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. MEKINIST is not indicated for treatment of patients who have progressed on prior BRAF-inhibitor therapy.

Efficacy—Metastatic

Study Designs and Patient Characteristics

Take advantage of a therapy indicated and approved for first-line treatment

TAFINLAR® (dabrafenib) capsules + MEKINIST® (trametinib) tablets was studied in first-line treatment for patients with BRAF V600E/K mutations in 2 phase 3 clinical trials1-4

DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.  aDefined as the time from randomization until radiologic disease progression or death from any cause.3 bDefined as time from randomization to death from any cause.4

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

BROAD PATIENT TYPES STUDIED ACROSS 2 PHASE 3 TRIALS3,4

TAFINLAR + MEKINIST patient types TAFINLAR + MEKINIST patient types

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

  • No patients with stage IIIB disease were included in COMBI-d or COMBI-v3,4

Overall Survival and Progression-free Survival

TAKE ADVANTAGE OF FIRST-LINE TAFINLAR + MEKINIST: EXTENSIVE EVIDENCE FOR IMPROVED SURVIVAL ACROSS 2 PHASE 3 TRIALS IN PATIENTS WITH BRAF V600E/K MUTATIONS1-4,9-16

PFS and OS results from COMBI-d1-3,10-12

Overall survival and progression-free survival with TAFINLAR + MEKINIST Overall survival and progression-free survival with TAFINLAR + MEKINIST

CI, confidence interval; HR, hazard ratio; NA, not applicable; NR, not reached; OS, overall survival; PFS, progression-free survival. aPrimary 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.1,3,10 bFirst 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 cUpdated PFS analysis in COMBI-d was conducted in January 2015 after 301 events (71%) as part of the prespecified final OS analysis. 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.3,16 ePer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.3 fThis analysis included all living patients with ≥36 months of follow-up from date of randomization.

  • In 3-year analyses of COMBI-d and COMBI-v
    • No formal statistical testing was planned9,13*
    • Both were based on intent-to-treat principle, by which any crossover benefit was applied to the randomized monotherapy arm estimates9,13
  • Crossover in COMBI-d was prohibited until the final analysis (January 2015)
  • By the cutoff date (February 2016), 25 patients had crossed over from the TAFINLAR group into the TAFINLAR + MEKINIST arm14
  • Presentation of 3-year efficacy data are not meant to suggest that this represents the overall efficacy of TAFINLAR + MEKINIST relative to TAFINLAR. These data were presented to highlight the survival benefit at this particular time point for the first-line treatment of patients with BRAF V600E/K mutation-positive melanoma

*Landmark analyses are not meant to represent event-driven analyses.

PFS and OS results from COMBI-v1,4,9,15

TAFINLAR + MEKINIST PFS and OS results from COMBI-v TAFINLAR + MEKINIST PFS and OS results from COMBI-v

HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival. aCOMBI-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.4,16 bUpdated OS analysis in COMBI-v was conducted in March 2015 after 349 events (50%). Nineteen patients in the vemurafenib arm had crossed over to receive TAFINLAR + MEKINIST, which may affect the median OS of vemurafenib.15 cPer study protocol, at least 5 years of follow-up were planned unless death, withdrawal of consent, or loss to follow-up occurred.

  • Crossover in COMBI-v was permitted after the preplanned interim overall survival analysis, when the prespecified stopping boundary (P<.0214) was crossed4
  • By the cutoff date (July 2016), 34 patients had crossed over from vemurafenib into the TAFINLAR + MEKINIST arm9

Overall Response Rates

BEST-OBSERVED DISEASE CONTROL RATE >90% ACROSS 2 PHASE 3 TRIALS9,14

3-YEAR DCRs for TAFINLAR + MEKINIST in COMBI-d and COMBI-v9,14

Disease control rates with TAFINLAR + MEKINIST Disease control rates with TAFINLAR + MEKINIST

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

  • In the 3-year analysis for COMBI-d, complete response (CR) for patients taking TAFINLAR monotherapy was 15%, partial response (PR) was 40%, and stable disease (SD) was 32% for a total disease control rate (DCR) of 87%14
  • In the 3-year analysis for COMBI-v for patients taking vemurafenib, CR was 12%, PR was 41%, and SD was 31% for a total DCR of 84%9
  • 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%10
  • 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%4
  • 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
  • Presentation of 3-year efficacy data is not meant to suggest that they represent the overall efficacy of TAFINLAR + MEKINIST relative to TAFINLAR. These data were presented to highlight the survival benefit at this particular time point for the first-line treatment of patients with BRAF V600E/K mutation-positive melanoma

Overall Survival in Low Tumor Burden Patients

IN COMBI-v, 70% OF PATIENTS WITH LOW TUMOR BURDEN WERE ALIVE AT 3 YEARS9

OS in patients with normal LDH and <3 organ sites with metastasis in COMBI-v (3-year analysis)9

Overall survival in low LDH patients with TAFINLAR + MEKINIST Overall survival in low LDH patients with TAFINLAR + MEKINIST

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

HR, hazard ratio; LDH, lactate dehydrogenase; NR, not reached; OS, overall survival; PFS, progression-free survival.

  • In the 3-year analyses of COMBI-v and COMBI-d
    • No formal statistical testing was planned for the 3-year analysis for COMBI-v9
    • Landmark analyses are not meant to represent event-driven analyses
    • In COMBI-v, by the cutoff date (July 2016), 34 patients had crossed over from vemurafenib into the TAFINLAR + MEKINIST arm
    • In COMBI-d, by the cutoff date (February 2016), 25 patients had crossed over from the TAFINLAR group into the TAFINLAR + MEKINIST arm
    • Analysis was based on intent-to-treat principle, by which any crossover benefit was applied to the randomized monotherapy arm estimates9

In patients with normal LDH, median overall survival was 41.8 months9

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 3. 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. 4. 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. 5. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. 6. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 7. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 8. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 9. Robert C, Karaszewska B, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib + trametinib in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Presented at: 2016 European Society for Medical Oncology Congress; October 7-11, 2016; Copenhagen, Denmark. 10. 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. COMBI-d median follow-up. Novartis Pharmaceuticals Corp, 2017. 12. Data on file. Clinical study report. MEK115306. Novartis Pharmaceuticals Corp; 2016. 13. Flaherty KT, Davies MA, Grob J, et al. Genomic analysis and 3-year efficacy and safety update of COMBI-d, a phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3, 2016; Chicago, IL. 14. Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639. 15. Robert C, Karaszewska B, Schachter J, et al. Two-year estimate of overall survival in COMBI-v, a randomized, open-label, phase 3 study comparing the combination of dabrafenib and trametinib vs vemurafenib as first-line therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. 16. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; January 15, 2015.

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. MEKINIST is not indicated for the treatment of patients who have progressed on prior BRAF-inhibitor therapy.

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. No dose modifications are required in patients who develop new primary cutaneous malignancies.

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 Melanoma. 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 MEKINIST and TAFINLAR 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 TAFINLAR 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 MEKINIST for up to 4 weeks, and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is <LLN. For symptomatic cardiomyopathy or persistent asymptomatic LV dysfunction of >20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose on the recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared with baseline.

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 the COMBI-d study, 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. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks.

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; for severe uveitis or iridocyclitis, interrupt TAFINLAR and treat as clinically indicated. Permanently discontinue TAFINLAR for persistent grade 2 or greater uveitis of >6 weeks duration.

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 Drug 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 and fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. About half of the patients on combination therapy who experienced pyrexia had 3 or more discrete episodes. 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.

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for fever higher than 104ºF. Withhold TAFINLAR and MEKINIST for any serious febrile reaction 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. Refer to the Prescribing Information for either agent for recommended dose modifications. 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 dehydration, hypotension, renal failure, or severe chills/rigors, 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. TAFINLAR and MEKINIST may be resumed at lower doses in patients with improvement or recovery from skin toxicity 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.

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 both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective nonhormonal contraception during treatment, and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their health care provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.

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.