mutation as detected by an FDA-approved test. (1.3)

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights d nt include all the infrmatin needed t use TAFINLAR safely and effectively. See full prescribing infrmatin fr TAFINLAR. TAFINLAR (dabrafenib) capsules, fr ral use Initial U.S. Apprval: RECENT MAJOR CHANGES Indicatins and Usage (1.3, 1.4) 6/2017 Dsage and Administratin (2.1) 6/2017 Warnings and Precautins (5.1, 5.2, 5.3, 5.4, 5.6, 5.8) 6/ INDICATIONS AND USAGE TAFINLAR is a kinase inhibitr indicated as a single agent fr the treatment f patients with unresectable r metastatic melanma with BRAF V600E mutatin as detected by an FDA-apprved test. (1.1) TAFINLAR is indicated, in cmbinatin with trametinib, fr the treatment f patients with: unresectable r metastatic melanma with BRAF V600E r V600K mutatins as detected by an FDA-apprved test. (1.2) metastatic nn-small cell lung cancer (NSCLC) with BRAF V600E mutatin as detected by an FDA-apprved test. (1.3) Limitatin f Use: TAFINLAR is nt indicated fr treatment f patients with wild-type BRAF melanma r wild-type BRAF NSCLC. (1.4, 5.2) DOSAGE AND ADMINISTRATION Melanma: Cnfirm the presence f BRAF V600E mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR as a single agent. (2.1) Cnfirm the presence f BRAF V600E r V600K mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR in cmbinatin with trametinib. (2.1) NSCLC: Cnfirm the presence f BRAF V600E mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR in cmbinatin with trametinib. (2.1) The recmmended dse f TAFINLAR is 150 mg rally twice daily. Take TAFINLAR at least 1 hur befre r at least 2 hurs after a meal. (2.2) DOSAGE FORMS AND STRENGTHS Capsules: 50 mg, 75 mg (3) CONTRAINDICATIONS Nne (4) WARNINGS AND PRECAUTIONS New primary malignancies, cutaneus and nn-cutaneus: Can ccur when TAFINLAR is administered as a single agent r with trametinib. Mnitr patients fr new malignancies prir t, r while n therapy, and fllwing discntinuatin f treatment. (5.1, 2.3) Tumr prmtin in BRAF wild-type tumrs: Increased cell prliferatin can ccur with BRAF inhibitrs. (5.2) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 BRAF V600E Mutatin-Psitive Unresectable r Metastatic Melanma 1.2 BRAF V600E r V600K Mutatin-Psitive Unresectable r Metastatic Melanma 1.3 BRAF V600E Mutatin-Psitive Metastatic NSCLC 1.4 Limitatin f Use 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selectin 2.2 Recmmended Dsing 2.3 Dse Mdificatins 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies 5.2 Tumr Prmtin in BRAF Wild-Type Tumrs 5.3 Hemrrhage 5.4 Cardimypathy 5.5 Uveitis 5.6 Serius Febrile Reactins 5.7 Serius Skin Txicity 5.8 Hyperglycemia 5.9 Glucse-6-Phsphate Dehydrgenase Deficiency 5.10 Embry-Fetal Txicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effects f Other Drugs n Dabrafenib Hemrrhage: Majr hemrrhagic events can ccur in patients receiving TAFINLAR with trametinib. Mnitr fr signs and symptms f bleeding. (5.3, 2.3) Cardimypathy: Assess LVEF befre treatment with TAFINLAR and trametinib, after ne mnth f treatment, then every 2 t 3 mnths thereafter. (5.4, 2.3) Uveitis: Perfrm phthalmlgic evaluatin fr any visual disturbances. (5.5, 2.3) Serius febrile reactins: Incidence and severity f pyrexia are increased with TAFINLAR and trametinib. (5.6, 2.3) Serius skin txicity: Mnitr fr skin txicities. Discntinue fr intlerable Grade 2 r fr Grade 3 r 4 rash nt imprving within 3 weeks despite interruptin f TAFINLAR. (5.7, 2.3) Hyperglycemia: Mnitr serum glucse levels in patients with preexisting diabetes r hyperglycemia. (5.8) Glucse-6-phsphate dehydrgenase deficiency: Clsely mnitr fr hemlytic anemia. (5.9) Embry-fetal txicity: Can cause fetal harm. Advise females f reprductive ptential f ptential risk t a fetus and t use an effective nn-hrmnal methd f cntraceptin. (5.10, 8.1, 8.3) ADVERSE REACTIONS Mst cmmn adverse reactins ( 20%) fr TAFINLAR as a single agent are hyperkeratsis, headache, pyrexia, arthralgia, papillma, alpecia, and palmar-plantar erythrdysesthesia syndrme. (6.1) Mst cmmn adverse reactins ( 20%) fr TAFINLAR, in cmbinatin with trametinib, include: Melanma: pyrexia, rash, chills, headache, arthralgia, and cugh. (6.1) NSCLC: pyrexia, fatigue, nausea, vmiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemrrhage, cugh, and dyspnea. (6.1) T reprt SUSPECTED ADVERSE REACTIONS, cntact Nvartis Pharmaceuticals Crpratin at r FDA at FDA r DRUG INTERACTIONS Avid cncurrent administratin f strng inhibitrs f CYP3A4 r CYP2C8. (7.1) Cncmitant use with agents that are sensitive substrates f CYP3A4, CYP2C8, CYP2C9, CYP2C19, r CYP2B6 may result in lss f efficacy f these agents. (7.2) USE IN SPECIFIC POPULATIONS Lactatin: D nt breastfeed. (8.2) Females and Males f Reprductive Ptential: May impair fertility. (8.3) See 17 fr PATIENT COUNSELING INFORMATION and Medicatin Guide. Revised: 6/ Effects f Dabrafenib n Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactatin 8.3 Females and Males f Reprductive Ptential 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 f Actin 12.2 Pharmacdynamics 12.3 Pharmackinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcingenesis, Mutagenesis, Impairment f Fertility 13.2 Animal Txiclgy and/r Pharmaclgy 14 CLINICAL STUDIES 14.1 BRAF V600E Mutatin-Psitive Unresectable r Metastatic Melanma TAFINLAR Administered as a Single Agent 14.2 BRAF V600E r V600K Unresectable r Metastatic Melanma TAFINLAR Administered with Trametinib 14.3 BRAF V600E Mutatin-Psitive Metastatic Nn-Small Cell Lung Cancer (NSCLC) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sectins r subsectins mitted frm the full prescribing infrmatin are nt listed.

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 BRAF V600E Mutatin-Psitive Unresectable r Metastatic Melanma TAFINLAR is indicated as a single agent fr the treatment f patients with unresectable r metastatic melanma with BRAF V600E mutatin as detected by an FDA-apprved test. 1.2 BRAF V600E r V600K Mutatin-Psitive Unresectable r Metastatic Melanma TAFINLAR is indicated, in cmbinatin with trametinib, fr the treatment f patients with unresectable r metastatic melanma with BRAF V600E r V600K mutatins, as detected by an FDA-apprved test. 1.3 BRAF V600E Mutatin-Psitive Metastatic NSCLC TAFINLAR is indicated, in cmbinatin with trametinib, fr the treatment f patients with metastatic nn-small cell lung cancer (NSCLC) with BRAF V600E mutatin as detected by an FDA-apprved test. 1.4 Limitatin f Use TAFINLAR is nt indicated fr treatment f patients with wild-type BRAF melanma r wild-type BRAF NSCLC [see Warnings and Precautins (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selectin Melanma Cnfirm the presence f BRAF V600E mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR as a single agent [see Warnings and Precautins (5.2) and Clinical Studies (14.1)]. Cnfirm the presence f BRAF V600E r V600K mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR and trametinib [see Warnings and Precautins (5.2) and Clinical Studies (14.1)]. Infrmatin n FDA-apprved tests fr the detectin f BRAF V600 mutatins in melanma is available at: NSCLC Cnfirm the presence f BRAF V600E mutatin in tumr specimens prir t initiatin f treatment with TAFINLAR and trametinib [see Clinical Studies (14.2)]. Infrmatin n FDA-apprved tests fr the detectin f BRAF V600E mutatins in NSCLC is available at: Recmmended Dsing The recmmended dsage regimen f TAFINLAR is 150 mg rally taken twice daily, apprximately 12 hurs apart as a single agent r with trametinib. Cntinue treatment until disease prgressin r unacceptable txicity ccurs. Take TAFINLAR at least 1 hur befre r 2 hurs after a meal [see Clinical Pharmaclgy (12.3)]. D nt take a missed dse f TAFINLAR within 6 hurs f the next dse f TAFINLAR. D nt pen, crush, r break TAFINLAR capsules. 2.3 Dse Mdificatins Review the Full Prescribing Infrmatin fr trametinib fr recmmended dse mdificatins. Dse mdificatins are nt recmmended fr TAFINLAR when administered with trametinib fr the fllwing adverse reactins f trametinib: retinal vein cclusin (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumnitis, and uncmplicated venus thrmbemblism. Fr New Primary Cutaneus Malignancies N dse mdificatins are required.

3 Fr New Primary Nn-Cutaneus Malignancies Permanently discntinue TAFINLAR in patients wh develp RAS mutatin-psitive nn-cutaneus malignancies. Table 1. Recmmended Dse Reductins Dse Reductins fr TAFINLAR First Dse Reductin 100 mg rally twice daily Secnd Dse Reductin Third Dse Reductin Subsequent Mdificatin 75 mg rally twice daily 50 mg rally twice daily Permanently discntinue TAFINLAR if unable t tlerate 50 mg rally twice daily Table 2. Recmmended Dse Mdificatins fr TAFINLAR Severity f Adverse Reactin a Febrile Drug Reactin TAFINLAR b Fever f F t 104 F Fever higher than 104 F Fever cmplicated by rigrs, hyptensin, dehydratin, r renal failure Withhld TAFINLAR until fever reslves. Then resume at same r lwer dse level. Withhld TAFINLAR until fever reslves. Then resume at a lwer dse level. Or Permanently discntinue TAFINLAR. Cutaneus Intlerable Grade 2 skin txicity Grade 3 r 4 skin txicity Withhld TAFINLAR fr up t 3 weeks. If imprved, resume at a lwer dse level. If nt imprved, permanently discntinue. Cardiac Symptmatic cngestive heart failure Abslute decrease in LVEF f greater than 20% frm baseline that is belw LLN Withhld TAFINLAR, if imprved, then resume at the same dse. Uveitis Uveitis including iritis and iridcyclitis If mild r mderate uveitis des nt respnd t cular therapy, r fr severe uveitis, withhld TAFINLAR fr up t 6 weeks. If imprved t Grade 0-1, then resume at the same r at a lwer dse level. If nt imprved, permanently discntinue.

4 Other Severity f Adverse Reactin a Intlerable Grade 2 adverse reactins Any Grade 3 adverse reactin First ccurrence f any Grade 4 adverse reactin Recurrent Grade 4 adverse reactin a b Withhld TAFINLAR. TAFINLAR b If imprved t Grade 0-1, resume at a lwer dse level. If nt imprved, permanently discntinue. Withhld TAFINLAR until adverse reactin imprves t Grade 0-1. Then resume at a lwer dse level. Or Permanently discntinue TAFINLAR. Permanently discntinue TAFINLAR. Natinal Cancer Institute Cmmn Terminlgy Criteria fr Adverse Events (NCI CTCAE) versin 4.0. See Table 1 fr recmmended dse reductins f TAFINLAR. 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. 4 CONTRAINDICATIONS Nne. 5 WARNINGS AND PRECAUTIONS Review the Full Prescribing Infrmatin fr trametinib fr infrmatin n the serius risks f trametinib prir t initiatin f TAFINLAR in cmbinatin with trametinib. 5.1 New Primary Malignancies New primary malignancies, cutaneus and nn-cutaneus, can ccur when TAFINLAR is administered as a single agent r when used with trametinib. Cutaneus Malignancies TAFINLAR results in an increased incidence f cutaneus squamus cell carcinma, keratacanthma, and melanma. In the BREAK-3 study in patients with melanma, cutaneus squamus cell carcinmas and keratacanthmas (cuscc) ccurred in 7% (14/187) f patients receiving TAFINLAR and in nne f the patients receiving dacarbazine. Acrss clinical trials f TAFINLAR (N = 586), the incidence f cuscc was 11%. The median time t first cuscc was 2.1 mnths (range: 7 days t 12.2 mnths). Of thse patients wh develped new cuscc, apprximately 33% develped ne r mre cuscc with cntinued administratin f TAFINLAR. The median time between diagnsis f the first cuscc and the secnd cuscc was 6 weeks. In the COMBI-d study in patients with melanma, the incidence f basal cell carcinma in patients receiving TAFINLAR in cmbinatin with trametinib was 3.3% (7/209) cmpared with 6% (13/211) f patients receiving single-agent TAFINLAR. The median time t first diagnsis f basal cell carcinma was 5.1 mnths (range: 2.8 t 23.9 mnths) in the TAFINLAR plus trametinib arm and was 4.4 mnths (range: 29 days t 16.5 mnths) in the single-agent TAFINLAR arm. Amng the 7 patients receiving TAFINLAR with trametinib wh develped basal cell carcinma, 2 (29%) experienced mre than ne ccurrence (range: 1 t 3).

5 Cutaneus squamus cell carcinma and keratacanthma ccurred in 3% f patients receiving TAFINLAR with trametinib and 10% f patients receiving single-agent TAFINLAR. The median time t first diagnsis f cuscc was 7.3 mnths (range: 1.8 t 16.8 mnths) in the TAFINLAR plus trametinib arm and 2 mnths (range: 9 days t 20.9 mnths) in the single-agent TAFINLAR arm. New primary melanma ccurred in 0.5% (1/209) f patients receiving TAFINLAR with trametinib and in 1.9% (4/211) f patients receiving single-agent TAFINLAR. In Study BRF in patients with NSCLC, cuscc ccurred in 3.2% (3/93) f patients with NSCLC receiving TAFINLAR plus trametinib with a time t nset f the first ccurrence f 25 days, 3.5 mnths, and 12.3 mnths. Perfrm dermatlgic evaluatins prir t initiatin f TAFINLAR, every 2 mnths while n therapy, and fr up t 6 mnths fllwing discntinuatin f TAFINLAR. N dse mdificatins f TAFINLAR are required in patients wh develp new primary cutaneus malignancies [see Dsage and Administratin (2.3)]. Nn-cutaneus Malignancies Based n its mechanism f actin, TAFINLAR may prmte the grwth and develpment f malignancies with activatin f RAS thrugh mutatin r ther mechanisms [see Warnings and Precautins (5.2)]. In the COMBI-d study, nn-cutaneus malignancies ccurred in 1.4% (3/209) f patients receiving TAFINLAR with trametinib and in 2.8% (6/211) f patients receiving single-agent TAFINLAR. In Study BRF113928, nncutaneus malignancies ccurred in 1.1% (1/93) f patients receiving TAFINLAR with trametinib. Mnitr patients receiving TAFINLAR fr signs r symptms f nn-cutaneus malignancies. Permanently discntinue TAFINLAR fr RAS mutatin-psitive nn-cutaneus malignancies [see Dsage and Administratin (2.3)]. 5.2 Tumr Prmtin in BRAF Wild-Type Tumrs In vitr experiments have demnstrated paradxical activatin f MAP-kinase signaling and increased cell prliferatin in BRAF wild-type cells which are expsed t BRAF inhibitrs. Cnfirm evidence f BRAF V600E r V600K mutatin status prir t initiatin f TAFINLAR as a single agent r in cmbinatin with trametinib [see Indicatins and Usage (1), Dsage and Administratin (2.1)]. 5.3 Hemrrhage Hemrrhage, including majr hemrrhage defined as symptmatic bleeding in a critical area r rgan, can ccur when TAFINLAR is administered with trametinib. In the COMBI-d study, the incidence f hemrrhagic events in patients receiving TAFINLAR with trametinib was 19% (40/209) cmpared with 15% (32/211) f patients receiving single-agent TAFINLAR. Gastrintestinal hemrrhage ccurred in 6% (12/209) f patients receiving TAFINLAR with trametinib cmpared with 3% (6/211) f patients receiving single-agent TAFINLAR. Intracranial hemrrhage was fatal in 1.4% (3/209) f patients receiving TAFINLAR with trametinib cmpared with nne f the patients receiving single-agent TAFINLAR. In Study BRF113928, fatal hemrrhagic events ccurred in 2.2% (2/93) f patients receiving TAFINLAR with trametinib; these events were retrperitneal hemrrhage and subarachnid hemrrhage. Permanently discntinue TAFINLAR fr all Grade 4 hemrrhagic events and fr any persistent Grade 3 hemrrhagic events. Withhld TAFINLAR fr Grade 3 hemrrhagic events; if imprved, resume at the next lwer dse level. 5.4 Cardimypathy Cardimypathy can ccur with TAFINLAR. In the COMBI-d study, all patients were required t have an echcardigram at baseline t dcument nrmal left ventricular ejectin fractin (LVEF) and serial echcardigrams at Week 4, Week 12, and every 12 weeks thereafter. In this study, cardimypathy, defined as a decrease in LVEF 10% frm baseline and belw the institutinal lwer limit f nrmal, ccurred in 6% (12/206) f patients receiving TAFINLAR with trametinib

6 and 2.9% (6/207) f patients receiving single-agent TAFINLAR. The median time t nset f cardimypathy n the TAFINLAR plus trametinib arm was 8.2 mnths (range: 28 days t 24.9 mnths), and was 4.4 mnths (range: 28 days t 19.1 mnths) n the TAFINLAR arm. In the COMBI-d study, cardimypathy was identified within the first mnth f initiatin f TAFINLAR with trametinib in 2 f 12 patients, and in 2 f 6 patients receiving single-agent TAFINLAR. Develpment f cardimypathy in patients receiving TAFINLAR and trametinib resulted in dse interruptin f TAFINLAR (4.4%) r discntinuatin f TAFINLAR (1.0%). In patients receiving single-agent TAFINLAR, develpment f cardimypathy resulted in dse interruptin (2.4%), dse reductin (0.5%), r discntinuatin (1.0%). Cardimypathy reslved in 10 f 12 patients receiving TAFINLAR with trametinib, and in 3 f 6 patients receiving single-agent TAFINLAR. In Study BRF113928, all patients were required t have an echcardigram at baseline t dcument nrmal left ventricular ejectin fractin (LVEF) and serial echcardigrams at Week 6, Week 15, and then every 9 weeks thereafter. Cardimypathy, defined as a decrease in LVEF belw the institutinal lwer limit f nrmal with an abslute decrease in LVEF >10% belw baseline, ccurred in 9% (8/93) f patients receiving TAFINLAR with trametinib. The median time t nset f cardimypathy was 6.7 mnths (range: 1.4 mnths t 14.1 mnths). Cardimypathy in patients receiving TAFINLAR and trametinib resulted in dse interruptin and permanent discntinuatin f TAFINLAR in 3.2% and 2.2%, respectively. Cardimypathy reslved in 4 f 8 patients receiving TAFINLAR and trametinib. Assess LVEF by echcardigram r multigated acquisitin (MUGA) scan befre initiatin f TAFINLAR with trametinib, ne mnth after initiatin f TAFINLAR, and then at 2- t 3-mnth intervals while n treatment. Withhld TAFINLAR fr symptmatic cardimypathy r asymptmatic LV dysfunctin f >20% frm baseline that is belw institutinal lwer limit f nrmal (LLN). Resume TAFINLAR at the same dse level upn recvery f cardiac functin t at least the institutinal LLN fr LVEF and abslute decrease 10% cmpared t baseline [see Dsage and Administratin (2.3)]. 5.5 Uveitis Uveitis (including iritis and iridcyclitis) can ccur with TAFINLAR. Uveitis ccurred in 1% (6/586) f patients receiving TAFINLAR acrss multiple clinical trials and in 2% (9/559) f patients receiving TAFINLAR with trametinib acrss randmized melanma trials. Treatment emplyed in clinical trials included sterid and mydriatic phthalmic drps. Mnitr patients fr visual signs and symptms f uveitis (e.g., change in visin, phtphbia, eye pain). If iritis is diagnsed, administer cular therapy and cntinue TAFINLAR withut dse mdificatin; fr severe uveitis r iridcyclitis, interrupt TAFINLAR and treat as clinically indicated. Permanently discntinue TAFINLAR fr persistent Grade 2 r greater uveitis f >6 weeks duratin [see Dsage and Administratin (2.3)]. 5.6 Serius Febrile Reactins Serius febrile reactins and fever f any severity cmplicated by hyptensin, rigrs r chills, dehydratin, r renal failure, can ccur with TAFINLAR. The incidence and severity f pyrexia are increased when TAFINLAR is administered with trametinib cmpared with TAFINLAR as a single agent [see Adverse Reactins (6.1)]. In the BREAK-3 study, the incidence f fever (serius and nn-serius) was 28% in patients receiving TAFINLAR and 10% in patients receiving dacarbazine. In patients receiving TAFINLAR, the median time t initial nset f fever (any severity) was 11 days (range: 1 day t 6.6 mnths) and the median duratin f fever was 3 days (range: 1 day t 4.2 mnths). Serius febrile reactins and fever f any severity cmplicated by hyptensin, rigrs r chills ccurred in 3.7% (7/187) f patients receiving TAFINLAR and in nne f the 59 patients receiving dacarbazine. In the COMBI-d and COMBI-v studies, fever ccurred in 54% (303/559) f patients receiving TAFINLAR with trametinib; the median time t nset f first ccurrence f fever was 1 mnth (range: 1 day t 23.5 mnths) and

7 the median duratin f fever was 3 days (range: 1 day t 11.3 mnths). Apprximately ne-half f the patients wh received TAFINLAR with trametinib and experienced pyrexia had 3 r mre discrete episdes. Serius febrile reactins r fever f any severity cmplicated by severe rigrs/chills, hyptensin, dehydratin, renal failure, r syncpe, ccurred in 17% (93/559) f patients with melanma receiving TAFINLAR with trametinib. Fever was cmplicated by severe chills/rigrs in 0.4% (2/559), dehydratin in 1.8% (10/559), renal failure in 0.5% (3/559), and syncpe in 0.7% (4/559) f patients. Withhld TAFINLAR fr fever f 101.3ºF r higher. Withhld TAFINLAR fr any serius febrile reactin r fever cmplicated by hyptensin, rigrs r chills, dehydratin, r renal failure and evaluate fr signs and symptms f infectin. Mnitr serum creatinine and ther evidence f renal functin during and fllwing severe pyrexia. Refer t Table 2 fr recmmended dse mdificatins fr adverse reactins [see Dsage and Administratin (2.3)]. Administer antipyretics as secndary prphylaxis when resuming TAFINLAR if patient had a prir episde f severe febrile reactin r fever assciated with cmplicatins. Administer crticsterids (e.g., prednisne 10 mg daily) fr at least 5 days fr secnd r subsequent pyrexia if temperature des nt return t baseline within 3 days f nset f pyrexia, r fr pyrexia assciated with cmplicatins such as dehydratin, hyptensin, renal failure r severe chills/rigrs, and there is n evidence f active infectin. 5.7 Serius Skin Txicity Serius skin txicity can ccur with TAFINLAR. Acrss clinical trials f TAFINLAR administered with trametinib (N = 559) in patients with melanma, serius skin txicity ccurred in 0.7% (4/559) f patients. Withhld TAFINLAR fr intlerable r severe skin txicity. TAFINLAR may be resumed at the next lwer dse level in patients with imprvement r recvery frm skin txicity within 3 weeks [see Dsage and Administratin (2.3)]. 5.8 Hyperglycemia Hyperglycemia can ccur with TAFINLAR. In the BREAK-3 study, 5 f 12 patients with a histry f diabetes required mre intensive hypglycemic therapy receiving TAFINLAR. The incidence f Grade 3 hyperglycemia based n labratry values was 6% (12/187) in patients receiving TAFINLAR cmpared with nne f the dacarbazine-treated patients. In the COMBI-d study, 27% (4/15) f patients with a histry f diabetes receiving TAFINLAR with trametinib and 13% (2/16) f patients with a histry f diabetes receiving single-agent TAFINLAR required mre intensive hypglycemic therapy. Grade 3 and Grade 4 hyperglycemia based n labratry values ccurred in 5% (11/208) and 0.5% (1/208) f patients, respectively, receiving TAFINLAR with trametinib cmpared with 4.3% (9/209) fr Grade 3 hyperglycemia and n patients with Grade 4 hyperglycemia fr patients receiving single-agent TAFINLAR. Mnitr serum glucse levels upn initiatin and as clinically apprpriate when TAFINLAR is administered in patients with pre-existing diabetes r hyperglycemia. 5.9 Glucse-6-Phsphate Dehydrgenase Deficiency TAFINLAR, which cntains a sulfnamide miety, cnfers a ptential risk f hemlytic anemia in patients with glucse-6-phsphate dehydrgenase (G6PD) deficiency. Mnitr patients with G6PD deficiency fr signs f hemlytic anemia while taking TAFINLAR Embry-Fetal Txicity Based n findings frm animal studies and its mechanism f actin, TAFINLAR can cause fetal harm when administered t a pregnant wman. Dabrafenib was teratgenic and embrytxic in rats at dses three times greater than the human expsure at the recmmended clinical dse. If TAFINLAR is used during pregnancy r if the patient becmes pregnant while taking TAFINLAR, advise the patient f the ptential risk t a fetus [see Use in Specific Ppulatins (8.1)].

8 Advise female patients f reprductive ptential t use an effective nn-hrmnal methd f cntraceptin since TAFINLAR can render hrmnal cntraceptives ineffective, during treatment and fr 2 weeks after the last dse f TAFINLAR. Advise patients t cntact their healthcare prvider if they becme pregnant, r if pregnancy is suspected, while taking TAFINLAR [see Drug Interactins (7.2), Use in Specific Ppulatins (8.3)]. 6 ADVERSE REACTIONS The fllwing adverse reactins are discussed in greater detail in anther sectin f the label: New Primary Malignancies [see Warnings and Precautins (5.1)] Tumr Prmtin in BRAF Wild-Type Melanma [see Warnings and Precautins (5.2)] Hemrrhage [see Warnings and Precautins (5.3)] Cardimypathy [see Warnings and Precautins (5.4)] Uveitis [see Warnings and Precautins (5.5)] Serius Febrile Reactins [see Warnings and Precautins (5.6)] Serius Skin Txicity [see Warnings and Precautins (5.7)] Hyperglycemia [see Warnings and Precautins (5.8)] Glucse-6-Phsphate Dehydrgenase Deficiency [see Warnings and Precautins (5.9)] 6.1 Clinical Trials Experience Because clinical trials are cnducted under widely varying cnditins, adverse reactin rates bserved in the clinical trials f a drug cannt be directly cmpared t rates in the clinical trials f anther drug and may nt reflect the rates bserved in practice. The data described in the Warnings and Precautins sectin reflect expsure t TAFINLAR administered as a single agent in 586 patients with varius slid tumrs and expsure t TAFINLAR administered with trametinib in 559 patients with melanma and 93 patients with NSCLC. The safety f TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutatin-psitive unresectable r metastatic melanma, previusly treated r untreated, wh received TAFINLAR 150 mg rally twice daily until disease prgressin r unacceptable txicity, including 181 patients treated fr at least 6 mnths and 86 additinal patients treated fr mre than 12 mnths. TAFINLAR was studied in pen-label, single-arm trials and in an pen-label, randmized, active-cntrlled trial. The median daily dse f TAFINLAR was 300 mg (range: 118 t 300 mg). Metastatic r Unresectable BRAF V600 Mutatin Psitive Melanma TAFINLAR as a Single Agent Table 3 and Table 4 present adverse drug reactins and labratry abnrmalities identified frm analyses f the BREAK-3 study [see Clinical Studies (14.1)].This study, a multicenter, internatinal, pen-label, randmized (3:1), cntrlled trial allcated 250 patients with unresectable r metastatic BRAF V600E mutatin-psitive melanma t receive TAFINLAR 150 mg rally twice daily (n = 187) r dacarbazine 1,000 mg/m 2 intravenusly every 3 weeks (n = 63). The trial excluded patients with abnrmal left ventricular ejectin fractin r cardiac valve mrphlgy ( Grade 2), crrected QT interval greater than r equal t 480 millisecnds n electrcardigram, r a knwn histry f glucse-6-phsphate dehydrgenase deficiency. The median duratin n treatment was 4.9 mnths fr patients treated with TAFINLAR and 2.8 mnths fr dacarbazine-treated patients. The ppulatin expsed t TAFINLAR was 60% male, 99% White, and had a median age f 53 years. The mst cmmnly ccurring adverse reactins ( 20%) in patients treated with TAFINLAR were, in rder f decreasing frequency: hyperkeratsis, headache, pyrexia, arthralgia, papillma, alpecia, and palmar-plantar erythrdysesthesia syndrme (PPES).

9 The incidence f adverse events resulting in permanent discntinuatin f study medicatin in the BREAK-3 study was 3% fr patients treated with TAFINLAR and 3% fr patients treated with dacarbazine. The mst frequent ( 2%) adverse reactins leading t dse reductin f TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). Table 3. Select Cmmn Adverse Reactins Occurring in 10% (All ) r 2% ( 3 r 4) f Patients Treated with TAFINLAR in the BREAK-3 Study a All TAFINLAR N = and 4 b Dacarbazine N = 59 All 3 and 4 Adverse Reactins Skin and subcutaneus tissue Hyperkeratsis Alpecia 22 NA f 2 NA f Palmar-plantar erythrdysesthesia syndrme Rash Nervus system Headache General disrders Pyrexia Musculskeletal Arthralgia Back pain Myalgia Neplasms Papillma c cuscc d, e Respiratry Cugh Gastrintestinal Cnstipatin Infectins Naspharyngitis a b c d e f Adverse drug reactins, reprted using MedDRA and graded using NCI CTCAE versin 4.0 fr assessment f txicity. Grade 4 adverse reactins limited t hyperkeratsis (n = 1) and cnstipatin (n = 1). Includes skin papillma and papillma. cuscc = cutaneus squamus cell carcinma, includes squamus cell carcinma f the skin and keratacanthma. Cases f cuscc were required t be reprted as Grade 3 per prtcl. NA = nt applicable.

10 Table 4. Incidence f Labratry Abnrmalities Increased frm Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in 1the BREAK-3 Study [Between-Arm Difference f 5% (All ) r 2% ( 3 r 4)] a All TAFINLAR N = and 4 All DTIC N = 59 3 and 4 Test Hyperglycemia Hypphsphatemia 37 6 b 14 2 Increased alkaline phsphatase Hypnatremia a b Adverse drug reactins, reprted using MedDRA and graded using NCI CTCAE versin 4.0 fr assessment f txicity. Grade 4 labratry abnrmality limited t hypphsphatemia (n = 1). Other clinically imprtant adverse reactins bserved in less than 10% f patients (N = 586) treated with TAFINLAR were: Gastrintestinal Disrders: Pancreatitis Immune System Disrders: Hypersensitivity manifesting as bullus rash Renal and Urinary Disrders: Interstitial nephritis TAFINLAR Administered with Trametinib The safety f TAFINLAR when administered with trametinib was evaluated in 559 patients with previusly untreated, unresectable r metastatic, BRAF V600E r V600K mutatin-psitive melanma wh received TAFINLAR in tw trials, the COMBI-d study (n = 209) a multicenter, duble-blind, randmized (1:1), active cntrlled trial and the COMBI-v study (n = 350) a multicenter, pen-label, randmized (1:1), active cntrlled trial. In the COMBI-d and COMBI-v studies, patients received TAFINLAR 150 mg rally twice daily and trametinib 2 mg rally nce daily until disease prgressin r unacceptable txicity. Bth trials excluded patients with abnrmal left ventricular ejectin fractin, histry f acute crnary syndrme within 6 mnths, histry f Class II r greater cngestive heart failure (New Yrk Heart Assciatin), histry f RVO r RPED, QTcB interval 480 msec, treatment refractry hypertensin, uncntrlled arrhythmias, active brain metastases, r a knwn histry f G6PD deficiency [see Clinical Studies (14.2)]. Amng these 559 patients, 199 (36%) were expsed t TAFINLAR fr >6 mnths t 12 mnths while 185 (33%) were expsed t TAFINLAR fr 1 year. The median age was 55 years (range: 18 t 91), 57% were male, 98% were White, 72% had baseline ECOG perfrmance status 0 and 28% had ECOG perfrmance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a histry f brain metastases. The mst cmmnly ccurring adverse reactins ( 20%) fr TAFINLAR in patients receiving TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cugh. Table 5 and Table 6 present adverse drug reactins and labratry abnrmalities, respectively, bserved in the COMBI-d study. The demgraphics and baseline tumr characteristics f patients enrlled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.2)]. Patients receiving TAFINLAR plus trametinib had a median duratin f expsure f 11 mnths (range: 3 days t 30 mnths) t TAFINLAR. Amng the 209 patients receiving TAFINLAR plus trametinib, 26% were expsed t TAFINLAR fr >6 mnths t 12 mnths while 46% were expsed t TAFINLAR fr >1 year. In the COMBI-d study, adverse reactins resulting in discntinuatin f TAFINLAR ccurred in 11% f patients receiving TAFINLAR plus trametinib; the mst cmmn was pyrexia (1.9%). Adverse reactins leading t dse reductins f TAFINLAR ccurred in 26% f patients receiving TAFINLAR plus trametinib; the mst cmmn were pyrexia (14%), neutrpenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactins

11 leading t dse interruptins f TAFINLAR ccurred in 56% f patients receiving TAFINLAR plus trametinib; the mst cmmn were pyrexia (35%), chills (11%), vmiting (7%), nausea (5%), and decreased ejectin fractin (5%). Table 5. Select Adverse Reactins Occurring in 10% (All ) f Patients Treated with TAFINLAR in Cmbinatin with Trametinib in the COMBI-d Study a Pled TAFINLAR plus Trametinib N = 559 All 3 and 4 b COMBI-d Study TAFINLAR plus Trametinib N = 209 TAFINLAR N = 211 All All 3 and 4 3 and 4 Adverse Reactins General Pyrexia Chills Gastrintestinal Cnstipatin Nervus system Headache Dizziness Musculskeletal Arthralgia Myalgia Skin Rash c Dry skin Respiratry Cugh Infectins Naspharyngitis a b c NCI CTCAE versin 4.0. Grade 4 adverse reactins limited t headache (n = 1). Includes rash generalized, rash pruritic, rash erythematus, rash papular, rash vesicular, rash macular, rash macul-papular, and rash flliculitis. Other clinically imprtant adverse reactins fr TAFINLAR acrss the COMBI-d and COMBI-v studies (N = 559) bserved in less than 10% f patients receiving TAFINLAR in cmbinatin with trametinib were: Gastrintestinal Disrders: Pancreatitis Subcutaneus Tissue Disrders: Panniculitis

12 Table 6. Select Treatment-Emergent Labratry Abnrmalities Occurring at 10% (All ) f Patients Receiving TAFINLAR with Trametinib in the COMBI-d Study COMBI-d Study Pled TAFINLAR plus Trametinib N = 559 a All 3 and 4 c TAFINLAR plus Trametinib N = 209 b All 3 and 4 c TAFINLAR N = 211 b All 3 and 4 c Test Liver Functin Tests Increased bld alkaline phsphatase Chemistry Hyperglycemia a b c Hypphsphatemia Hypnatremia Fr these labratry tests the denminatr is 556. Fr these labratry tests the denminatr is 208 fr the cmbinatin arm, fr the TAFINLAR arm. Grade 4 adverse reactins limited t hyperglycemia (n = 4), hypnatremia and hypphsphatemia (each n = 1), in the pled cmbinatin arm; hyperglycemia (n = 1) in the COMBI-d study cmbinatin arm; hypphsphatemia (n = 1) in the TAFINLAR arm. Metastatic, BRAF V600E-Mutatin Psitive, Nn-Small Cell Lung Cancer (NSCLC) The safety f TAFINLAR when administered with trametinib was evaluated in 93 patients with previusly untreated (n = 36) and previusly treated (n = 57) metastatic BRAF V600E mutatin-psitive NSCLC in a multicenter, multi-chrt, nn-randmized, pen-label trial (Study BRF113928). Patients received TAFINLAR 150 mg rally twice daily and trametinib 2 mg rally nce daily until disease prgressin r unacceptable txicity. The trial excluded patients with abnrmal left ventricular ejectin fractin, histry f acute crnary syndrme within 6 mnths, histry f Class II r greater cngestive heart failure (New Yrk Heart Assciatin), QTc interval 480 msec, treatment refractry hypertensin, uncntrlled arrhythmias, active brain metastases, histry f interstitial lung disease r pneumnitis, r histry r current retinal vein cclusin [see Clinical Studies (14.3)]. Amng these 93 patients, 53 (57%) were expsed t TAFINLAR and trametinib fr >6 mnths and 27 (29%) were expsed t TAFINLAR and trametinib fr 1 year. The median age was 65 years (range: 41 t 91); 46% were male; 85% were White; 32% had baseline ECOG perfrmance status 0 and 61% had ECOG perfrmance status 1; 98% had nn-squamus histlgy; and 12% were current smkers, 60% were frmer smkers, and 28% had never smked. The mst cmmnly ccurring adverse reactins ( 20%) in these 93 patients were: pyrexia, fatigue, nausea, vmiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemrrhage, cugh, and dyspnea. Adverse reactins resulting in discntinuatin f TAFINLAR ccurred in 18% f patients; the mst cmmn were pyrexia (2.2%), ejectin fractin decreased (2.2%), and respiratry distress (2.2%). Adverse reactins leading t dse reductins f TAFINLAR ccurred in 35% f patients; the mst cmmn were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vmiting (4.3%), and neutrpenia (3.2%). Adverse reactins leading t dse interruptins f TAFINLAR ccurred in 62% f patients; the mst cmmn were pyrexia (27%), vmiting (11%), neutrpenia (8%), and chills (6%). Table 7 and Table 8 present adverse drug reactins and labratry abnrmalities, respectively, f TAFINLAR in Study BRF

13 Table 7. Adverse Reactins Occurring in 20% (All ) f Patients Treated with TAFINLAR in Cmbinatin with Trametinib in Study BRF a TAFINLAR plus Trametinib N = 93 All 3 and 4 b Adverse Reactins General Pyrexia 55 5 Fatigue b 51 5 Edema c 28 0 Chills Gastrintestinal Nausea 45 0 Vmiting Diarrhea Decreased appetite 29 0 Respiratry system Cugh 22 0 Dyspnea 20 5 Skin Dry skin Rash d Vascular Hemrrhage e a b c d e NCI CTCAE versin 4.0. Includes fatigue, malaise, and asthenia Includes peripheral edema, edema, and generalized edema. Includes rash, rash generalized, rash papular, rash macular, rash macul-papular, and rash pustular. Includes hemptysis, hematma, epistaxis, purpura, hematuria, subarachnid hemrrhage, gastric hemrrhage, urinary bladder hemrrhage, cntusin, hematchezia, injectin site hemrrhage, pulmnary hemrrhage, and retrperitneal hemrrhage. Other clinically imprtant adverse reactins fr TAFINLAR bserved in less than 10% f patients with NSCLC receiving TAFINLAR in cmbinatin with trametinib were: Gastrintestinal Disrders: Pancreatitis Renal and Urinary Disrders: Tubulinterstitial nephritis

14 Table 8. Treatment-Emergent Labratry Abnrmalities Occurring in 20% (All ) f Patients Receiving TAFINLAR with Trametinib in Study BRF TAFINLAR plus Trametinib N = 93 Test All 3 and 4 Hematlgy a Leukpenia 48 8 Anemia Neutrpenia 44 8 Lymphpenia Liver Functin Tests b Increased bld alkaline phsphatase 64 0 Increased AST Increased ALT 32 6 Chemistry b Hyperglycemia 71 9 a b Hypnatremia Hypphsphatemia 36 7 Increased creatinine Fr these labratry tests the denminatr is 91. Fr these labratry tests the denminatr is DRUG INTERACTIONS 7.1 Effects f Other Drugs n Dabrafenib Dabrafenib is primarily metablized by CYP2C8 and CYP3A4. Strng inhibitrs f CYP3A4 r CYP2C8 may increase cncentratins f dabrafenib [see Clinical Pharmaclgy (12.3)]. Substitutin f strng inhibitrs f CYP3A4 r CYP2C8 is recmmended during treatment with TAFINLAR. If cncmitant use f strng inhibitrs (e.g., ketcnazle, nefazdne, clarithrmycin, gemfibrzil) f CYP3A4 r CYP2C8 is unavidable, mnitr patients clsely fr adverse reactins when taking strng inhibitrs. 7.2 Effects f Dabrafenib n Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic expsures f midazlam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmaclgy (12.3)]. Mnitr internatinal nrmalized rati (INR) levels mre frequently in patients receiving warfarin during initiatin r discntinuatin f dabrafenib. Cadministratin f TAFINLAR with ther substrates f these enzymes, including dexamethasne r hrmnal cntraceptives, can result in decreased cncentratins and lss f efficacy [see Use in Specific Ppulatins (8.1, 8.3)]. Substitute fr these medicatins r mnitr patients fr lss f efficacy if use f these medicatins is unavidable. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based n findings frm animal reprductin studies and its mechanism f actin, TAFINLAR can cause fetal harm when administered t a pregnant wman [see Clinical Pharmaclgy (12.1)]. There is insufficient data in pregnant wmen expsed t TAFINLAR t assess the risks. Dabrafenib was teratgenic and embrytxic in rats at dses three times greater than the human expsure at the recmmended clinical dse f 150 mg twice daily

15 [see Data]. If TAFINLAR is used during pregnancy r if the patient becmes pregnant while taking TAFINLAR, advise the patient f the ptential risk t a fetus. In the U.S. general ppulatin, the estimated backgrund risk f majr birth defects and miscarriage in clinically recgnized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data: In a cmbined female fertility and embry-fetal develpment study in rats cnducted during the perid f rgangenesis, develpmental txicity cnsisted f embry-lethality, ventricular septal defects, and variatin in thymic shape at a dabrafenib dse f 300 mg/kg/day (apprximately three times the human expsure at the recmmended dse based n AUC). At dses f 20 mg/kg/day r greater (equivalent t the human expsure at the recmmended dse based n AUC), rats demnstrated delays in skeletal develpment and reduced fetal bdy weight. 8.2 Lactatin Risk Summary There are n data n the presence f dabrafenib in human milk, r the effects f dabrafenib n the breastfed infant, r n milk prductin. Because f the ptential fr serius adverse reactins frm TAFINLAR in breastfed infants, advise wmen nt t breastfeed during treatment with TAFINLAR and fr 2 weeks fllwing the last dse f TAFINLAR. 8.3 Females and Males f Reprductive Ptential Based n data frm animal studies and its mechanism f actin, TAFINLAR can cause fetal harm when administered t pregnant wmen [see Use in Specific Ppulatins (8.1)]. Cntraceptin Females Advise female patients f reprductive ptential t use effective cntraceptin during treatment with TAFINLAR and fr 2 weeks after the last dse f TAFINLAR. Cunsel patients t use a nn-hrmnal methd f cntraceptin since TAFINLAR can render hrmnal cntraceptives ineffective [see Drug Interactins (7.1)]. Advise patients t cntact their healthcare prvider if they becme pregnant, r if pregnancy is suspected, while taking TAFINLAR. Infertility Females Advise female patients f reprductive ptential that TAFINLAR may impair fertility. A reductin in fertility was bserved in female rats at dse expsures equivalent t the human expsure at the recmmended dse. A reductin in the number f crpra lutea was nted in pregnant rats at dse expsures apprximately three times the human expsure at the recmmended dse [see Nnclinical Txiclgy (13.1)]. Males Advise male patients f the ptential risk fr impaired spermatgenesis which may be irreversible. Effects n spermatgenesis have been bserved in animals treated with dabrafenib at dse expsures up t three times the human expsure at the recmmended dse [see Nnclinical Txiclgy (13.1)]. 8.4 Pediatric Use The safety and effectiveness f TAFINLAR as a single agent r with trametinib have nt been established in pediatric patients. Juvenile Animal Data In a repeat-dse txicity study in juvenile rats, an increased incidence f kidney cysts and tubular depsits were nted at dses as lw as 0.2 times the human expsure at the recmmended adult dse based n AUC.

16 Additinally, frestmach hyperplasia, decreased bne length, and early vaginal pening were nted at dses as lw as 0.8 times the human expsure at the recmmended adult dse based n AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) f 586 patients in clinical trials f TAFINLAR administered as a single agent and 40 (21%) f the 187 patients receiving TAFINLAR in the BREAK-3 study were greater than r equal t 65 years f age. N verall differences in the effectiveness r safety f TAFINLAR were bserved in elderly patients as cmpared t yunger patients in the BREAK-3 study. Of the 559 patients with melanma randmized t receive TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies, 24% were aged 65 years and lder and 6% patients aged 75 years and lder. N verall differences in the effectiveness f TAFINLAR plus trametinib were bserved in elderly patients as cmpared t yunger patients. The incidences f peripheral edema (26% vs. 12%) and anrexia (21% vs. 9%) were increased in elderly patients as cmpared t yunger patients. Clinical studies f TAFINLAR in NSCLC did nt include sufficient numbers f subjects aged 65 and ver t determine whether they respnd differently frm yunger subjects. 8.6 Hepatic Impairment N frmal pharmackinetic trial in patients with hepatic impairment has been cnducted. Dse adjustment is nt recmmended fr patients with mild hepatic impairment based n the results f the ppulatin pharmackinetic analysis. As hepatic metablism and biliary secretin are the primary rutes f eliminatin f dabrafenib and its metablites, patients with mderate t severe hepatic impairment may have increased expsure. An apprpriate dse has nt been established fr patients with mderate t severe hepatic impairment [see Clinical Pharmaclgy (12.3)]. 8.7 Renal Impairment N frmal pharmackinetic trial in patients with renal impairment has been cnducted. Dse adjustment is nt recmmended fr patients with mild r mderate renal impairment based n the results f the ppulatin pharmackinetic analysis. An apprpriate dse has nt been established fr patients with severe renal impairment [see Clinical Pharmaclgy (12.3)]. 10 OVERDOSAGE There is n infrmatin n verdsage f TAFINLAR. Since dabrafenib is highly bund t plasma prteins, hemdialysis is likely t be ineffective in the treatment f verdse with TAFINLAR. 11 DESCRIPTION Dabrafenib mesylate is a kinase inhibitr. The chemical name fr dabrafenib mesylate is N-{3-[5-(2-amin-4- pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazl-4-yl]-2-flurphenyl}-2,6-diflurbenzene sulfnamide, methanesulfnate salt. It has the mlecular frmula C 23 H 20 F 3 N 5 O 2 S 2 CH 4 O 3 S and a mlecular weight f Dabrafenib mesylate has the fllwing chemical structure:

17 Dabrafenib mesylate is a white t slightly clred slid with three pk a s: 6.6, 2.2, and It is very slightly sluble at ph 1 and practically insluble abve ph 4 in aqueus media. TAFINLAR (dabrafenib) capsules are supplied as 50 mg and 75 mg capsules fr ral administratin. Each 50 mg capsule cntains mg dabrafenib mesylate equivalent t 50 mg f dabrafenib free base. Each 75 mg capsule cntains mg dabrafenib mesylate equivalent t 75 mg f dabrafenib free base. The inactive ingredients f TAFINLAR are cllidal silicn dixide, magnesium stearate, and micrcrystalline cellulse. Capsule shells cntain hyprmellse, red irn xide (E172), and titanium dixide (E171). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism f Actin Dabrafenib is an inhibitr f sme mutated frms f BRAF kinases with in vitr IC 50 values f 0.65, 0.5, and 1.84 nm fr BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib als inhibits wild-type BRAF and CRAF kinases with IC 50 values f 3.2 and 5.0 nm, respectively, and ther kinases such as SIK1, NEK11, and LIMK1 at higher cncentratins. Sme mutatins in the BRAF gene, including thse that result in BRAF V600E, can result in cnstitutively activated BRAF kinases that may stimulate tumr cell grwth [see Indicatins and Usage (1)]. Dabrafenib inhibits cell grwth f varius BRAF V600 mutatinpsitive tumrs in vitr and in viv. Dabrafenib and trametinib target tw different kinases in the RAS/RAF/MEK/ERK pathway. Use f dabrafenib and trametinib in cmbinatin resulted in greater grwth inhibitin f BRAF V600 mutatin-psitive tumr cell lines in vitr and prlnged inhibitin f tumr grwth in BRAF V600 mutatin psitive tumr xengrafts cmpared with either drug alne Pharmacdynamics Cardiac Electrphysilgy The ptential effect f TAFINLAR n QT prlngatin was assessed in a dedicated multiple-dse study in 32 patients with BRAF V600 mutatin-psitive tumrs. N large changes in the mean QT interval (i.e., >20 ms) were detected with dabrafenib 300 mg administered twice daily (tw times the recmmended dsage). In clinical trials, QTc (heart rate-crrected QT) prlngatin t 500 ms ccurred in 0.8% (2/264) f patients receiving TAFINLAR plus trametinib and in 1.5 % (4/264) f patients receiving TAFINLAR as a single agent. The QTc was increased >60 ms frm baseline in 3.8% (10/264) f patients receiving TAFINLAR plus trametinib and 3% (8/264) f patients treated with TAFINLAR as a single agent Pharmackinetics Absrptin After ral administratin, median time t achieve peak plasma cncentratin (T max ) is 2 hurs. Mean abslute biavailability f ral dabrafenib is 95%. Fllwing a single dse, dabrafenib expsure (C max and AUC) increased in a dse-prprtinal manner acrss the dse range f 12 t 300 mg, but the increase was less than

18 dse-prprtinal after repeat twice-daily dsing. After repeat twice-daily dsing f 150 mg, the mean accumulatin rati was 0.73 and the inter-subject variability (CV%) f AUC at steady-state was 38%. Administratin f dabrafenib with a high-fat meal decreased C max by 51%, decreased AUC by 31%, and delayed median T max by 3.6 hurs as cmpared with the fasted state [see Dsage and Administratin (2.2)]. Distributin Dabrafenib is 99.7% bund t human plasma prteins. The apparent vlume f distributin (V c /F) is 70.3 L. Metablism The metablism f dabrafenib is primarily mediated by CYP2C8 and CYP3A4 t frm hydrxy-dabrafenib. Hydrxy-dabrafenib is further xidized via CYP3A4 t frm carbxy-dabrafenib and subsequently excreted in bile and urine. Carbxy-dabrafenib is decarbxylated t frm desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsrbed frm the gut. Desmethyl-dabrafenib is further metablized by CYP3A4 t xidative metablites. Mean metablite-t-parent AUC ratis fllwing repeat-dse administratin are 0.9, 11, and 0.7 fr hydrxy-, carbxy-, and desmethyl-dabrafenib, respectively. Based n systemic expsure, relative ptency, and pharmackinetic prperties, bth hydrxy- and desmethyl-dabrafenib are likely t cntribute t the clinical activity f dabrafenib. Eliminatin The mean terminal half-life f dabrafenib is 8 hurs after ral administratin. Hydrxy-dabrafenib terminal half-life (10 hurs) parallels that f dabrafenib while the carbxy- and desmethyl-dabrafenib metablites exhibit lnger half-lives (21 t 22 hurs). The apparent clearance f dabrafenib is 17.0 L/h after single dsing and 34.4 L/h after 2 weeks f twice-daily dsing. Fecal excretin is the majr rute f eliminatin accunting fr 71% f radiactive dse while urinary excretin accunted fr 23% f ttal radiactivity as metablites nly. Specific Ppulatins Age, Bdy Weight, and Gender: Based n the ppulatin pharmackinetics analysis, age has n effect n dabrafenib pharmackinetics. Pharmackinetic differences based n gender and n weight are nt clinically relevant. Pediatric: Pharmackinetics f dabrafenib has nt been studied in pediatric patients. Renal Impairment: N frmal pharmackinetic trial in patients with renal impairment has been cnducted. The pharmackinetics f dabrafenib were evaluated using a ppulatin analysis in 233 patients with mild renal impairment (GFR 60 t 89 ml/min/1.73 m 2 ) and 30 patients with mderate renal impairment (GFR 30 t 59 ml/min/1.73 m 2 ) enrlled in clinical trials. Mild r mderate renal impairment has n effect n systemic expsure t dabrafenib and its metablites. N data are available in patients with severe renal impairment. Hepatic Impairment: N frmal pharmackinetic trial in patients with hepatic impairment has been cnducted. The pharmackinetics f dabrafenib was evaluated using a ppulatin analysis in 65 patients with mild hepatic impairment enrlled in clinical trials. Mild hepatic impairment has n effect n systemic expsure t dabrafenib and its metablites. N data are available in patients with mderate t severe hepatic impairment. Drug Interactins Effect f Strng Inhibitrs f CYP3A4 r CYP2C8 n Dabrafenib: In vitr studies shw that dabrafenib is a substrate f CYP3A4 and CYP2C8 while hydrxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Cadministratin f dabrafenib 75 mg twice daily and ketcnazle 400 mg nce daily (a strng CYP3A4 inhibitr) fr 4 days increased dabrafenib AUC by 71%, hydrxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. Cadministratin f dabrafenib 75 mg twice daily and gemfibrzil 600 mg twice daily (a strng CYP2C8 inhibitr) fr 4 days increased dabrafenib AUC by 47%, with n change in the AUC f dabrafenib metablites.

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