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.

Efficacy—Metastatic

Study Designs and Patient Characteristics

TAKE ADVANTAGE OF FIRST-LINE TAFINLAR + MEKINIST: IMPROVED SURVIVAL DEMONSTRATED ACROSS THE MOST EXTENSIVE CLINICAL EVIDENCE FOR COMBINATION TARGETED THERAPY IN PATIENTS WITH BRAF V600E/K MUTATIONS1-6

 

TAFINLAR® (dabrafenib) capsules + MEKINIST® (trametinib) tablets was studied in first-line treatment for patients with BRAF V600E/K mutations in 2 phase 3 clinical trials1,2,7,8

TAFINLAR + MEKINIST study design TAFINLAR + MEKINIST study design

DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
aDefined as the time from randomization until radiologic or photographic disease progression or death from any cause.7 bDefined as time from randomization to death from any cause.8

TAFINLAR + MEKINIST was studied in patients with a wide range of characteristics

BROAD PATIENT TYPES IN THE TAFINLAR + MEKINIST ARMS STUDIED ACROSS 2 PHASE 3 TRIALS7,8

TAFINLAR + MEKINIST patient characteristics TAFINLAR + MEKINIST patient characteristics

LDH, lactate dehydrogenase; ULN, upper limit of normal.

  • No patients with stage IIIB disease were included in COMBI-d or COMBI-v7,8

Primary Analysis—Overall Survival and Progression-Free Survival

 

PFS and OS results from COMBI-d and COMBI-v1,2,7-12

Primary analysis of COMBI-d and COMBI-v studies in TAFINLAR + MEKINIST Primary analysis of COMBI-d and COMBI-v studies in TAFINLAR + MEKINIST

DOR, duration of response; HR, hazard ratio; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
aDefined as the time from randomization until radiologic or photographic disease progression or death from any cause.7,11 bPrimary PFS analysis in COMBI-d was conducted in August 2013 with median follow-up of 9 months (range, 0-16) after 211 events (50%). The study was continued without crossover to preserve the integrity of the OS analysis.1,7,9 cFirst OS analysis in COMBI-d was an interim analysis conducted in August 2013 after 95 events (22%) at the time of prespecified primary PFS analysis. Results did not cross the prespecified efficacy-stopping boundary (P<.00028) and the study was continued.9 dFinal OS analysis in COMBI-d was completed in January 2015 after 222 events (52%). Patients will continue to be followed until death, withdrawal of consent, loss to follow-up, or when they have had at least 5 years of follow-up.7,11 ePer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.11 fDefined as time from randomization to death from any cause.8 gCOMBI-v was stopped early by the Independent Data Monitoring Committee after the preplanned interim analysis (222 events; 32%) conducted in April 2014 showed OS results that crossed the prespecified efficacy stopping boundary (P<.0214), at which point the interim analysis became final. Patients will continue to be followed until death, withdrawal of consent, loss to follow-up, or have had at least 5 years of follow-up.8,12 hPer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.12

5-Year Pooled Analysis—Overall Survival and Progression-Free Survival

Long-term outcomes in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma

THE FIRST AND ONLY TARGETED COMBINATION THERAPY WITH 5-YEAR OVERALL SURVIVAL DATA13-16

A pooled analysis of COMBI-d and COMBI-v at 5 years13

TAFINLAR + MEKINIST study overviews for 5-year analysis
  • The pooled population consisted of 563 first-line patients with BRAF V600E/K-mutant unresectable or metastatic melanoma
  • All patients in the analysis had been randomized to receive TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily in either COMBI-d or COMBI-v
  • Median follow-up was 22 months (range, 0-76)

Results at 5 years were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error.

An updated analysis of the most extensive phase 3 clinical trial program in BRAF+ advanced melanoma across combination targeted therapies An updated analysis of the most extensive phase 3 clinical trial program in BRAF+ advanced melanoma across combination targeted therapies

LANDMARK 5-YEAR DATA

In the pooled analysis of the intention-to-treat population in COMBI-d and COMBI-v

More than 1 in 3 patients were alive at 5 years with TAFINLAR + MEKINIST treatment More than 1 in 3 patients were alive at 5 years with TAFINLAR + MEKINIST treatment
  • 34% of patients taking TAFINLAR + MEKINIST were alive at 5 years (N=563, 95% Cl, 30-38)
  • In COMBI-d, 32% of patients taking TAFINLAR + MEKINIST (n=211) were alive at 5 years vs 27% of patients taking TAFINLAR + placebo (n=212)
  • In COMBI-v, 36% of patients taking TAFINLAR + MEKINIST (n=352) were alive at 5 years vs 23% of patients taking vemurafenib (n=352)
  • Landmark analyses are not meant to represent event-driven analyses
  • Crossover was permitted after the final overall survival (OS) analysis in COMBI-d and after an interim OS analysis demonstrating significant benefit in COMBI-v
  • No censoring was performed for crossover patients for OS

Nearly 1 in 5 patients were alive and progression free at 5 years with TAFINLAR + MEKINIST treatment Nearly 1 in 5 patients were alive and progression free at 5 years with TAFINLAR + MEKINIST treatment
  • 19% of patients taking TAFINLAR + MEKINIST were progression free and alive at 5 years (N=563, 95% CI, 15-22)
  • In COMBI-d, 17% of patients taking TAFINLAR + MEKINIST (n=211) were progression free and alive at 5 years vs 13% of patients taking TAFINLAR + placebo (n=212)
  • In COMBI-v, 20% of patients taking TAFINLAR + MEKINIST (n=352) were progression free and alive at 5 years vs 9% of patients taking vemurafenib (n=352)
  • For progression-free survival (PFS) analysis, patients were censored at the last adequate assessment prior to any new anticancer therapy; therefore, patients who crossed over from monotherapy arms were censored prior to starting TAFINLAR + MEKINIST

Results at 5 years were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error.

Overall Survival in Low Tumor Burden Patients

TAFINLAR + MEKINIST: AN ESTABLISHED THERAPY OFFERING DURABLE OVERALL SURVIVAL AT 5 YEARS13

More than half of patients with low tumor burden were alive at 5 years in the pooled analysis of COMBI-d and COMBI-v (n=216)13

  • Low tumor burden is defined as baseline lactate dehydrogenase (LDH) ≤ upper limit of normal and fewer than 3 organ sites with metastasis

Chart showing overall survival in low tumor burden patients Chart showing overall survival in low tumor burden patients

NOTE: Elevated LDH levels have been shown to be a predictor of poor outcome in patients with advanced melanoma.17 It is unknown whether data suggesting better outcomes in the subgroup of patients with normal LDH at baseline compared with all patients treated with TAFINLAR + MEKINIST are a result of their underlying disease status and prognosis or a treatment effect. Further prospective controlled studies are necessary to determine whether baseline LDH is a predictor of PFS and OS in patients treated with TAFINLAR + MEKINIST.

  • Results at 24, 36, 48, and 60 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

Overall Response Rates

RAISE YOUR EXPECTATIONS: A CHANCE FOR A COMPLETE RESPONSE

Overall Response Rate = Complete Response Rate + Partial Response Rate

Chart showing complete response and disease control rate for COMBI-d and COMBI-v studies Chart showing complete response and disease control rate for COMBI-d and COMBI-v studies

CR, complete response; DCR, disease control rate; PR, partial response; SD, stable disease.

  • In the primary analysis for COMBI-d, complete response (CR) for patients taking TAFINLAR + MEKINIST was 10%, partial response (PR) was 56%, and stable disease (SD) was 26%, for a total disease control rate (DCR) of 92%. For patients taking TAFINLAR monotherapy, CR was 9%, PR was 43%, and SD was 33%, for a total DCR of 85%9
  • In the interim analysis for COMBI-v, CR for patients taking TAFINLAR + MEKINIST was 13%, PR was 51%, and SD was 26%, for a total DCR of 90%. For patients taking vemurafenib, CR was 8%, PR was 44%, and SD was 30%, for a total DCR of 82%
  • DCR is defined as CR+PR+SD. SD is not a component of overall response rate and can reflect the natural progression of disease rather than a direct therapeutic effect18

NEARLY 1 IN 5 PATIENTS HAD A COMPLETE RESPONSE IN THE POOLED ANALYSIS OF COMBI-d AND COMBI-v (n=561)13*

19% CR in patients with CR at 5 years led to 71% OS 19% CR in patients with CR at 5 years led to 71% OS

*Two patients are excluded from this analysis because they had no measurable disease at baseline.13

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 3. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. 4. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 5. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 6. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 7. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. 8. 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. 9. 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. 10. Data on file. Clinical study report. MEK115306. Novartis Pharmaceuticals Corp; 2016. 11. Supplement to: Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. 12. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; January 15, 2015. 13. 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.] 14. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315-1327. 15. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. Published online March 21, 2018. Accessed May 23, 2019. 16. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. 17. Palmer S, Erickson L, Ichetovkin I, et al. Circulating serologic and molecular biomarkers in malignant melanoma. Mayo Clin Proc. 2011;86(10):981-990. 18. Hickey R, Vouche M, Sze D, et al. Cancer concepts and principles: primer for the interventional oncologist-part 1. J Vasc Interv Radiol. 2013;24(8):1157-1164.

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.