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 C 23 H 20 F 3 N 5 O 2 S 2 •CH 4 O 3 S and a molecular weight of 615.68 g/mol. Dabrafenib mesylate has the following chemical structure: Dabrafenib mesylate is a white to slightly colored solid with three pK a s: 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 for oral use 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 capsules are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Capsule shells contain hypromellose, red iron oxide (E172), and titanium dioxide (E171). TAFINLAR (dabrafenib) tablets for oral suspension are supplied as 10 mg tablets for oral administration. Each 10 mg tablet contains 11.85 mg dabrafenib mesylate equivalent to 10 mg of dabrafenib base. The inactive ingredients of TAFINLAR tablets are acesulfame potassium, artificial berry flavor, colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose. The following chemical structure for 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.

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

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

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

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma TAFINLAR is indicated, in combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection

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

BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors TAFINLAR is indicated, in combination with trametinib, for the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options . This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR) . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s)

BRAF V600E Mutation-Positive Low-Grade Glioma TAFINLAR is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy

Limitations of Use TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition . TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors .

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

The recommended dosage of TAFINLAR in adult patients is 150 mg (two 75 mg capsules) orally twice daily. The recommended dosage for TAFINLAR in pediatric patients is based on body weight. Take TAFINLAR at least 1 hour before or 2 hours after a meal

Patient Selection Melanoma 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 and trametinib . 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 . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib . Information on FDA-approved tests for the detection of BRAF V600E mutations in ATC is available at: http://www.fda.gov/CompanionDiagnostics . Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib . An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available. Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib . An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available

Recommended Dosage TAFINLAR Capsules Adult Patients The recommended dosage for TAFINLAR capsules in adult patients is 150 mg taken orally twice daily . Pediatric Patients The recommended dosage for TAFINLAR capsules in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) . A recommended dosage of TAFINLAR capsules has not been established in patients who weigh less than 26 kg. Table 1. Recommended Dosage for TAFINLAR Capsules in Pediatric Patients (Weight-based) Body Weight Recommended Dosage 26 to 37 kg 75 mg orally twice daily 38 to 50 kg 100 mg orally twice daily 51 kg or greater 150 mg orally twice daily TAFINLAR Tablets for Oral Suspension Adult and Pediatric Patients The recommended dosage for TAFINLAR tablets for oral suspension for adult and pediatric patients is based on body weight (Table 2) . Table 2. Recommended Dosage for TAFINLAR Tablets for Oral Suspension in Adult and Pediatric Patients (Weight-based) Body Weight Recommended Dosage 8 to 9 kg 20 mg twice daily 10 to 13 kg 30 mg twice daily 14 to 17 kg 40 mg twice daily 18 to 21 kg 50 mg twice daily 22 to 25 kg 60 mg twice daily 26 to 29 kg 70 mg twice daily 30 to 33 kg 80 mg twice daily 34 to 37 kg 90 mg twice daily 38 to 41 kg 100 mg twice daily 42 to 45 kg 110 mg twice daily 46 to 50 kg 130 mg twice daily ≥ 51 kg 150 mg twice daily Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity. Combination Therapy with Trametinib Refer to the trametinib prescribing information for recommended trametinib dosing information

Administration Take TAFINLAR at the same time each day, approximately 12 hours apart. Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR. If vomiting occurs after TAFINLAR administration, do not take an additional dose. Take the next dose at its scheduled time. TAFINLAR Capsules Take TAFINLAR capsules on an empty stomach (at least 1 hour before or 2 hours after a meal) . Do not open, crush, or break TAFINLAR capsules. TAFINLAR Tablets for Oral Suspension Prior to use of the oral suspension, instruct caregivers (and if appropriate, patients) on proper dosing and administration of TAFINLAR tablets for oral suspension. Take the oral suspension on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions . Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension. Preparation and Administration Prepare the oral suspension with approximately 5 mL of water for 1 to 4 tablets, and approximately 10 mL of water for 5 to 15 tablets in the provided dosing cup. Gently stir the water and prescribed number of tablets with the handle of a teaspoon until the tablets are fully dissolved. It may take at least 3 minutes to fully dissolve the tablets. Once the tablets are dissolved, the oral suspension will be cloudy white. Administer the oral suspension immediately after preparation from a dosing cup, oral syringe or feeding tube (10 French gauge or larger for 1 to 3 tablets; 12 French gauge or larger for 4 to 15 tablets). Discard the oral suspension if not administered within 30 minutes after preparation

Dosage Modifications for Adverse Reactions Dose reductions for adverse reactions associated with TAFINLAR are presented in Tables 3 and 4. Table 3. Recommended Dosage Reductions for TAFINLAR Capsules for Adverse Reactions Recommended Dosage 75 mg orally twice daily 100 mg orally twice daily 150 mg orally twice daily First dose reduction 50 mg orally twice daily 75 mg orally twice daily 100 mg orally twice daily Second dose reduction N/A 50 mg orally twice daily 75 mg orally twice daily Third dose reduction N/A N/A 50 mg orally twice daily Subsequent modification Permanently discontinue if unable to tolerate TAFINLAR capsules 50 mg orally twice daily. Table 4. Recommended Dosage Reductions for TAFINLAR Tablets for Oral Suspension for Adverse Reactions Body Weight (Recommended dosage) First Dose Reduction Second Dose Reduction Third Dose Reduction Tablets for oral suspension twice daily 8 to 9 kg (20 mg twice daily) 10 mg twice daily N/A N/A 10 to 13 kg (30 mg twice daily) 20 mg twice daily 10 mg twice daily N/A 14 to 17 kg (40 mg twice daily) 30 mg twice daily 20 mg twice daily 10 mg twice daily 18 to 21 kg (50 mg twice daily) 30 mg twice daily 20 mg twice daily 10 mg twice daily 22 to 25 kg (60 mg twice daily) 40 mg twice daily 30 mg twice daily 20 mg twice daily 26 to 29 kg (70 mg twice daily) 50 mg twice daily 40 mg twice daily 20 mg twice daily 30 to 33 kg (80 mg twice daily) 50 mg twice daily 40 mg twice daily 30 mg twice daily 34 to 37 kg (90 mg twice daily) 60 mg twice daily 50 mg twice daily 30 mg twice daily 38 to 41 kg (100 mg twice daily) 70 mg twice daily 50 mg twice daily 30 mg twice daily 42 to 45 kg (110 mg twice daily) 70 mg twice daily 60 mg twice daily 40 mg twice daily 46 to 50 kg (130 mg twice daily) 90 mg twice daily 70 mg twice daily 40 mg twice daily ≥ 51 kg (150 mg twice daily) 100 mg twice daily 80 mg twice daily 50 mg twice daily Dosage modifications for adverse reactions associated with TAFINLAR are presented in Table 5. Table 5. Recommended Dosage Modifications for TAFINLAR for Adverse Reactions a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of TAFINLAR. c 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. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies. Severity of Adverse Reaction a Dosage Modification for TAFINLAR b New Primary Malignancies Non-Cutaneous RAS Mutation-positive Malignancies Permanently discontinue TAFINLAR. Cardiomyopathy Symptomatic cardiomyopathy Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below the institutional lower limit of normal (LLN) Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume TAFINLAR at same dose. Uveitis Uveitis, including iritis and iridocyclitis For mild or moderate uveitis that 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 TAFINLAR at same or lower dose. If not improved, permanently discontinue TAFINLAR. Febrile Reactions Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) Withhold TAFINLAR until fever resolves, then resume TAFINLAR at same or lower dose. Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume TAFINLAR at lower dose. Or Permanently discontinue TAFINLAR. Skin Toxicities Intolerable Grade 2 Grade 3 or 4 Withhold TAFINLAR for up to 3 weeks. If improved, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. Severe cutaneous adverse reactions (SCARs) Permanently discontinue TAFINLAR. Other Adverse Reactions c , including Hemorrhage Intolerable Grade 2 Any Grade 3 Withhold TAFINLAR. If improved to Grade 0-1, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. First occurrence of any Grade 4 Withhold TAFINLAR until improves to Grade 0-1, then resume TAFINLAR at lower dose. Or Permanently discontinue TAFINLAR. Recurrent Grade 4 Permanently discontinue TAFINLAR. Refer to the trametinib prescribing information for dose modifications for adverse reactions associated with trametinib.

New Primary Malignancies, Cutaneous and Non-Cutaneous : Can occur when TAFINLAR is administered as a single agent or with trametinib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. Tumor Promotion in BRAF Wild-type Tumors : Increased cell proliferation can occur with BRAF inhibitors. Hemorrhage : Major hemorrhagic events can occur in patients receiving TAFINLAR with trametinib. Monitor for signs and symptoms of bleeding. Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before treatment with TAFINLAR and trametinib, after one month of treatment, then every 2 to 3 months thereafter. Uveitis : Perform ophthalmological evaluation for any visual disturbances. Serious Febrile Reactions : Incidence and severity of pyrexia are increased with TAFINLAR and trametinib. Serious Skin Toxicities : Monitor for skin toxicities. Discontinue for intolerable Grade 2 or for Grade 3 or 4 rash not improving within 3 weeks despite interruption of TAFINLAR. Permanently discontinue for severe cutaneous adverse reactions (SCARs). Hyperglycemia : Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. Glucose-6-phosphate Dehydrogenase Deficiency (G6PD) : Closely monitor for hemolytic anemia. Hemophagocytic Lymphohistiocytosis (HLH) : Interrupt treatment for suspected HLH. Discontinue treatment if HLH is confirmed. Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.12 , 8.1 , 8.3 ) 5.1 New Primary Malignancies Cutaneous Malignancies TAFINLAR Monotherapy (Adult) : In the pooled safety population , cutaneous squamous cell carcinomas (cuSCC), and keratoacanthomas occurred in 11% and 4% of patients, respectively. Basal cell carcinoma and new primary melanoma occurred in 4% and 1% of patients, respectively. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population , the incidence of cuSCC (including keratoacanthomas) occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and < 1% of patients, respectively. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, new primary melanoma occurred in < 1% of patients. Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. Non-Cutaneous Malignancies Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms . In the pooled adult safety populations of TAFINLAR monotherapy and TAFINLAR administered with trametinib , non-cutaneous malignancies occurred in 1% of patients. Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies

Tumor Promotion in BRAF Wild-Type Tumors In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or in combination with trametinib

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

Cardiomyopathy TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population , cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and < 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received TAFINLAR administered with trametinib. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN. Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease to less than or equal to 10% compared to baseline

Uveitis TAFINLAR Monotherapy (Adult) : In the pooled safety population , uveitis occurred in 1% of patients. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population , uveitis occurred in 2% of patients. Cases of biocular panuveitis or biocular iridocyclitis have been reported in the post-marketing setting. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, uveitis occurred in 1.2% of patients. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (i.e., iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold TAFINLAR and treat as clinically indicated. Resume TAFINLAR at the same or lower dose if improves to Grade 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks

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 . TAFINLAR Monotherapy (Adult) : In the pooled safety population , fever (serious and non-serious) occurred in 30% of patients. Approximately 13% of these patients experienced 3 or more discrete episodes. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population , fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in < 1% of patients. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population , pyrexia occurred in 66% of patients. Withhold TAFINLAR when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patient’s temperature is ≥ 100.4°F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia . Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, TAFINLAR, or both TAFINLAR and trametinib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at the same or lower dose . 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

Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with TAFINLAR administered with trametinib . TAFINLAR Administered with Trametinib (Adult): In the pooled safety population , other serious skin toxicity occurred in < 1% of patients. TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients. Monitor for new or worsening serious skin reactions. Permanently discontinue TAFINLAR for SCARs . For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity. Resume TAFINLAR at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within 3 weeks

Hyperglycemia TAFINLAR Monotherapy (Adult) : In the pooled safety population , 14% of patients with a history of diabetes that received TAFINLAR required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 3% of patients. TAFINLAR Administered with Trametinib (Adult) : In the pooled safety population , 15% of patients with a history of diabetes who had received TAFINLAR with trametinib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 2% of patients. TAFINLAR Administered with Trametinib (Pediatric) : In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% of patients. Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated

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

Risks Associated with Combination Treatment TAFINLAR is indicated for use in combination with trametinib. Review the prescribing information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR with trametinib

Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when TAFINLAR was administered with trametinib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH

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 adult clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective non-hormonal contraception, since TAFINLAR can render hormonal contraceptives ineffective, during treatment with TAFINLAR and for 2 weeks after the last dose .

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

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

Effects of TAFINLAR on Other Drugs Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) . 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 . Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.