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.

Safety Profile

Adverse Reactions—Adjuvant and Metastatic

Well-characterized safety profile based on phase 3 data1,2

Adverse reactions occurring in ≥20% (all grades) of patients in COMBI-d, COMBI-v, and COMBI-ADa

TAFINLAR + MEKINIST adverse reactions TAFINLAR + MEKINIST adverse reactions

aAdverse reactions occurring in ≥20% (all grades) of patients treated with TAFINLAR + MEKINIST in COMBI-d. This table comprises the original analyses but does not include data from the 3-year landmark analysis, where the safety profile was found to be similar to previous reports for TAFINLAR + MEKINIST, with no additional unexpected toxicities. bNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4. cGrade 4 adverse reactions include 3 patients in the pooled combination arm (headache, hemorrhage [hepatic hematoma and duodenal ulcer]) and 2 patients in the vemurafenib arm (hypertension, constipation); each n=1. dIncludes the following terms: peripheral edema, edema, lymphedema, localized edema, and generalized edema. eIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculopapular rash, and folliculitis rash. fIncludes pyrexia and hyperpyrexia. gIncludes fatigue, asthenia, and malaise. hIncludes headache and tension headache. iIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain. jIncludes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular.

Discontinuation Rates—Adjuvant

Discontinuations, dose reductions, and dose interruptions for TAFINLAR1

  • Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most common for each were pyrexia and chills

Discontinuations, dose reductions, and dose interruptions for MEKINIST2

  • Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most common for each were pyrexia and chills 
  • Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most common were pyrexia and ejection fraction decrease 

Discontinuation Rates—Metastatic

Two phase 3 clinical studies evaluating TAFINLAR + MEKINIST reported a consistent rate of discontinuation due to adverse reactions1-3

  • 11% discontinuation rate in COMBI-d (n=209)
  • 13% discontinuation rate in COMBI-v (n=350)

Adverse reactions in COMBI-d leading to dose modifications of TAFINLAR1

  • Most common adverse reaction resulting in permanent discontinuation of TAFINLAR was pyrexia (1.9%) 
  • Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients
    • Most commonly cited reasons for dose reductions were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%) 
  • Adverse reactions leading to dose interruptions of TAFINLAR occurred in 56% of patients
    • Most commonly cited reasons for dose interruptions were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%) 

Adverse reactions in COMBI-d leading to dose modifications of MEKINIST2

  • Most common adverse reactions resulting in permanent discontinuation of MEKINIST were pyrexia (1.4%) and decreased ejection fraction (1.4%) 
  • Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients
    • Most commonly cited reasons for dose reductions were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%)  
  • Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients
    • Most commonly cited reasons for dose interruptions were pyrexia (18%), chills (7%), vomiting (6%), and decreased ejection fraction (4.8%)

Strategies for Managing Pyrexia

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

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

ALL TREATMENTS FOR ADVANCED MELANOMA MAY CAUSE PYREXIA WITH VARYING FREQUENCY1-16

Pyrexia occurring in patients taking TAFINLAR + MEKINIST in COMBI-AD, COMBI-d, and COMBI-v16-21

TAFINLAR + MEKINIST and pyrexia TAFINLAR + MEKINIST and pyrexia
  • 1 out of 994 patients experienced grade 4 pyrexia17,18
  • 6% of patients discontinued TAFINLAR + MEKINIST due to pyrexia19,20
  • Fever occurred no more than 2 times in 53% of patients receiving TAFINLAR + MEKINIST16
  • The median duration of fever was 3 days21
  • The median time to onset of first occurrence of fever was 28 days21

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

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

Recommended dose modifications for pyrexia1,2

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

Patient counseling

  • Inform patients that fever is common during treatment with TAFINLAR + MEKINIST but may also be serious. When taking TAFINLAR + MEKINIST, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever
  • Advise patients to tell their health care provider right away if they get a fever during treatment with TAFINLAR + MEKINIST

ADMINISTER ANTIPYRETICS OR CORTICOSTEROIDS DEPENDING ON EPISODE AND SEVERITY1,2

  • Administer acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) 
    • As secondary prophylaxis when resuming TAFINLAR if patient had a prior episode of severe febrile reaction or fever associated with complications
  • Administer corticosteroids
    • For at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia. For pyrexia associated with complications such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection
  • Monitor renal function during and following severe pyrexia and monitor serum creatinine and other evidence of renal function during and following severe pyrexia

Learn about the incidence of pyrexia with TAFINLAR + MEKINIST and strategies for managing it.

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

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 3. Data on file. Clinical study report. MEK116513. Novartis Pharmaceuticals Corp; 2015. 4. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. 5. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 6. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 7. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 8. Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2018. 9. Sylatron [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2015. 10. Proleukin [prescribing information]. Vevey, Switzerland: Prometheus Laboratories Inc; 2012. 11. Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2018. 12. Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2018. 13. Intron A [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2018. 14. Imlygic [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2017. 15. Dacarbazine [prescribing information]. Lake Forest, IL: Hospira, Inc; 2016. 16. Data on file. BRF113928/BRF115532/MEK116513/ MEK115306 Summary of Characteristics of Pyrexia as a Single Preferred Term. Novartis Pharmaceuticals Corp. 2018. 17. Data on file. T1403010311. Novartis Pharmaceuticals Corp. 2018. 18. Data on file. MEK115306 and MEK116513 Characteristics PT Pyrexia. Novartis Pharmaceuticals Corp. 2018. 19. Data on file. COMBI-AD CSR BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp. 2018. 20. Data on file. COMBI-d/v CSR Summary of Clinical Safety. Novartis Pharmaceuticals Corp. 2018. 21. Data on file. BRF113928/BRF115532/MEK116513/ MEK115306 Summary of Onset and Duration of the First Occurrence of Pyrexia as a Single Preferred Term. Novartis Pharmaceuticals Corp. 2018.

INDICATIONS

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

TAFINLAR, in combination with MEKINIST, is indicated for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.

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