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.
BRAFTOVI (NDA-210496)
(ENCORAFENIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/24/2026 (SUPPL-19)
02/24/2026 (SUPPL-21)
12/20/2024 (SUPPL-17)
09/12/2024 (SUPPL-16)
10/13/2023 (SUPPL-15)
10/11/2023 (SUPPL-14)
5 Warnings and Precautions
5.1 New Primary MalignanciesAdditions and/or revisions underlined:
…
In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in combination with binimetinib.
...
New subsection added:
Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN with an absolute decreased in LVEF greater than or equal to 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving BRAFTOVI plus binimetinib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving BRAFTOVI in combination with binimetinib was 3.6 months (range 0 to 21 months).
Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib.
In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF greater than or equal to 10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving BRAFTOVI in combination with binimetinib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and every 2 to 3 months during treatment. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with BRAFTOVI.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
New subsection added:
Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.
Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].
Additions and/or revisions underlined:
…
In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).
…
Additions and/or revisions underlined:
… In PHAROS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 1%.
…
Additions and/or revisions underlined:
BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology (12.2)]. In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib.
Additions and/or revisions underlined:
…
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of BRAFTOVI [see Use in Specific Populations (8.1, 8.3)].
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]
Cardiomyopathy [see Warnings and Precautions (5.3)]
Hepatotoxicity [see Warnings and Precautions (5.4)]
Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)]
Risks Associated with BRAFTOVI as a Single Agent [see Warnings and Precautions (5.9)]
Risks Associated with Combination Treatment [see Warnings and Precautions (5.10)]
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
The safety of BRAFTOVI in combination with binimetinib was evaluated in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in an open-label, single-arm trial (PHAROS).
The PHAROS trial [see Clinical Studies (14.3)] excluded patients with abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for BRAFTOVI and binimetinib was 9.2 and 8.4 months, respectively.
The most common (greater than or equal to 25%) adverse reactions in patients receiving BRAFTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 59% of patients receiving BRAFTOVI; the most common (greater than or equal to 5%) were diarrhea (17%); nausea (13%); musculoskeletal pain, fatigue (8% each); AST increased (7%); ALT increased, anemia, hemorrhage, vomiting (6% each); and acute kidney
injury (5%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI; the most common (greater than or equal to 5%) were diarrhea, nausea (8% each); AST increased and fatigue (5% each). A total of 16% of patients receiving BRAFTOVI experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common (greater than or equal to 2%) were diarrhea, musculoskeletal pain (3.1% each); fatigue, rash, nausea, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than 1 patient.
Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with binimetinib. Serious adverse reactions occurring in greater than or equal to 2% of patients were hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received BRAFTOVI (450 mg once daily) in combination with binimetinib, including intracranial hemorrhage and myocardial infarction (1% each).
Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.
Please refer to label to view Table 9 and Table 10.
…
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:
Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis
Gastrointestinal disorders: Pancreatitis
Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema
Immune system disorders: Drug hypersensitivity
…
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
…
Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies (14.3)].
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
…
New Primary Malignancies
Advise patients that BRAFTOVI increases the risk of developing new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions [see Warnings and Precautions (5.1)].
Tumor Promotion in BRAF Wild-Type Tumors
Advise patients of the need to confirm BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Warnings and Precautions (5.2)].
Cardiomyopathy
Advise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3)].
Hepatotoxicity
Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with BRAFTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see Warnings and Precautions (5.4)].
…
MEDICATION GUIDE
Additions and/or revisions underlined:
…
What is BRAFTOVI?
…
in combination with a medicine called binimetinib to treat adults with a type of lung cancer called non-small cell lung cancer (NSCLC):
that has spread to other parts of the body, and
that has a certain type of abnormal “BRAF” gene
…
What are the possible side effects of BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
See “What is the most important information I should know about BRAFTOVI?”
Heart problems, including heart failure. BRAFTOVI, when taken with binimetinib, can cause heart problems. Your healthcare provider will check your heart function before and during treatment with BRAFTOVI. Tell your healthcare provider right away if you get any of the following signs and symptoms of a heart problem:
feeling like your heart is pounding or racing
shortness of breath
swelling in your hands, ankles legs or feet
feeling faint or lightheaded
Liver problems. BRAFTOVI, when taken with binimetinib, can cause liver problems. Your healthcare provider will perform blood tests to check your liver function before and during treatment with BRAFTOVI. Tell your healthcare provider if you get any of the following signs and symptoms of a liver problem:
yellowing of your skin or your eyes
tiredness
dark or brown (tea-colored) urine
bruising
nausea or vomiting
bleeding
loss of appetite
…
The most common side effects of BRAFTOVI when taken in combination with binimetinib for NSCLC include:
fatigue
blurred vision, loss of vision, or other vision changes
nausea
constipation
diarrhea
shortness of breath
muscle or joint pain
rash
vomiting
cough
stomach-area (abdominal) pain
…
02/11/2022 (SUPPL-13)
04/08/2020 (SUPPL-6)
5 Warnings and Precautions
Hemorrhage(Newly added information)
In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%) and rectal hemorrhage (2.3%).
(Newly added information)
In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab.
(Additions and/or revisions underlined)
In COLUMBUS, Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib.
(Additions and/or revisions underlined)
BRAFTOVI
is indicated for
use as part of a regimen
in combination with binimetinib or cetuximab. Refer to
the prescribing information for binimetinib
and cetuximab for
additional risk information.
6 Adverse Reactions
(Newly added subsection)
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.2)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.
The most common (greater than or equal to 25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9% of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in combination with cetuximab experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than one patient (>0.5%).
Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.
(Newly added tables)
(Newly added subsection)
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
8 Use in Specific Populations
Geriatric Use(Newly added information)
Of the 216 patients with BRAF V600E mutation positive metastatic CRC who received BRAFTOVI 300 mg QD in combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies (14.2)].
No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib or BRAFTOVI plus cetuximab were observed in elderly patients as compared to younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Extensive changes; please refer to label)
(Newly added information)
Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose [Use in Specific Populations (8.3)].