Label: TAFINLAR- dabrafenib capsule

  • NDC Code(s): 0173-0846-08, 0173-0847-08, 0173-0847-65
  • Packager: GlaxoSmithKline LLC
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated November 20, 2015

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use TAFINLAR safely and effectively. See full prescribing information for TAFINLAR.


    TAFINLAR (dabrafenib) capsules, for oral use
    Initial U.S. Approval: 2013

    RECENT MAJOR CHANGES

    Indications and Usage (1.2)

    11/2015

    Dosage and Administration (2)

    11/2015

    Warnings and Precautions (5)

    11/2015

    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, 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, 14.2)

    Limitation of Use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. (1.3, 5.2)

    DOSAGE AND ADMINISTRATION

    Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent.
    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)
    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)

    DOSAGE FORMS AND STRENGTHS

    Capsules: 50 mg, 75 mg. (3)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    New primary malignancies, cutaneous and non-cutaneous: Can occur when TAFINLAR is administered as a single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. ( 5.1, 2.3)
    Tumor promotion in BRAF wild-type melanoma: Increased cell proliferation can occur with BRAF inhibitors. ( 5.2)
    Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR with trametinib. Monitor for signs and symptoms of bleeding. ( 5.3, 2.3)
    Cardiomyopathy: Assess LVEF before treatment with TAFINLAR and trametinib, after one month of treatment, then every 2 to 3 months thereafter. ( 5.4, 2.3)
    Uveitis: Perform ophthalmologic evaluation for any visual disturbances. ( 5.5, 2.3)
    Serious febrile reactions: Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. ( 5.6, 2.3)
    Serious skin toxicity: Monitor for skin toxicities. Discontinue for intolerable Grade 2, 3, or 4 rash not improving within 3 weeks despite interruption of TAFINLAR. ( 5.7, 2.3)
    Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. ( 5.8)
    Glucose-6-phosphate dehydrogenase deficiency: Closely monitor for hemolytic anemia. ( 5.9)
    Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.10, 8.1, 8.3)

    ADVERSE REACTIONS

    Most common adverse reactions (≥20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. ( 6.1)
    Most common adverse reactions (≥20%) for TAFINLAR, in combination with trametinib, are pyrexia, rash, chills, headache, arthralgia, and cough. ( 6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8. ( 7.1)
    Avoid concurrent administration of strong inducers 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)

    USE IN SPECIFIC POPULATIONS

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

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 11/2015

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma

    1.2 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

    1.3 Limitation of Use

    2 DOSAGE AND ADMINISTRATION

    2.1 Patient Selection

    2.2 Recommended Dosing

    2.3 Dose Modifications

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 New Primary Malignancies

    5.2 Tumor Promotion in BRAF Wild-Type Melanoma

    5.3 Hemorrhage

    5.4 Cardiomyopathy

    5.5 Uveitis

    5.6 Serious Febrile Reactions

    5.7 Serious Skin Toxicity

    5.8 Hyperglycemia

    5.9 Glucose-6-Phosphate Dehydrogenase Deficiency

    5.10 Embryo-Fetal Toxicity

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    7 DRUG INTERACTIONS

    7.1 Effects of Other Drugs on Dabrafenib

    7.2 Effects of Dabrafenib on Other Drugs

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.3 Females and Males of Reproductive Potential

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Hepatic Impairment

    8.7 Renal Impairment

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.2 Pharmacodynamics

    12.3 Pharmacokinetics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2 Animal Toxicology and/or Pharmacology

    14 CLINICAL STUDIES

    14.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma – TAFINLAR Administered as a Single Agent

    14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma – TAFINLAR Administered with Trametinib

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1 INDICATIONS AND USAGE

    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 Limitation of Use

    TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Patient Selection

    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)]. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma 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, retinal pigment epithelial detachment, interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism.

    For New Primary Cutaneous Malignancies

    No dose modifications are required.

    For New Primary Non-Cutaneous 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
    Reactiona
    TAFINLARb

    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.
     
    bSee Table 1 for recommended dose reductions of TAFINLAR.
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  • 3 DOSAGE FORMS AND STRENGTHS

    50 mg capsules: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’.

    75 mg capsules: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’.

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  • 4 CONTRAINDICATIONS

    None.

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  • 5 WARNINGS AND PRECAUTIONS

    Review the Full Prescribing Information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR in combination with trametinib.

    5.1 New Primary Malignancies

    New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used with trametinib.

    Cutaneous Malignancies

    TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma.

    In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients receiving TAFINLAR and in none of the patients receiving dacarbazine.

    Across clinical trials of TAFINLAR (N = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 2.1 months (range: 7 days to 12.2 months). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

    In Trial 2, the incidence of basal cell carcinoma in patients receiving TAFINLAR in combination with trametinib was 3.3% (7/209) compared with 6% (13/211) of patients receiving single-agent TAFINLAR. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the TAFINLAR plus trametinib arm and was 4.4 months (range: 29 days to 16.5 months) in the single-agent TAFINLAR arm. Among the 7 patients receiving TAFINLAR with trametinib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3).

    Cutaneous squamous cell carcinoma and keratoacanthoma occurred in 3% of patients receiving TAFINLAR with trametinib and 10% of patients receiving single-agent TAFINLAR. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the Tafinlar plus trametinib arm and was 2 months (range: 9 days to 20.9 months) in the single-agent TAFINLAR arm.

    New primary melanoma occurred in 0.5% (1/209) of patients receiving TAFINLAR with trametinib and in 1.9% (4/211) of patients receiving single-agent TAFINLAR.

    Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR are required in patients who develop new primary cutaneous malignancies [see Dosage and Administration (2.3)].

    Non-cutaneous Malignancies

    Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving TAFINLAR with trametinib and in 2.8% (6/211) of patients receiving single-agent TAFINLAR.

    Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.3)].

    5.2 Tumor Promotion in BRAF Wild-Type Melanoma

    In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or in combination with trametinib [see Indications and Usage (1), Dosage and Administration (2.1)].

    5.3 Hemorrhage

    Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is administered with trametinib.

    In Trial 2, the incidence of hemorrhagic events in patients receiving TAFINLAR with trametinib was 19% (40/209) compared with 15% (32/211) of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving TAFINLAR with trametinib compared with 3% (6/211) of patients receiving single-agent TAFINLAR. Intracranial hemorrhage was fatal in 1.4% (3/209) of patients receiving TAFINLAR with trametinib compared with none of the patients receiving single-agent TAFINLAR.

    Permanently discontinue TAFINLAR for all Grade 4 hemorrhagic events and for any persistent Grade 3 hemorrhagic events. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

    5.4 Cardiomyopathy

    Cardiomyopathy can occur with TAFINLAR.

    In Trial 2, all patients were required to have an echocardiogram at baseline to document normal left ventricular ejection fraction (LVEF) and serial echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. Cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional lower limit of normal, occurred in 6% (12/206) of patients receiving TAFINLAR with trametinib and 2.9% (6/207) of patients receiving single-agent TAFINLAR. The median time to onset of cardiomyopathy on the TAFINLAR plus trametinib arm was 8.2 months (range: 28 days to 24.9 months), and was 4.4 months (range: 28 days to 19.1 months) on the TAFINLAR arm.

    In Trial 2, cardiomyopathy was identified within the first month of initiation of TAFINLAR with trametinib in 2 of 12 patients, and in 2 of 6 patients receiving single-agent TAFINLAR. Development of cardiomyopathy in patients receiving TAFINLAR and trametinib resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%). In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption (2.4%), dose reduction (0.5%), or discontinuation (1.0%). Cardiomyopathy resolved in 10 of 12 patients receiving TAFINLAR with trametinib, and in 3 of 6 patients receiving single-agent TAFINLAR.

    Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR with trametinib, one month after initiation of TAFINLAR, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal (LLN). Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared to baseline [see Dosage and Administration (2.3)].

    5.5 Uveitis

    Uveitis (including iritis and iridocyclitis) can occur with TAFINLAR.

    Uveitis occurred in 1% (6/586) of patients receiving TAFINLAR across multiple clinical trials and in 2% (9/559) of patients receiving TAFINLAR with trametinib across Trials 2 and 3. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

    Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification; for severe uveitis or iridocyclitis, interrupt TAFINLAR and treat as clinically indicated. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of >6 weeks duration [see Dosage and Administration (2.3)].

    5.6 Serious Febrile Reactions

    Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR.

    The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

    In Trial 1, the incidence of fever (serious and non-serious) was 28% in patients receiving TAFINLAR and 10% in patients receiving dacarbazine. In patients receiving TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 day to 6.6 months) and the median duration of fever was 3 days (range: 1 day to 4.2 months). Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 3.7% (7/187) of patients receiving TAFINLAR and in none of the 59 patients receiving dacarbazine.

    In Trials 2 and 3, fever occurred in 54% (303/559) of patients receiving TAFINLAR with trametinib; the median time to onset of first occurrence of fever was 1 month (range: 1 day to 23.5 months) and the median duration of fever was 3 days (range: 1 day to 11.3 months). Approximately one-half of the patients who received TAFINLAR with trametinib and experienced pyrexia had 3 or more discrete episodes.

    Serious febrile reactions or fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving TAFINLAR with trametinib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients.

    Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold TAFINLAR for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension, renal failure or severe chills/rigors, and there is no evidence of active infection.

    5.7 Serious Skin Toxicity

    Serious skin toxicity can occur with TAFINLAR.

    Across clinical trials of TAFINLAR administered with trametinib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients.

    Withhold TAFINLAR for intolerable or severe skin toxicity. TAFINLAR may be resumed at the next lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)].

    5.8 Hyperglycemia

    Hyperglycemia can occur with TAFINLAR.

    In Trial 1, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy receiving TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients receiving TAFINLAR compared with none of the dacarbazine-treated patients.

    In Trial 2, 27% (4/15) of patients with a history of diabetes receiving TAFINLAR with trametinib and 13% (2/16) of patients with a history of diabetes receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients, respectively, receiving TAFINLAR with trametinib compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent TAFINLAR.

    Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with pre-existing diabetes or hyperglycemia.

    5.9 Glucose-6-Phosphate Dehydrogenase Deficiency

    TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

    5.10 Embryo-Fetal Toxicity

    Based on findings from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. If TAFINLAR is used during pregnancy or if the patient becomes pregnant while taking TAFINLAR, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)].

    Advise female patients of reproductive potential to use an effective non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of TAFINLAR. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (8.3)].

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  • 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)]

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with trametinib.

    TAFINLAR Administered as a Single Agent

    The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

    Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14.1)]. Trial 1, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/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 Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).

    Table 3. Select Common Adverse Reactions Occurring in ≥10% (All Grades) or ≥2% (Grades 3 or 4) of Patients Treated with TAFINLARa

    Primary System Organ Class

    Preferred Term

    TAFINLAR
    N = 187

    Dacarbazine
    N = 59

    All

    Grades (%)

    Grades

    3 and 4b

    (%)

    All

    Grades (%)

    Grades

    3 and 4

    (%)

    Skin and subcutaneous tissue disorders

     
    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 disorders

     
    Headache

    32

    0

    8

    0

    General disorders and administration site conditions

     
    Pyrexia

    28

    3

    10

    0

    Musculoskeletal and connective tissue disorders

     
    Arthralgia

    27

    1

    2

    0

     
    Back pain

    12

    3

    7

    0

     
    Myalgia

    11

    0

    0

    0

    Neoplasms benign, malignant, and unspecified (including cysts and polyps)

     
    Papilloma c

    27

    0

    2

    0

     
    cuSCC d, e

    7

    4

    0

    0

    Respiratory, thoracic, and mediastinal disorders

     
    Cough

    12

    0

    5

    0

    Gastrointestinal disorders

     
    Constipation

    11

    2

    14

    0

    Infections and infestations

     
    Nasopharyngitis

    10

    0

    3

    0

     
    aAdverse drug reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.
     
    b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).
     
    c Includes skin papilloma and papilloma.
     
    d cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma.
     
    e Cases of cuSCC were required to be reported as Grade 3 per protocol.
     
    f NA = not applicable.

    Table 4. Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in Trial 1 [Between-Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4)]a

    Test

    TAFINLAR

    N = 187

    DTIC

    N = 59

    All

    Grades

    (%)

    Grades

    3 and 4

    (%)

    All

    Grades

    (%)

    Grades

    3 and 4

    (%)

    Hyperglycemia

    50

    6

    43

    0

    Hypophosphatemia

    37

    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, Trial 2 (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and Trial 3 (n = 350) a multicenter, open-label, randomized (1:1), active controlled trial. In Trials 2 and 3, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies (14.2)].

    Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a history of brain metastases.

    The most commonly occurring adverse reactions (≥20%) for TAFINLAR in patients receiving TAFINLAR plus trametinib in Trials 2 and 3 were: pyrexia, rash, chills, headache, arthralgia, and cough. 

    Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, observed in Trial 2.

    The demographics and baseline tumor characteristics of patients enrolled in Trial 2 are summarized in Clinical Studies [see Clinical Studies (14.2)]. Patients receiving TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients receiving TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for >6 months to 12 months while 46% were exposed to TAFINLAR for >1 year.

    In Trial 2, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients receiving TAFINLAR plus trametinib; the most common was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of Tafinlar occurred in 56% of patients receiving TAFINLAR plus trametinib; the most common were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%).

    Table 5. Select Adverse Reactions Occurring in ≥10% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Trial 2a

    Trial 2

    Pooled TAFINLAR plus Trametinib

    N = 559

    TAFINLAR plus Trametinib N =209

    TAFINLAR

    N = 211

    Adverse Reactions

    All

    Grades

    (%)

    Grades

    3 and 4b

    (%)

    All

    Grades

    (%)

    Grades

    3 and 4

    (%)

    All

    Grades

    (%)

    Grades

    3 and 4

    (%)

    General disorders and administrative site conditions

     
    Pyrexia

    54

    5

    57

    7

    33

    1.9

     
    Chills

    31

    0.5

    31

    0

    17

    0.5

    Gastrointestinal disorders

     
    Constipation

    13

    0.2

    13

    0.5

    10

    0

    Nervous system disorders

     
    Headache

    30

    0.9

    33

    0.5

    30

    1.4

     
    Dizziness

    11

    0.2

    14

    0

    7

    0

    Musculoskeletal, connective tissue, and bone disorders

     
    Arthralgia

    25

    0.9

    26

    0.9

    31

    0

     
    Myalgia

    15

    0.2

    13

    0.5

    13

    0

    Skin and subcutaneous tissue disorders

     
    Rash c

    32

    1.1

    42

    0

    27

    1.4

     
    Dry skin

    10

    0

    12

    0

    16

    0

    Respiratory, thoracic, and mediastinal disorders

     
    Cough

    20

    0

    21

    0

    21

    0

    Infections and infestations

     
    Nasopharyngitis

    12

    0

    12

    0

    10

    0

     
    aNCI CTCAE version 4
     
    bGrade 4 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.

    Other clinically important adverse reactions for TAFINLAR across Trials 2 and 3 (N = 559) observed in less than 10% of patients receiving TAFINLAR in combination with trametinib were:

    Gastrointestinal Disorders: pancreatitis

    Subcutaneous Tissue Disorders: panniculitis

    Table 6. Select Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Trial 2

    Trial 2

    Pooled TAFINLAR plus Trametinib

    N = 559a

    TAFINLAR plus Trametinib

    N = 209b

    TAFINLAR

    N = 211b

    Test

    All

    Grades

    (%)

    Grades

    3 and 4c

    (%)

    All

    Grades

    (%)

    Grades

    3 and 4c

    (%)

    All

    Grades

    (%)

    Grades

    3 and 4c

    (%)

    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

     
    aFor 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 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the Trial 2 combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.
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  • 7 DRUG INTERACTIONS

    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 and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

    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.

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  • 8 USE IN SPECIFIC POPULATIONS

    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 Trial 1 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 Trial 1.

    Of the 559 patients randomized to receive TAFINLAR plus trametinib in Trials 2 and 3, 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.

    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)].

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  • 10 OVERDOSAGE

    There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.

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  • 11 DESCRIPTION

    Dabrafenib mesylate is a kinase inhibitor. The chemical name for dabrafenib mesylate is N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt. It has the molecular formula C23H20F3N5O2S2•CH4O3S and a molecular weight of 615.68. Dabrafenib mesylate has the following chemical structure.

    dabrafenib mesylate chemical structure

    Dabrafenib mesylate is a white to slightly colored solid with three pKas: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

    TAFINLAR (dabrafenib) capsules are supplied as 50 mg and 75 mg capsules for oral administration. Each 50 mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base. Each 75 mg capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.

    The inactive ingredients of TAFINLAR are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Capsule shells contain hypromellose, red iron oxide (E172), and titanium dioxide (E171).

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  • 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 BRAF V600 mutation-positive melanoma cell growth 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 melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

    12.2 Pharmacodynamics

    Cardiac Electrophysiology

    A dedicated study to evaluate the QT prolongation potential has not been conducted for TAFINLAR. In clinical trials, QTc (heart rate-corrected QT) prolongation to ≥500 ms occurred in 0.8% (2/264) of patients receiving TAFINLAR plus trametinib and in 1.5 % (4/264) of patients receiving TAFINLAR as a single agent. The QTc was increased >60 ms from baseline in 3.8% (10/264) of patients receiving TAFINLAR plus trametinib and 3% (8/264) of patients treated with TAFINLAR as a single agent.

    12.3 Pharmacokinetics

    Absorption

    After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 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%.

    Administration of dabrafenib with a high-fat meal decreased Cmax by 51%, decreased AUC by 31%, and delayed median Tmax by 3.6 hours as compared with the fasted state [see Dosage and Administration (2.2)].

    Distribution

    Dabrafenib is 99.7% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 70.3 L.

    Metabolism

    The 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.

    Elimination

    The mean terminal half-life of dabrafenib is 8 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 2 weeks of twice-daily dosing.

    Fecal 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 Populations

    Age, Body Weight, and Gender: Based on the population pharmacokinetics analysis, age has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on gender and on weight are not clinically relevant.

    Pediatric: Pharmacokinetics of dabrafenib has not been studied in pediatric patients.

    Renal Impairment: No formal pharmacokinetic trial in patients with renal impairment has been conducted. The pharmacokinetics of dabrafenib were evaluated using a population analysis in 233 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m2) and 30 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2) enrolled in clinical trials. Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment.

    Hepatic Impairment: No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. The pharmacokinetics of dabrafenib was evaluated using a population analysis in 65 patients with mild 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 to severe hepatic impairment.

    Drug Interactions

    Effect of Strong Inhibitors of CYP3A4 or CYP2C8 on Dabrafenib: In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for 4 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 4 days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites.

    Effect of Dabrafenib on CYP Substrates: In vitro data demonstrate that dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (a CYP3A4/CYP1A2 substrate) by 33% [see Drug Interactions (7.2)].

    Effect of Transporters on Dabrafenib: Dabrafenib is a substrate of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of organic cation transporter (OCT1) or organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) in vitro. Hydroxy-dabrafenib and desmethyl-dabrafenib are not substrates of OATP1B1 or OATP1B3 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 BCRP in vitro.

    Effect of Trametinib on Dabrafenib: Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of hydroxy-dabrafenib as compared with administration of dabrafenib.

    Effect of Acid Reducing Agents on Dabrafenib: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When TAFINLAR is coadministered with a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of TAFINLAR is unknown.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.

    Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay, and was not clastogenic in an in vivo rat bone marrow micronucleus test.

    In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC).

    Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively.

    13.2 Animal Toxicology and/or Pharmacology

    Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day (approximately five times the human exposure at the recommended dose based on AUC) or greater, when administered for up to 4 weeks. Adverse effects consisted of coronary arterial degeneration/necrosis and hemorrhage, as well as cardiac atrioventricular valve hypertrophy/hemorrhage.

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  • 14 CLINICAL STUDIES

    14.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma – TAFINLAR Administered as a Single Agent

    In Trial 1, the safety and efficacy of TAFINLAR as a single agent were demonstrated in an international, multicenter, randomized (3:1), open-label, active-controlled trial 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 1,000 mg/m2 intravenously every 3 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 objective response rate (ORR), and duration of response.

    The median age of patients in Trial 1 was 52 years. The majority of the trial population was male (60%), White (99%), had an ECOG performance status of 0 (67%), M1c disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID™-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.

    Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with TAFINLAR. Table 7 and Figure 1 summarize the PFS results.

    Table 7. Investigator-Assessed Progression-Free Survival and Confirmed Objective Response Results in Trial 1

    Investigator-Assessed Endpoints

    TAFINLAR

    N = 187

    Dacarbazine

    N = 63

    Progression-Free Survival

     
    Number of Events (%)

    78 (42%)

    41 (65%)

     
    Progressive Disease

    76

    41

     
    Death

    2

    0

     
    Median, months (95% CI)

    5.1 (4.9, 6.9)

    2.7 (1.5, 3.2)

     
    HR a (95% CI)

    0.33 (0.20, 0.54)

     
    P-value b

    P <0.0001

    Confirmed Tumor Responses

     
    Objective Response Rate

    52%

    17%

     
    (95% CI)

    (44, 59)

    (9, 29)

     
    CR, n (%)

    6 (3%)

    0

     
    PR, n (%)

    91 (48%)

    11 (17%)

     
    Duration of Response
     
    Median, months (95% CI)

    5.6 (5.4, NR)

    NR (5.0, NR)

     
    CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.
     
    a Pike estimator, stratified by disease state.
     
    b Stratified log-rank test.

    Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival in Trial 1

    Figure 1

    In supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the THxID™-BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.

    The activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in a single-arm, open-label, two-cohort multicenter trial. All patients received TAFINLAR 150 mg twice daily. Patients in Cohort A (n = 74) had received no prior local therapy for brain metastases, while patients in Cohort B (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 B were required to have evidence of disease progression in a 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 primary outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.

    The median age of patients in Cohort A was 50 years, 72% were male, 100% were White, 59% had a pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline. The median age of patients in Cohort B was 51 years, 63% were male, 98% were White, 66% had a pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline. Efficacy results as determined by an independent radiology review committee, masked to investigator response assessments, are provided in Table 8.

    Table 8. Efficacy Results in Patients with BRAF V600E Melanoma Brain Metastases

    IRRC-assessed Endpoints

    Cohort A

    n = 74

    Cohort B

    n = 65

    Overall Intracranial Response Rate (OIRR)

     
    % (95% CI)

    18 (9.7, 28.2)

    18 (9.9, 30.0)

    Duration of OIRR

    (n = 13)

    (n = 12)

    Median, months (95% CI)

    4.6 (2.8, NR)

    4.6 (1.9, 4.6)

    IRRC = Independent radiology review committee; CI = Confidence interval; NR = Not reached.

    14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma – TAFINLAR Administered with Trametinib

    The safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (Trial 2) and one open-label trial (Trial 3).

    Trial 2 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 2 mg once daily or TAFINLAR 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (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).

    Trial 3 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 2 mg once daily or vemurafenib 960 mg twice daily. Randomization was stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (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 Trial 2, 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 a normal LDH, and 2 patients had a 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 Trial 3, 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 a normal LDH, 70% had ECOG performance status of 0, 89% had BRAF V600E mutation-positive melanoma, and one patient had a history of brain metastases.

    Trial 2 and Trial 3 demonstrated statistically significant improvements in OS and PFS (see Table 9 and Figures 2 and 3).

    Table 9. Efficacy Results in Patients with BRAF V600E or V600K Melanomaa

    Endpoint

    Trial 2

    Trial 3

    TAFINLAR plus Trametinib

    N=211

    TAFINLAR

    plus Placebo

    N=212

    TAFINLAR plus Trametinib

    N=352

    Vemurafenib

    N=352

    Overall 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)

     
    P value (log-rank test)

    0.01

    0.005a

    Progression-Free Survival (PFS)b

     
    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)

     
    P value (log-rank test)

    0.035

    <0.001

    Overall Response Rate (ORR)b

     
    ORR, %
     
    (95% CI)

    66

    (60, 73)

    51

    (44, 58)

    64

    (59, 69)

    51

    (46, 56)

     
    P value

    <0.001

    <0.001

     
    CR, %

    10

    8

    13

    8

     
    PR, %

    56

    42

    51

    43

     
    Median duration of response, months (95% CI)

    9.2

    (7.4, NR)

    10.2

    (7.5, NR)

    13.8

    (11.0, NR)

    7.5

    (7.3, 9.3)

     
    CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.
     
    a P -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.

    Figure 2. Kaplan-Meier Curves for Overall Survival in Trial 2

    Figure 2

    Figure 3. Kaplan-Meier Curves for Overall Survival in Trial 3

    Figure 3
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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    50 mg capsules: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’ available in bottles of 120 (NDC 0173-0846-08). Each bottle contains a silica gel desiccant.

    75 mg capsules: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’ available in bottles of 120 (NDC 0173-0847-08). Each bottle contains a silica gel desiccant.

    Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

    Close
  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Inform patients of the following:

    Confirmation of BRAF V600E or V600K mutation

    TAFINLAR as a single agent: Evidence of BRAF V600E mutation in the tumor specimen using an FDA-approved test is necessary to identify patients for whom treatment is indicated [see Dosage and Administration (2.1)].
    TAFINLAR with trametinib: Evidence of BRAF V600 mutation in tumor specimens using an FDA-approved test is necessary to identify patients for whom treatment is indicated [see Dosage and Administration (2.1)].
     
    New cutaneous and non-cutaneous malignancies
     
    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)].
     
    Hemorrhage
     
    TAFINLAR when administered with trametinib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients 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) ].
     
    Cardiomyopathy
     
    TAFINLAR can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.4) ].
     
    Uveitis
     
    TAFINLAR can cause uveitis, including iritis and iridocyclitis. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.5) ].
     
    Serious febrile reactions
     
    TAFINLAR can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with trametinib. Instruct patients to contact their healthcare provider if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.6) ].
     
    Serious skin toxicities
     
    TAFINLAR can cause serious skin toxicities. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.7) ].
     
    Hyperglycemia
     
    TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their healthcare provider to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.8)].
     
    Glucose-6-phosphate dehydrogenase (G6PD) deficiency
     
    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 toxicity
     
    TAFINLAR can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3)].
     
    Females and males of reproductive potential
     
    Instruct females of reproductive potential to use non-hormonal, effective non-hormonal contraception during treatment and for 2 weeks after discontinuation of treatment with TAFINLAR. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3)].
     
    Infertility
     
    Advise males and females of reproductive potential of the potential risk for impaired fertility with TAFINLAR [see Use in Specific Populations (8.3)].
     
    Lactation
     
    Advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks after the last dose of TAFINLAR [see Use in Specific Populations (8.2)].
     
    Instructions for taking Tafinlar
     
    Instruct patients to take TAFINLAR at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.2)].

    TAFINLAR is a registered trademark of the GSK group of companies.

    THxID™ is a trademark of bioMérieux.

    GlaxoSmithKline

    Research Triangle Park, NC 27709

    ©2015, GSK group of companies. All rights reserved.

    TFR:4PI

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  • MEDICATION GUIDE

    MEDICATION GUIDE

    TAFINLAR® (TAFF-in-lar)

    (dabrafenib)

    capsules

    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 I should know about TAFINLAR?

    TAFINLAR may cause serious side effects, including the risk of new cancers:

    TAFINLAR, when used alone or with trametinib, may cause a type of skin cancer, called cutaneous squamous cell carcinoma (cuSCC). New melanoma lesions may happen in people who take TAFINLAR alone or with trametinib.

    TAFINLAR with trametinib, may cause new cancers including basal cell carcinoma.

    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 a mole

    Your healthcare provider should check your skin before treatment with TAFINLAR, every two months during treatment with TAFINLAR, and for up to 6 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 TAFINLAR?

    TAFINLAR is a prescription medicine used alone or with a medicine called trametinib, to treat people with a type of skin cancer called melanoma:

    that has spread to other parts of the body or cannot be removed by surgery, and
    that has a certain type of abnormal “BRAF” gene.

    Your healthcare provider will perform a test to make sure that TAFINLAR is right for you.

    TAFINLAR alone or with trametinib is not used to treat people with a type of skin cancer called wild-type BRAF melanoma.

    It is not known if TAFINLAR alone or TAFINLAR with trametinib is safe and effective in children.

    What should I tell my healthcare provider before taking TAFINLAR?

    Before you take TAFINLAR, tell your healthcare provider 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 a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme
    have any other medical conditions are pregnant or plan to become pregnant. TAFINLAR can harm your unborn baby.
    Females who are able to become pregnant should use birth control (contraception) during treatment with TAFINLAR, and for 2 weeks after the last dose of TAFINLAR alone, or for 4 months after the last dose when taking TAFINLAR with trametinib.
    Birth control methods that contain hormones (such as birth control pills, injections, or patches) may not work as well during treatment with TAFINLAR alone or TAFINLAR and trametinib. You should use another effective method of birth control during treatment with TAFINLAR alone or TAFINLAR and trametinib.
    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 alone or TAFINLAR and trametinib.
    are breastfeeding or plan to breastfeed. It is not known if TAFINLAR passes into your breast milk.
    Do not breastfeed during treatment and for 2 weeks after your last dose of TAFINLAR alone, or for 4 months after your last dose of TAFINLAR with trametinib. 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. TAFINLAR and certain other medicines can affect each other, causing side effects. TAFINLAR may affect the way other medicines work, and other medicines may affect how TAFINLAR works. You can ask your pharmacist for a list of medicines that may interact with TAFINLAR.

    Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

    How should I take TAFINLAR?

    Take TAFINLAR exactly as your healthcare provider tells you. Do not change your dose or stop TAFINLAR unless your healthcare provider tells you.
    Take TAFINLAR 2 times a day, about 12 hours apart.
    Take TAFINLAR at least 1 hour before or 2 hours after a meal.
    Do not open, crush, or break TAFINLAR capsules.
    If you miss a dose of TAFINLAR, take it as soon as you remember. But, if it is within 6 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 TAFINLAR?

    TAFINLAR may cause serious side effects, including:

    See “What is the most important information I should know about TAFINLAR?”
    TAFINLAR, when taken with trametinib, can cause serious bleeding problems, especially in your brain or stomach, and 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 a heart problem:
    feeling like your heart is pounding or racing
    shortness of breath
    swelling of your ankles or feet
    feeling lightheaded
    eye problems. TAFINLAR, when taken alone or with trametinib, 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 alone or with trametinib, 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 a fever during treatment with TAFINLAR.
    skin reactions. Rash is a common side effect of TAFINLAR when taken alone, or with trametinib. TAFINLAR, when taken alone or with trametinib, can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe, and may need to be treated in a hospital. Call your healthcare provider if you get any of the following symptoms:
    skin rash that bothers your or does not go away
    acne
    redness, swelling, peeling, or tenderness of hands or feet
    skin redness
    increased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR, alone or with trametinib. If you are diabetic, your healthcare provider should check your blood sugar levels closely during treatment with TAFINLAR alone or with trametinib. 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 a 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

    The most common side effects of TAFINLAR alone or with trametinib include:

    thickening of the outer layers of the skin
    headache
    joint aches
    warts
    hair loss
    redness, swelling, peeling, or tenderness of hands or feet
    cough

    TAFINLAR may cause fertility problems in females. This could affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.

    TAFINLAR may cause lower sperm counts in males. This could affect the ability to father a child. Talk to your healthcare provider if this is a concern for you.

    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

    These are not all of the possible side effects of TAFINLAR. For more information about side effects, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store TAFINLAR?

    Store TAFINLAR at room temperature, between 68°F to 77°F (20°C to 25°C).
     
    Keep TAFINLAR and all medicine out of the reach of children.

    General information about the safe and effective use of TAFINLAR

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TAFINLAR for a 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 TAFINLAR?

    Active ingredient: dabrafenib

    Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose

    Capsule shells: hypromellose, red iron oxide (E172), titanium dioxide (E171).

    GlaxoSmithKline

    Research Triangle Park, NC 27709

    Revised: November 2015

    TAFINLAR is a registered trademark of the GSK group of companies.

    ©2015, GSK group of companies. All rights reserved.

    TFR:4MG

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC 0173-0846-08

    Tafinlar®

    (Dabrafenib) Capsules

    50 mg

    Rx only

    120 Capsules

    Federal Law requires dispensing of TAFINLAR® with the Medication Guide provided with this bottle.

    Each capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg dabrafenib.

    Dosage: See accompanying prescribing information.

    Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

    Do not use if printed safety seal under cap is broken or missing.

    GlaxoSmithKline

    RTP, NC 27709

     
    10000000124205 Rev. 3/14
    Tafinlar 50mg 120 count label
    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC 0173-0847-08

    Tafinlar®

    (Dabrafenib) Capsules

    75 mg

    Rx only

    120 Capsules

    Federal Law requires dispensing of TAFINLAR® with the Medication Guide provided with this bottle.

    Each capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg dabrafenib.

    Dosage: See accompanying prescribing information.

    Store at 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

    Do not use if printed safety seal under cap is broken or missing.

    GlaxoSmithKline

    RTP, NC 27709

     
    10000000124207 Rev. 3/14
    Tafinlar 75mg 120 count label
    Close
  • INGREDIENTS AND APPEARANCE
    TAFINLAR 
    dabrafenib capsule
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0173-0846
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    DABRAFENIB MESYLATE (UNII: B6DC89I63E) (DABRAFENIB - UNII:QGP4HA4G1B) DABRAFENIB 50 mg
    Inactive Ingredients
    Ingredient Name Strength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Color RED Score no score
    Shape OVAL Size 18mm
    Flavor Imprint Code GSTEW;50mg
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0173-0846-08 120 in 1 BOTTLE; Type 0: Not a Combination Product 06/10/2013
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202806 06/10/2013
    TAFINLAR 
    dabrafenib capsule
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0173-0847
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    DABRAFENIB MESYLATE (UNII: B6DC89I63E) (DABRAFENIB - UNII:QGP4HA4G1B) DABRAFENIB 75 mg
    Inactive Ingredients
    Ingredient Name Strength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Color RED Score no score
    Shape OVAL Size 20mm
    Flavor Imprint Code GSLHF;75mg
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0173-0847-08 120 in 1 BOTTLE; Type 0: Not a Combination Product 06/10/2013
    2 NDC:0173-0847-65 56 in 1 BOTTLE; Type 0: Not a Combination Product 10/08/2014
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA202806 06/10/2013
    Labeler - GlaxoSmithKline LLC (167380711)
    Close