April 30, 2016
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Tafinlar

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Tafinlar

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Review the Full Prescribing Information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR in combination with trametinib.

New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used with trametinib.

Cutaneous Malignancies

TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma.

In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients receiving TAFINLAR and in none of the patients receiving dacarbazine.

Across clinical trials of TAFINLAR (N = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 2.1 months (range: 7 days to 12.2 months). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In Trial 2, the incidence of basal cell carcinoma in patients receiving TAFINLAR in combination with trametinib was 3.3% (7/209) compared with 6% (13/211) of patients receiving single-agent TAFINLAR. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the TAFINLAR plus trametinib arm and was 4.4 months (range: 29 days to 16.5 months) in the single-agent TAFINLAR arm. Among the 7 patients receiving TAFINLAR with trametinib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3).

Cutaneous squamous cell carcinoma and keratoacanthoma occurred in 3% of patients receiving TAFINLAR with trametinib and 10% of patients receiving single-agent TAFINLAR. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the Tafinlar plus trametinib arm and was 2 months (range: 9 days to 20.9 months) in the single-agent TAFINLAR arm.

New primary melanoma occurred in 0.5% (1/209) of patients receiving TAFINLAR with trametinib and in 1.9% (4/211) of patients receiving single-agent TAFINLAR.

Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR are required in patients who develop new primary cutaneous malignancies [see DOSAGE AND ADMINISTRATION].

Non-cutaneous Malignancies

Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Tumor Promotion in BRAF Wild-Type Melanoma]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving TAFINLAR with trametinib and in 2.8% (6/211) of patients receiving single-agent TAFINLAR.

Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies [see DOSAGE AND ADMINISTRATION].

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, DOSAGE AND ADMINISTRATION].

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.

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].

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].

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].

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 101.3°F 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]. 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.

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].

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.

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

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].

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, Use In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the following:

Confirmation of BRAF V600E or V600K Mutation
  • TAFINLAR as a single agent: Evidence of BRAF V600E mutation in the tumor specimen using an FDA-approved test is necessary to identify patients for whom treatment is indicated [see DOSAGE AND ADMINISTRATION].
  • TAFINLAR with trametinib: Evidence of BRAF V600 mutation in tumor specimens using an FDA-approved test is necessary to identify patients for whom treatment is indicated [see DOSAGE AND ADMINISTRATION].
New Cutaneous And Non-Cutaneous Malignancies

TAFINLAR increases the risk of developing new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their healthcare provider immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies [see WARNINGS AND PRECAUTIONS].

Hemorrhage

TAFINLAR when administered with trametinib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see WARNINGS AND PRECAUTIONS].

Cardiomyopathy

TAFINLAR can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Uveitis

TAFINLAR can cause uveitis, including iritis and iridocyclitis. Advise patients to contact their healthcare provider if they experience any changes in their vision [see WARNINGS AND PRECAUTIONS].

Serious Febrile Reactions

TAFINLAR can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with trametinib. Instruct patients to contact their healthcare provider if they develop fever while taking TAFINLAR [see WARNINGS AND PRECAUTIONS].

Serious Skin Toxicities

TAFINLAR can cause serious skin toxicities. Advise patients to contact their healthcare provider for progressive or intolerable rash [see WARNINGS AND PRECAUTIONS].

Hyperglycemia

TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their healthcare provider to report symptoms of severe hyperglycemia [see WARNINGS AND PRECAUTIONS].

Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

TAFINLAR may cause hemolytic anemia in patients with G6PD deficiency. Advise patients with known G6PD deficiency to contact their healthcare provider to report signs or symptoms of anemia or hemolysis [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

TAFINLAR can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Females And Males Of Reproductive Potential

Instruct females of reproductive potential to use non-hormonal, effective non-hormonal contraception during treatment and for 2 weeks after discontinuation of treatment with TAFINLAR. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Infertility

Advise males and females of reproductive potential of the potential risk for impaired fertility with TAFINLAR [see Use in Specific Populations].

Lactation

Advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks after the last dose of TAFINLAR [see Use in Specific Populations].

Instructions For Taking Tafinlar

Instruct patients to take TAFINLAR at least 1 hour before or at least 2 hours after a meal [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.

Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay, and was not clastogenic in an in vivo rat bone marrow micronucleus test.

In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC).

Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There is insufficient data in pregnant women exposed to TAFINLAR to assess the risks. 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 [see Data]. 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.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data: In a combined female fertility and embryo-fetal development study in rats conducted during the period of organogenesis, 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.

Lactation

Risk Summary

There are no data on the presence of dabrafenib in human milk, or the effects of dabrafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from TAFINLAR in breastfed infants, advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks following the last dose of TAFINLAR.

Females And Males Of Reproductive Potential

Based on data from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to pregnant women [see Use in Specific Populations].

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with TAFINLAR and for 2 weeks after the last dose of TAFINLAR. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective [see DRUG INTERACTIONS]. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR.

Infertility

Females

Advise female patients of reproductive potential that TAFINLAR may impair fertility. A reduction in fertility was observed in female rats at dose exposures equivalent to the human exposure at the recommended dose. A reduction in the number of corpora lutea was noted in pregnant rats at dose exposures approximately three times the human exposure at the recommended dose [see Nonclinical Toxicology].

Males

Advise male patients of the potential risk for impaired spermatogenesis which may be irreversible. Effects on spermatogenesis have been observed in animals treated with dabrafenib at dose exposures up to three times the human exposure at the recommended dose [see Nonclinical Toxicology].

Pediatric Use

The safety and effectiveness of TAFINLAR as a single agent or with trametinib have not been established in pediatric patients.

Juvenile Animal Data

In a repeat-dose toxicity study 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.

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 greater than or equal to 65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in elderly patients as compared to younger patients in Trial 1.

Of the 559 patients randomized to receive TAFINLAR plus trametinib in Trials 2 and 3, 24% were aged 65 years and older and 6% patients aged 75 years and older. No overall differences in the effectiveness of TAFINLAR plus trametinib were observed in elderly patients as compared to younger patients. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in elderly patients as compared to younger patients.

Hepatic Impairment

No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see CLINICAL PHARMACOLOGY].

Renal Impairment

No formal pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/22/2016

Warnings
Precautions

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