TAFINLAR is a
kinase inhibitor indicated as a single agent for the treatment of patients with
unresectable or metastatic melanoma with BRAF V600E mutation as detected by an
FDA-approved test.
TAFINLAR is
indicated, in combination with trametinib, for:
· the treatment of patients with
unresectable or metastatic melanoma with BRAF V600E or V600K mutations as
detected by an FDA-approved test.
· 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.
Limitations of
Use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF
melanoma.
MEKINIST is a
kinase inhibitor indicated as a single agent for the treatment of
BRAF-inhibitor treatment-naïve patients with unresectable or metastatic
melanoma with BRAF V600E or V600K mutations as detected by an FDA approved
test.
MEKINIST is
indicated, in combination with dabrafenib, for:
· the treatment of patients with
unresectable or metastatic melanoma with BRAF V600E or V600K mutations as
detected by an FDA-approved test.
· 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.
Please see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.
TAFINLAR Dosage
and Administration
·
The
recommended dosage of TAFINLAR is 150 mg orally twice daily. Take TAFINLAR at
least 1 hour before or at least 2 hours after a meal.
·
Capsules:
50 mg, 75 mg
MEKINIST Dosage
and Administration
·
The
recommended dosage of MEKINIST is 2 mg orally once daily. Take MEKINIST at
least 1 hour before or at least 2 hours after a meal.
· Tablets: 0.5 mg, 2 mg
Please see full Prescribing Information for TAFINLAR and full
Prescribing Information for MEKINIST.
12/20
MAF-1237265
Please
see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.
Indications and Important Safety Information
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%), 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.