For:
Metastatic Non-Small Cell Lung Cancer (NSCLC) With BRAF V600E Mutation
Important Safety Information

New Primary Malignancies. Cutaneous Malignancies: Across clinical trials of TAFINLAR® (dabrafenib) capsules administered with MEKINIST® (trametinib) tablets (“the combination”), the incidence of cu...

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Indication TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.

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

Safety Profile

Adverse Reactions

TAFINLAR + MEKINIST SAFETY PROFILE BASED ON PHASE 2 NSCLC DATA

Adverse reactions occurring in ≥20% (all grades) of patients treated with TAFINLAR® (dabrafenib) capsules + MEKINIST® (trametinib) tablets1,2

 

Metastatic NSCLC
(n=93)

Adverse reactions   All grades,a % Grades 3/4, %   
General disorders and administrative site conditions        
Pyrexia   55 5  
   
Chills   23 1.1  
   
Peripheral edemab   28 0  
   
Fatiguec   51 5  
Gastrointestinal disorders        
Nausea   45 0  
   
Diarrhea   32 2.2  
   
Decreased appetite   29 0  
   
Vomiting   33 3.2  
Respiratory, thoracic, and mediastinal disorders        
Cough   22 0  
   
Dyspnea   20 5  
Skin and subcutaneous tissue disorders        
Dry skin   31 1.1  
   
Rashd   28 3.2  
Vascular disorders        
Hemorrhagee   23 3.2  

 
aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.
bIncludes peripheral edema, edema, and generalized edema.
cIncludes fatigue, malaise, and asthenia.
dIncludes rash, rash generalized, rash papular, rash macular, rash maculo papular, and rash pustular.
eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

 

Treatment-Emergent Laboratory Abnormalities

Treatment-emergent laboratory abnormalities occurring at ≥20% (all grades) of patients receiving TAFINLAR + MEKINIST1,2

 

Metastatic NSCLC
(n=93)

    All grades,b % Grades 3/4, %   
Hematologya        
Leukopenia   48 8  
   
Anemia   46 10  
   
Neutropenia   44 8  
   
Lymphopenia   42 14  
Liver function testsb        
Increased blood alkaline phosphatase   64 0  
   
Increased AST   61 4.4  
   
Increased ALT   32 6  
Chemistryb        
Hyperglycemia   71 9  
   
Hyponatremia   57 17  
   
Hypophosphatemia   36 7  
   
Increased creatinine   21 1.1  

ALT, alanine aminotransferase; AST, aspartate aminotransferase; NSCLC, non-small cell lung cancer.
aFor these laboratory tests the denominator is 91.
bFor these laboratory tests the denominator is 90.

 

Discontinuation Rates

PERCENTAGES OF PATIENTS WHOSE DOSE OF TAFINLAR + MEKINIST WAS DISCONTINUED, REDUCED, OR INTERRUPTED DUE TO ADVERSE REACTIONS

TAFINLAR

  • 18% TAFINLAR discontinuation rate due to adverse reactions; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%)1
  • Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients receiving TAFINLAR + MEKINIST; the most common were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%)1
  • Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most common were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%)1

MEKINIST

  • 19% MEKINIST discontinuation rate due to adverse reactions; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%)2
  • Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients receiving MEKINIST + TAFINLAR; the most common were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia (3.2%)2
  • Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients receiving MEKINIST + TAFINLAR; the most common were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and ejection fraction decreased (5%)2

Incidence of Pyrexia

ACROSS CLINICAL TRIALS, PYREXIA WAS THE MOST COMMON ADVERSE REACTION OBSERVED WITH TAFINLAR + MEKINIST

In patients treated with combination therapy across the metastatic melanoma clinical studies, fever occurred in 54% of patients receiving TAFINLAR with MEKINIST. Serious febrile reactions or 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.1,2

Incidence of pyrexia in the NSCLC study (N=93)1-3

  • 55% of patients experienced pyrexia

Incidence of pyrexia in metastatic NSCLC with TAFINLAR + MEKINIST

Pyrexia occurred in patients taking TAFINLAR + MEKINIST in the NSCLC study

 

  • No patients experienced grade 4 pyrexia
  • 2.2% of patients discontinued TAFINLAR + MEKINIST due to pyrexia

In patients receiving the combination who experienced fever3

Instances, duration, and time to first occurrence of pyrexia in metastatic NSCLC with TAFINLAR + MEKINIST

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

 

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

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 3. Data on file. CDRB436E2201 Interim clinical study report. Novartis Pharmaceuticals Corp; 2017.

 

INDICATION

TAFINLAR® (dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.

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

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 EventsAcross 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)/PneumonitisAcross 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 NSCLC clinical trial, the most commonly occurring adverse reactions (≥20%) in patients receiving the combination were pyrexia (55%), fatigue (51%), nausea (45%), vomiting (33%), diarrhea (32%), dry skin (31%), decreased appetite (29%), edema (28%), rash (28%), chills (23%), hemorrhage (23%), cough (22%), and dyspnea (20%). The most common grade 3 or 4 adverse reactions (incidence ≥2%) were pyrexia (5%), fatigue (5%), dyspnea (5%), hemorrhage (3.2%), rash (3.2%), vomiting (3.2%), and diarrhea (2.2%).

Other Clinically Important Adverse Reactions. The other clinically important adverse reactions observed in ≤10% of patients with NSCLC receiving the combination were pancreatitis and tubulointerstitial nephritis.

Laboratory Abnormalities. In the NSCLC clinical trial, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were hyperglycemia (71%), increased blood alkaline phosphatase (64%), increased aspartate aminotransferase (AST) (61%), hyponatremia (57%), leukopenia (48%), anemia (46%), neutropenia (44%), lymphopenia (42%), hypophosphatemia (36%), increased alanine aminotransferase (ALT) (32%), and creatinine (21%). The most common grade 3 or 4 laboratory abnormalities (incidence ≥10%) were hyponatremia (17%), lymphopenia (14%), and anemia (10%).

Please see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.