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.

Safety Profile

Adverse Reactions—Adjuvant

In COMBI-AD–For the adjuvant treatment of patients with BRAF V600E/K melanoma and involvement of lymph node(s), following complete resection

OFFER AN ADJUVANT THERAPY WITH AN ESTABLISHED SAFETY PROFILE1-3

Adverse reactions occurring in ≥20% of patients in the COMBI-AD study (as of June 30, 2017, data cutoff)1-3,a

TAFINLAR + MEKINIST adverse reactions in adjuvant therapy

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 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.

  • During the 5-year follow-up, updated safety analyses were not performed because no patients remained on therapy during the extended follow‐up period4

NEARLY ALL TREATMENT-RELATED ADVERSE EVENTS LEADING TO DISCONTINUATION RESOLVED UPON WITHDRAWAL5

In the TAFINLAR + MEKINIST treatment group of COMBI-AD:

Adverse Reactions—Metastatic

In the pooled analysis of COMBI-d and COMBI-v–For the first-line treatment of patients with BRAF V600E/K unresectable or metastatic melanoma

AMONG THE MOST COMMON ADVERSE EVENTS, FEW WERE GRADE 3 OR HIGHER6

Adverse reactions in ≥20% of patients taking TAFINLAR + MEKINIST2,3,6,7

TAFINLAR + MEKINIST adverse reactions in metastatic melanoma

NR, not reported in the Prescribing Information.
aNCI CTCAE, 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. 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.2,3,6

Most pyrexia-related events were mild to moderate in patients taking TAFINLAR + MEKINIST6

  • With TAFINLAR + MEKINIST, 4% of patients discontinued due to pyrexia7
  • There were no instances of grade 4 pyrexia in the COMBI-d/v trials8
Give patients the assurance of a well-established safety profile

Adverse Events Declined Over Time

In both adjuvant and metastatic settings, AEs occurred most frequently within 3 months of treatment initiation and decreased over the 12-month treatment period9

Adjuvant Setting

Patient exposure occurrences in an adjuvant setting

AE, adverse event; ALT, alanine aminotransferase. 
aExposure-adjusted AE occurrences were calculated per 3 months of patient exposure to TAFINLAR + MEKINIST. bSpecific AEs listed are those of any causality that occurred in ≥15% of patients treated with TAFINLAR + MEKINIST in COMBI-AD.

  • Exposure-adjusted all-cause adverse event (AE) occurrence rates per patient were highest during the initial 3 months of TAFINLAR + MEKINIST treatment and decreased substantially over the 12-month treatment period9
  • Dose reductions and interruptions were more commonly used than treatment discontinuation to manage AEs9
    • Pyrexia was the most common AE leading to discontinuation, dose reduction, or interruption
    • Other AEs that commonly led to dose modification were chills and fatigue

Metastatic Setting

Patient exposure occurrences in metastatic setting

AE, adverse event.
aExposure-adjusted AE occurrences were calculated per 3 months of patient exposure to TAFINLAR + MEKINIST. bSpecific AEs listed are those of any causality that occurred in ≥15% of patients treated with TAFINLAR + MEKINIST in COMBI-d and COMBI-v.

  • Exposure-adjusted all-cause AE occurrence rates per patient were highest during the initial 3 months of TAFINLAR + MEKINIST treatment and decreased substantially over the 12-month treatment period9
  • Dose reductions and interruptions were more commonly used than treatment discontinuation to manage AEs9
    • Pyrexia was the most common AE leading to discontinuation, dose reduction, or interruption
    • Other AEs that commonly led to dose modification were ejection fraction decrease and chills

Strategies for Managing Pyrexia

Across clinical trials, pyrexia (fever) was the most common adverse reaction observed with TAFINLAR + MEKINIST2,3

  • Across clinical trials of TAFINLAR administered with MEKINIST, 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 patients2,3

ALL TREATMENTS FOR ADVANCED MELANOMA MAY CAUSE PYREXIA WITH VARYING FREQUENCY2,3,10-21

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

  • In the 3 studies, 1 of 994 patients experienced grade 4 pyrexia22
Patients receiving the combination who experience pyrexia

Three simple steps toward pyrexia management2,3,a

Three simple steps toward pyrexia management

aSee the Prescribing Information for TAFINLAR and Prescribing Information for MEKINIST for additional details.

CLINICAL TRIAL RESULTS FOR PYREXIA-RELATED OUTCOMES USING THE UPDATED PYREXIA MANAGEMENT ALGORITHM

High-grade pyrexia and pyrexia-related events in clinical trials2,3,9,24,25

High-grade pyrexia and pyrexia-related events in clinical trials

aDehydration, hypotension, renal dysfunction, syncope, and severe chills.

 

The 12-month RFS was 88% (95% CI, 85%-91%) and 92% (95% CI, 89%-94%), respectively, in COMBI-AD and COMBI-APlus1,26,27

 

The simplified pyrexia management algorithm is shown to reduce the rates of pyrexia-related events

COMBI-APlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients who received TAFINLAR administered with MEKINIST in the adjuvant treatment of BRAF V600E/K mutation–positive melanoma after complete resection. The pyrexia management algorithm interrupted both TAFINLAR and MEKINIST when a patient’s temperature was ≥100.4°F.2,3,26

 

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.

References: 1. 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. 2. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 3. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. 4. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383(12):1139-1148. 5. Data on file. COMBI-AD Adverse Event Documentation. RITM2419303. Novartis Pharmaceuticals Corp; March 30, 2021. 6. 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. 7. 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. 8. Data on file. Clinical study report. MEK115306 & MEK116513. Novartis Pharmaceuticals Corp; March 13, 2015. 9. Data on file. Adverse event kinetics in patients treated with dabrafenib + trametinib in the metastatic and adjuvant setting. Novartis Pharmaceuticals Corp; 2019. 10. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2020. 11. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 12. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2020. 13. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2020. 14. Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2020. 15. Proleukin [prescribing information]. Vevey, Switzerland: Prometheus Laboratories Inc; 2019. 16. Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2020. 17. Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2020. 18. Intron A [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2016. 19. Imlygic [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2019. 20. Dacarbazine [prescribing information]. Lake Forest, IL: Hospira, Inc; 2018. 21. Tecentriq [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2020. 22. Data on file. BRF113928/BRF115532/MEK116513/MEK115306 Summary of Characteristics of Pyrexia as a Single Preferred Term. Novartis Pharmaceuticals Corp; 2018. 23. 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. 24. Data on file. Clinical study report. BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp; October 21, 2017. 25. Data on file. Pyrexia 2020. DRB436F2301. Novartis Pharmaceuticals Corp; January 2022. 26. Atkinson V, Robert C, Grob JJ, et al. Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event management algorithm in patients treated with adjuvant dabrafenib plus trametinib: primary results of COMBI-APlus. Eur J Cancer. 2022;163:79-87. 27. Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600–mutant stage III melanoma. J Clin Oncol. 2018;36(35):3441-3449.

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.

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 and MEKINIST for temperature of ≥100.4ºF. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Upon 24 hours after resolution, if appropriate, resume both TAFINLAR and MEKINIST at the same or a 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.