Prescription Drug Information: Tafinlar (Page 2 of 6)

5.2 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 which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or in combination with trametinib [see Indications and Usage (1), Dosage and Administration (2.1)].

5.3 Hemorrhage

Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is administered with trametinib.

In Trial 2, the incidence of hemorrhagic events in patients receiving TAFINLAR with trametinib was 19% (40/209) compared with 15% (32/211) of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving TAFINLAR with trametinib compared with 3% (6/211) of patients receiving single-agent TAFINLAR. Intracranial hemorrhage was fatal in 1.4% (3/209) of patients receiving TAFINLAR with trametinib compared with none of the patients receiving single-agent TAFINLAR.

Permanently discontinue TAFINLAR for all Grade 4 hemorrhagic events and for any persistent Grade 3 hemorrhagic events. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

5.4 Cardiomyopathy

Cardiomyopathy can occur with TAFINLAR.

In Trial 2, all patients were required to have an echocardiogram at baseline to document normal left ventricular ejection fraction (LVEF) and serial echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. Cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional lower limit of normal, occurred in 6% (12/206) of patients receiving TAFINLAR with trametinib and 2.9% (6/207) of patients receiving single-agent TAFINLAR. The median time to onset of cardiomyopathy on the TAFINLAR plus trametinib arm was 8.2 months (range: 28 days to 24.9 months), and was 4.4 months (range: 28 days to 19.1 months) on the TAFINLAR arm.

In Trial 2, cardiomyopathy was identified within the first month of initiation of TAFINLAR with trametinib in 2 of 12 patients, and in 2 of 6 patients receiving single-agent TAFINLAR. Development of cardiomyopathy in patients receiving TAFINLAR and trametinib resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%). In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption (2.4%), dose reduction (0.5%), or discontinuation (1.0%). Cardiomyopathy resolved in 10 of 12 patients receiving TAFINLAR with trametinib, and in 3 of 6 patients receiving single-agent TAFINLAR.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR with trametinib, one month after initiation of TAFINLAR, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic LV dysfunction of >20% from baseline that is below institutional lower limit of normal (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 [see Dosage and Administration (2.3)].

5.5 Uveitis

Uveitis (including iritis and iridocyclitis) can occur with TAFINLAR.

Uveitis occurred in 1% (6/586) of patients receiving TAFINLAR across multiple clinical trials and in 2% (9/559) of patients receiving TAFINLAR with trametinib across Trials 2 and 3. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, 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 [see Dosage and Administration (2.3)].

5.6 Serious Febrile Reactions

Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR.

The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 1, the incidence of fever (serious and non-serious) was 28% in patients receiving TAFINLAR and 10% in patients receiving dacarbazine. In patients receiving TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 day to 6.6 months) and the median duration of fever was 3 days (range: 1 day to 4.2 months). Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 3.7% (7/187) of patients receiving TAFINLAR and in none of the 59 patients receiving dacarbazine.

In Trials 2 and 3, fever occurred in 54% (303/559) of patients receiving TAFINLAR with trametinib; the median time to onset of first occurrence of fever was 1 month (range: 1 day to 23.5 months) and the median duration of fever was 3 days (range: 1 day to 11.3 months). Approximately one-half of the patients who received TAFINLAR with trametinib and experienced pyrexia had 3 or more discrete episodes.

Serious febrile reactions or fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving TAFINLAR with trametinib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients.

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold TAFINLAR 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 Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., 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.

5.7 Serious Skin Toxicity

Serious skin toxicity can occur with TAFINLAR.

Across clinical trials of TAFINLAR administered with trametinib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients.

Withhold TAFINLAR for intolerable or severe skin toxicity. TAFINLAR may be resumed at the next lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)].

5.8 Hyperglycemia

Hyperglycemia can occur with TAFINLAR.

In Trial 1, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy receiving TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients receiving TAFINLAR compared with none of the dacarbazine-treated patients.

In Trial 2, 27% (4/15) of patients with a history of diabetes receiving TAFINLAR with trametinib and 13% (2/16) of patients with a history of diabetes receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients, respectively, receiving TAFINLAR with trametinib compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent TAFINLAR.

Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with pre-existing diabetes or hyperglycemia.

5.9 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.

5.10 Embryo-Fetal Toxicity

Based on findings from animal studies and 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. If TAFINLAR is used during pregnancy or if the patient becomes pregnant while taking TAFINLAR, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use an effective non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of TAFINLAR. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (8.3)].

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)]
Cardiomyopathy [see Warnings and Precautions (5.4)]
Uveitis [see Warnings and Precautions (5.5)]
Serious Febrile Reactions [see Warnings and Precautions (5.6)]
Serious Skin Toxicity [see Warnings and Precautions (5.7)]
Hyperglycemia [see Warnings and Precautions (5.8)]
Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.9)]

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