Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 10 November 2017

Indication(s)

1 INDICATIONS AND USAGE 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) 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) metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. (1.3) Limitation of Use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma or wild-type BRAF NSCLC. (1.4, 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. 1.3 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. 1.4 Limitation of Use TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma or wild-type BRAF NSCLC [see Warnings and Precautions (5.2)] .

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contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: New Primary Malignancies [see Warnings and Precautions (5. 1 )] Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] Hemorrhage [see Warnings and Precautions (5.3)] Cardiomyopathy [see Warnings and Precautions (5. 4 )] Uveitis [see Warnings and Precautions (5. 5 )] Serious Febrile Reactions [see Warnings and Precautions (5. 6 )] Serious Skin Toxicity [see Warnings and Precautions (5. 7 )] Hyperglycemia [see Warnings and Precautions (5. 8 )] Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5. 9 )] Most common adverse reactions (≥20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. (6.1) Most common adverse reactions (≥20%) for TAFINLAR, in combination with trametinib, include: Melanoma: pyrexia, rash, chills, headache, arthralgia, and cough. (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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section reflect exposure to TAFINLAR administered as a single agent in 586 patients with various solid tumors and exposure to TAFINLAR administered with trametinib in 559 patients with melanoma and 93 patients with NSCLC. The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg). Metastatic or Unresectable BRAF V600 Mutation Positive Melanoma TAFINLAR as a Single Agent Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of the BREAK-3 study [see Clinical Studies (14 .1 )].This study, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (≥ Grade 2), corrected QT interval greater than or equal to 480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% White, and had a median age of 53 years. The most commonly occurring adverse reactions (≥20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES). The incidence of adverse events resulting in permanent discontinuation of study medication in 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 3. Select Common Adverse Reactions Occurring in ≥10% (All Grades) or ≥2% (Grades 3 or 4) of Patients Treated with TAFINLAR in the BREAK-3 Studya 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 NAf 2 NAf Palmar-plantar erythrodysesthesia syndrome 20 2 2 0 Rash 17 0 0 0 Nervous system Headache 32 0 8 0 General disorders Pyrexia 28 3 10 0 Musculoskeletal Arthralgia 27 1 2 0 Back pain 12 3 7 0 Myalgia 11 0 0 0 Neoplasms Papillomac 27 0 2 0 cuSCCd, e 7 4 0 0 Respiratory Cough 12 0 5 0 Gastrointestinal Constipation 11 2 14 0 Infections Nasopharyngitis 10 0 3 0 a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). c Includes skin papilloma and papilloma. d cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma. e Cases of cuSCC were required to be reported as Grade 3 per protocol. f NA = not applicable. Table 4. Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in 1the BREAK-3 Study [Between-Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4)]a TAFINLAR N = 187 DTIC N = 59 Test All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hyperglycemia 50 6 43 0 Hypophosphatemia 37 6b 14 2 Increased alkaline phosphatase 19 0 14 2 Hyponatremia 8 2 3 0 a Adverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1). Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were: Gastrointestinal Disorders: Pancreatitis Immune System Disorders: Hypersensitivity manifesting as bullous rash Renal and Urinary Disorders: Interstitial nephritis TAFINLAR Administered with Trametinib The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, the COMBI-d study (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n = 350) a 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 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies (14.2)]. Among these 559 patients, 199 (36%) were exposed to TAFINLAR for >6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a history of brain metastases. The most commonly occurring adverse reactions (≥20%) for TAFINLAR in patients receiving TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, observed in the COMBI-d study. 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 receiving TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients receiving TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for >6 months to 12 months while 46% were exposed to TAFINLAR for >1 year. In the COMBI-d study, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients receiving TAFINLAR plus trametinib; the most common was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 56% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). Table 5. Select Adverse Reactions Occurring in ≥10% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in the COMBI-d Studya Pooled TAFINLAR plus T rametinib N = 559 COMBI-d Study TAFINLAR plus Trametinib N = 209 TAFINLAR N = 211 Adverse Reactions All Grades (%) Grades 3 and 4 b (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia 54 5 57 7 33 1.9 Chills 31 0.5 31 0 17 0.5 Gastrointestinal Constipation 13 0.2 13 0.5 10 0 Nervous system Headache 30 0.9 33 0.5 30 1.4 Dizziness 11 0.2 14 0 7 0 Musculoskeletal Arthralgia 25 0.9 26 0.9 31 0 Myalgia 15 0.2 13 0.5 13 0 Skin Rashc 32 1.1 42 0 27 1.4 Dry skin 10 0 12 0 16 0 Respiratory Cough 20 0 21 0 21 0 Infections Nasopharyngitis 12 0 12 0 10 0 a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to headache (n = 1). c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis. Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients receiving TAFINLAR in combination with trametinib were: Gastrointestinal Disorders: Pancreatitis Subcutaneous Tissue Disorders: Panniculitis Table 6. Select Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in the COMBI-d Study Test Pooled TAFINLAR plus T rametinib N = 559 a COMBI-d Study TAFINLAR plus Trametinib N = 209 b TAFINLAR N = 211 b All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Liver Function Tests Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Chemistry Hyperglycemia 60 4.7 65 6 57 4.3 Hypophosphatemia 38 6 38 3.8 35 7 Hyponatremia 25 8 24 6 14 2.9 a For these laboratory tests the denominator is 556. b For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm. c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the COMBI-d study combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm. Metastatic, BRAF V600E-Mutation Positive, Non-Small Cell Lung Cancer (NSCLC) The 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 a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current retinal vein occlusion [see Clinical Studies (14.3)]. 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 ≥1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were White; 32% had baseline ECOG performance status 0 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 commonly occurring 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 common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most common 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 common were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%). Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, of TAFINLAR in Study BRF113928. Table 7. Adverse Reactions Occurring in ≥20% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Study BRF113928a Adverse Reactions TAFINLAR plus T rametinib N = 93 All Grades (%) Grades 3 and 4 b (%) General Pyrexia 55 5 Fatigueb 51 5 Edemac 28 0 Chills 23 1.1 Gastrointestinal Nausea 45 0 Vomiting 33 3.2 Diarrhea 32 2.2 Decreased appetite 29 0 Respiratory system Cough 22 0 Dyspnea 20 5 Skin Dry skin 31 1.1 Rashd 28 3.2 Vascular Hemorrhagee 23 3.2 a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage. Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR in combination with trametinib were: Gastrointestinal Disorders: Pancreatitis Renal and Urinary Disorders: Tubulointerstitial nephritis Table 8. Treatment-Emergent Laboratory Abnormalities Occurring in ≥20% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Study BRF113928 Test TAFINLAR plus Trametinib N = 93 All Grades (%) Grades 3 and 4 (%) Hematology a Leukopenia 48 8 Anemia 46 10 Neutropenia 44 8 Lymphopenia 42 14 Liver Function Tests b Increased blood alkaline phosphatase 64 0 Increased AST 61 4.4 Increased ALT 32 6 Chemistry b Hyperglycemia 71 9 Hyponatremia 57 17 Hypophosphatemia 36 7 Increased creatinine 21 1.1 a For these laboratory tests the denominator is 91. b For these laboratory tests the denominator is 90.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Melanoma: Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent. ( 2.1 ) Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR in combination with trametinib. (2.1) NSCLC: Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR in combination with trametinib. (2.1) The recommended dose of TAFINLAR is 150 mg orally twice daily. Take TAFINLAR at least 1 hour before or at least 2 hours after a meal. (2.2) 2.1 Patient Selection Melanoma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent [see Warnings and Precautions (5.2) and 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) and Clinical Studies (14.1)] . Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. NSCLC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies ( 14 .2)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosing The recommended dosage regimen of TAFINLAR is 150 mg orally taken twice daily, approximately 12 hours apart as a single agent or with trametinib. Continue treatment until disease progression or unacceptable toxicity occurs. Take TAFINLAR at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR. Do not open, crush, or break TAFINLAR capsules. 2.3 Dose Modifications Review the Full Prescribing Information for trametinib for recommended dose modifications. Dose 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. For New Primary Cutaneous Malignancie s No dose modifications are required. For New Primary Non- C utaneous Malignancies Permanently discontinue TAFINLAR in patients who develop RAS mutation-positive non-cutaneous malignancies. Table 1. Recommended Dose Reductions Dose Reductions for TAFINLAR First Dose Reduction 100 mg orally twice daily Second Dose Reduction 75 mg orally twice daily Third Dose Reduction 50 mg orally twice daily Subsequent Modification Permanently discontinue TAFINLAR if unable to tolerate 50 mg orally twice daily Table 2. Recommended Dose Modifications for TAFINLAR Severity of Adverse Reaction a TAFINLAR b Febrile Drug Reaction Fever of 101.3°F to 104°F Withhold TAFINLAR until fever resolves. Then resume at same or lower dose level. Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold TAFINLAR until fever resolves. Then resume at a lower dose level. Or Permanently discontinue TAFINLAR. Cutaneous Intolerable Grade 2 skin toxicity Grade 3 or 4 skin toxicity Withhold TAFINLAR for up to 3 weeks. If improved, resume at a lower dose level. If not improved, permanently discontinue. Cardiac Symptomatic congestive heart failure Absolute decrease in LVEF of greater than 20% from baseline that is below LLN Withhold TAFINLAR, if improved, then resume at the same dose. Uveitis Uveitis including iritis and iridocyclitis If mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR for up to 6 weeks. If improved to Grade 0-1, then resume at the same or at a lower dose level. If not improved, permanently discontinue. Other Intolerable Grade 2 adverse reactions Any Grade 3 adverse reaction Withhold TAFINLAR. If improved to Grade 0-1, resume at a lower dose level. If not improved, permanently discontinue. First occurrence of any Grade 4 adverse reaction Withhold TAFINLAR until adverse reaction improves to Grade 0-1. Then resume at a lower dose level. Or Permanently discontinue TAFINLAR. Recurrent Grade 4 adverse reaction Permanently discontinue TAFINLAR. a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Table 1 for recommended dose reductions of TAFINLAR.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 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, TAFINLAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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]. If TAFINLAR is used during pregnancy or if the patient becomes pregnant while taking TAFINLAR, advise the patient of the potential risk to a fetus. 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. 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 dose based on 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 Summary There 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 from TAFINLAR in breastfed infants, advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks following the last dose of TAFINLAR. 8.3 Females and Males of Reproductive Potential 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 )]. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with TAFINLAR and for 2 weeks after the last dose of TAFINLAR. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective [see Drug Interactions (7.1)] . Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR. 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 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 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 dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR as a single agent or with trametinib have not been established in pediatric patients. Juvenile Animal 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 One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in the BREAK-3 study were greater than or equal to 65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in elderly patients as compared to younger patients in the BREAK-3 study. Of the 559 patients with melanoma randomized to receive TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies, 24% were aged 65 years and older and 6% patients aged 75 years and older. No overall differences in the effectiveness of TAFINLAR plus trametinib were observed in elderly patients as compared to younger patients. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in elderly patients as compared to younger patients. Clinical studies of TAFINLAR in NSCLC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe 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)]. 8.7 Renal Impairment No formal pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS 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 Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations 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 (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors. 7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. 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.

More information

Category Value
Authorisation number NDA202806
Agency product number B6DC89I63E
Orphan designation No
Product NDC 0078-0681,0078-0682
Date First Approved 29-05-2013
Date Last Revised 22-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1425230
Marketing authorisation holder Novartis Pharmaceuticals Corporation