Oncology - Volume 11, Part 6, November 2015

Withhold TAFINLAR, and MEKINIST if used in combination, 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. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5. 8 Serious Skin Toxicity

Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.

Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5. 9 Hyperglycemia

Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.

In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5. 10 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.

5. 11 Embryofetal Toxicity

TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions ( 5. 1)]

• Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions ( 5. 2)]

• Hemorrhage [see Warnings and Precautions ( 5. 3)]

• Venous Thromboembolism [see Warnings and Precautions ( 5. 4)]

• Cardiomyopathy [see Warnings and Precautions ( 5. 5)]

• Ocular Toxicities [see Warnings and Precautions ( 5. 6)]

• Interstitial Lung Disease [see Warnings and Precautions ( 5. 6)]

• Serious Febrile Reactions [see Warnings and Precautions ( 5. 7)]

• Serious Skin Toxicity [see Warnings and Precautions ( 5. 8)]

• Hyperglycemia [see Warnings and Precautions ( 5. 9)]

• Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions ( 5. 10)]

6. 1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.

BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg
twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally
twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent
150 mg orally twice daily (n = 53) [see Clinical Studies ( 14. 2)]. Patients with abnormal LVEF, history
of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive
heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment
refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung
disease, or a known history of G6PD deficiency were excluded. The median duration of treatment
was 10. 9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group)
when used in combination, 10. 6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily
treatment group) when used in combination, and 6. 1 months for TAFINLAR as a single agent.
In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse
reactions resulting in permanent discontinuation of trial medication(s). The most common
adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions
led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR
in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited
for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common
reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.
Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5%
(Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions
TAFINLAR plus
MEKINIST 2 mg
N = 55

TAFINLAR plus
MEKINIST 1 mg
N = 54

TAFINLAR N = 53

All

Gradesa Grades

3 and 4

All
Gradesa
Grades

3 and 4

All
Gradesa
Grades
3 and 4
General disorders and administrative site conditions

Pyrexia 71 5 69 9 26 0 Chills 58 2 50 2 17 0 Fatigue 53 4 57 2 40 6

Edema peripheralb 31 0 28 0 17 0 Skin and subcutaneous tissue disorders

Rashc 45 0 43 2 53 0 Night Sweats 24 0 15 0 6 0 Dry skin 18 0 9 0 6 0 Dermatitis acneiform 16 0 11 0 4 0 Actinic keratosis 15 0 7 0 9 0 Erythema 15 0 6 0 2 0