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

New Primary Malignancies. Cutaneous Malignancies: Across clinical trials of TAFINLAR administered with MEKINIST (“the combination”), the incidence of cutaneous squamous cell carcinomas (cuSCCs), in...

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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 + MEKINIST was studied in first-line treatment for patients with BRAF V600E/K mutations in 2 phase 3 clinical trials1,2,7,8

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) 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

  • The pooled population consisted of 563 first-line patients with BRAF V600E/K-mutant unresectable or metastatic melanoma9
  • All patients in the analysis had been randomized to receive TAFINLAR® (dabrafenib) capsules 150 mg twice daily + MEKINIST® (trametinib) tablets 2 mg once daily in either COMBI-d or COMBI-v9
  • Median follow-up was 22 months (range, 0-76)9
  • Results at 5 years were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error9

 

An updated 5-year analysis of the most extensive phase 3 clinical trial program in BRAF+ advanced melanoma across combination targeted therapies

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

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

  • No patients with stage IIIB disease were included in COMBI-d or COMBI-v7,8
Most extensively studied combination targeted therapy in first-line unresectable or metastatic melanoma

Primary Analysis—Overall Survival and Progression-Free Survival

 

PFS and OS results from COMBI-d and COMBI-v1,2,7,8,10-12

 PFS and OS results from COMBI-d study
 PFS and OS results from COMBI-v study

DOR, duration of response; HR, hazard ratio; NA, not applicable; NR, not reached; 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.7,12 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.1,7,10 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.10 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.7,12 ePer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.12 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.8,13 hPer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.13

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 COMBINATION TARGETED THERAPY WITH 5-YEAR OS IN PHASE 3 CLINICAL TRIALS9,14-16

A pooled analysis of COMBI-d and COMBI-v at 5 years9

  • 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 to 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

 

In the intention-to-treat population of COMBI-d and COMBI-v at 5 years

51% of patients had <3 sites of metastasis and 65% of patients LDH ≤ ULN

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

 

  • In the pooled analysis of COMBI-d and COMBI-v, 38% of patients had low tumor burden (n=216/563)9*

*Low tumor burden is defined as baseline lactate dehydrogenase (LDH) ≤ upper limit of normal (ULN) and <3 organ sites with metastasis.9

  • In the overall intention-to-treat population (N=563), overall survival (OS) was 52%, 44%, 37% (95% CI, 33-42) and 34% (95% CI, 30-38) at 2, 3, 4, and 5 years, respectively9
    • 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)17
    • In COMBI-v, 36% of patients taking TAFINLAR + MEKINIST (n=352) were alive at 5 years vs 23% of patients taking vemurafenib (n=352)17
  • Landmark analyses are not meant to represent event-driven analyses
  • Crossover was permitted after the final OS analysis in COMBI-d and after an interim OS analysis demonstrating significant benefit in COMBI-v17
  • No censoring was performed for crossover patients for OS17
  • Results at 2, 3, 4, and 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

LANDMARK 5-YEAR DATA

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

OS (5-year pooled analysis)

At 5 years more than 1 in 3 patients were alive
  • 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 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

PFS (5-year pooled analysis)

At 5 years nearly 1 in 5 patients were alive and progression-free
  • 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 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 YEARS9

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)9

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

OS rates for patients with low tumor burden (n=216) in the 5-year pooled analysis of COMBI-d and COMBI-va

OS rates for patients with low tumor burden (n=216) in the 5-year pooled analysis of COMBI-d and COMBI-v

NOTE: Elevated LDH levels have been shown to be a predictor of poor outcome in patients with advanced melanoma.18 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.

aLow tumor burden is defined as baseline LDH ≤ ULN and fewer than 3 organ sites with metastasis.

  • 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
More than 1 in 2 patients were alive at 5 years

Overall Response Rates

RAISE YOUR EXPECTATIONS: A CHANCE FOR A COMPLETE RESPONSE AT 5 YEARS

Overall Response Rate = Complete Response Rate + Partial Response Rate

  • Disease control rate (DCR) is defined as complete response (CR) + partial response (PR) + stable disease (SD). SD is not a component of overall response rate and can reflect the natural progression of disease rather than a direct therapeutic effect19
TAFINLAR + MEKINIST complete response rate

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

  • In the primary analysis for COMBI-d, CR for patients taking TAFINLAR + MEKINIST was 10%, PR was 56%, and SD was 26%, for a total DCR of 92%. For patients taking TAFINLAR monotherapy, CR was 9%, PR was 43%, and SD was 33%, for a total DCR of 85%
  • 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%

NEARLY 1 IN 5 PATIENTS HAD A CR IN THE POOLED ANALYSIS OF COMBI-d AND COMBI-v (n=561)a

19% of patients had complete response at 5 years with 71% OS

 

CR, complete response; OS, overall survival.

a

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

  • In the pooled analysis of COMBI-d and COMBI-v (5-year analysis), CR for patients taking TAFINLAR + MEKINIST was 19%, PR was 49%, and SD was 23%, for a total DCR of 91%
  • In the primary analysis for COMBI-d, CR for patients taking TAFINLAR + MEKINIST was 10%, PR was 56%, and SD was 26%, for a total DCR of 92%. For patients taking TAFINLAR monotherapy, CR was 9%, PR was 43%, and SD was 33%, for a total DCR of 85%
  • 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 effect
  • 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

Long-Term Experience

TRUST THE TARGETED COMBINATION THERAPY WITH THE MOST EXTENSIVE EVIDENCE IN MELANOMA1-6,15,20-22

TAFINLAR + MEKINIST has been extensively studied in patients with BRAF mutations

Studied in more than 1,000 patients who were BRAF+ in 4 pivotal trials across 2 melanoma indications

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 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. Robert C, Grob D, Stroyakovskiy B, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-63610. 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. 11. Data on file. Clinical study report. MEK115306. Novartis Pharmaceuticals Corp; 2016. 12. 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. 13. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; January 15, 2015. 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. Supplement to: Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636. 18. Palmer S, Erickson L, Ichetovkin I, et al. Circulating serologic and molecular biomarkers in malignant melanoma. Mayo Clin Proc. 2011;86(10):981-990. 19. 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. 20. Long GV, Eroglu Z, Infante J, et al. Long-term outcomes in patients with BRAF V600–mutant metastatic melanoma who received dabrafenib combined with trametinib. J Clin Oncol. 2018;36(7):667-673. 21. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. 22. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatement for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395(10240):1835-1844.

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

Across clinical trials of TAFINLAR administered with MEKINIST (“the combination”), the incidence of cutaneous squamous cell carcinomas (cuSCCs), including keratoacanthomas, occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and <1% of patients, respectively. 

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

Noncutaneous Malignancies

Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of monomeric G protein (RAS) through mutation or other mechanisms. Across clinical trials of TAFINLAR monotherapy and the combination, noncutaneous malignancies occurred in 1% of patients.

Monitor patients receiving the combination for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for RAS-mutation–positive noncutaneous malignancies. No dose modification is required for MEKINIST in 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. Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with the combination. Fatal cases have been reported.

Across clinical trials of the combination, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received the combination. Intracranial hemorrhage occurred in 0.6% of patients who received the combination. Fatal hemorrhage occurred in 0.5% of patients who received the combination. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

Permanently discontinue TAFINLAR for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for grade 3 hemorrhagic events; if improved, resume at the next lower dose level. Permanently discontinue MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold 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 of the combination, colitis occurred in <1% of patients and gastrointestinal perforation occurred in <1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.

Venous Thromboembolic Events. Across clinical trials of the combination, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. 

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 MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. Across clinical trials of the combination, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and <1% of patients, respectively, and in 3% and <1% of patients receiving MEKINIST, respectively. Cardiomyopathy resolved in 45 of 50 patients who received the combination.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of the combination, 1 month after initiation, and 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 to baseline. For an asymptomatic absolute decrease in LVEF of 10% or greater 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): There were no cases of RVO across clinical trials of the combination. 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 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)/Pneumonitis. Across clinical trials of the combination, interstitial lung disease or pneumonitis occurred in 1% of patients.

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. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur. The incidence and severity of pyrexia are increased when TAFINLAR is administered with MEKINIST.

Across clinical trials of the combination, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients.

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 Toxicities. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with the combination. Across clinical trials of the combination, other serious skin toxicity occurred in <1% of patients. 

Monitor for new or worsening serious skin reactions. Permanently discontinue the combination for SCARs. For other skin toxicities, withhold TAFINLAR and/or MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and/or MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and/or MEKINIST if skin toxicity has not improved within 3 weeks.

Hyperglycemia. Across clinical trials of the combination, 15% of patients with a history of diabetes required more intensive hypoglycemic therapy. Grade 3 and grade 4 hyperglycemia occurred in 2% of patients.

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. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

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.

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%), rhabdomyolysis (<1%), and sarcoidosis (<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.