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.

Dosing & Administration

Recommended Dosing

At the starting dose, TAFINLAR + MEKINIST offers your patients the lowest pill burden of any oral melanoma therapy1-6

 

The only FDA-approved oral therapy for the treatment of both BRAF+ metastatic melanoma and adjuvant treatment of BRAF+ melanoma with lymph-node involvement following complete resection

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) dosing schedule

Capsules and tablet shown are not actual size.

Both TAFINLAR and MEKINIST should be taken at least 1 hour before or 2 hours after a meal
  • Do not take a missed dose of TAFINLAR® (dabrafenib) capsules within 6 hours of the next dose, or a missed dose of MEKINIST® (trametinib) tablets within 12 hours of next dose
  • Do not open, crush, or break TAFINLAR capsules
  • MEKINIST should be stored in the refrigerator between 36°F to 46°F (2°C-8°C). Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes
  • TAFINLAR should be stored at room temperature at 68°F-77°F (20°C-25°C); excursions permitted between 59°F and 86°F (15°C-30°C)
  • Keep TAFINLAR, MEKINIST, and all medicine out of the reach of children

Adjuvant Dosing:

  • Continue treatment with TAFINLAR + MEKINIST for a period of 12 months; or until disease recurrence or unacceptable toxicity occurs

Metastatic Dosing:

  • Treatment with TAFINLAR + MEKINIST should continue until disease progression or unacceptable toxicity occurs

 

Dose Reductions

The overall management of certain adverse reactions may require treatment interruption, dose reduction, or treatment discontinuation, depending on severity1,2

 

 

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) dose reductions

Recommended Dose Modifications

Severity of Adverse Reactiona TAFINLARb MEKINISTc
Hemorrhage
  • Grade 3
  Withhold MEKINIST
  • If improved, resume MEKINIST at lower dose
  • If not improved, permanently discontinue MEKINIST
  • Grade 4
  Permanently discontinue MEKINIST
New Primary Malignancies
  • Noncutaneous RAS mutation-positive malignancies
Permanently discontinue TAFINLAR Do not modify dose of MEKINIST
Venous Thromboembolism
  • Uncomplicated DVT or PE
Do not modify the dose of TAFINLAR Withhold MEKINIST for up to 3 weeks
  • If improved to grade 0/1, resume at a lower dose
  • If not improved, permanently discontinue
  • Life threatening PE
Permanently discontinue TAFINLAR Permanently discontinue MEKINIST
Cardiomyopathy
  • Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is below institutional LLN from pretreatment value
No dose adjustment recommended for TAFINLAR Withhold MEKINIST for up to 4 weeks
  • If improved to normal LVEF value, resume at a lower dose
  • If not improved to normal LVEF value, permanently discontinue
  • Symptomatic congestive heart failure
  • Absolute decrease in LVEF of greater than 20% from baseline that is below LLN
Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume at same dose  
  • Symptomatic cardiomyopathy
  • Absolute decrease in LVEF of greater than 20% from baseline that is below LLN
  Permanently discontinue MEKINIST
Ocular Toxicities
  • RPED
Do not modify the dose of TAFINLAR Withhold MEKINIST for up to 3 weeks
  • If improved, resume MEKINIST at same or lower dose
  • If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose
  • Retinal vein occlusion
Do not modify the dose of TAFINLAR Permanently discontinue MEKINIST
  • Uveitis (including iritis and iridocyclitis) that is mild or moderate but does not respond to ocular therapy
  • Severe uveitis
Withhold TAFINLAR for up to 6 weeks
  • If improved to grade 0/1, then resume at the same or at a lower dose
  • If not improved, permanently discontinue 
Do not modify the dose of MEKINIST
Pulmonary 
  • Interstitial lung disease/pneumonitis
Do not modify the dose of TAFINLAR Permanently discontinue MEKINIST
Febrile Drug Reaction
  • Fever of 101.3°F to 104°F
Withhold TAFINLAR until fever resolves. Then resume at the same or lower dose No dose adjustment recommended for MEKINIST
  • Fever higher than 104°F
  • Fever complicated by rigors, hypotension, dehydration, or renal failure
  • Withhold TAFINLAR until fever resolves, then resume at lower dose
Or
  • Permanently discontinue TAFINLAR
Withhold MEKINIST until fever resolves. Then resume MEKINIST at same or lower dose
Skin Toxicities
  • Intolerable grade 2
  • Grade 3 or 4
Withhold TAFINLAR for up to 3 weeks
  • If improved, resume at a lower dose
  • If not improved, permanently discontinue
Withhold MEKINIST for up to 3 weeks
  • If improved, resume at a lower dose
  • If not improved, permanently discontinue
  • Severe cutaneous adverse reactions
Permanently discontinue TAFINLAR Permanently discontinue MEKINIST
Other Adverse Reactionsc
  • Intolerable grade 2
  • Any grade 3
Withhold TAFINLAR
  • If improved to grade 0/1, then resume at a lower dose
  • If not improved, permanently discontinue
Withhold MEKINIST
  • If improved to grade 0/1, resume at a lower dose
  • If not improved, permanently discontinue
  • First occurrence of any grade 4
  • Withhold TAFINLAR until adverse reaction improves to grade 0/1. Then resume at a lower dose
Or
  • Permanently discontinue TAFINLAR
  • Withhold MEKINIST until adverse reaction improves to grade 0/1. Then resume at a lower dose
Or
  • Permanently discontinue
  • Recurrent grade 4
Permanently discontinue TAFINLAR Permanently discontinue MEKINIST

 

DVT, deep venous thromboembolism; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; PE, pulmonary embolism; RAS, noncutaneous monomeric G protein; RPED, retinal pigment epithelial detachment.

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. bDose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), RPED, interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies. cDose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: noncutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies.

 

NEXT: Mechanism of Action

 

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.

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.