For:
BRAF V600E/K Mutation-Positive Unresectable or Metastatic Melanoma
Important Safety Information

New primary malignancies, cutaneous and noncutaneous, can occur. In the COMBI-d study, the incidence of cutaneous malignancies in patients receiving the combination vs TAFINLAR alone was: basal cel...

See More

Indication 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. 

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 received prior BRAF-inhibitor therapy.

Efficacy

Trial Designs

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma
CHOOSE A THERAPY WITH THE CLINICAL EVIDENCE TO SUPPORT FIRST-LINE USE IN PATIENTS WITH BRAF MUTATIONS

TAFINLAR + MEKINIST is supported by a robust body of evidence gathered from two phase 3 clinical trials vs BRAF-inhibitor monotherapy1,2

TAFINLAR(R) (dabrafenib) + MEKINIST(R) (trametinib) Study Designs

COMBI-d was a head-to-head, double-blind, randomized phase 3 study. Patients were randomly assigned to receive 150 mg TAFINLAR monotherapy twice daily + matching placebo (n=212) or 150 mg TAFINLAR twice daily + 2 mg MEKINIST once daily (n=211). The primary end point was investigator-assessed PFS, defined as the time from randomization until radiologic disease progression or death from any cause. Secondary end points included OS, overall response rate (ORR), duration of response (DOR), and safety.3

COMBI-v was a head-to-head, open-label, randomized phase 3 study. Patients were randomly assigned to receive 960 mg vemurafenib monotherapy twice daily (n=352) or 150 mg TAFINLAR twice daily + 2 mg MEKINIST once daily (n=352). The primary end point was OS, defined as the time from randomization to death from any cause. Secondary end points included PFS, ORR, DOR, and safety.4

Patient Characteristics

ALL PATIENTS IN PHASE 3 REGISTRATION TRIALS OF TAFINLAR + MEKINIST HAD RECEIVED NO PRIOR SYSTEMIC TREATMENT3,4

 TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Prior Therapy

For unresectable or metastatic disease. Prior systemic treatment in the adjuvant setting was allowed.

 

TAFINLAR + MEKINIST WERE EVALUATED BROADLY IN PATIENTS WITH NORMAL LDH AND GOOD PERFORMANCE STATUS

Range of baseline LDH levels and ECOG scores across phase 3 clinical trials1,2

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Patient Characteristics

ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status; ULN, upper limit of normal.

  • All other patients had ECOG PS 1

Overall Survival and Progression-free Survival

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma

SUPERIOR EFFICACY VS BRAF-INHIBITOR MONOTHERAPY ACROSS TWO PIVOTAL PHASE 3 CLINICAL TRIALS1-5

Median OS and PFS in 2 clinical trials 
TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Efficacy Overview

bInvestigator-assessed.
cIntention-to-treat population.
dPrimary 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.3,6
eFirst 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.6
fFinal PFS analysis in COMBI-d was conducted in January 2015 after 301 events (71%) as part of the prespecified final OS analysis.3
gFinal 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 have had at least 5 years of follow-up.3,7
hCOMBI-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.4,8
iUpdated OS analysis in COMBI-v was conducted in March 2015 after 349 events (50%). 19 patients in the vemurafenib arm had crossed over to receive TAFINLAR + MEKINIST, which may affect the median OS of vemurafenib.5 

 

Important Safety Information

New Primary Malignancies. New primary malignancies, cutaneous and noncutaneous, can occur.

Cutaneous Malignancies: In the COMBI-d study, the incidence of cutaneous malignancies in patients receiving TAFINLAR in combination with MEKINIST (the combination) compared with patients receiving TAFINLAR as a single agent was as follows: basal cell carcinoma 3.3% (7/209) vs 6% (13/211); cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma 3% vs 10%; new primary melanoma 0.5% (1/209) vs 1.9% (4/211).

The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8-23.9 months) in patients receiving the combination and 4.4 months (range: 29 days-16.5 months) in patients receiving TAFINLAR as a single agent. Among the 7 patients receiving the combination that developed basal cell carcinoma, 2 (29%) experienced more than 1 occurrence (range: 1-3).

The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8-16.8 months) in patients receiving the combination and 2 months (range: 9 days-20.9 months) in patients receiving TAFINLAR as a single agent.

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% (3/209) of patients who received the combination and in 2.8% (6/211) of patients who received TAFINLAR as a single agent. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for RAS-mutation-positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.

 

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma

TAFINLAR + MEKINIST DEMONSTRATED OVERALL SURVIVAL OF 25.1 MONTHS (MEDIAN)1-3

Median OS in COMBI-d (final analysis)1-3

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) COMBI-d Overall Survival

  • Final analysis: TAFINLAR + MEKINIST demonstrated a 29% reduction in the risk of death vs TAFINLAR (HR=0.71; 95% CI: 0.55-0.92; P=.01). The preplanned final OS analysis was conducted after 222 events (52%) and a median follow-up of 20 months1-3

  • Crossover was prohibited until the final OS analysis3

 

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma

TAFINLAR + MEKINIST DEMONSTRATED OS SUPERIORITY VS VEMURAFENIB IN A HEAD-TO-HEAD PHASE 3 TRIAL1,4,5

Median OS in COMBI-v (interim and updated analyses)1,4,5

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) COMBI-v Overall Survival

  • Interim analysis: TAFINLAR + MEKINIST demonstrated a 31% reduction in the risk of death vs vemurafenib (HR=0.69; 95% CI: 0.53-0.89; P=.005). The prespecified efficacy boundary (P<.0214) was crossed and the study was stopped early by the Independent Data Monitoring Committee, at which point the interim analysis became final. The preplanned interim OS analysis was conducted after 222 events (32%) and a median follow-up of 11 months1,4

  • Updated analysis: TAFINLAR + MEKINIST reduced the risk of death by 34% vs vemurafenib (HR=0.66; 95% CI: 0.53-0.81; P<.001). The updatd OS analysis was conducted after 349 events (50%) and a median follow-up of 19 months5

 

Important Safety Information

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase 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.

  

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma

TAFINLAR + MEKINIST SIGNIFICANTLY PROLONGED PFS VS TAFINLAR1-3,6

Median PFS in COMBI-d (investigator-assessed primary and final analyses)3,6,j

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) COMBI-d Progression-Free Survival

jCrossover was prohibited until the final OS analysis.3

  • Primary analysis: Median PFS for TAFINLAR + MEKINIST was 9.3 months (95% CI: 7.7-11.1) vs 8.8 months (95% CI: 5.9-10.9) for TAFINLAR (HR: 0.75; 95% CI: 0.57-0.99; P=.035). The primary analysis was conducted after 211 events (50%) and a median follow-up of 9 months1,2,6
  • Final analysis: Median PFS for TAFINLAR + MEKINIST was 11.0 months (95% CI: 8.0-13.9) vs 8.8 months (95% CI: 5.9-9.3) for TAFINLAR (HR: 0.67; 95% CI: 0.53-0.84; P=.0004). The final analysis was conducted after 301 events (71%) and a median follow-up of 20 months3

 

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma

TAFINLAR + MEKINIST SIGNIFICANTLY PROLONGED PFS VS VEMURAFENIB1,4,5

Median PFS in COMBI-v (investigator-assessed interim and updated analyses)1,4,5

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) COMBI-v Progression-Free Survival

  • Interim analysis: Median PFS for TAFINLAR + MEKINIST was 11.4 months (95% CI: 9.9-14.9) vs 7.3 months (95% CI: 5.8-7.8) for vemurafenib (HR: 0.56; 95% CI: 0.46-0.69; P<.001). The interim analysis was conducted after 383 events (54%) and a median follow-up of 11 months1,4
  • Updated analysis: Median PFS for TAFINLAR + MEKINIST was 12.6 months (95% CI: 10.7-15.5) vs 7.3 months (95% CI: 5.8-7.8) for vemurafenib (HR: 0.61; 95% CI: 0.51-0.73; P<.001). The updated analysis was conducted after 460 events (65%) and a median follow-up of 19 months5

 

Important Safety Information

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 compared with TAFINLAR as a single agent was 19% (40/209) vs 15% (32/211), respectively. Gastrointestinal hemorrhage occurred in 6% of 209 patients treated with the combination compared with 3% of 211 patients treated with TAFINLAR alone. Intracranial hemorrhage was fatal in 1.4% of 209 patients receiving the combination compared with no patients receiving TAFINLAR as a single agent.

Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events, and for any persistent grade 3 hemorrhagic events. Withhold the combination for grade 3 hemorrhagic events; if improved, resume at a lower dose.

 

Overall Response Rate

For the first-line treatment of patients with BRAF V600E/K mutation–positive unresectable or metastatic melanoma 
SIGNIFICANTLY MORE PATIENTS ACHIEVED OBJECTIVE RESPONSES WITH TAFINLAR + MEKINIST1-3,5

ORR in two phase 3 clinical trials (investigator-assessed)1-3,5,k

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Overall Response

kORRs were assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, for confirmed complete response (disappearance of all target lesions) and partial response (≥30% decrease from baseline in the sum of diameters of target lesions).1-4,9
lPrimary analysis of ORR in COMBI-d was conducted at the time of the primary PFS analysis.6
mFinal analysis of ORR in COMBI-d was conducted at the time of the prespecified final OS analysis. Best response included patients who had measurable disease at baseline (n=210 in each arm).3
nInterim analysis of ORR in COMBI-v was conducted with 11-month median follow-up at the time of the prespecified interim OS analysis.4
oUpdated analysis of ORR in COMBI-v was conducted with 19-month median follow-up at the time of the updated OS analysis. Best response included patients who had measurable disease at baseline (n=351 in the combination arm; n=350 in the vemurafenib arm).5
CR, complete response; PR, partial response.

 

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Objective Response by RECIST

 

 

Duration of Response

For the first-line treatment of patients with BRAF V600E/K mutationpositive unresectable or metastatic melanoma 
TAFINLAR + MEKINIST PRODUCED DURABLE RESPONSES OF UP TO 13.8 MONTHS (MEDIAN)1-3,5

Median DOR in two phase 3 clinical trials (investigator-assessed)1-3,5,p 

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Duration of Response

pDOR was assessed by the investigators as time from first documented RECIST objective response (v1.1) to progression or death due to any cause.3,4
q60% of investigator-assessed responses were ongoing at the time of the primary analysis of DOR in COMBI-d. These ongoing responses were censored at the primary analysis.6

rFinal analysis of DOR in COMBI-d included all responding patients (144 for TAFINLAR + MEKINIST and 113 for TAFINLAR monotherapy) at the time of the prespecified final OS analysis.3
sInterim analysis of DOR in COMBI-v was conducted with 11-month median follow-up at the time of the prespecified interim OS analysis.4
tUpdated analysis of DOR in COMBI-v was conducted with 19-month median follow-up at the time of the updated OS analysis.5

 

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017. 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. 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; Vienna, Austria. 6. 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. 7. Supplement to: 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):444-451.8. Data on File. Novartis Pharmaceuticals Corp. 9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 

Indication

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.

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 received prior BRAF-inhibitor therapy.

Important Safety Information

New Primary Malignancies. New primary malignancies, cutaneous and noncutaneous, can occur.

Cutaneous Malignancies: In the COMBI-d study, the incidence of cutaneous malignancies in patients receiving TAFINLAR in combination with MEKINIST (the combination) compared with patients receiving TAFINLAR as a single agent was as follows: basal cell carcinoma 3.3% (7/209) vs 6% (13/211); cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma 3% vs 10%; new primary melanoma 0.5% (1/209) vs 1.9% (4/211).

The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8-23.9 months) in patients receiving the combination and 4.4 months (range: 29 days-16.5 months) in patients receiving TAFINLAR as a single agent. Among the 7 patients receiving the combination that developed basal cell carcinoma, 2 (29%) experienced more than 1 occurrence (range: 1-3).

The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8-16.8 months) in patients receiving the combination and 2 months (range: 9 days-20.9 months) in patients receiving TAFINLAR as a single agent.

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% (3/209) of patients who received the combination and in 2.8% (6/211) of patients who received TAFINLAR as a single agent. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for 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 MAP-kinase 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 compared with TAFINLAR as a single agent was 19% (40/209) vs 15% (32/211), respectively. Gastrointestinal hemorrhage occurred in 6% of 209 patients treated with the combination compared with 3% of 211 patients treated with TAFINLAR alone. Intracranial hemorrhage was fatal in 1.4% of 209 patients receiving the combination compared with no patients receiving TAFINLAR as a single agent.

Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events, and for any persistent grade 3 hemorrhagic events. Withhold the combination for grade 3 hemorrhagic events; if improved, resume at a lower dose.

Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials of MEKINIST administered as a single agent (N=329) and in combination with TAFINLAR (N=559), 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 209 patients treated with the combination vs 0.9% of 211 patients treated with TAFINLAR as a single agent.

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 with MEKINIST. 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% (12/206) of patients treated with the combination and in 2.9% (6/207) of patients treated with TAFINLAR alone. The median time to onset of cardiomyopathy in patients treated with the combination was 8.2 months (range: 28 days-24.9 months), and was 4.4 months (range: 28 days-19.1 months) in patients treated with TAFINLAR as a single agent.

Cardiomyopathy was identified within the first month of treatment with the combination in 2 of 12 patients, and in 2 of 6 patients treated with TAFINLAR as a single agent. Development of cardiomyopathy resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%) of patients receiving the combination and in dose interruption (2.4%), dose reduction (0.5%), or discontinuation (1.0%) of patients receiving TAFINLAR as a single agent. Cardiomyopathy resolved in 10 of 12 patients receiving the combination and in 3 of 6 patients receiving TAFINLAR as a single agent.

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 to baseline.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials including MEKINIST, the incidence of RVO was 0.2% (4/1749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmic 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 ophthalmic 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 ophthalmic evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks.

Uveitis: Uveitis (including iritis and iridocyclitis) occurred in 1% of 586 patients across multiple clinical trials treated with TAFINLAR as a single agent, and uveitis (including iridocyclitis) in 2% of 559 patients treated with the combination. 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 (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In the COMBI-d study, 1.0% (2/209) of patients treated with the combination developed pneumonitis compared with none of the patients receiving TAFINLAR as a single agent. 

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 COMBI-d and COMBI-v studies, the incidence of fever was 54% (303/559) and serious febrile reactions and fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope occurred in 17% (93/559). Fever was complicated by severe chills/rigors in 0.4%, dehydration in 1.8% renal failure in 0.5%, and syncope in 0.7% of 559 patients receiving the combination.

In patients treated with the combination, the median time to onset of first occurrence of fever was 1 month (range: 1 day-23.5 months) and the median duration of fever was 3 days (range: 1 day-11.3 months). About one-half of the patients on combination therapy, who experienced pyrexia, had 3 or more discrete episodes.

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, serious skin toxicity occurred in 0.7% of 559 patients.

In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving the combination compared with 55% for patients receiving TAFINLAR as a single agent. No serious or severe cases of skin toxicity occurred in patients treated with the combination. The median time to initial onset of skin toxicity, in patients treated with the combination, was 1.9 months (range: 1 day-22.1 months) and median time to resolution of skin toxicity was 1.2 months (range: 1 day-24.4 months). 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 15 patients with a history of diabetes receiving the combination and 13% of 16 patients receiving TAFINLAR as a single agent required more intensive hypoglycemic therapy. The incidence of grade 3 and grade 4 hyperglycemia based on laboratory values was 5% and 0.5% of 208 patients treated with the combination, respectively, compared with 4.3% and 0 of 209 patients treated with TAFINLAR as a single agent, respectively.

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%).

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.

Laboratory Abnormalities.  In the COMBI-d and COMBI-v studies, treatment-emergent laboratory abnormalities occurring at ≥10% of patients receiving the combination were hyperglycemia (60%), increased AST (59%), increased blood alkaline phosphatase (49%), increased ALT (48%), hypoalbuminemia (48%), neutropenia (46%), anemia (43%), hypophosphatemia (38%), lymphopenia (32%), hyponatremia (25%), and thrombocytopenia (21%).

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