aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.
bIncludes the following terms: peripheral edema, edema, and lymphedema.
cIncludes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash
papular, rash vesicular, rash macular, and rash maculo-papular.
dIncludes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower,
and abdominal discomfort.
eIncludes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric
hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage
intracranial, eye hemorrhage, and vitreous hemorrhage.
fIncludes the following terms: renal failure and renal failure acute.
Other clinically important adverse reactions (N = 202) observed in <10% of patients treated
with TAFINLAR in combination with MEKINIST were:
Eye Disorders: Vision blurred, transient blindness.
Gastrointestinal Disorders: Stomatitis, pancreatitis.
General Disorders and Administration Site Conditions: Asthenia.
Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.
Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.
Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome,
Vascular Disorders: Hypertension.
Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2%
(Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2
MEKINIST 2 mg
N = 55
MEKINIST 1 mg
N = 54
N = 53
3 and 4
3 and 4
3 and 4a
Leukopenia 62 5 46 4 21 0
Lymphopenia 55 22 59 19 40 6
Neutropenia 55 13 37 2 9 2
Anemia 55 4 46 7 28 0
Thrombocytopenia314312 8 0
Liver Function Tests
Increased AST 60 5 54 0 15 0
phosphatase 60 2 67 6 26 2
Increased ALT 42 4 35 4 11 0
Hyperbilirubinemia 15 0 7 4 0 0
Hyperglycemia 58 5 67 6 49 2
Increased GGT 56 11 54 17 38 2
Hyponatremia 55 11 48 15 36 2
Hypoalbuminemia 53 0 43 2 23 0
Hypophosphatemia 47 5 41 11 40 0
Hypokalemia 29 2 15 2 23 6
Increased creatinine245202 9 0
Hypomagnesemia 18 2 2 0 6 0
Hyperkalemia 18 0 22 0 15 4
Hypercalcemia 15 0 19 2 4 0
Hypocalcemia 13 0 20 0 9 0
aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma
QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated
with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as
a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients
treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR
as a single agent.
7 DRUG INTERACTIONS
7. 1 Effects of Other Drugs on Dabrafenib
Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8
may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease
concentrations of dabrafenib [see Clinical Pharmacology ( 12. 3)]. Substitution of strong inhibitors
or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If
concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or
strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4
or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors
or loss of efficacy when taking strong inducers.
7. 2 Effects of Dabrafenib on Other Drugs
Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam
(a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate)
[see Clinical Pharmacology ( 12. 3)]. Monitor international normalized ratio (INR) levels more frequently
in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration
of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal
contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific
Populations ( 8. 1, 8. 6)]. Substitute for these medications or monitor patients for loss of efficacy if use
of these medications is unavoidable.
7. 3 Trametinib
Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no
clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology ( 12. 3)].
8 USE IN SPECIFIC POPULATIONS
8. 1 Pregnancy
Pregnancy Category D
Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered
to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times
greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on
AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions ( 5. 11)].
Animal Data: In a combined female fertility and embryofetal development study in rats, developmental
toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape
at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the
recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human
exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development
and reduced fetal body weight.
Pregnancy Category D
Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib
was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in
exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus [see Warnings and Precautions ( 5. 10)].
Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of
organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day
(approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at
a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose,
there was maternal toxicity and an increase in post-implantation loss.
In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in
decreased fetal body weight and increased incidence of variations in ossification at doses greater than
or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended
dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times
the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.
8. 3 Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are present
in human milk and because of the potential for serious adverse reactions from TAFINLAR and
MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance of the drug to the mother.
8. 4 Pediatric Use
The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric
patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of
kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at
the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone
length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at
the recommended adult dose based on AUC.
8. 5 Geriatric Use
One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a
single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No
overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.
Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an
insufficient number of patients aged 65 years and over to determine whether they respond
differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and
2 patients (4%) were 75 years of age and older.
8. 6 Females and Males of Reproductive Potential
Contraception: Females: Advise female patients of reproductive potential to use highly effective
contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least
4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to
use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives