Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

TAFINLAR (NDA-202806)

(DABRAFENIB MESYLATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/26/2026 (SUPPL-40)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Table 14. Adverse Reactions (greater than or equal to 20%) in Adult Patients Treated with TAFINLAR Plus Trametinib in Study BRF117019

…

Clinically relevant adverse reactions for TAFINLAR in Study BRF117019 observed in less than 20% of patients who received TAFINLAR in combination with trametinib were: peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block (2.9%), uveitis (1.9%), hypersensitivity (1.9%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%).

…

04/07/2025 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Uveitis

Additions and/or revisions underlined:

…

Cases of biocular panuveitis or biocular iridocyclitis have been reported in the post-marketing setting.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies

(N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

…

Nervous System: Peripheral neuropathy, Guillain-Barré syndrome

…

Other clinically important adverse reactions for TAFINLAR in the COMBI-AD study observed in less than 20% of patients who received TAFINLAR administered with trametinib were: blurred vision (6%), decreased ejection fraction (5%), peripheral neuropathy (2.5%), rhabdomyolysis (< 1%), atrioventricular block (< 1%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%).

…

03/19/2025 (SUPPL-37)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG

The safety and effectiveness of TAFINLAR in combination with trametinib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of TAFINLAR in combination with trametinib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years of age) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)].

. . .

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 586 patients with various solid tumors who received single agent TAFINLAR, 22% were aged 65 years and older. Of the 187 patients with melanoma who received single-agent TAFINLAR in the BREAK-3 study, 21% were aged 65 years and older [see Clinical Studies (14.1)]. No overall differences in the effectiveness or safety of TAFINLAR were observed between geriatric patients as compared to younger adults in the BREAK-3 study.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Females who are able to become pregnant:

Your healthcare provider will do a test to see if you are pregnant before starting treatment with TAFINLAR.
You should use effective non-hormonal birth control (contraception) during treatment with TAFINLAR and for 2 weeks after your last dose of TAFINLAR.

. . .

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking TAFINLAR with certain other medicines may affect the way TAFINLAR and the other medicines work and may increase your risk of side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take or give TAFINLAR?

. . .

TAFINLAR capsules:

Take TAFINLAR 2 times a day, at the same time each day, about 12 hours apart.
Take TAFINLAR on an empty stomach (at least 1 hour before or 2 hours after a meal).
Take TAFINLAR capsules whole. Do not open, crush, or break TAFINLAR capsules.
If TAFINLAR capsules are prescribed for your child weighing at least 57 pounds (26 kg), your child’s healthcare provider will adjust their dose as your child grows.
Tell your healthcare provider if you or your child is not able to swallow TAFINLAR capsules whole.

TAFINLAR tablets for oral suspension:

If TAFINLAR tablets for oral suspension are prescribed for your child, your child’s healthcare provider will adjust their dose as your child grows.
TAFINLAR tablets for oral suspension are to be taken or given as a suspension only.
Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension.
See the “Instructions for Use” that comes with the medicine for instructions on how to correctly prepare and take or give a dose of the TAFINLAR oral suspension.
After the TAFINLAR tablets for oral suspension are dispersed into an oral suspension, take or give the medicine right away from a dosing cup, oral syringe or feeding tube (10 French gauge or larger for 1 to 3 tablets, 12 French gauge or larger for 4 to 15 tablets).
Take or give TAFINLAR oral suspension 2 times a day, at the same time each day, about 12 hours apart.
Take or give each dose of TAFINLAR oral suspension on an empty stomach (at least 1 hour before or 2 hours after a meal). If necessary, breastfeeding or baby formula may be given on demand.
Throw away (dispose of) the prepared TAFINLAR oral suspension if it is not used within 30 minutes.

What are the possible side effects of TAFINLAR? TAFINLAR may cause serious side effects, including:

. . .

increased blood sugar (hyperglycemia). Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR. If you are diabetic, your healthcare provider should check your blood sugar levels closely before and during treatment with TAFINLAR. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar:

increased thirst
urinating more often than normal, or urinating an increased amount of urine

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Administration

Instruct patients to take TAFINLAR capsules on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Dosage and Administration (2.3)].
Instruct patients to take the oral suspension on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions [see Dosage and Administration (2.3)].

03/07/2025 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Cardiomyopathy

Additions and/or revisions underline:

…

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the 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 to less than or equal to 10% compared to baseline [see Dosage and Administration (2.4)].

07/11/2024 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Other clinically important adverse reactions for TAFINLAR in a pool of TAFINLAR monotherapy clinical studies observed in less than 10% of patients who received TAFINLAR were:

Gastrointestinal: Pancreatitis

Immune System: Hypersensitivity manifesting as bullous rash

Nervous System: Peripheral neuropathy

Renal and Urinary: Interstitial nephritis

Skin and Subcutaneous Tissue: Photosensitivity

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

Cardiac: Atrioventricular block, bundle branch block Gastrointestinal: Colitis, gastrointestinal perforation, pancreatitis Immune System: Sarcoidosis

Nervous System: Peripheral neuropathy

Skin and Subcutaneous Tissue: Panniculitis, photosensitivity

…

Other clinically important adverse reactions for TAFINLAR in Study BRF113928 observed in less than 20% of patients who received TAFINLAR administered with trametinib were:

Cardiac: Atrioventricular block

Gastrointestinal: Pancreatitis

Nervous System: Peripheral neuropathy

Renal and Urinary: Tubulointerstitial nephritis

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

…

Tell your healthcare provider right away if you develop any new or worsening symptoms of a severe skin reaction, including:…

…

03/29/2024 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies

(N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

Cardiac: Atrioventricular block, bundle branch block

Gastrointestinal: Colitis, gastrointestinal perforation, pancreatitis

Immune System: Sarcoidosis

Skin and Subcutaneous Tissue: Panniculitis, photosensitivity

…

Other clinically important adverse reactions for TAFINLAR in the COMBI-AD study observed in less than 20% of patients who received TAFINLAR administered with trametinib were: blurred vision (6%), decreased ejection fraction (5%), rhabdomyolysis (< 1%), atrioventricular block (< 1%), and sarcoidosis (< 1%).

…

Other clinically important adverse reactions for TAFINLAR in Study BRF113928 observed in less than 20% of patients who received TAFINLAR administered with trametinib were:

Cardiac: Atrioventricular block

…

Clinically relevant adverse reactions for TAFINLAR in Study BRF117019 observed in less than 20% of patients who received TAFINLAR in combination with trametinib were: decreased ejection fraction (8%), atrioventricular block (2.9%), uveitis (1.9%), and hypersensitivity (1.9%).

…

Clinically relevant adverse reactions for TAFINLAR in Study X2101 observed in less than 20% of patients (N=48) who received TAFINLAR in combination with trametinib were: atrioventricular block (2.1%).

…

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Cardiac: Atrioventricular block complete

Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.11)]

Skin and Subcutaneous Tissue: SCAR (including DRESS and SJS) [see Warnings and Precautions (5.7)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What are the possible side effects of TAFINLAR?

TAFINLAR may cause serious side effects, including:

…

heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with TAFINLAR. Call your healthcare provider right away if you have any of the following signs and symptoms of a heart problem:
- feeling like your heart is pounding, racing, or beating irregularly
- shortness of breath
- swelling of your ankles or feet
- feeling lightheaded
  …

02/27/2024 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were:

…

TAFINLAR as a Single Agent

…

Skin and Subcutaneous Tissue: Photosensitivity

TAFINLAR with Trametinib

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies

(N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

…

Skin and Subcutaneous Tissue: Panniculitis, photosensitivity

…

08/31/2023 (SUPPL-27)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG

(Additions and/or revisions underlined)

The safety and effectiveness of TAFINLAR in combination with trametinib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of TAFINLAR in combination with trametinib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)].

The safety and effectiveness of TAFINLAR in combination with trametinib have not been established for these indications in pediatric patients less than 1 year old.

05/26/2023 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Cardiomyopathy

(Additions and/or revisions underlined)

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) greater than or equal to 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. Cardiomyopathy resolved in 45 of 50 patients who received TAFINLAR administered with trametinib.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF less than or equal to 10% from baseline and below the institutional LLN, occurred in 9% of patients.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, 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 LLN. Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease less than or equal to 10% compared to baseline [see Dosage and Administration (2.4)].

5.7 Serious Skin Toxicities

(Additions and/or revisions underlined)

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 TAFINLAR administered with trametinib [see Adverse Reactions (6.2)].

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], other serious skin toxicity occurred in < 1% of patients.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients.

Monitor for new or worsening serious skin reactions. Permanently discontinue TAFINLAR for SCARs. [see Dosage and Administration (2.4)]. For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity. Resume TAFINLAR at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within 3 weeks [see Dosage and Administration (2.4)].

5.11 Hemophagocytic Lymphohistiocytosis

(Newly added subsection)

Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when TAFINLAR was administered with trametinib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling:

· New Primary Malignancies [see Warnings and Precautions (5.1)]

· Tumor Promotion in BRAF Wild-Type Tumors [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 Toxicities [see Warnings and Precautions (5.7)]

· Hyperglycemia [see Warnings and Precautions (5.8)]

· Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.9)]

· Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

(Extensive changes; please refer to label for complete information)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of TAFINLAR in combination with trametinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: SCAR (including DRESS and SJS) [see Warnings and Precautions (5.7)]

Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.11)]

8 Use in Specific Populations

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

Dose adjustment is not recommended for patients with mild (bilirubin less than or equal to upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) to severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment may have increased exposure. An appropriate dosage has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

03/16/2023 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

Extensive changes; please refer to label

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary
Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], TAFINLAR can cause fetal harm when administered to a pregnant woman. 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 adult clinical dose of 150 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.
…

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 adult dose based on area under the curve (AUC)]. At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended adult dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.
…

8.2 Lactation

Additions and/or revisions underlined:

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

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

…

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 adult 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 adult dose [see Nonclinical Toxicology (13.1)].

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 adult dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Additions and/or revisions underlined:

BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG
The safety and effectiveness of TAFINLAR in combination with trametinib have been established in pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; and patients 1 year of age and older with LGG with BRAF V600E mutation who require systemic therapy. Use of TAFINLAR in combination with trametinib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6, 14.7)].

The safety and effectiveness of TAFINLAR in combination with trametinib have not been established in pediatric patients younger than 1 year old with LGG with BRAF V600E mutation, and in patients < 6 years old with unresectable or metastatic solid tumors with BRAF V600E mutation.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:
TAFINLAR® (TAFF-in-lar) (dabrafenib) capsules

TAFINLAR® (TAFF-in-lar) (dabrafenib) tablets for oral suspension

…

What is TAFINLAR?
…

in combination with trametinib to treat a type of brain tumor called glioma in children 1 year and older

that is low-grade glioma (LGG), and
that have a certain type of abnormal “BRAF” gene, and
who require a medicine by mouth or injection (systemic therapy).

TAFINLAR is not for use in treating people with colorectal cancer or wild-type BRAF solid tumors. Your healthcare provider will perform a test to make sure that TAFINLAR is right for you.

It is not known if TAFINLAR used in combination with trametinib is safe and effective in children younger than 1 year of age.

It is not known if TAFINLAR used alone is safe and effective in children.

…

How should I take TAFINLAR?

…

TAFINLAR capsules:

Take TAFINLAR 2 times a day, at the same time each day, about 12 hours apart.
Take TAFINLAR at least 1 hour before or 2 hours after a meal.
Take TAFINLAR capsules whole. Do not open, crush, or break TAFINLAR capsules.
If TAFINLAR capsules are prescribed for your child 6 years of age or older, your child’s healthcare provider will adjust their dose as your child grows.
Tell your healthcare provider if you or your child is not able to swallow TAFINLAR capsules whole.
If you miss a dose of TAFINLAR, take it as soon as you remember. Do not take a missed dose of TAFINLAR if it is less than 6 hours before your next scheduled dose. Just skip the missed dose and take your next dose of TAFINLAR at your regular time.

If you vomit after taking a dose of TAFINLAR, do not take an additional dose. Take the next dose of TAFINLAR at your regular time.

TAFINLAR tablets for oral suspension:

If TAFINLAR tablets for oral suspension are prescribed for your child 1 year of age or older, your child’s healthcare provider will adjust their dose as your child grows.
TAFINLAR tablets for oral suspension are to be taken as a suspension only.
Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension.
See the “Instructions for Use” that comes with the medicine for instructions on how to correctly prepare and take or give a dose of the oral suspension.
After the TAFINLAR tablets for oral suspension are dispersed into an oral suspension, take or give the medicine right away from a cup, oral dosing syringe or feeding tube.
Take or give TAFINLAR oral suspension 2 times a day, at the same time each day, about 12 hours apart.
Take or give each dose of TAFINLAR oral suspension at least 1 hour before or 2 hours after a meal.
Throw away the prepared oral suspension if it is not used within 30 minutes.
If you miss a dose of TAFINLAR, take or give it as soon as you remember. Do not take or give a missed dose of TAFINLAR if it is less than 6 hours before your next scheduled dose. Just skip the missed dose and take or give the next dose of TAFINLAR at the regular time.

If vomiting happens after giving or taking a dose of TAFINLAR, do not take or give an additional dose. Take or give the next dose of TAFINLAR at the regular time.

What are the possible side effects of TAFINLAR?

The most common side effects of TAFINLAR when taken with trametinib to help prevent melanoma from coming back after the cancer has been removed by surgery include:

fever
chills
tiredness
diarrhea (call your doctor if there is a severe diarrhea)
nausea
vomiting
headache
joint aches
rash

muscle aches

…

The most common side effects of TAFINLAR when taken with trametinib in adults with solid tumors that cannot be removed by surgery or have spread to other parts of the body include:

fever
bleeding
tiredness
cough
nausea
vomiting
rash
constipation
chills
diarrhea (call your doctor if there is a severe diarrhea)
headache
muscle and joint aches

swelling of your arms and legs

…

The most common side effects of TAFINLAR when taken with trametinib in children 1 year of age and older with low-grade glioma include:

fever
dry skin
rash
diarrhea (call your doctor if there is a severe diarrhea)
headache
nausea
vomiting
bleeding

muscle and bone pain
stomach-area (abdomen) pain
tiredness

acne

…

How should I store TAFINLAR? TAFINLAR Capsules:

Store TAFINLAR capsules at room temperature between 68°F to 77°F (20°C to 25°C).
Keep TAFINLAR capsules in the original bottle.
The bottle of TAFINLAR capsules contains a cannister with a drying agent (desiccant) to help keep your medicine dry. Do not throw away the desiccant cannister.

TAFINLAR tablets for oral suspension:
Store the bottle of TAFINLAR tablets for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
Store the bottle of TAFINLAR tablets for oral suspension, along with the two plastic cannisters inside the original packaging, with the cap tightly closed. The cannisters contain a drying agent (desiccant) to help keep your medicine dry.
TAFINLAR tablets for oral suspension come in a bottle with a child-resistant cap.

Throw away (dispose of) any mixed oral suspension if it is not taken or given within 30 minutes after it is prepared.

Keep TAFINLAR and all medicine out of the reach of children.

…
What are the ingredients in TAFINLAR?

…

Tablets for oral suspension:

Active ingredient: dabrafenib

Inactive ingredients: acesulfame potassium, artificial berry flavor, colloidal silicone dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
…

05/27/2022 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Metastatic or Unresectable BRAF V600E or V600K Mutation-Positive Melanoma

…

TAFINLAR with Trametinib

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies

(N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

Gastrointestinal: Colitis, Gastrointestinal perforation, Pancreatitis

Immunologic: Sarcoidosis

Subcutaneous Tissue: Panniculitis

…

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

…

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received TAFINLAR administered with trametinib were blurred vision (6%), ejection fraction decreased (5%), rhabdomyolysis (< 1%), and sarcoidosis (< 1%).

…

01/28/2022 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

• New Primary Malignancies [see Warnings and Precautions (5.1)]

• Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]

12/03/2021 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Serious Febrile Reactions

Additions and/or revisions underlined:

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)].

Across clinical trials of TAFINLAR monotherapy, fever (serious and non-serious) occurred in 30% of patients. Approximately 13% of these patients experienced 3 or more discrete episodes. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients.

Across clinical trials of TAFINLAR administered with trametinib, 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 when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patient’s temperature is greater than or equal to 100.4°F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions (6.1)]. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection, and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, TAFINLAR, or both TAFINLAR and trametinib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at the same or lower dose [see Dosage and Administration (2.7)].

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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Trial COMBI-APlus (Pyrexia Management Study)

COMBI-APlus evaluated the impact of pyrexia related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is greater than or equal to 100.4°F.

Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

fever. Fever is common during treatment with TAFINLAR, but may also be serious. When taking TAFINLAR with trametinib, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever.
Call your healthcare provider right away if you get a fever during treatment with TAFINLAR.
Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of TAFINLAR with trametinib if you have fevers. Your healthcare provider will treat you as needed for your fever and any signs and symptoms of infection, and should check your kidney function during and after you have had severe fever.
…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serious Febrile Reactions

Advise patients that TAFINLAR can cause pyrexia, including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib. Instruct patients to contact their healthcare provider if they develop a fever while taking TAFINLAR [see Warnings and Precautions (5.6)].

…

05/07/2021 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies

(N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

Gastrointestinal: Colitis, Gastrointestinal perforation, Pancreatitis

Immunologic: Sarcoidosis

Subcutaneous Tissue: Panniculitis

…

04/09/2020 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

Cardiomyopathy

(Extensive changes; please refer to label)

Hemorrhage

(Additions and/or revisions underlined)

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

Across clinical trials of TAFINLAR administered with trametinib, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received TAFINLAR administered with trametinib. Intracranial hemorrhage occurred in 0.6% of patients who received TAFINLAR administered with trametinib. Fatal hemorrhage occurred in 0.5% of patients who received TAFINLAR administered with trametinib. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

Hyperglycemia

(Extensive changes; please refer to label)

New Primary Malignancies

(Extensive changes; please refer to label)

Serious Febrile Reactions

(Additions and/or revisions underlined)

Serious Skin Toxicities

(Additions and/or revisions underlined)

Across clinical trials of TAFINLAR administered with trametinib, other serious skin toxicity occurred in < 1% of patients.

Monitor for new or worsening serious skin reactions. Permanently discontinue TAFINLAR for SCARs. For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity.

Uveitis

(Additions and/or revisions underlined)

Across clinical trials, uveitis occurred in 1% of patients who received TAFINLAR monotherapy and in 2% of patients who received TAFINLAR administered with trametinib.

6 Adverse Reactions

Clinical Trials Experience

(Extensive changes; please refer to label)

Postmarketing Experience

(Newly added subsection)

Dermatologic: SCAR (including DRESS and SJS)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions underlined)

In some cases these rashes and other skin reactions can be severe or serious, and may need to be

treated in a hospital or lead to death.

-Tell your healthcare provider if you get a skin rash or acne that bothers you or worsens.

-Tell your healthcare provider right away if you develop any of the following signs or symptoms of a severe

skin reaction, including:

o blisters or peeling of your skin

o blisters on your lips, or around your mouth or eyes

o mouth sores

o high fever or flu-like symptoms

o enlarged lymph nodes

PATIENT COUNSELING INFORMATION

(Newly added information)

Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of a severe skin reaction.

07/16/2019 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Uveitis

(additions underlined)

…

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. If severe uveitis (i.e., 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 improves to Grade 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks.

5.7 Serious Skin Toxicity

(additions underlined)

…

Withhold TAFINLAR for intolerable or severe skin toxicity. Resume TAFINLAR at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within 3 weeks.

5.8 Hyperglycemia

(additions underlined)

… Initiate or optimize anti-hyperglycemic medications as clinically indicated..

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Gastrointestinal: Colitis, Gastrointestinal perforation, Pancreatitis

…

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(additions underlined)

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating TAFINLAR.

…

Males

To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for at least 2 weeks after the last dose.

…

8.5 Geriatric Use

(additions and revision underlined)

Of the 586 patients with various solid tumors who received single agent TAFINLAR, 22% were aged 65 years and older. Of the 187 patients with melanoma who received single-agent TAFINLAR in the BREAK-3 study, 21% were aged 65 years or older. No overall differences in the effectiveness or safety of TAFINLAR were observed between geriatric patients as compared to younger adults in the BREAK-3 study.

Of the 994 patients with melanoma who received TAFINLAR plus trametinib in the COMBI-d, COMBI-v, and COMBI-AD studies,21% were aged 65 years and older and 5% were aged 75 years and older. No overall differences in the effectiveness of TAFINLAR plus trametinib were observed between geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in geriatric patients as compared to younger adults in these studies.

Of the 171 patients with NSCLC who received TAFINLAR in Study BRF113928, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger.

Of the 26 patients with ATC who received TAFINLAR in Study BRF117019, 77% were aged 65 years and older and 31% were aged 75 years and older.This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

8.6 Renal Impairment

(subsection revised)

Dose adjustment is not recommended for patients with mild (GFR 60 to 89 mL/min/1.73 m2) or moderate (GFR 30 to 59 mL/min/1.73 m2) renal impairment. An appropriate dose has not been established for patients with severe (GFR less than or equal to 30 mL/min/1.73 m2) renal impairment.

8.7 Hepatic Impairment

(additions underlined)

Dose adjustment is not recommended for patients with mild (bilirubin ? ULN and AST > ULN or bilirubin >1x to 1.5x ULN and any AST) hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate (bilirubin >1.5x to 3x ULN and any AST) to severe (bilirubin >3x to 10x ULN and any AST) hepatic impairment may have increased exposure.

An appropriate dose has not been established for patients with moderate to severe hepatic impairment

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

Before you take TAFINLAR, tell your healthcare provider about all of your medical conditions, including if you:

…

are a male (including one who has had a vasectomy) with a female partner of reproductive potential

Males (including those who have had a vasectomy) should use condoms during sexual intercourse during treatment with TAFINLAR and for at least 2 weeks after the last dose of TAFINLAR

…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females to contact their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 2 weeks after discontinuation of treatment with TAFINLAR.
Advise male patients with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for at least 2 weeks after the last dose.

05/04/2018 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Table 6 has been revised; please refer to label)

(Directly after Table 10, the following has been added)

…

Locally Advanced or Metastatic, BRAF V600E-Mutation Positive, Anaplastic Thyroid Cancer (ATC)

The safety of TAFINLAR when administered with trametinib was evaluated in a nine-cohort, multicenter, non- randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, a total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of TAFINLAR or trametinib. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.

Among these 100 patients, 46 (46%) were exposed to TAFINLAR and trametinib for > 6 months and 23 (23%) were exposed to TAFINLAR and trametinib for greater than or equal to 1 year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were White; and 31% had baseline ECOG performance status 0 and 59% had ECOG performance status 1.

The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Significant changes made, please refer to the label)

04/30/2018 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

(Additions and/or revisions are underlined)

Cutaneous Malignancies

In the BREAK-3 study in patients with unresectable or metastatic melanoma, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% of patients receiving TAFINLAR.

Across clinical trials of TAFINLAR monotherapy, the incidence of cuSCC was 11%. Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR.

In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR in combination with trametinib was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with trametinib who developed basal cell carcinoma, 2 experienced more than one occurrence (range: 1 to 3). cuSCC and new primary melanoma occurred in 3% and 0.5% of patients receiving TAFINLAR with trametinib, respectively.

In the COMBI-AD study in the adjuvant treatment of melanoma, cuSCC and new primary melanoma occurred in 1% and < 1% of patients receiving TAFINLAR plus trametinib, respectively.

In Study BRF113928 in patients with NSCLC, cuSCC occurred in 3.2% of patients receiving TAFINLAR plus trametinib.

Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR.

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. In the COMBI-d, COMBI-AD, and BRF113928 studies, non-cutaneous malignancies occurred in 1.4%, 1%, and 1.1% of patients receiving TAFINLAR with trametinib, respectively.

…

5.10 Risks Associated with Combination Treatment

(Newly added subsection)

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

5.3 Hemorrhage

(Additions and/or revisions are underlined)

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

In the COMBI-d study, the incidence of hemorrhagic events in patients receiving TAFINLAR with trametinib was 19% compared with 15% of patients receiving single agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients receiving TAFINLAR with trametinib compared with 3% of patients receiving single agent TAFINLAR. Intracranial hemorrhage was fatal in 1.4% of patients receiving TAFINLAR with trametinib. No fatal hemorrhagic events were observed in the COMBI-AD study. In Study BRF113928, fatal hemorrhagic-events occurred in 2.2% of patients receiving TAFINLAR with trametinib; these events were retroperitoneal hemorrhage and subarachnoid 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.

5.4 Cardiomyopathy

(Additions and/or revisions are underlined)

In the COMBI-d study, cardiomyopathy, defined as a decrease in LVEF ? 10% from baseline and below the institutional lower limit of normal, occurred in 6% of patients receiving TAFINLAR with trametinib and 2.9% of patients receiving single agent TAFINLAR. Development of cardiomyopathy in patients receiving TAFINLAR and trametinib resulted in dose interruption or discontinuation of TAFINLAR in 4.4% and 1.0% of patients, respectively. In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption, reduction, or discontinuation in 2.4%, 0.5%, and 1.0% of patients, respectively. Cardiomyopathy resolved in 10 of 12 patients receiving TAFINLAR with trametinib and in 3 of 6 patients receiving single agent TAFINLAR.

In the COMBI-AD study, cardiomyopathy, defined as a decrease in LVEF below the institutional lower limit of normal with an absolute decrease in LVEF > 10% below screening, occurred in 3% of patients receiving TAFINLAR with trametinib and resulted in discontinuation, dose reduction, and dose interruption of drug in 0.2%, 1.6%, and 2.1% of patients, respectively. Cardiomyopathy resolved in 12 of 14 patients receiving TAFINLAR with trametinib.

In Study BRF113928, cardiomyopathy, defined as a decrease in LVEF below the institutional lower limit of normal with an absolute decrease in LVEF > 10% below baseline, occurred in 9% of patients receiving TAFINLAR with trametinib and resulted in dose interruption and permanent discontinuation of TAFINLAR in 3.2% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving TAFINLAR and trametinib.

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.

5.5 Uveitis

(Additions and/or revisions are underlined)

Uveitis occurred in 1% of patients receiving TAFINLAR across multiple clinical trials and in 2% of patients receiving TAFINLAR with trametinib across randomized unresectable or metastatic melanoma trials. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

...

5.6 Serious Febrile Reactions

Additions and/or revisions are underlined)

…

Serious febrile reactions or fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope, occurred in 17% of patients with unresectable or metastatic melanoma receiving TAFINLAR with trametinib. Fever was complicated by severe chills/rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% of patients.

…

5.7 Serious Skin Toxicity

(Additions and/or revisions are underlined)

Across clinical trials of TAFINLAR administered with trametinib in patients with unresectable or metastatic melanoma, serious skin toxicity occurred in 0.7% of patients.

….

5.8 Hyperglycemia

(Additions and/or revisions are underlined)

…

In the COMBI-d study, 27% of patients with a history of diabetes receiving TAFINLAR with trametinib and 13% 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% and 0.5% of patients, respectively, receiving TAFINLAR with trametinib. For patients receiving single agent TAFINLAR, 4.3% of patients had Grade 3 hyperglycemia based on laboratory values and no patients had Grade 4 hyperglycemia.

…

6 Adverse Reactions

(Additions and/or revisions are underlined)

…

There are additional adverse reactions associated with trametinib. Refer to the trametinib prescribing information for additional information.

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…

The data described in the Warnings and Precautions section reflect exposure to TAFINLAR administered as a single agent in 586 patients with various solid tumors and exposure to TAFINLAR administered with trametinib in 559 patients with unresectable or metastatic melanoma and 93 patients with NSCLC. The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

Metastatic or Unresectable BRAF V600E or V600K Mutation-Positive Melanoma.

…

Table 6. Select Laboratory Abnormalities Worsening from Baseline Occurring at greater than or equal to 10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in the COMBI-d Study

…

(Newly added subsection)

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

The safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily for 12 months. The trial excluded patients with abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval greater than or equal to 480 msec; treatment-refractory hypertension; uncontrolled arrhythmias; or history of retinal vein occlusion. The median age of patients who received TAFINLAR in combination with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status of 1. Patients receiving TAFINLAR in combination with trametinib had a median duration of exposure of 11 months (range: 0 to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for > 6 months.

The most commonly occurring adverse reactions (? 20%) in patients receiving TAFINLAR in combination with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most common for each were pyrexia and chills.

Table 7 summarizes adverse reactions that occurred in at least 20% of patients receiving TAFINLAR in combination with trametinib.

(Table has been added; please refer to label)

Table 7. Adverse Reactions Occurring in greater than or equal to 20% of Patients in the COMBI-AD Study

…

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study receiving TAFINLAR in combination with trametinib were blurred vision (6%), ejection fraction decreased (5%), and rhabdomyolysis (less than 1%).

The most common laboratory abnormalities are summarized in Table 8.

(Table has been added; please refer to label)

Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in greater than or equal to 20% of Patients in the COMBI-AD study

…

Metastatic, BRAF V600E-Mutation Positive, Non-Small Cell Lung Cancer (NSCLC)

…

Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, of TAFINLAR in combination with trametinib in Study BRF113928.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

…

Of the 994 patients with melanoma randomized to receive TAFINLAR plus trametinib in the COMBI-d, COMBI-v, and COMBI-AD studies, 21% were aged 65 years and older and 5% were 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 across the melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in elderly patients as compared to younger patients in the metastatic melanoma studies.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Significant changes made, please refer to the label)

Patient Counseling Information

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the following:

Confirmation of BRAF V600 mutation

...

04/19/2018 (SUPPL-9)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

The most common side effects of TAFINLAR alone include:

thickening of the outer layers of the skin
warts
headache
fever
joint aches
hair loss
redness, swelling, peeling, or tenderness of hands or feet

…

06/22/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

In the BREAK-3 study in patients with melanoma replaces In trial 1

In the COMBI-d study in patients with melanoma replaces In trial 2

Addition of the following:

In Study BRF113928 in patients with NSCLC, cuSCC occurred in 3.2% (3/93) of patients with NSCLC receiving TAFINLAR plus trametinib with a time to onset of the first occurrence of 25 days, 3.5 months, and 12.3 months.

Non-cutaneous Malignancies

COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113928, non- cutaneous malignancies occurred in 1.1% (1/93) of patients receiving TAFINLAR with trametinib.

5.2 Tumor Promotion in BRAF Wild-Type Tumors

Tumors replaced Melanoma in subsection title.

5.3 Hemorrhage

COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113928, fatal hemorrhagic events occurred in 2.2% (2/93) of patients receiving TAFINLAR with trametinib; these events were retroperitoneal hemorrhage and subarachnoid hemorrhage.

5.4 Cardiomyopathy

COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113928, all patients were required to have an echocardiogram at baseline to document normal left ventricular ejection fraction (LVEF) and serial echocardiograms at Week 6, Week 15, and then every 9 weeks thereafter. Cardiomyopathy, defined as a decrease in LVEF below the institutional lower limit of normal with an absolute decrease in LVEF >10% below baseline, occurred in 9% (8/93) of patients receiving TAFINLAR with trametinib. The median time to onset of cardiomyopathy was 6.7 months (range: 1.4 months to

14.1 months). Cardiomyopathy in patients receiving TAFINLAR and trametinib resulted in dose interruption and permanent discontinuation of TAFINLAR in 3.2% and 2.2%, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving TAFINLAR and trametinib.

5.5 Uveitis

Randomized melanoma trials replace Trials 2 and 3

5.6 Serious Febrile Reactions

The BREAK-3 study replaces Trial 1

The COMBI-d and COMBI-v studies replace Trials 2 and 3

Additions and/or revisions are underlined:

… occurred in 17% (93/559) of patients with melanoma receiving TAFINLAR …

5.7 Serious Skin Toxicity

Additions and/or revisions are underlined:

Across clinical trials of TAFINLAR administered with trametinib (N = 559) in patients with melanoma, serious skin toxicity …

5.8 Hyperglycemia

The BREAK-3 study replaces Trial 1

The COMBI-d study replaces Trial 2

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The data described in the Warnings and Precautions section reflect exposure to TAFINLAR administered as a single agent in 586 patients with various solid tumors and exposure to TAFINLAR administered with trametinib in 559 patients with melanoma and 93 patients with NSCLC. The safety of TAFINLAR as a single agent …

Addition of the following:

Metastatic or Unresectable BRAF V600 Mutation Positive Melanoma

TAFINLAR as a Single Agent

The BREAK-3 study replaces Trial 1

In the BREAK-3 study added to the Table 3 and Table 4 titles

TAFINLAR Administered with Trametinib

The COMBI-d and COMBI-v studies replace Trials 2 and 3

The COMBI-d Studya replaces Trial 2ain the title of Table 5

The COMBI-d study replaces Trial 2 in the title of Table 6

Addition of the following after Table 6:

Metastatic, BRAF V600E-Mutation Positive, Non-Small Cell Lung Cancer (NSCLC)

The safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n equals 57) metastatic BRAF V600E mutation-positive NSCLC in a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval greater than or equal to 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current retinal vein occlusion.

Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for greater than 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for greater than or equal to1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were White; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.

The most commonly occurring adverse reactions (greater than or equal to 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of TAFINLAR occurred in 18% of patients; ; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most common were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most common were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).

Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, of TAFINLAR in Study BRF113928.

Table 7 Adverse Reactions Occurring in greater than or equal to 20% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Study BRF113928a Table newly added; please refer to label.

Newly added information following Table 7:

Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR in combination with trametinib were:

Gastrointestinal Disorders: Pancreatitis

Renal and Urinary Disorders: Tubulointerstitial nephritis

Table 8. Treatment-Emergent Laboratory Abnormalities Occurring in greater than or equal to 20% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Study BRF113928 Table newly added; please refer to label.

8 Use in Specific Populations

8.5 Geriatric Use

The BREAK-3 study replaces Trial 1 throughout subsection

Additions and/or revisions underlined:

Of the 559 patients with melanoma randomized …

The COMBI-d and COMBI-v studies replace Trials 2 and 3

Newly added information:

Clinical studies of TAFINLAR in NSCLC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.