Dabrafenib

TAFINLAR is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ( 1.1 , 2.1 ) TAFINLAR is indicated, in combination with trametinib , for: the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. ( 1.2 , 2.1 ) the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. ( 1.3 , 2.1 ) the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. ( 1.4 , 2.1 ) the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options. ( 1.5 , 2.1 ) the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1.6 , 2.1 ) the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. ( 1.7 , 2.1 ) Limitations of Use : TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. ( 1.8 , 12.1 ) TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors. ( 5.2 ) 1.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma TAFINLAR ® is indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. 1.2 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1)] .

1.3 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma TAFINLAR is indicated, in combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection [see Dosage and Administration (2.1)] . 1.4 BRAF V600E Mutation-Positive Metastatic NSCLC TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and Administration (2.1)] . 1.5 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)] . 1.6 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors TAFINLAR is indicated, in combination with trametinib, for the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options [see Dosage and Administration (2.1)] . This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR) [see Clinical Studies (14.6)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.7 BRAF V600E Mutation-Positive Low-Grade Glioma TAFINLAR is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy [see Dosage and Administration (2.1)] .

1.8 Limitations of Use TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition [see Indications and Usage (1.6), Clinical Pharmacology (12.1)] . TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors [see Warnings and Precautions (5.2)] .

TAFINLAR Capsules: 50 mg: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’. 75 mg: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’. TAFINLAR Tablets for Oral Suspension: 10 mg: White to slightly yellow, round, biconvex 6 mm tablet debossed with “D” on one side and “NVR” on the other, contains berry flavor. TAFINLAR Capsules: 50 mg, 75 mg ( 3 ) TAFINLAR Tablets for Oral Suspension: 10 mg ( 3 )

None. None. ( 4 )

New Primary Malignancies, Cutaneous and Non-Cutaneous : Can occur when TAFINLAR is administered as a single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. ( 5.1 , 2.4 ) 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 2 to 3 months thereafter. ( 5.4 , 2.4 ) Uveitis : Perform ophthalmological evaluation for any visual disturbances. ( 5.5 , 2.4 ) Serious Febrile Reactions : Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. ( 5.6 , 2.4 ) Serious Skin Toxicities : Monitor for skin toxicities. Discontinue for intolerable Grade 2 or for Grade 3 or 4 rash not improving within 3 weeks despite interruption of TAFINLAR. Permanently discontinue for severe cutaneous adverse reactions (SCARs). ( 5.7 , 2.4 ) 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 ) Hemophagocytic Lymphohistiocytosis (HLH) : Interrupt treatment for suspected HLH. Discontinue treatment if HLH is confirmed. ( 5.11 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.12 , 8.1 , 8.3 )

5.1 New Primary Malignancies Cutaneous Malignancies TAFINLAR Monotherapy (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, new primary melanoma occurred in < 1% of patients. Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. Non-Cutaneous Malignancies Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)] . In the pooled adult safety populations of TAFINLAR monotherapy and TAFINLAR administered with trametinib [see Adverse Reactions (6.1)] , 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 (2.4)] .

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 a 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 a critical area or organ, can occur when TAFINLAR is administered with trametinib. Fatal cases have been reported. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%), uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%). Permanently discontinue TAFINLAR for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved, resume TAFINLAR at the next lower dose level.

5.4 Cardiomyopathy TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , cardiomyopathy, defined as a 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. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the 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 to less than or equal to 10% compared to baseline [see Dosage and Administration (2.4)] .

5.5 Uveitis TAFINLAR Monotherapy (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , uveitis occurred in 1% of patients. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , uveitis occurred in 2% of patients. Cases of biocular panuveitis or biocular iridocyclitis have been reported in the post-marketing setting. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, uveitis occurred in 1.2% of patients. 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 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks [see Dosage and Administration (2.4)] .

5.6 Serious Febrile Reactions Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR. The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)] . […]

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 (5.4)] Uveitis [see Warnings and Precautions (5.5)] Serious Febrile Reactions [see Warnings and Precautions (5.6)] Serious Skin Toxicities [see Warnings and Precautions (5.7)] Hyperglycemia [see Warnings and Precautions (5.8)] Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.9)] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.11)] There are additional adverse reactions associated with trametinib. Refer to the trametinib prescribing information for additional information. Most common adverse reactions (≥ 20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. ( 6.1 ) Most common adverse reactions (≥ 20%) for TAFINLAR in combination with trametinib 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 ) Adult patients with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. ( 6.1 ) Pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia. ( 6.1 ) Pediatric patients with LGG: pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. ( 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 .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily as a 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. Among these 586 patients who received TAFINLAR as a single agent, 46% were exposed for 6 months or longer and 15% were exposed for greater than one year. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily, administered in combination with trametinib 2 mg orally, once daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC. Among these 1087 patients who received TAFINLAR administered with trametinib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year. Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based TAFINLAR orally, twice daily administered in combination with trametinib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43) [see Clinical Studies (14.6, 14.7)] . Among 166 patients who received TAFINLAR administered with trametinib, 84% were exposed for 6 months or longer and 70% were exposed for greater than one year. The most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (> 2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%). Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive Melanoma TAFINLAR as a Single Agent The safety of TAFINLAR was evaluated in BREAK-3, a multi-center, international, open-label, randomized (3:1), controlled trial that 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/m 2 intravenously every 3 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 a 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 a 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 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study. Table 6. Select Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated with TAFINLAR in the BREAK-3 Study a Abbreviations: cuSCC, cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma; NA, not applicable. a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). c Includes skin papilloma and papilloma. d Cases of cuSCC were required to be reported as Grade 3 per protocol. TAFINLAR N = 187 Dacarbazine N = 59 Adverse Reactions All Grades (%) Grades 3 and 4 b (%) All Grades (%) Grades 3 and 4 (%) Skin and subcutaneous tissue Hyperkeratosis 37 1 0 0 Alopecia 22 NA 2 NA Palmar-plantar erythrodysesthesia syndrome 20 2 2 0 Rash 17 0 0 0 Nervous system Headache 32 0 8 0 General Pyrexia 28 3 10 0 Musculoskeletal and connective tissue Arthralgia 27 1 2 0 Back pain 12 3 7 0 Myalgia 11 0 0 0 Neoplasms Papilloma c 27 0 2 0 cuSCC d 7 4 0 0 Respiratory system Cough 12 0 5 0 Gastrointestinal Constipation 11 2 14 0 Infections and infestations Nasopharyngitis 10 0 3 0 Table 7. Laboratory Abnormalities Worsening from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in the BREAK-3 Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)] a a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. […]

Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8. ( 7.1 ) Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. ( 7.2 )

7.1 Effects of Other Drugs on TAFINLAR Strong inhibitors of CYP3A4 or CYP2C8 may increase the concentration of dabrafenib [see Clinical Pharmacology (12.3)] . Substitution of strong inhibitors of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors.

7.2 Effects of TAFINLAR on Other Drugs Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)] . Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives , can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8. 3 )] . Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Lactation : Do not breastfeed. ( 8.2 ) Females and Males of Reproductive Potential : May impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)] , TAFINLAR can cause fetal harm when administered to a 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 adult clinical dose of 150 mg twice daily (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a 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 a dabrafenib dose of 300 mg/kg/day [approximately three times the human exposure at the recommended adult 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 adult dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

8.2 Lactation Risk Summary There are no data on the presence of dabrafenib in human milk, or the effects of dabrafenib on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks following the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TAFINLAR. Contraception Based 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 )]. Females Advise female patients of reproductive potential to use effective contraception during treatment with TAFINLAR and for 2 weeks after the last dose. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective [see Drug Interactions (7.2)] . Males To 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 2 weeks after the last dose. Infertility Females Advise female patients of reproductive potential that TAFINLAR may impair fertility. A reduction in fertility was observed in female rats at dose exposures equivalent to the human exposure at the recommended adult dose. A reduction in the number of corpora lutea was noted in pregnant rats at dose exposures approximately three times the human exposure at the recommended adult dose [see Nonclinical Toxicology (13.1)]. Males Advise 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 adult dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of TAFINLAR in combination with trametinib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of TAFINLAR in combination with trametinib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years of age) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)] . The safety and effectiveness of TAFINLAR in combination with trametinib have not been established for these indications in pediatric patients less than 1 year old. The safety and effectiveness of TAFINLAR as a single agent in pediatric patients have not been established. Juvenile Animal Toxicity Data In a 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 and 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 in 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 aspartate 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 dosage has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)] .

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC 50 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 IC 50 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. In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.8)].