For:
BRAF+ Advanced Melanoma or BRAF+ Melanoma Involving Lymph Nodes After Surgery
Important Safety Information

New Primary Malignancies. Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR wit...

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Indications TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

TAFINLAR, in combination with MEKINIST, is indicated 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.

Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma.

Safety Profile

Adverse Reactions—Adjuvant

AN ADJUVANT THERAPY WITH AN ESTABLISHED SAFETY PROFILE1,2

Adverse Reactions Occurring in ≥20% of Patients in the COMBI-AD Studya

TAFINLAR + MEKINIST adverse reactions in adjuvant therapy TAFINLAR + MEKINIST adverse reactions in adjuvant therapy

aNational Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. bIncludes pyrexia and hyperpyrexia. cIncludes fatigue, asthenia, and malaise. dIncludes headache and tension headache. eIncludes rash, rash maculopapular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. fIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain.

  • 26% of patients discontinued TAFINLAR® (dabrafenib) capsules + MEKINIST® (trametinib) tablets due to an adverse reaction, vs 3% with placebo alone3
    • 72% completed the scheduled 12-month treatment regimen (66% had dose interruptions and 38% had dose reductions due to AEs)4
  • The most common cause of discontinuation in the treatment arm was pyrexia (9%)4

Adverse Reactions—Metastatic

AN ESTABLISHED SAFETY PROFILE, WITH EXTENSIVE CLINICAL EVIDENCE

Adverse events in ≥20% of patients taking TAFINLAR + MEKINISTa

TAFINLAR + MEKINIST adverse reactions in metastatic melanoma TAFINLAR + MEKINIST adverse reactions in metastatic melanoma

NR, not reported in the Prescribing Information.
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4. bAdverse reactions occurring in ≥20% (all grades) of patients treated with TAFINLAR + MEKINIST in COMBI-d. This table comprises the original analyses. cGrade 4 adverse reactions include 3 patients in the pooled combination arm (headache, hemorrhage [hepatic hematoma and duodenal ulcer]) and the following events in the vemurafenib arm: hypertension, constipation, squamous-cell carcinoma.1,2,6 dIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculopapular rash, and folliculitis rash. eIncludes peripheral edema, edema, lymphedema, localized edema, and generalized edema.

  • In the primary analysis of COMBI-d and COMBI-v, 9% of patients and 13% of patients discontinued TAFINLAR + MEKINIST due to an adverse reaction, respectively6,7
    • In the combination group, pyrexia was the most common cause of discontinuation in COMBI-d; pyrexia and decreased ejection fraction were the most common causes of discontinuation in COMBI-v

Strategies for Managing Pyrexia

Across clinical trials pyrexia (fever) was the most common adverse reaction observed with TAFINLAR + MEKINIST1,2

  • In patients treated with combination therapy across the metastatic melanoma studies, serious febrile reactions and fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. Fever was complicated by severe chills/rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% in patients receiving the combination

ALL TREATMENTS FOR ADVANCED MELANOMA MAY CAUSE PYREXIA WITH VARYING FREQUENCY1,2,8-21

Pyrexia occurring in patients taking TAFINLAR + MEKINIST in COMBI-AD, COMBI-d, and COMBI-v21-26

TAFINLAR + MEKINIST and pyrexia TAFINLAR + MEKINIST and pyrexia
  • 1 of 994 patients experienced grade 4 pyrexia22,23
  • 6% of patients discontinued TAFINLAR + MEKINIST due to pyrexia24,25
  • Fever occurred no more than 2 times in 53% of patients receiving TAFINLAR + MEKINIST21
  • The median duration of fever was 3 days26
  • The median time to onset of first occurrence of fever was 28 days26

Grade 1: Temperature of 100.4°F to 102.2°F
Grade 2: Temperature of 102.3°F to 104°F
Grade 3: Temperature of >104°F for ≤24 hours
Grade 4: Temperature of >104°F for >24 hours

PYREXIA MAY BE MANAGED WITH DOSE INTERRUPTION AND DOSE MODIFICATIONS, GENERALLY ALLOWING TREATMENT TO RESUME

Recommended dose modifications for pyrexia1,2

Recommended TAFINLAR + MEKINIST dose modifications for pyrexia Recommended TAFINLAR + MEKINIST dose modifications for pyrexia

Patient counseling

  • Inform patients that fever is common during treatment with TAFINLAR + MEKINIST but may also be serious. When taking TAFINLAR + MEKINIST, 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
  • Advise patients to tell their health care provider right away if they get a fever during treatment with TAFINLAR + MEKINIST

ADMINISTER ANTIPYRETICS OR CORTICOSTEROIDS DEPENDING ON EPISODE AND SEVERITY1,2

  • Administer acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) 
    • As secondary prophylaxis when resuming TAFINLAR + MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications
  • Administer corticosteroids
    • 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
  • Monitor renal function during and following severe pyrexia and monitor serum creatinine and other evidence of renal function during and following severe pyrexia

LEARN ABOUT THE INCIDENCE OF PYREXIA WITH TAFINLAR + MEKINIST AND STRATEGIES FOR MANAGEMENT

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Click here for TAFINLAR + MEKINIST Dose Modifications for certain adverse reactions, including pyrexia.

Download a brochure to learn how to manage pyrexia in patients receiving TAFINLAR + MEKINIST.

Download a brochure to learn how to manage pyrexia in patients receiving TAFINLAR + MEKINIST.

Download

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 3. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. 4. Data on file. Clinical study report. BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp; October 12, 2017. 5. Robert C, Grob D, Stroyakovskiy B, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019 June 4. doi:10.1056/NEJMoa1904059. [Epub ahead of print.] 6. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. 7. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888. 8. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; 2015. 9. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. 10. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 11. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 12. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 13. Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2018. 14. Sylatron [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2015. 15. Proleukin [prescribing information]. Vevey, Switzerland: Prometheus Laboratories Inc; 2012. 16. Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2018. 17. Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2018. 18. Intron A [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2018. 19. Imlygic [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2017. 20. Dacarbazine [prescribing information]. Lake Forest, IL: Hospira, Inc; 2016. 21. Data on file. BRF113928/BRF115532/MEK116513/ MEK115306 Summary of Characteristics of Pyrexia as a Single Preferred Term. Novartis Pharmaceuticals Corp. 2018. 22. Data on file. T1403010311. Novartis Pharmaceuticals Corp. 2018. 23. Data on file. MEK115306 and MEK116513 Characteristics PT Pyrexia. Novartis Pharmaceuticals Corp. 2018. 24. Data on file. COMBI-AD CSR BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp. 2018. 25. Data on file. COMBI-d/v CSR Summary of Clinical Safety. Novartis Pharmaceuticals Corp. 2018. 26. Data on file. BRF113928/BRF115532/MEK116513/ MEK115306 Summary of Onset and Duration of the First Occurrence of Pyrexia as a Single Preferred Term. Novartis Pharmaceuticals Corp. 2018.

Indications

TAFINLAR® (dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.

TAFINLAR, in combination with MEKINIST, is indicated 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.

Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma.

Important Safety Information

New Primary Malignancies.

Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR with MEKINIST was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with MEKINIST who developed basal cell carcinoma, 2 experienced more than 1 occurrence (range: 1 to 3). Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma, and new primary melanoma occurred in 3% and 0.5% of patients receiving TAFINLAR with MEKINIST, respectively.

In the COMBI-AD study, cuSCC and new primary melanoma occurred in 1% and <1% of patients receiving TAFINLAR with MEKINIST, respectively.

Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy and for up to 6 months following discontinuation of TAFINLAR.

Noncutaneous Malignancies: In the COMBI-d study, noncutaneous malignancies occurred in 1.4% of patients receiving TAFINLAR with MEKINIST. In the COMBI-AD study, noncutaneous malignancies occurred in 1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.

Tumor Promotion in BRAF Wild-type Tumors. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of therapy.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the COMBI-d study, intracranial hemorrhage was fatal in 1.4% of patients receiving the combination. No fatal hemorrhagic events were observed in the COMBI-AD study.

Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR and MEKINIST for grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials with MEKINIST, colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively. Monitor patients closely for colitis and gastrointestinal perforations.

Venous Thromboembolism. In the COMBI-d study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of patients treated with the combination. In the COMBI-AD study, DVT and PE occurred in 2% of patients receiving TAFINLAR with MEKINIST.

Advise patients to immediately seek medical care if they develop symptoms of DVT or PE such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT or PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose.

Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the COMBI-d study, 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 treated with the combination and 2.9% of patients receiving single-agent TAFINLAR, and resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Development of cardiomyopathy resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%) in patients receiving the combination. In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption, reduction, or discontinuation in 2.4%, 0.5%, and 1.0% of patients, respectively. Cardiomyopathy resolved in 10 of 12 patients receiving the combination and in 3 of 6 patients receiving single-agent TAFINLAR.

In the COMBI-AD study, cardiomyopathy, defined as a decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >10% below screening, occurred in 3% of patients receiving TAFINLAR with MEKINIST and resulted in discontinuation, dose reduction, and dose interruption of drug in 0.2%, 1.6%, and 2.1% of patients, respectively. Cardiomyopathy resolved in 12 of 14 patients receiving TAFINLAR with MEKINIST.

Assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic left ventricular dysfunction of >20% from baseline that is below 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 ≤10% compared with baseline. For an asymptomatic absolute decrease in LVEF of ≥10% from baseline that is below the LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of >20% from baseline that is below LLN, permanently discontinue MEKINIST.

Ocular Toxicities.

Retinal Vein Occlusion (RVO): Across all clinical trials including MEKINIST, the incidence of RVO was 0.2%. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmologic evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO.

Retinal Pigment Epithelial Detachment (RPED): RPED can occur. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In clinical trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.

Perform ophthalmologic evaluation periodically, and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume MEKINIST at the same or a reduced dose. If no improvement after 3 weeks, resume at a reduced dose or permanently discontinue MEKINIST.

Uveitis: Uveitis occurred in 2% of patients treated with the combination across metastatic melanoma trials. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, and eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (ie, 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 uveitis improves to grade 0 or 1. Permanently discontinue TAFINLAR for persistent grade 2 or greater uveitis of >6 weeks.

Interstitial Lung Disease (ILD). In clinical trials of MEKINIST as a single agent, ILD or pneumonitis occurred in 2% of patients. In the COMBI-d study, 1.0% of patients treated with the combination developed pneumonitis. In the COMBI-AD study, <1% of patients treated with the combination developed pneumonitis.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

Serious Febrile Reactions. The incidence and severity of pyrexia are increased when the combination is used compared with TAFINLAR as a single agent.

In patients treated with the combination in the metastatic melanoma studies, the incidence of fever was 54% and serious febrile reactions or fever of any severity complicated by severe rigors or chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. About half of the patients taking combination therapy who experienced pyrexia had 3 or more discrete episodes. Fever was complicated by severe chills or rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% in patients receiving the combination.

Withhold TAFINLAR for temperature of ≥101.3ºF or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Withhold MEKINIST for a temperature of >104ºF 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. Upon resolution, resume at same or lower dose. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR and/or MEKINIST if the patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, 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 hypotension, severe rigors or chills, dehydration, or renal failure, and there is no evidence of active infection.

Serious Skin Toxicity. Across clinical trials of the combination in unresectable metastatic melanoma, serious skin toxicity occurred in 0.7% of patients.

In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving the combination. No serious or severe cases of skin toxicity occurred in patients treated with the combination. Reductions in the dose of MEKINIST were required in 5% of patients receiving the combination, and no patient required permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Withhold TAFINLAR and MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and MEKINIST at a lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and MEKINIST if skin toxicity has not improved within 3 weeks.

Hyperglycemia. In the COMBI-d study, 27% of patients with a history of diabetes receiving the combination and 13% of patients receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. The incidence of grade 3 and grade 4 hyperglycemia based on laboratory values was 5% and 0.5% of patients treated with the combination, respectively. For patients receiving single-agent TAFINLAR, 4.3% of patients had grade 3 hyperglycemia based on laboratory values and no patients had grade 4 hyperglycemia.

Monitor serum glucose levels upon initiation, and as clinically appropriate in patients with preexisting diabetes or hyperglycemia. Initiate or optimize antihyperglycemic 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. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryo-fetal Toxicity. TAFINLAR and MEKINIST can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective nonhormonal contraception during treatment, and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.

Most Common Adverse Reactions. In the COMBI-d and COMBI-v studies, the most common adverse reactions (≥20%) for the combination were pyrexia (54%), nausea (35%), rash (32%), chills (31%), diarrhea (31%), headache (30%), vomiting (27%), hypertension (26%), arthralgia (25%), peripheral edema (21%), and cough (20%). In the COMBI-d and COMBI-v studies, the most common grade 3 or 4 adverse reactions (≥2%) for the combination were hypertension (11%), pyrexia (5%), and hemorrhage (2%). In the COMBI-AD study, the most common adverse reactions (≥20%) for the combination were pyrexia (63%), fatigue (59%), nausea (40%), headache (39%), rash (37%), chills (37%), diarrhea (33%), vomiting (28%), arthralgia (28%), and myalgia (20%). The most common grade 3 or 4 adverse reactions (≥2%) for the combination were pyrexia (5%) and fatigue (5%).

Other Clinically Important Adverse Reactions. In the COMBI-d and COMBI-v studies, other clinically important adverse reactions observed in <10% of patients receiving the combination were pancreatitis, panniculitis, bradycardia, and rhabdomyolysis. In the COMBI-AD study, other clinically important adverse reactions observed in <20% of patients receiving the combination were blurred vision (6%), decreased ejection fraction (5%), and rhabdomyolysis (<1%).

Laboratory Abnormalities. In the COMBI-d and COMBI-v studies, treatment-emergent laboratory abnormalities occurring in ≥10% of patients receiving the combination were hyperglycemia (60%), increased aspartate aminotransferase (AST) (59%), increased blood alkaline phosphatase (49%), increased alanine aminotransferase (ALT) (48%), hypoalbuminemia (48%), neutropenia (46%), anemia (43%), hypophosphatemia (38%), lymphopenia (32%), hyponatremia (25%), and thrombocytopenia (21%). In the COMBI-AD study, treatment-emergent laboratory abnormalities occurring in ≥20% of patients receiving the combination were hyperglycemia (63%), increased AST (57%), increased ALT (48%), neutropenia (47%), hypophosphatemia (42%), increased blood alkaline phosphatase (38%), lymphopenia (26%), anemia (25%), and hypoalbuminemia (25%).

Please see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.