130.5130Respiratory Cough200210210Gastrointestinal Constipation130.2130.5100Infections Nasopharyngitis120120100Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:Gastrointestinal: Colitis, Gastrointestinal perforation, PancreatitisSubcutaneous Tissue: PanniculitisTable 6. Select Laboratory Abnormalities Worsening from Baseline Occurring at >= 10% (All Grades) of Patients Who Received TAFINLAR With Trametinib in the COMBI-d StudyaFor these laboratory tests the denominator is 556.bFor these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm.cGrade adverse reactions limited to hyperglycemia (n 4), hyponatremia and hypophosphatemia (each = 1), in the pooled combination arm; hyperglycemia (n 1) in the COMBI-d study combination arm; hypophosphatemia (n 1) in the TAFINLAR arm.Laboratory AbnormalityPooled TAFINLAR plus TrametinibN 559a COMBI-d Study TAFINLAR plus Trametinib = 209bTAFINLARN 211bAllGrades(%)Grades3 and 4c(%)AllGrades(%)Grades3 and 4c(%)AllGrades(%)Grades3 and 4c(%)Chemistry Hyperglycemia604.7656574.3 Hypophosphatemia386383.8357 Hyponatremia258246142.9Hepatic Increased blood alkaline phosphatase492.7501.0250.5Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive MelanomaThe safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study [see Clinical Studies (14.3)]. Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily for 12 months. The trial excluded patients with abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or stenting within months; Class II or greater congestive heart failure (New York Heart Association); QTc interval >= 480 msec; treatment-refractory hypertension; uncontrolled arrhythmias; or history of RVO. The median age of patients who received TAFINLAR administered with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were white, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status of 1. Patients who received TAFINLAR in combination with trametinib had median duration of exposure of 11 months (range: to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for 6 months.The most common adverse reactions (>= 20%) in patients who received TAFINLAR administered with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most frequent for each were pyrexia and chills.Table summarizes adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib.Table 7. Adverse Reactions Occurring in >= 20% of Patients in the COMBI-AD Studya aNCI CTCAE version 4.0.bIncludes pyrexia and hyperpyrexia.cIncludes fatigue, asthenia, and malaise.dIncludes headache and tension headache.eIncludes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular.fIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain.Adverse ReactionsTAFINLAR plus TrametinibN 435 Placebo = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexiab 63511< Fatiguec 59537< Chills37140Gastrointestinal Nausea40< 1200 Diarrhea33< 115< Vomiting28< 1100Nervous system Headached 391240Skin Rashe 37< 116< 1Musculoskeletal Arthralgia28< 1140 Myalgiaf 20< 1140Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received TAFINLAR administered with trametinib were blurred vision (6%), ejection fraction decreased (5%), and rhabdomyolysis (< 1%).The laboratory abnormalities are summarized in Table 8.Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients in the COMBI-AD StudyAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aThe incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: TAFINLAR plus Trametinib (range: 429 to 431) and placebo arm (range: 426 to 428).Laboratory AbnormalityTAFINLAR plus Trametiniba = 435 Placeboa = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Chemistry Hyperglycemia633472 Hypophosphatemia42710< Hypoalbuminemia25< 1< 10Hepatic Increased AST57611< Increased ALT48518< Increased blood alkaline phosphatase3816< 1Hematology Neutropenia47612< Lymphopenia2656< Anemia25< 16< 1Trial COMBI-APlus (Pyrexia Management Study)COMBI-APlus evaluated the impact of pyrexia related outcomes of revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patients temperature is >= 100.4F.Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients.Metastatic, BRAF V600E-Mutation Positive Non-Small Cell Lung CancerThe safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n 36) and previously treated (n 57) metastatic BRAF V600E mutation-positive NSCLC in multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval >= 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current RVO [see Clinical Studies (14.4)]. Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for >= year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were white; 32% had baseline ECOG performance status and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.The most common adverse reactions (>= 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.Adverse reactions resulting in discontinuation of TAFINLAR occurred in 18% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most frequent were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most frequent were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).Table and Table 10 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928.Table 9. Adverse Reactions Occurring in >= 20% (All Grades) of Patients Treated With TAFINLAR Administered With Trametinib in Study BRF113928a aNCI CTCAE version 4.0.bIncludes fatigue, malaise, and asthenia.cIncludes peripheral edema, edema, and generalized edema.dIncludes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.Adverse ReactionsTAFINLAR plus TrametinibN 93AllGrades(%)Grades3 and 4b(%)General Pyrexia555 Fatigueb 515 Edemac 280 Chills231.1Gastrointestinal Nausea450 Vomiting333.2 Diarrhea322.2 Decreased appetite290Skin Dry skin311.1 Rashd 283.2Vascular Hemorrhagee 233.2Respiratory system Cough220 Dyspnea205Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR administered with trametinib were:Gastrointestinal: PancreatitisRenal and Urinary: Tubulointerstitial nephritisTable 10. Treatment-Emergent Laboratory Abnormalities Occurring in >= 20% (All Grades) of Patients Who Received TAFINLAR With Trametinib in Study BRF113928Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aFor these laboratory tests the denominator is 90. bFor these laboratory tests the denominator is 91.Laboratory AbnormalityTAFINLAR plus TrametinibN 93AllGrades(%)Grades3 and 4(%)Chemistrya Hyperglycemia719 Hyponatremia5717 Hypophosphatemia367 Increased creatinine211.1Hepatica Increased blood alkaline phosphatase640 Increased AST614.4 Increased ALT326Hematologyb Leukopenia488 Anemia4610 Neutropenia448 Lymphopenia4214Locally Advanced or Metastatic, BRAF V600E-Mutation Positive Anaplastic Thyroid CancerThe safety of TAFINLAR when administered with trametinib was evaluated in nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of TAFINLAR or trametinib. Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity.Among these 100 patients, 46 (46%) were exposed to TAFINLAR and trametinib for 6 months and 23 (23%) were exposed to TAFINLAR and trametinib for >= year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were white; and 31% had baseline ECOG performance status and 59% had ECOG performance status 1.The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of TAFINLAR in combination with trametinib. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Dermatologic: SCAR (including DRESS and SJS).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases, such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see Indications and Usage (1)]. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe potential effect of TAFINLAR on QT interval was assessed in dedicated multiple-dose study in 32 patients with BRAF V600 mutation-positive tumors. No large changes in the mean QT interval (i.e., 20 ms) were detected with dabrafenib 300 mg administered twice daily (two times the recommended dosage).In clinical trials, QTc (heart rate-corrected QT) prolongation to >= 500 ms occurred in 0.8% (2/264) of patients who received TAFINLAR plus trametinib and in 1.5% (4/264) of patients who received TAFINLAR as single agent. The QTc was increased 60 ms from baseline in 3.8% (10/264) of patients who received TAFINLAR plus trametinib and 3% (8/264) of patients treated with TAFINLAR as single agent. 12.3 Pharmacokinetics. AbsorptionAfter oral administration, median time to achieve peak plasma concentration (Tmax) is hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following single dose, dabrafenib exposure (Cmax and AUC) increased in dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeat twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%.Effect of FoodAdministration of dabrafenib with high-fat meal (approximately 1000 calories, 58-75 grams fat, 58 grams carbohydrates, and 33 grams protein) decreased Cmax by 51%, decreased AUC by 31%, and delayed median Tmax by 3.6 hours as compared with the fasted state.DistributionDabrafenib is 99.7% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 70.3 L.EliminationThe mean terminal half-life of dabrafenib is hours after oral administration. Hydroxy-dabrafenib terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). The apparent clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after weeks of twice-daily dosing.MetabolismThe metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 11, and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on systemic exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.ExcretionFecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.Specific PopulationsAge, Body Weight, and SexAge has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on sex, weight and renal impairment (eGFR 15 to 89 mL/min/1.73 m2) are not clinically relevant. Patients with Hepatic ImpairmentThe pharmacokinetics of dabrafenib was evaluated using population analysis in 65 patients with mild (bilirubin <= ULN and AST ULN or bilirubin 1x to 1.5x ULN and any AST) hepatic impairment enrolled in clinical trials. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate (bilirubin 1.5x to 3x ULN and any AST) to severe (bilirubin 3x to 10x ULN and any AST) hepatic impairment.Drug Interaction StudiesEffect of Trametinib on Dabrafenib: Coadministration of trametinib mg daily with dabrafenib 150 mg twice daily resulted in 23% increase in AUC of dabrafenib, 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of hydroxy-dabrafenib as compared with administration of dabrafenib.Effect of Strong Inhibitors of CYP3A4 or CYP2C8 on Dabrafenib: Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. Coadministration of dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily (a strong CYP2C8 inhibitor) for days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites.Effect of Strong Inducers of CYP3A4 or Moderate Inducers CYP2C8 on Dabrafenib: Coadministration of dabrafenib 150 mg twice daily and rifampin 600 mg once daily (a strong CYP3A4 and moderate CYP2C8 inducer) for 10 days decreased dabrafenib AUC by 34%, had no effect on hydroxy-dabrafenib AUC, and decreased desmethyl-dabrafenib AUC by 30%.Effect of Acid Reducing Agents on Dabrafenib: Coadministration of dabrafenib 150 mg twice daily and rabeprazole 40 mg once daily for days resulted in 3% increase in AUC of dabrafenib, 15% decrease in AUC of desmethyl-dabrafenib, and 5% increase in AUC of hydroxy-dabrafenib as compared to administration of dabrafenib alone. The changes in exposure of dabrafenib and its metabolites were not clinically relevant.Effect of Dabrafenib on CYP Substrates: In vitro data demonstrate that dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism. Coadministration of TAFINLAR 150 mg twice daily for 15 days and single dose of midazolam mg (a CYP3A4 substrate) decreased midazolam AUC by 65%. Coadministration of dabrafenib 150 mg twice daily for 15 days and single dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (CYP3A4/CYP1A2 substrate) by 33%.Effect of Transporters on Dabrafenib: Dabrafenib and its metabolites, hydroxyl-dabrafenib and desmethyl-dabrafenib, are substrates of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but are not substrates of organic cation transporter (OCT1) or organic anion transporting polypeptide (OATP1A2, OATP1B1, OATP1B3, OATP2B1) in vitro.Effect of Dabrafenib on Transporters: Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib, are inhibitors of OATP1B1, OATP1B3, and organic anion transporter (OAT1 and OAT3) in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of OCT2 and BCRP in vitro. Coadministration of TAFINLAR 150 mg twice daily with single dose of rosuvastatin (a sensitive OATP1B1 and OATP1B3 substrate) increased rosuvastatin Cmax by 2.6-fold, but did not change its AUC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival in the BREAK-3 Study. Figure 2. Kaplan-Meier Curves for Overall Survival in the COMBI-d Study. Figure 3. Kaplan-Meier Curves for Overall Survival in the COMBI-v Study. Figure 4. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma. 14.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma TAFINLAR As Single Agent. BREAK-3 StudyThe safety and efficacy of TAFINLAR as single agent were evaluated in an international, multicenter, randomized (3:1), open-label, active-controlled trial (the BREAK-3 study; NCT01227889) conducted in 250 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma. Patients with any prior use of BRAF inhibitors or MEK inhibitors were excluded. Patients were randomized to receive TAFINLAR 150 mg orally twice daily (n 187) or dacarbazine 1000 mg/m2 intravenously every weeks (n 63). Randomization was stratified by disease stage at baseline [unresectable Stage III (regional nodal or in-transit metastases), M1a (distant skin, subcutaneous, or nodal metastases), or M1b (lung metastases) versus M1c melanoma (all other visceral metastases or elevated serum LDH)]. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. In addition, an independent radiology review committee (IRRC) assessed the following efficacy outcome measures in pre-specified supportive analyses: PFS, confirmed overall response rate (ORR), and duration of response (DoR).The median age of patients in the BREAK-3 study was 52 years. The majority of the trial population was male (60%), white (99%), had an ECOG performance status of (67%), M1c disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by clinical trial assay at centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID(TM)-BRAF assay.The median durations of follow-up prior to initiation of alternative treatment in patients randomized to receive TAFINLAR was 5.1 months and in the dacarbazine arm was 3.5 months. Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR.The BREAK-3 study demonstrated statistically significant increase in progression-free survival in the patients treated with TAFINLAR. Table 11 and Figure summarize the PFS results.Table 11. Investigator-Assessed Progression-Free Survival and Confirmed Overall Response Results in the BREAK-3 StudyAbbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. aPike estimator, stratified by disease state. bStratified log-rank test.Investigator-Assessed EndpointsTAFINLARN 187DacarbazineN 63Progression-Free Survival Number of Events (%)78 (42%)41 (65%) Progressive Disease7641 Death20 Median, months (95% CI)5.1 (4.9, 6.9)2.7 (1.5, 3.2) HRa (95% CI)0.33 (0.20, 0.54) valueb 0.0001Confirmed Tumor Responses Overall Response Rate (95% CI)52% (44%, 59%)17% (9%, 29%) Complete Response, (%)6 (3%)0 Partial Response, (%)91 (48%)11 (17%) Duration of Response Median DoR, months (95% CI)5.6 (5.4, NR)NR (5.0, NR)Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival in the BREAK-3 StudyIn supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the THxID(TM)-BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.BREAK-MB StudyThe activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in single-arm, open-label, two-cohort multicenter trial (the BREAK-MB study; NCT01266967). All patients received TAFINLAR 150 mg twice daily. Patients in Cohort (n 74) had received no prior local therapy for brain metastases, while patients in Cohort (n 65) had received at least one local therapy for brain metastases, including, but not limited to, surgical resection, whole brain radiotherapy, or stereotactic radiosurgery, such as gamma knife, linear-accelerated-based radiosurgery, or charged particles. In addition, patients in Cohort were required to have evidence of disease progression in previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The major efficacy outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.The median age of patients in Cohort was 50 years, 72% were male, 100% were white, 59% had pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline. The median age of patients in Cohort was 51 years, 63% were male, 98% were white, 66% had pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline. The intracranial response rate as determined by an independent radiology review committee, masked to investigator response assessments, was 18% (95% CI: 10%, 28%) in Cohort and 18% (95% CI: 10%, 30%) in Cohort B. The median duration of intracranial response was 4.6 months in both cohorts.. 14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma TAFINLAR With Trametinib. COMBI-d Study and COMBI-v StudyThe safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (the COMBI-d study; NCT01584648) and one open-label trial (the COMBI-v study; NCT01597908). The COMBI-d study compared TAFINLAR and trametinib to TAFINLAR and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib mg once daily or TAFINLAR 150 mg twice daily plus matching placebo. Randomization was stratified by LDH level (> ULN vs. <= ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).The COMBI-v study compared TAFINLAR and trametinib to vemurafenib as first-line treatment therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib mg once daily or vemurafenib 960 mg twice daily. Randomization was stratified by lactate dehydrogenase (LDH) level (> ULN vs. <= ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were PFS and ORR as assessed by investigator per RECIST v1.1.In the COMBI-d study, 423 patients were randomized to TAFINLAR plus trametinib (n 211) or TAFINLAR plus placebo (n 212). The median age was 56 years (range: 22 to 89 years), 53% were male, 99% were white, 72% had ECOG performance status of 0, 4% had Stage IIIC, 66% had M1c disease, 65% had normal LDH, and patients had history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.In the COMBI-v study, 704 patients were randomized to TAFINLAR plus trametinib (n 352) or single-agent vemurafenib (n 352). The median age was 55 years (range: 18 to 91 years), 96% were white, and 55% were male, 6% percent of patients had Stage IIIC, 61% had M1c disease, 67% had normal LDH, 70% had ECOG performance status of 0, 89% had BRAF V600E mutation-positive melanoma, and one patient had history of brain metastases. The COMBI-d and COMBI-v studies demonstrated statistically significant improvements in OS and PFS. Table 12 and Figures and summarize the efficacy results.Table 12. Efficacy Results in Patients With BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanomaa Abbreviations: DoR, duration of response; ORR, overall response rate; CI, confidence interval; HR, hazard ratio; NR, not reached. aP-value is comparing with the allocated alpha of 0.021 for the interim analysis based on 77% information. bPFS and ORR were assessed by investigator.EndpointCOMBI-d StudyCOMBI-v StudyTAFINLAR plus TrametinibN 211TAFINLARplus PlaceboN 212TAFINLAR plus TrametinibN 352VemurafenibN 352Overall Survival Number of Deaths (%)99 (47%)123 (58%)100 (28%)122 (35%) Median, months (95% CI)25.1 (19.2, NR)18.7 (15.2, 23.1)NR (18.3, NR)17.2 (16.4, NR) HR (95% CI)0.71 (0.55, 0.92)0.69 (0.53, 0.89) value (log-rank test)0.010.005a Progression-Free Survivalb Number of Events (%)102 (48%)109 (51%)166 (47%)217 (62%) Median, months (95% CI)9.3 (7.7, 11.1)8.8 (5.9, 10.9)11.4 (9.9, 14.9)7.3 (5.8, 7.8) HR (95% CI)0.75 (0.57, 0.99)0.56 (0.46, 0.69) value (log-rank test)0.035< 0.001Overall Response Rateb ORR (95% CI)66% (60%, 73%)51% (44%, 58%)64% (59%, 69%)51% (46%, 56%) value< 0.001< 0.001 Complete Response10%8%13%8% Partial Response56%42%51%43% Median DoR, months(95% CI)9.2 (7.4, NR)10.2 (7.5, NR)13.8 (11.0, NR)7.5 (7.3, 9.3)Figure 2. Kaplan-Meier Curves for Overall Survival in the COMBI-d StudyFigure 3. Kaplan-Meier Curves for Overall Survival in the COMBI-v StudyCOMBI-MB StudyThe activity of TAFINLAR with trametinib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in non-randomized, open-label, multi-center, multi-cohort trial (the COMBI-MB study; NCT02039947). Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than cm in diameter, ocular melanoma, or primary mucosal melanoma. Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least mm in diameter, as assessed by independent review.The COMBI-MB study enrolled 121 patients with BRAF V600E (85%) or V600K (15%) mutation. The median age was 54 years (range: 23 to 84 years), 58% were male, 100% were white, 8% were from the United States, 65% had normal LDH value at baseline, and 97% had an ECOG performance status of or 1. Intracranial metastases were asymptomatic in 87% and symptomatic in 13% of patients, 22% received prior local therapy for brain metastases, and 87% also had extracranial metastases.The intracranial response rate was 50% (95% CI: 41, 60), with complete response rate of 4.1% and partial response rate of 46%. The median duration of intracranial response was 6.4 months (range: to 31 months). Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response.. 14.3 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma. COMBI-AD (NCT 01682083) was an international, multi-center, randomized, double-blind, placebo-controlled trial that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the THxID(TM)-BRAF assay and pathologic involvement of regional lymph node(s). Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib mg once daily or two placebos for up to year. Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anticancer treatment, including radiotherapy. Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7th Edition) stage (IIIa, IIIb, or IIIc). The major efficacy outcome measure was relapse-free survival (RFS), defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients underwent imaging for tumor recurrence every months for the first two years and every months thereafter.In COMBI-AD, total of 870 patients were randomized: 438 to TAFINLAR administered with trametinib and 432 to placebo. Median age was 51 years (range 18-89), 55% were male, 99% were white, and 91% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIa (18%), Stage IIIb (41%), Stage IIIc (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic lymph nodes (65%); and tumor ulceration (41%). The median duration of follow-up (time from randomization to last contact or death) was 2.8 years.COMBI-AD showed statistically significant improvement in RFS in patients randomized to TAFINLAR administered with trametinib compared to those randomized to placebo. Efficacy results are presented in Table 13 and Figure 4.Table 13. Efficacy Results in COMBI-AD in the Adjuvant Treatment of MelanomaAbbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable. aPike estimator obtained from the stratified log-rank test estimator. bLog-rank test stratified by disease stage (IIIA vs. IIIB vs. IIIC) and BRAF V600 mutation type (V600E vs. V600K).TAFINLAR plus TrametinibN 438PlaceboN 432Relapse-Free Survival Number of Events (%)166 (38)248 (57) Median, months (95% CI)NE (44.5, NE)16.6 (12.7, 22.1) HR (95% CI)a 0.47 (0.39, 0.58) valueb 0.0001Figure 4. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma. 14.4 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer. The safety and efficacy of TAFINLAR alone or administered with trametinib were evaluated in multi-center, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928, NCT01336634). Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK-inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts and were required to have received at least one previous platinum-based chemotherapy regimen for NSCLC with demonstrated disease progression but no more than three prior systemic regimens. Patients enrolled in Cohort could not have received prior systemic therapy for metastatic NSCLC. Patients in Cohort received TAFINLAR 150 mg twice daily. Patients in Cohorts and received TAFINLAR 150 mg twice daily and trametinib mg once daily. The major efficacy outcome measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and DoR.There were total of 171 patients enrolled which included 78 patients enrolled in Cohort A, 57 patients enrolled in Cohort B, and 36 patients enrolled in Cohort C. The characteristics of the study population were median age of 66 years, 48% male; 81% white, 14% Asian, 3% black, and 2% Hispanic; 60% were former smokers, 32% were never smokers, and 8% current smokers; 27% had ECOG performance status (PS) 0, 63% had ECOG PS 1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and 14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting and 58% of the 135 previously treated patients had only one line of prior systemic therapy for metastatic disease; and 98% had non-squamous histology.Efficacy results are summarized in Table 14.Table 14. Efficacy Results Based on Independent Review in Study BRF113928Abbreviations: CI, confidence interval; DoR, duration of response; NE, not estimable.TreatmentTAFINLARTAFINLAR TrametinibPopulationPreviously TreatedN 78Previously TreatedN 57Treatment NaiveN 36Overall Response Rate ORR (95% CI)27% (18%, 38%)63% (49%, 76%)61% (44%, 77%) Complete Response1%4%3% Partial Response26%60%58%Duration of Responsen 21n 36n 22 Median DoR, months (95% CI)9.9 (4.2, NE)12.6 (5.8, NE)NE (6.9, NE) with DoR >= months52%64%59%In subgroup analysis of patients with retrospectively, centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine(TM) Dx Target Test, the ORR results were similar to those presented in Table 14.. 14.5 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer. The safety and efficacy of TAFINLAR administered with trametinib was evaluated in an activity estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction. Patients received TAFINLAR 150 mg twice daily and trametinib mg once daily. The major efficacy outcome measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and DoR.Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The median age was 71 years (range: 47-85); 44% were male, 50% white, 44% Asian; and 94% had ECOG performance status of or 1. Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%).Efficacy results are summarized in Table 15.Table 15. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019Abbreviations: ATC, anaplastic thyroid cancer; DoR, duration of response; CI, confidence interval; NE, not estimable.ATC Cohort Population = 36Overall Response Rate ORR (95% CI)53% (35.5%, 69.6%) Complete Response6% Partial Response47%Duration of Responsen 19Median DoR, months (95% CI)13.6 (3.8, NE) with DoR >= months68% with DoR >= 12 months53%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety populations described in the WARNINGS AND PRECAUTIONS reflect exposure to TAFINLAR as single agent in 586 patients with various solid tumors, including BRAF V600 mutation-positive unresectable or metastatic melanoma, enrolled in BREAK-2, BREAK-3, BREAK-MB, BRF113220, and BRF112680 and that to TAFINLAR administered with trametinib in 1087 patients enrolled in METRIC, MEK113583, MEK111504, COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among these 586 patients who received TAFINLAR as single agent, 46% were exposed for months or longer and 15% were exposed for greater than one year. Among the 1087 patients who received TAFINLAR administered with trametinib, 70% were exposed for months or longer and 21% were exposed for greater than one year.Metastatic or Unresectable BRAF V600E or V600K Mutation-Positive MelanomaTAFINLAR as Single AgentThe safety of TAFINLAR was evaluated in BREAK-3, 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 1000 mg/m2 intravenously every weeks (n 63) [see Clinical Studies (14.1)]. The trial excluded patients with abnormal LVEF or cardiac valve morphology (>= Grade 2), corrected QT interval >= 480 milliseconds on electrocardiogram, or known history of G6PD 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 median age of 53 years.The most common 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 the BREAK-3 study 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 and Table present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as single agent in the BREAK-3 study.Table 3. Select Adverse Reactions Occurring in >= 10% (All Grades) or >= 2% (Grades or 4) of Patients Treated With TAFINLAR in the BREAK-3 Studya Abbreviations: cuSCC, cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma; NULL, not applicable. aAdverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. bGrade adverse reactions limited to hyperkeratosis (n 1) and constipation (n 1). cIncludes skin papilloma and papilloma. dCases of cuSCC were required to be reported as Grade per protocol.TAFINLARN 187Dacarbazine = 59Adverse ReactionsAllGrades(%)Grades3 and 4b(%)AllGrades(%)Grades3 and 4(%)Skin and subcutaneous tissue Hyperkeratosis37100 Alopecia22NA2NA Palmar-plantar erythrodysesthesia syndrome20220 Rash17000Nervous system Headache32080General Pyrexia283100Musculoskeletal Arthralgia27120 Back pain12370 Myalgia11000Neoplasms Papillomac 27020 cuSCCd 7400Respiratory Cough12050Gastrointestinal Constipation112140Infections Nasopharyngitis10030Table 4. Laboratory Abnormalities Worsening from Baseline Occurring at Higher Incidence in Patients Treated With TAFINLAR in the BREAK-3 Study [Between-Arm Difference of >= 5% (All Grades) or >= 2% (Grades or 4)]a aAdverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. bGrade laboratory abnormality limited to hypophosphatemia (n 1).TAFINLARN 187Dacarbazine = 59Laboratory AbnormalityAllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Hyperglycemia506430Hypophosphatemia376b 142Increased alkaline phosphatase190142Hyponatremia8230Other clinically important adverse reactions observed in less than 10% of patients (N 586) treated with TAFINLAR were:Gastrointestinal: PancreatitisImmune System: Hypersensitivity manifesting as bullous rashRenal and Urinary: Interstitial nephritisTAFINLAR with TrametinibThe 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, the COMBI-d study (n 209) multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n 350) multicenter, open-label, randomized (1:1), active controlled trial. In the COMBI-d and COMBI-v studies, patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within months, history of Class II or greater congestive heart failure (New York Heart Association), history of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED), QTcB interval >= 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or 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 >= year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were white, 72% had baseline ECOG performance status and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline and 0.5% had history of brain metastases.The most common adverse reactions (>= 20%) for TAFINLAR in patients who received TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.2)]. Patients who received TAFINLAR plus trametinib had median duration of exposure of 11 months (range: days to 30 months) to TAFINLAR. Among the 209 patients who received TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for 6 months to 12 months while 46% were exposed to TAFINLAR for 1 year.In the COMBI-d study, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients who received TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients who received TAFINLAR plus trametinib; the most frequent 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 who received TAFINLAR plus trametinib; the most frequent were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). Table and Table present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.Table 5. Select Adverse Reactions Occurring in >= 10% (All Grades) of Patients Treated With TAFINLAR Administered With Trametinib in the COMBI-d Studya aNCI CTCAE version 4.0.bGrade adverse reactions limited to headache (n 1).cIncludes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.Pooled TAFINLAR plus TrametinibN 559COMBI-d StudyTAFINLAR plus Trametinib = 209TAFINLARN 211Adverse ReactionsAllGrades(%)Grades3 and 4b(%)AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexia545577331.9 Chills310.5310170.5Skin Rashc 321.1420271.4 Dry skin100120160Nervous system Headache300.9330.5301.4 Dizziness110.214070Musculoskeletal Arthralgia250.9260.9310 Myalgia150.2130.5130Respiratory Cough200210210Gastrointestinal Constipation130.2130.5100Infections Nasopharyngitis120120100Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:Gastrointestinal: Colitis, Gastrointestinal perforation, PancreatitisSubcutaneous Tissue: PanniculitisTable 6. Select Laboratory Abnormalities Worsening from Baseline Occurring at >= 10% (All Grades) of Patients Who Received TAFINLAR With Trametinib in the COMBI-d StudyaFor these laboratory tests the denominator is 556.bFor these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm.cGrade adverse reactions limited to hyperglycemia (n 4), hyponatremia and hypophosphatemia (each = 1), in the pooled combination arm; hyperglycemia (n 1) in the COMBI-d study combination arm; hypophosphatemia (n 1) in the TAFINLAR arm.Laboratory AbnormalityPooled TAFINLAR plus TrametinibN 559a COMBI-d Study TAFINLAR plus Trametinib = 209bTAFINLARN 211bAllGrades(%)Grades3 and 4c(%)AllGrades(%)Grades3 and 4c(%)AllGrades(%)Grades3 and 4c(%)Chemistry Hyperglycemia604.7656574.3 Hypophosphatemia386383.8357 Hyponatremia258246142.9Hepatic Increased blood alkaline phosphatase492.7501.0250.5Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive MelanomaThe safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study [see Clinical Studies (14.3)]. Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily for 12 months. The trial excluded patients with abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or stenting within months; Class II or greater congestive heart failure (New York Heart Association); QTc interval >= 480 msec; treatment-refractory hypertension; uncontrolled arrhythmias; or history of RVO. The median age of patients who received TAFINLAR administered with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were white, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status of 1. Patients who received TAFINLAR in combination with trametinib had median duration of exposure of 11 months (range: to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for 6 months.The most common adverse reactions (>= 20%) in patients who received TAFINLAR administered with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most frequent for each were pyrexia and chills.Table summarizes adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib.Table 7. Adverse Reactions Occurring in >= 20% of Patients in the COMBI-AD Studya aNCI CTCAE version 4.0.bIncludes pyrexia and hyperpyrexia.cIncludes fatigue, asthenia, and malaise.dIncludes headache and tension headache.eIncludes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular.fIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain.Adverse ReactionsTAFINLAR plus TrametinibN 435 Placebo = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)General Pyrexiab 63511< Fatiguec 59537< Chills37140Gastrointestinal Nausea40< 1200 Diarrhea33< 115< Vomiting28< 1100Nervous system Headached 391240Skin Rashe 37< 116< 1Musculoskeletal Arthralgia28< 1140 Myalgiaf 20< 1140Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received TAFINLAR administered with trametinib were blurred vision (6%), ejection fraction decreased (5%), and rhabdomyolysis (< 1%).The laboratory abnormalities are summarized in Table 8.Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients in the COMBI-AD StudyAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aThe incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: TAFINLAR plus Trametinib (range: 429 to 431) and placebo arm (range: 426 to 428).Laboratory AbnormalityTAFINLAR plus Trametiniba = 435 Placeboa = 432 AllGrades(%)Grades3 and 4(%)AllGrades(%)Grades3 and 4(%)Chemistry Hyperglycemia633472 Hypophosphatemia42710< Hypoalbuminemia25< 1< 10Hepatic Increased AST57611< Increased ALT48518< Increased blood alkaline phosphatase3816< 1Hematology Neutropenia47612< Lymphopenia2656< Anemia25< 16< 1Trial COMBI-APlus (Pyrexia Management Study)COMBI-APlus evaluated the impact of pyrexia related outcomes of revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patients temperature is >= 100.4F.Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients.Metastatic, BRAF V600E-Mutation Positive Non-Small Cell Lung CancerThe safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n 36) and previously treated (n 57) metastatic BRAF V600E mutation-positive NSCLC in multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval >= 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current RVO [see Clinical Studies (14.4)]. Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for >= year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were white; 32% had baseline ECOG performance status and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.The most common adverse reactions (>= 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.Adverse reactions resulting in discontinuation of TAFINLAR occurred in 18% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most frequent were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most frequent were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).Table and Table 10 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928.Table 9. Adverse Reactions Occurring in >= 20% (All Grades) of Patients Treated With TAFINLAR Administered With Trametinib in Study BRF113928a aNCI CTCAE version 4.0.bIncludes fatigue, malaise, and asthenia.cIncludes peripheral edema, edema, and generalized edema.dIncludes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.Adverse ReactionsTAFINLAR plus TrametinibN 93AllGrades(%)Grades3 and 4b(%)General Pyrexia555 Fatigueb 515 Edemac 280 Chills231.1Gastrointestinal Nausea450 Vomiting333.2 Diarrhea322.2 Decreased appetite290Skin Dry skin311.1 Rashd 283.2Vascular Hemorrhagee 233.2Respiratory system Cough220 Dyspnea205Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR administered with trametinib were:Gastrointestinal: PancreatitisRenal and Urinary: Tubulointerstitial nephritisTable 10. Treatment-Emergent Laboratory Abnormalities Occurring in >= 20% (All Grades) of Patients Who Received TAFINLAR With Trametinib in Study BRF113928Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aFor these laboratory tests the denominator is 90. bFor these laboratory tests the denominator is 91.Laboratory AbnormalityTAFINLAR plus TrametinibN 93AllGrades(%)Grades3 and 4(%)Chemistrya Hyperglycemia719 Hyponatremia5717 Hypophosphatemia367 Increased creatinine211.1Hepatica Increased blood alkaline phosphatase640 Increased AST614.4 Increased ALT326Hematologyb Leukopenia488 Anemia4610 Neutropenia448 Lymphopenia4214Locally Advanced or Metastatic, BRAF V600E-Mutation Positive Anaplastic Thyroid CancerThe safety of TAFINLAR when administered with trametinib was evaluated in nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of TAFINLAR or trametinib. Patients received TAFINLAR 150 mg orally twice daily and trametinib mg orally once daily until disease progression or unacceptable toxicity.Among these 100 patients, 46 (46%) were exposed to TAFINLAR and trametinib for 6 months and 23 (23%) were exposed to TAFINLAR and trametinib for >= year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were white; and 31% had baseline ECOG performance status and 59% had ECOG performance status 1.The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of TAFINLAR is 150 mg orally twice daily. Take TAFINLAR at least hour before or at least hours after meal. (2). The recommended dosage of TAFINLAR is 150 mg orally twice daily. Take TAFINLAR at least hour before or at least hours after meal. (2). 2.1 Patient Selection. MelanomaConfirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as single agent [see Warnings and Precautions (5.2), Clinical Studies (14.1)].Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)].Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.NSCLCConfirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.4)].Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.ATCConfirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.5)]. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.. Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as single agent [see Warnings and Precautions (5.2), Clinical Studies (14.1)].. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)].. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.. Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.4)].. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.. Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.5)]. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.. 2.2 Recommended Dosage for Unresectable or Metastatic Melanoma. The recommended dosage of TAFINLAR is 150 mg orally taken twice daily, as single agent or in combination with trametinib, until disease progression or unacceptable toxicity. Refer to the trametinib prescribing information for recommended trametinib dosing information.. 2.3 Recommended Dosage for the Adjuvant Treatment of Melanoma. The recommended dosage of TAFINLAR is 150 mg orally taken twice daily in combination with trametinib until disease recurrence or unacceptable toxicity for up to year. Refer to the trametinib prescribing information for recommended trametinib dosing information.. 2.4 Recommended Dosage for NSCLC. The recommended dosage of TAFINLAR is 150 mg orally taken twice daily, in combination with trametinib until disease recurrence or unacceptable toxicity. Refer to the trametinib prescribing information for recommended trametinib dosing information.. 2.5 Recommended Dosage for ATC. The recommended dosage of TAFINLAR is 150 mg orally taken twice daily, in combination with trametinib until disease recurrence or unacceptable toxicity. Refer to the trametinib prescribing information for recommended trametinib dosing information.. 2.6 Administration. Take TAFINLAR at doses approximately 12 hours apart.Take TAFINLAR at least hour before or hours after meal [see Clinical Pharmacology (12.3)].Do not take missed dose of TAFINLAR within hours of the next dose of TAFINLAR.Do not open, crush, or break TAFINLAR capsules.. Take TAFINLAR at doses approximately 12 hours apart.. Take TAFINLAR at least hour before or hours after meal [see Clinical Pharmacology (12.3)].. Do not take missed dose of TAFINLAR within hours of the next dose of TAFINLAR.. Do not open, crush, or break TAFINLAR capsules.. 2.7 Dosage Modifications for Adverse Reactions. Dose reductions for adverse reactions associated with TAFINLAR are presented in Table 1.Table 1. Recommended Dose Reductions for TAFINLAR for Adverse ReactionsActionRecommended DoseFirst Dose Reduction 100 mg orally twice dailySecond Dose Reduction75 mg orally twice dailyThird Dose Reduction50 mg orally twice dailySubsequent ModificationPermanently discontinue if unable to tolerate TAFINLAR 50 mg orally twice dailyDosage modifications for adverse reactions associated with TAFINLAR are presented in Table 2.Table 2. Recommended Dosage Modifications for TAFINLAR for Adverse ReactionsaNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.bSee Table for recommended dose reductions of TAFINLAR.cDose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies.Severity of Adverse Reactiona Dosage Modification for TAFINLARbNew Primary Malignancies [see Warnings and Precautions (5.1)]Non-Cutaneous RAS Mutation-positive MalignanciesPermanently discontinue TAFINLAR.Cardiomyopathy [see Warnings and Precautions (5.4)]Symptomatic congestive heart failure Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below lower limit of normal (LLN)Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume at same dose.Uveitis [see Warnings and Precautions (5.5)]Uveitis, including iritis and iridocyclitisFor mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR for up to weeks.If improved to Grade 0-1, then resume TAFINLAR at same or lower dose.If not improved, permanently discontinue TAFINLAR. Febrile Reactions [see Warnings and Precautions (5.6)]Fever of 100.4F to 104F (or first symptoms in case of recurrence)Withhold TAFINLAR until fever resolves, then resume at same or lower dose.Fever higher than 104F Fever complicated by rigors, hypotension, dehydration, or renal failureWithhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume at lower dose.OrPermanently discontinue TAFINLAR.Skin Toxicities [see Warnings and Precautions (5.7)]Intolerable Grade Grade or 4Withhold TAFINLAR for up to weeks.If improved, resume TAFINLAR at lower dose.If not improved, permanently discontinue TAFINLAR. Severe cutaneous adverse reactions (SCARs)Permanently discontinue TAFINLAR.Other Adverse Reactionsc, including Hemorrhage [see Warnings and Precautions (5.3)]Intolerable Grade Any Grade 3Withhold TAFINLAR.If improved to Grade 0-1, resume TAFINLAR at lower dose.If not improved, permanently discontinue TAFINLAR. First occurrence of any Grade 4Withhold TAFINLAR until improves to Grade 0-1, then resume at lower dose.OrPermanently discontinue TAFINLAR.Recurrent Grade 4Permanently discontinue TAFINLAR.Refer to the trametinib prescribing information for dose modifications for adverse reactions associated with trametinib.. Symptomatic congestive heart failure Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below lower limit of normal (LLN). Uveitis, including iritis and iridocyclitis. If improved to Grade 0-1, then resume TAFINLAR at same or lower dose.. If not improved, permanently discontinue TAFINLAR.. Fever of 100.4F to 104F (or first symptoms in case of recurrence). Fever higher than 104F Fever complicated by rigors, hypotension, dehydration, or renal failure. Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume at lower dose.. Permanently discontinue TAFINLAR.. Intolerable Grade . Grade or 4. If improved, resume TAFINLAR at lower dose.. If not improved, permanently discontinue TAFINLAR.. Severe cutaneous adverse reactions (SCARs). Intolerable Grade . Any Grade 3. If improved to Grade 0-1, resume TAFINLAR at lower dose.. If not improved, permanently discontinue TAFINLAR.. First occurrence of any Grade 4. Withhold TAFINLAR until improves to Grade 0-1, then resume at lower dose.. Permanently discontinue TAFINLAR.. Recurrent Grade 4.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).New Cutaneous and Non-Cutaneous MalignanciesAdvise patients that TAFINLAR increases the risk of developing new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their healthcare provider immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies [see Warnings and Precautions (5.1)].HemorrhageAdvise patients that TAFINLAR when administered with trametinib increases the risk of intracranial and gastrointestinal hemorrhage and to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].CardiomyopathyAdvise patients that TAFINLAR can cause cardiomyopathy and to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.4)].UveitisAdvise patients that TAFINLAR can cause uveitis, including iritis and iridocyclitis and to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.5)].Serious Febrile ReactionsAdvise patients that TAFINLAR can cause pyrexia, including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib. Instruct patients to contact their healthcare provider if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.6)].Serious Skin ToxicitiesAdvise patients that TAFINLAR can cause serious skin toxicities and to contact their healthcare provider for progressive or intolerable rash. Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of severe skin reaction [see Warnings and Precautions (5.7)].HyperglycemiaAdvise patients that TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment and to contact their healthcare provider to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.8)].Glucose-6-phosphate Dehydrogenase (G6PD) DeficiencyAdvise patients that TAFINLAR may cause hemolytic anemia in patients with G6PD deficiency. Advise patients with known G6PD deficiency to contact their healthcare provider to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.9)].Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3)].Advise females to contact their healthcare provider of known or suspected pregnancy.Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for weeks after discontinuation of treatment with TAFINLAR.Advise male patients with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for at least weeks after the last dose.InfertilityAdvise males and females of reproductive potential of the potential risk for impaired fertility with TAFINLAR [see Use in Specific Populations (8.3)]. LactationAdvise women not to breastfeed during treatment with TAFINLAR and for weeks after the last dose of TAFINLAR [see Use in Specific Populations (8.2)]. AdministrationInstruct patients to take TAFINLAR at least hour before or at least hours after meal [see Dosage and Administration (2.6)].THxID(TM) is trademark of bioMerieux.Oncomine(TM) Dx Target Test is trademark of Life Technologies Corporation, part of Thermo Fisher Scientific Inc.Distributed by: Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2022-05. Advise pregnant women and females of reproductive potential of the potential risk to fetus [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3)].. Advise females to contact their healthcare provider of known or suspected pregnancy.. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for weeks after discontinuation of treatment with TAFINLAR.. Advise male patients with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for at least weeks after the last dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter oral administration, median time to achieve peak plasma concentration (Tmax) is hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following single dose, dabrafenib exposure (Cmax and AUC) increased in dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeat twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%.Effect of FoodAdministration of dabrafenib with high-fat meal (approximately 1000 calories, 58-75 grams fat, 58 grams carbohydrates, and 33 grams protein) decreased Cmax by 51%, decreased AUC by 31%, and delayed median Tmax by 3.6 hours as compared with the fasted state.DistributionDabrafenib is 99.7% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 70.3 L.EliminationThe mean terminal half-life of dabrafenib is hours after oral administration. Hydroxy-dabrafenib terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). The apparent clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after weeks of twice-daily dosing.MetabolismThe metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 11, and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on systemic exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.ExcretionFecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.Specific PopulationsAge, Body Weight, and SexAge has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on sex, weight and renal impairment (eGFR 15 to 89 mL/min/1.73 m2) are not clinically relevant. Patients with Hepatic ImpairmentThe pharmacokinetics of dabrafenib was evaluated using population analysis in 65 patients with mild (bilirubin <= ULN and AST ULN or bilirubin 1x to 1.5x ULN and any AST) hepatic impairment enrolled in clinical trials. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate (bilirubin 1.5x to 3x ULN and any AST) to severe (bilirubin 3x to 10x ULN and any AST) hepatic impairment.Drug Interaction StudiesEffect of Trametinib on Dabrafenib: Coadministration of trametinib mg daily with dabrafenib 150 mg twice daily resulted in 23% increase in AUC of dabrafenib, 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of hydroxy-dabrafenib as compared with administration of dabrafenib.Effect of Strong Inhibitors of CYP3A4 or CYP2C8 on Dabrafenib: Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. Coadministration of dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily (a strong CYP2C8 inhibitor) for days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites.Effect of Strong Inducers of CYP3A4 or Moderate Inducers CYP2C8 on Dabrafenib: Coadministration of dabrafenib 150 mg twice daily and rifampin 600 mg once daily (a strong CYP3A4 and moderate CYP2C8 inducer) for 10 days decreased dabrafenib AUC by 34%, had no effect on hydroxy-dabrafenib AUC, and decreased desmethyl-dabrafenib AUC by 30%.Effect of Acid Reducing Agents on Dabrafenib: Coadministration of dabrafenib 150 mg twice daily and rabeprazole 40 mg once daily for days resulted in 3% increase in AUC of dabrafenib, 15% decrease in AUC of desmethyl-dabrafenib, and 5% increase in AUC of hydroxy-dabrafenib as compared to administration of dabrafenib alone. The changes in exposure of dabrafenib and its metabolites were not clinically relevant.Effect of Dabrafenib on CYP Substrates: In vitro data demonstrate that dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism. Coadministration of TAFINLAR 150 mg twice daily for 15 days and single dose of midazolam mg (a CYP3A4 substrate) decreased midazolam AUC by 65%. Coadministration of dabrafenib 150 mg twice daily for 15 days and single dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (CYP3A4/CYP1A2 substrate) by 33%.Effect of Transporters on Dabrafenib: Dabrafenib and its metabolites, hydroxyl-dabrafenib and desmethyl-dabrafenib, are substrates of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but are not substrates of organic cation transporter (OCT1) or organic anion transporting polypeptide (OATP1A2, OATP1B1, OATP1B3, OATP2B1) in vitro.Effect of Dabrafenib on Transporters: Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib, are inhibitors of OATP1B1, OATP1B3, and organic anion transporter (OAT1 and OAT3) in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of OCT2 and BCRP in vitro. Coadministration of TAFINLAR 150 mg twice daily with single dose of rosuvastatin (a sensitive OATP1B1 and OATP1B3 substrate) increased rosuvastatin Cmax by 2.6-fold, but did not change its AUC.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: December 2021MEDICATION GUIDETAFINLAR(R) (TAFF-in-lar)(dabrafenib)capsulesImportant information: If your healthcare provider prescribes TAFINLAR for you to be taken with trametinib, also read the Patient Information leaflet that comes with trametinib.What is the most important information should know about TAFINLARTAFINLAR may cause serious side effects, including:Risk of new cancers. TAFINLAR, when used alone or with trametinib, may cause skin cancers, called cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, basal cell carcinoma, or melanoma.Talk with your healthcare provider about your risk for these cancers.Check your skin and tell your healthcare provider right away about any skin changes, including a: new wart skin sore or reddish bump that bleeds or does not heal change in size or color of moleYour healthcare provider should check your skin before treatment with TAFINLAR, every months during treatment with TAFINLAR, and for up to months after you stop taking TAFINLAR to look for any new skin cancers.Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with TAFINLAR.See What are the possible side effects of TAFINLAR for more information about side effects.What is TAFINLARTAFINLAR is prescription medicine used:alone or in combination with medicine called trametinib to treat type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, and that has certain type of abnormal BRAF gene.in combination with trametinib, to help prevent melanoma that has certain type of abnormal BRAF gene from coming back after the cancer has been removed by surgery.in combination with trametinib to treat type of lung cancer called non-small cell lung cancer (NSCLC): that has spread to other parts of the body, and that has certain type of abnormal BRAF gene.in combination with trametinib to treat type of thyroid cancer called anaplastic thyroid cancer (ATC): that has spread to other parts of the body and you have no satisfactory treatment options and that has certain type of abnormal BRAF gene.TAFINLAR should not be used to treat people with wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC.Your healthcare provider will perform test to make sure that TAFINLAR is right for you.It is not known if TAFINLAR alone or TAFINLAR with trametinib is safe and effective in children.Before you take TAFINLAR, tell your healthcare provider about all of your medical conditions, including if you:have had bleeding problems have heart problems have eye problems have liver or kidney problems have diabetes plan to have surgery, dental, or other medical procedures have deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme are male (including one who has had vasectomy) with female partner of reproductive potential Males (including those who have had vasectomy) should use condoms during sexual intercourse during treatment with TAFINLAR and for at least weeks after the last dose of TAFINLARare pregnant or plan to become pregnant. TAFINLAR can harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with TAFINLAR and for weeks after the last dose of TAFINLAR. Birth control methods that contain hormones (such as birth control pills, injections, or transdermal systems) may not work as well during treatment with TAFINLAR. You should use another effective method of birth control during treatment with TAFINLAR. Talk to your healthcare provider about birth control methods that may be right for you during this time. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with TAFINLAR. are breastfeeding or plan to breastfeed. It is not known if TAFINLAR passes into your breast milk. Do not breastfeed during treatment and for weeks after your last dose of TAFINLAR. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take TAFINLARTake TAFINLAR exactly as your healthcare provider tells you. Do not change your dose or stop TAFINLAR unless your healthcare provider tells you. Your healthcare provider may change your dose of TAFINLAR, temporarily stop, or completely stop your treatment with TAFINLAR if you develop certain side effects. Take TAFINLAR times day, about 12 hours apart. Take TAFINLAR at least hour before or hours after meal. Do not open, crush, or break TAFINLAR capsules. If you miss dose of TAFINLAR, take it as soon as you remember. If it is within hours of your next scheduled dose, just take your next dose at your regular time. Do not make up for the missed dose.What are the possible side effects of TAFINLARTAFINLAR may cause serious side effects, including:See What is the most important information should know about TAFINLARbleeding problems. TAFINLAR, when taken with trametinib, can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: headaches, dizziness, or feeling weak cough up blood or blood clots vomit blood or your vomit looks like coffee grounds red or black stool that looks like tar heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with TAFINLAR. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem: feeling like your heart is pounding or racing shortness of breath swelling of your ankles or feet feeling lightheaded eye problems. TAFINLAR can cause severe eye problems that can lead to blindness. Call your healthcare provider right away if you get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes see color dots halo (see blurred outline around objects) eye pain, swelling, or redness fever. Fever is common during treatment with TAFINLAR, but may also be serious. When taking TAFINLAR with trametinib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever.Call your healthcare provider right away if you get fever during treatment with TAFINLAR.Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of TAFINLAR with trametinib if you have fevers. Your healthcare provider will treat you as needed for your fever and any signs and symptoms of infection, and should check your kidney function during and after you have had severe fever.serious skin reactions. Skin rash is common side effect of TAFINLAR. TAFINLAR can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe or serious, and may need to be treated in hospital or lead to death.Tell your healthcare provider if you get skin rash or acne that bothers you or worsens. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including: blisters or peeling of your skin mouth sores blisters on your lips, or around your mouth or eyes high fever or flu-like symptoms enlarged lymph nodesincreased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with TAFINLAR. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar: increased thirst urinating more often than normal, or urinating an increased amount of urine TAFINLAR may cause healthy red blood cells to break down too early in people with G6PD deficiency. This may lead to type of anemia called hemolytic anemia where the body does not have enough healthy red blood cells. Tell your healthcare provider if you have any of the following signs or symptoms: yellow skin (jaundice) weakness or dizziness shortness of breathThe most common side effects of TAFINLAR when taken alone include:o thickening of the outer layers of the skino wartso headacheo hair losso fevero redness, swelling, peeling, or tenderness of hands or feeto joint achesThe most common side effects of TAFINLAR when taken with trametinib in people with melanoma that has spread to other parts of the body or cannot be removed by surgery include:o fevero chillso rasho joint acheso headacheo coughThe most common side effects of TAFINLAR when taken with trametinib to help prevent melanoma from coming back after the cancer has been removed by surgery include: fevero chillso fatigueo diarrheao nauseao vomitingo headacheo joint acheso rasho muscle achesThe most common side effects of TAFINLAR when taken with trametinib in people with NSCLC include:o fevero rasho fatigueo swelling of face, arms, and legso nauseao chillso vomitingo bleedingo diarrheao cougho dry skino shortness of breatho decreased appetiteTAFINLAR may cause fertility problems in females. This could affect your ability to become pregnant. Talk to your healthcare provider if this is concern for you.TAFINLAR may cause lower sperm counts in males. This could affect the ability to father child. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of TAFINLAR.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Novartis Pharmaceuticals Corporation at 1-888-669-6682.How should store TAFINLARStore TAFINLAR at room temperature between 68F to 77F (20C to 25C).Keep TAFINLAR and all medicine out of the reach of children.General information about the safe and effective use of TAFINLARMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TAFINLAR for condition for which it was not prescribed. Do not give TAFINLAR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TAFINLAR that is written for health professionals.What are the ingredients in TAFINLARActive ingredient: dabrafenibInactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline celluloseCapsule shells: hypromellose, red iron oxide (E172), titanium dioxide (E171).Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936For more information, go to www.TAFINLAR.com or call 1-888-669-6682.T2021-152. new wart skin sore or reddish bump that bleeds or does not heal change in size or color of mole. alone or in combination with medicine called trametinib to treat type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, and that has certain type of abnormal BRAF gene.. in combination with trametinib, to help prevent melanoma that has certain type of abnormal BRAF gene from coming back after the cancer has been removed by surgery.. in combination with trametinib to treat type of lung cancer called non-small cell lung cancer (NSCLC): that has spread to other parts of the body, and that has certain type of abnormal BRAF gene.. in combination with trametinib to treat type of thyroid cancer called anaplastic thyroid cancer (ATC): that has spread to other parts of the body and you have no satisfactory treatment options and that has certain type of abnormal BRAF gene.. have had bleeding problems have heart problems have eye problems have liver or kidney problems have diabetes plan to have surgery, dental, or other medical procedures have deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme are male (including one who has had vasectomy) with female partner of reproductive potential Males (including those who have had vasectomy) should use condoms during sexual intercourse during treatment with TAFINLAR and for at least weeks after the last dose of TAFINLAR. are pregnant or plan to become pregnant. TAFINLAR can harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with TAFINLAR and for weeks after the last dose of TAFINLAR. Birth control methods that contain hormones (such as birth control pills, injections, or transdermal systems) may not work as well during treatment with TAFINLAR. You should use another effective method of birth control during treatment with TAFINLAR. Talk to your healthcare provider about birth control methods that may be right for you during this time. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with TAFINLAR. are breastfeeding or plan to breastfeed. It is not known if TAFINLAR passes into your breast milk. Do not breastfeed during treatment and for weeks after your last dose of TAFINLAR. Talk to your healthcare provider about the best way to feed your baby during this time.. Take TAFINLAR exactly as your healthcare provider tells you. Do not change your dose or stop TAFINLAR unless your healthcare provider tells you. Your healthcare provider may change your dose of TAFINLAR, temporarily stop, or completely stop your treatment with TAFINLAR if you develop certain side effects. Take TAFINLAR times day, about 12 hours apart. Take TAFINLAR at least hour before or hours after meal. Do not open, crush, or break TAFINLAR capsules. If you miss dose of TAFINLAR, take it as soon as you remember. If it is within hours of your next scheduled dose, just take your next dose at your regular time. Do not make up for the missed dose.. See What is the most important information should know about TAFINLAR. bleeding problems. TAFINLAR, when taken with trametinib, can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: headaches, dizziness, or feeling weak cough up blood or blood clots vomit blood or your vomit looks like coffee grounds red or black stool that looks like tar heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with TAFINLAR. Call your healthcare provider right away if you have any of the following signs and symptoms of heart problem: feeling like your heart is pounding or racing shortness of breath swelling of your ankles or feet feeling lightheaded eye problems. TAFINLAR can cause severe eye problems that can lead to blindness. Call your healthcare provider right away if you get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes see color dots halo (see blurred outline around objects) eye pain, swelling, or redness fever. Fever is common during treatment with TAFINLAR, but may also be serious. When taking TAFINLAR with trametinib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever.Call your healthcare provider right away if you get fever during treatment with TAFINLAR.Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of TAFINLAR with trametinib if you have fevers. Your healthcare provider will treat you as needed for your fever and any signs and symptoms of infection, and should check your kidney function during and after you have had severe fever.. serious skin reactions. Skin rash is common side effect of TAFINLAR. TAFINLAR can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe or serious, and may need to be treated in hospital or lead to death.Tell your healthcare provider if you get skin rash or acne that bothers you or worsens. Tell your healthcare provider right away if you develop any of the following signs or symptoms of severe skin reaction, including: increased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with TAFINLAR. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar: increased thirst urinating more often than normal, or urinating an increased amount of urine TAFINLAR may cause healthy red blood cells to break down too early in people with G6PD deficiency. This may lead to type of anemia called hemolytic anemia where the body does not have enough healthy red blood cells. Tell your healthcare provider if you have any of the following signs or symptoms: yellow skin (jaundice) weakness or dizziness shortness of breath. Store TAFINLAR at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Do not breastfeed. (8.2) Females and Males of Reproductive Potential: May impair fertility. (8.3). Lactation: Do not breastfeed. (8.2) Females and Males of Reproductive Potential: May impair fertility. (8.3). 8.1 Pregnancy. Risk SummaryBased on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], TAFINLAR can cause fetal harm when administered to pregnant woman. There is insufficient data in pregnant women exposed to TAFINLAR to assess the risks. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily (see Data). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataIn combined female fertility and embryo-fetal development study in rats conducted during the period of organogenesis, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at dabrafenib dose of 300 mg/kg/day [approximately three times the human exposure at the recommended dose based on area under the curve (AUC)]. At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.. 8.2 Lactation. Risk SummaryThere are no data on the presence of dabrafenib in human milk, or the effects of dabrafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with TAFINLAR and for weeks following the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TAFINLAR.ContraceptionBased on data from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 )]. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with TAFINLAR and for weeks after the last dose. Counsel patients to use non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].MalesTo avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for at least weeks after the last dose.InfertilityFemalesAdvise female patients of reproductive potential that TAFINLAR may impair fertility. reduction in fertility was observed in female rats at dose exposures equivalent to the human exposure at the recommended dose. reduction in the number of corpora lutea was noted in pregnant rats at dose exposures approximately three times the human exposure at the recommended dose [see Nonclinical Toxicology (13.1)]. MalesAdvise male patients of the potential risk for impaired spermatogenesis which may be irreversible. Effects on spermatogenesis have been observed in animals treated with dabrafenib at dose exposures up to three times the human exposure at the recommended dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of TAFINLAR as single agent or with trametinib have not been established in pediatric patients.Juvenile Animal Toxicity DataIn repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.. 8.5 Geriatric Use. Of the 586 patients with various solid tumors who received single agent TAFINLAR, 22% were aged 65 years and older. Of the 187 patients with melanoma who received single-agent TAFINLAR in the BREAK-3 study, 21% were aged 65 years or older [see Clinical Studies (14.1)]. No overall differences in the effectiveness or safety of TAFINLAR were observed between geriatric patients as compared to younger adults in the BREAK-3 study.Of the 994 patients with melanoma who received TAFINLAR plus trametinib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.2, 14.3)], 21% were aged 65 years and older and 5% were aged 75 years and older. No overall differences in the effectiveness of TAFINLAR plus trametinib were observed between geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in geriatric patients as compared to younger adults in these studies.Of the 171 patients with NSCLC who received TAFINLAR in Study BRF113928, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger adults [see Clinical Studies (14.4)].Of the 26 patients with ATC who received TAFINLAR in Study BRF117019, 77% were aged 65 years and older, and 31% were aged 75 years and older [see Clinical Studies (14.5)]. This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.. 8.6 Hepatic Impairment. Dose adjustment is not recommended for patients with mild (bilirubin <= upper limit of normal (ULN) and alanine aminotransferase (AST) ULN or bilirubin 1x to 1.5x ULN and any AST) hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate (bilirubin 1.5x to 3x ULN and any AST) to severe (bilirubin 3x to 10x ULN and any AST) hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. New Primary Malignancies, Cutaneous, and Non-cutaneous can occur when TAFINLAR is administered as single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. (5.1, 2.7) Tumor Promotion in BRAF Wild-type Tumors: Increased cell proliferation can occur with BRAF inhibitors. (5.2, 2.1) Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR with trametinib. Monitor for signs and symptoms of bleeding. (5.3)Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before treatment with TAFINLAR and trametinib, after one month of treatment, then every to months thereafter. (5.4, 2.7)Uveitis: Perform ophthalmologic evaluation for any visual disturbances. (5.5, 2.7)Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. (5.6, 2.7)Serious Skin Toxicities: Monitor for skin toxicities. Discontinue for intolerable Grade or for Grade or rash not improving within weeks despite interruption of TAFINLAR. Permanently discontinue for severe cutaneous adverse reactions (SCARs). (5.7, 2.7) Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. (5.8)Glucose-6-phosphate Dehydrogenase Deficiency (G6PD): Closely monitor for hemolytic anemia. (5.9) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use an effective non-hormonal method of contraception. (5.11, 8.1, 8.3). New Primary Malignancies, Cutaneous, and Non-cutaneous can occur when TAFINLAR is administered as single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. (5.1, 2.7) Tumor Promotion in BRAF Wild-type Tumors: Increased cell proliferation can occur with BRAF inhibitors. (5.2, 2.1) Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR with trametinib. Monitor for signs and symptoms of bleeding. (5.3). Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before treatment with TAFINLAR and trametinib, after one month of treatment, then every to months thereafter. (5.4, 2.7). Uveitis: Perform ophthalmologic evaluation for any visual disturbances. (5.5, 2.7). Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. (5.6, 2.7). Serious Skin Toxicities: Monitor for skin toxicities. Discontinue for intolerable Grade or for Grade or rash not improving within weeks despite interruption of TAFINLAR. Permanently discontinue for severe cutaneous adverse reactions (SCARs). (5.7, 2.7) Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. (5.8). Glucose-6-phosphate Dehydrogenase Deficiency (G6PD): Closely monitor for hemolytic anemia. (5.9) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use an effective non-hormonal method of contraception. (5.11, 8.1, 8.3). 5.1 New Primary Malignancies. Cutaneous MalignanciesAcross clinical trials of TAFINLAR monotherapy, cutaneous squamous cell carcinomas (cuSCC), and keratoacanthomas occurred in 11% and 4% of patients, respectively. Basal cell carcinoma and new primary melanoma occurred in 4% and 1% of patients, respectively.Across clinical trials of TAFINLAR administered with trametinib, the incidence of cuSCC (including keratoacanthomas) occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and 1% of patients, respectively.Perform dermatologic evaluations prior to initiation of TAFINLAR, every months while on therapy, and for up to months following discontinuation of TAFINLAR.Non-Cutaneous MalignanciesBased 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)]. Across clinical trials of TAFINLAR monotherapy and TAFINLAR administered with trametinib, non-cutaneous malignancies occurred in 1% of patients.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 (2.7)].. 5.2 Tumor Promotion in BRAF Wild-Type Tumors. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as single agent or in combination with trametinib [see Indications and Usage (1.6), Dosage and Administration (2.1)].. 5.3 Hemorrhage. Hemorrhage, including major hemorrhage defined as symptomatic bleeding in critical area or organ, can occur when TAFINLAR is administered with trametinib. Fatal cases have been reported.Across clinical trials of TAFINLAR administered with trametinib, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received TAFINLAR administered with trametinib. Intracranial hemorrhage occurred in 0.6% of patients who received TAFINLAR administered with trametinib. Fatal hemorrhage occurred in 0.5% of patients who received TAFINLAR administered with trametinib. The fatal events were cerebral hemorrhage and brainstem hemorrhage. Permanently discontinue TAFINLAR for all Grade hemorrhagic events and for any Grade hemorrhagic events that do not improve. Withhold TAFINLAR for Grade hemorrhagic events; if improved, resume at the next lower dose level.. 5.4 Cardiomyopathy. Across clinical trials of TAFINLAR administered with trametinib, cardiomyopathy, defined as decrease in left ventricular ejection fraction (LVEF) >= 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received TAFINLAR administered with trametinib.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 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 (2.7)].. 5.5 Uveitis. Across clinical trials, uveitis occurred in 1% of patients who received TAFINLAR monotherapy and in 2% of patients who received TAFINLAR administered with trametinib. 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. If severe uveitis (i.e., iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold TAFINLAR and treat as clinically indicated. Resume TAFINLAR at the same or lower dose if improves to Grade or 1. Permanently discontinue TAFINLAR for persistent Grade or greater uveitis of 6 weeks [see Dosage and Administration (2.7)].. 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 single agent [see Adverse Reactions (6.1)].Across clinical trials of TAFINLAR monotherapy, fever (serious and non-serious) occurred in 30% of patients. Approximately 13% of these patients experienced or more discrete episodes. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients.Across clinical trials of TAFINLAR administered with trametinib, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in 1% of patients.Withhold TAFINLAR when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patients temperature is >= 100.4F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions (6.1)]. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection, and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, TAFINLAR, or both TAFINLAR and trametinib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at the same or lower dose [see Dosage and Administration (2.7)]. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR if patient had prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least days for second or subsequent pyrexia if temperature does not return to baseline within 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 Toxicities. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with TAFINLAR administered with trametinib [see Adverse Reactions (6.2)].Across clinical trials of TAFINLAR administered with trametinib, other serious skin toxicity occurred in 1% of patients.Monitor for new or worsening serious skin reactions. Permanently discontinue TAFINLAR for SCARs. For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity. Resume TAFINLAR at lower dose in patients with improvement or recovery from skin toxicity within weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within weeks [see Dosage and Administration (2.7)].. 5.8 Hyperglycemia. Across clinical trials of TAFINLAR monotherapy, 14% of patients with history of diabetes that received TAFINLAR required more intensive hypoglycemic therapy. Grade and Grade hyperglycemia occurred in 3% of patients.Across clinical trials of TAFINLAR administered with trametinib, 15% of patients with history of diabetes who had received TAFINLAR with trametinib required more intensive hypoglycemic therapy. Grade and Grade hyperglycemia occurred in 2% of patients. Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.. 5.9 Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains sulfonamide moiety, confers 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 Risks Associated With Combination Treatment. TAFINLAR is indicated for use in combination with trametinib. Review the Prescribing Information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR with trametinib.. 5.11 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to fetus. Advise female patients of reproductive potential to use effective non-hormonal contraception, since TAFINLAR can render hormonal contraceptives ineffective, during treatment with TAFINLAR and for weeks after the last dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)].

INSTRUCTIONS FOR USE SECTION.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: May 2023INSTRUCTIONS FOR USETAFINLAR(R) (TAFF-in-lar)(dabrafenib)tablets for oral suspensionThis Instructions for Use contains information on how to prepare and take or give TAFINLAR tablets for oral suspension as an oral suspension.Important information you need to know before taking or giving TAFINLAR tablets for oral suspension (TAFINLAR tablets).Read this Instructions for Use carefully before you prepare and use TAFINLAR tablets for the first time and each time you get refill. There may be new information.This Instructions for Use does not take the place of talking with your healthcare provider about you or your childs medical condition and treatment.Your healthcare provider or pharmacist should show you how to prepare and take or give dose of TAFINLAR tablets correctly. Always take or give TAFINLAR tablets exactly as your healthcare provider tells you to.If you have any questions about how to prepare and take or give dose of TAFINLAR tablets, talk to the healthcare provider or pharmacist.Always use the dosing cup that comes with your TAFINLAR tablets pack. If your pack does not contain dosing cup, contact the healthcare provider or pharmacist.Use only clean water to rinse. Do not use soap or dishwashing liquid to clean the dosing cup.If at any time TAFINLAR oral suspension gets on your or your childs skin, wash the area well with soap and water.If at any time TAFINLAR oral suspension gets in your or your childs eyes, rinse the eyes well with cool water.If you spill any TAFINLAR oral suspension, follow the instructions at the end of this Instructions for Use in the section called How to clean up any spilled TAFINLAR oral suspension.The TAFINLAR tablets pack should contain:You will receive the TAFINLAR tablets prescription in sealed bottle which contains tablets. The TAFINLAR tablets must be mixed in water before taking or giving dose of TAFINLAR oral suspension. The tablets break apart (disperse) in the water and may not fully dissolve. Follow the instructions below to mix the tablets in water.1 bottle containing TAFINLAR tablets2 reusable dosing cupsInstructions for Use leaflet (this document) and Patient InformationYou will also need drinking water.For taking or giving dose of the mixed TAFINLAR oral suspension by swallowing, go to Section A. For taking or giving dose of the mixed TAFINLAR oral suspension through feeding tube or using an oral syringe, go to Section B.SECTION A. Preparing and taking or giving dose of the mixed TAFINLAR oral suspension by swallowing directly from the dosing cup.If any of the TAFINLAR oral suspension comes into contact with your skin or eyes, when you are following the steps below, follow instructions below in Section E. How to clean up any spilled TAFINLAR oral suspension. To prepare and take or give dose of TAFINLAR oral suspension, you will need:the prescribed number of tablets1 dosing cup1 teaspoondrinking waterTo take or give dose of TAFINLAR oral suspension by mouth (swallowing the oral suspension), you or your child can drink it directly from the dosing cup.Step 1. Wash and dry your hands before preparing TAFINLAR tablets as an oral suspension.Add cool drinking water up to the markings on the dosing cup, as follows: Note: The amount of water does not need to be exact.If the prescribed dose is to tablets, you will need about mL of water.If the prescribed dose is to 15 tablets, you will need about 10 mL of water. Step 2. Remove the bottle cap by pushing down and turning counter-clockwise in the direction of the arrow, as shown.Do not throw away (dispose of) the cap.If you are opening the bottle for the first time, remove the seal from the bottle. Step 3. Count out the prescribed number of tablets into your hand.Add the prescribed number of tablets into the water in your dosing cup.The bottle contains plastic canisters to keep the tablets dry. If either canister falls out when you are taking out the tablets, re-insert it back into the bottle.Step 4. Place the cap back onto the bottle and turn it clockwise in the direction of the arrow, as shown to close it.Step 5. With one hand, tilt the dosing cup.With your other hand, gently stir the water and tablets with the handle of teaspoon until the tablets break apart (disperse).It may take minutes or more for the tablets to disperse. After the tablets disperse, the oral suspension should be cloudy white, but may contain small pieces.Take or give the TAFINLAR oral suspension no later than 30 minutes after the tablets have been dispersed in water.If more than 30 minutes have passed, dispose of the TAFINLAR oral suspension following local regulations and restart from the beginning of Section A. If you are not sure how to dispose of the TAFINLAR oral suspension, ask your healthcare provider or pharmacist. Step 6. Drink the TAFINLAR oral suspension from the dosing cup. Important: After swallowing, there will be some medicine (residue) still inside the cup. The residue may be difficult to see. Follow Steps through to take or give any medicine residue still in the cup so that you give the full dose of TAFINLAR.Step 7. Add about mL of water to the empty dosing cup.Step 8. Stir with the handle of teaspoon to loosen the remaining medicine residue.Step 9. Drink the water and residue mixture.If the prescribed dose is to tablets: Do Steps through one time.If the prescribed dose is to 15 tablets: Do Steps through two times.It is important to take or give all of the medicine residue so that you get the full dose of TAFINLAR.Step 10. Go to Section C. Cleaning the dose cup and syringe (if used). SECTION B. Preparing and giving TAFINLAR tablets as an oral suspension via feeding tube or oral syringe. Important administration information.Make sure all the tablets are dispersed before administering the TAFINLAR oral suspension.The minimum feeding tube size you may use to administer the TAFINLAR oral suspension:If the prescribed dose is to tablets, the minimum size feeding tube that may be used is 10 French.If the prescribed dose is to 15 tablets, the minimum size feeding tube that may be used is 12 French.If any of the TAFINLAR oral suspension comes into contact with your skin or eyes when you are following the steps below, follow the instructions in the section Important information you need to know before taking or giving TAFINLAR for oral suspension.If any of the TAFINLAR oral suspension spills, follow the instruction in the section How to clean up any spilled TAFINLAR oral suspension. Wash and dry your hands before giving dose of TAFINLAR oral suspension.Step 1. Follow Steps through in Section to disperse the TAFINLAR tablets. If using feeding tube, flush the tube with drinking water then continue with step below. Step 2. Draw up all of the TAFINLAR oral suspension from the dosing cup into syringe by pulling back on the plunger. Be sure to use syringe that can be used with the feeding tube or to give the TAFINLAR oral suspension by mouth. Ask your healthcare provider if you are not sure what syringe to use.Step 3. If giving the dose through feeding tube, give the TAFINLAR oral suspension into the feeding tube according to the feeding tube manufacturers instructions. If giving dose of TAFINLAR oral suspension using an oral syringe, place the open end of the oral syringe inside the mouth with the tip pointing toward the inside of either cheek. If you are giving dose of the TAFINLAR oral suspension to child, make sure they are sitting upright. Slowly push the plunger all the way down on the plunger to give the full dose. Warning: Giving TAFINLAR oral suspension directly into the throat or pushing down on the plunger too fast may cause choking.Step 4. Add about mL of water to the empty dosing cup.Step 5. Stir to loosen the medicine residue inside the cup.Step 6. Draw up the water and medicine residue mixture.Step 7. Give the water and medicine residue mixture through the solution into the feeding tube or into the inside of the cheek.It is important to give all of the medicine that is left in the syringe and feeding tube (residue). Repeat Step through Step three times to make sure that you give full dose of TAFINLAR. Step 8. After repeating Step through Step three times, flush the feeding tube with drinking water. Then go to the cleaning steps in Section C.Section C. Cleaning the dosing cup and syringe (if used).Use only clean water to rinse the dosing cup. Do not use soap or dishwashing liquid when cleaning the dosing cup.Step 1. Rinse the dosing cup under clean cool water right away after dosing.Shake off excess water then wipe dry using clean paper towels. Note: Keep the dosing cup away from other kitchen texts.Step 2. Rinse the teaspoon in clean cold water then wash in warm soapy water and dry using clean paper towels.You can also wash the teaspoon in dishwasher. Step 3. Clean the oral syringe or the other syringe, as instructed by your healthcare provider, according to the manufacturers instructions.Section D. How to throw away (dispose of) TAFINLAR tablets that are expired or no longer needed, or old dosing cups.Throw away (dispose of) unused tablets or suspension, or old dosing cups into the trash. Do not pour suspension down the drain.Ask your healthcare provider or pharmacist about how to safely throw away (dispose of) TAFINLAR if you are not sure. Section E. How to clean up any spilled TAFINLAR oral suspension.If you accidentally spill any TAFINLAR oral suspension, clean up the spill as follows: 1. Put on plastic gloves.2. Soak up the spilled TAFINLAR oral suspension completely using an absorbent material, such as paper towels soaked with either mixture of water and household disinfectant or with ethanol 70% (or higher grade).3. Repeat the cleaning with fresh soaked absorbent material at least three times until the area is clean.4. Dry the area with paper towels.5. Throw away all the disposable materials used to clean the spillage into sealable plastic bag.6. Dispose of the bags into the trash.7. Wash your hands well with soap and water.How should store TAFINLAR tablets for oral suspensionStore the TAFINLAR tablets bottle with the two plastic canisters inside and the cap tightly closed. The canisters help keep the medicine dry and protect it from moisture.Store the bottle and dosing cups in the original packaging to protect from light and moisture.Store at 68F to 77F (20C to 25C).Keep TAFINLAR tablets and all medicines out of the reach of children.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 (C) Novartis T2023-28. Read this Instructions for Use carefully before you prepare and use TAFINLAR tablets for the first time and each time you get refill. There may be new information.. This Instructions for Use does not take the place of talking with your healthcare provider about you or your childs medical condition and treatment.. Your healthcare provider or pharmacist should show you how to prepare and take or give dose of TAFINLAR tablets correctly. Always take or give TAFINLAR tablets exactly as your healthcare provider tells you to.. If you have any questions about how to prepare and take or give dose of TAFINLAR tablets, talk to the healthcare provider or pharmacist.. Always use the dosing cup that comes with your TAFINLAR tablets pack. If your pack does not contain dosing cup, contact the healthcare provider or pharmacist.. Use only clean water to rinse. Do not use soap or dishwashing liquid to clean the dosing cup.. If at any time TAFINLAR oral suspension gets on your or your childs skin, wash the area well with soap and water.. If at any time TAFINLAR oral suspension gets in your or your childs eyes, rinse the eyes well with cool water.. If you spill any TAFINLAR oral suspension, follow the instructions at the end of this Instructions for Use in the section called How to clean up any spilled TAFINLAR oral suspension.. bottle containing TAFINLAR tablets. reusable dosing cups. Instructions for Use leaflet (this document) and Patient Information. the prescribed number of tablets. dosing cup. teaspoon. drinking water. Add cool drinking water up to the markings on the dosing cup, as follows:. If the prescribed dose is to tablets, you will need about mL of water.. If the prescribed dose is to 15 tablets, you will need about 10 mL of water.. Do not throw away (dispose of) the cap.. If you are opening the bottle for the first time, remove the seal from the bottle.. Add the prescribed number of tablets into the water in your dosing cup.. The bottle contains plastic canisters to keep the tablets dry. If either canister falls out when you are taking out the tablets, re-insert it back into the bottle.. With your other hand, gently stir the water and tablets with the handle of teaspoon until the tablets break apart (disperse).. It may take minutes or more for the tablets to disperse. After the tablets disperse, the oral suspension should be cloudy white, but may contain small pieces.. Take or give the TAFINLAR oral suspension no later than 30 minutes after the tablets have been dispersed in water.. If more than 30 minutes have passed, dispose of the TAFINLAR oral suspension following local regulations and restart from the beginning of Section A. If you are not sure how to dispose of the TAFINLAR oral suspension, ask your healthcare provider or pharmacist.. If the prescribed dose is to tablets: Do Steps through one time.. If the prescribed dose is to 15 tablets: Do Steps through two times.. If the prescribed dose is to tablets, the minimum size feeding tube that may be used is 10 French.. If the prescribed dose is to 15 tablets, the minimum size feeding tube that may be used is 12 French.. If any of the TAFINLAR oral suspension comes into contact with your skin or eyes when you are following the steps below, follow the instructions in the section Important information you need to know before taking or giving TAFINLAR for oral suspension.. If any of the TAFINLAR oral suspension spills, follow the instruction in the section How to clean up any spilled TAFINLAR oral suspension. Wash and dry your hands before giving dose of TAFINLAR oral suspension.. It is important to give all of the medicine that is left in the syringe and feeding tube (residue). Repeat Step through Step three times to make sure that you give full dose of TAFINLAR. Shake off excess water then wipe dry using clean paper towels. You can also wash the teaspoon in dishwasher.. Throw away (dispose of) unused tablets or suspension, or old dosing cups into the trash. Do not pour suspension down the drain.. Ask your healthcare provider or pharmacist about how to safely throw away (dispose of) TAFINLAR if you are not sure. Store the TAFINLAR tablets bottle with the two plastic canisters inside and the cap tightly closed. The canisters help keep the medicine dry and protect it from moisture.. Store the bottle and dosing cups in the original packaging to protect from light and moisture.. Store at 68F to 77F (20C to 25C).. Tafinlar-IFU-illustrations-1. Tafinlar-IFU-illustrations-2. Tafinlar-IFU-illustrations-3. Tafinlar-IFU-illustrations-4. Tafinlar-IFU-illustrations-5. Tafinlar-IFU-illustrations-6. Tafinlar-IFU-illustrations-7. Tafinlar-IFU-illustrations-8. Tafinlar-IFU-illustrations-9. Tafinlar-IFU-illustrations-10. Tafinlar-IFU-illustrations-11. Tafinlar-IFU-illustrations-12. Tafinlar-IFU-illustrations-13. Tafinlar-IFU-illustrations-14. Tafinlar-IFU-illustrations-15. Tafinlar-IFU-illustrations-16. Tafinlar-IFU-illustrations-17. Tafinlar-IFU-illustrations-18. Tafinlar-IFU-illustrations-19. 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