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.

MEKTOVI (NDA-210498)

(BINIMETINIB)

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

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09/12/2024 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

…

Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were:

…

Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity

…

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

…

Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib were:

…

Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity

…

10/11/2023 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

New subsection added:

New primary malignancies, cutaneous and non-cutaneous, can occur when MEKTOVI is used in combination with encorafenib.

In PHAROS, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients who received MEKTOVI in combination with encorafenib.

Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment [see Dosage and Administration (2.3)].

5.2 Cardiomyopathy

Additions and/or revisions underlined:

…

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 MEKTOVI in combination with encorafenib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving MEKTOVI plus encorafenib.

…

5.3 Venous Thromboembolism

Additions and/or revisions underlined:

… In PHAROS, VTE occurred in 7% of patients receiving MEKTOVI in combination with encorafenib, including 1% of patients who developed pulmonary embolism.

…

5.4 Ocular Toxicities

Additions and/or revisions underlined:

…

In PHAROS, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness treated with MEKTOVI in combination with encorafenib. No patient permanently discontinued MEKTOVI due to serous retinopathy; 1% of patients required dose interruptions.

…

Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%. In PHAROS, uveitis occurred in 1% of patients receiving MEKTOVI in combination with encorafenib.

…

5.5 Interstitial Lung Disease

Additions and/or revisions underlined:

… In PHAROS,1 patient (1%) receiving MEKTOVI with encorafenib developed pneumonitis.

…

5.6 Hepatotoxicity

Additions and/or revisions underlined:

… In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

…

5.7 Rhabdomyolysis

Additions and/or revisions underlined:

… In PHAROS, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients treated with MEKTOVI in combination with encorafenib. No patient experienced rhabdomyolysis.

…

5.8 Hemorrhage

Additions and/or revisions underlined:

…

In PHAROS, hemorrhage occurred in 12% of patients receiving MEKTOVI in combination with encorafenib 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).

…

5.9 Embryo-Fetal Toxicity

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 effective contraception during treatment with MEKTOVI and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

New Primary Malignancies [see Warnings and Precautions (5.1)]
Embryo-Fetal Toxicity [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:
…The data described in WARNINGS AND PRECAUTIONS reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily in a randomized open-label, active-controlled trial (COLUMBUS) [see Clinical Studies (14.1)] or, for rare events, exposure of 690 patients with BRAF V600 mutation positive melanoma to MEKTOVI 45 mg twice daily in combination with encorafenib once daily across multiple clinical trials (NCT03915951, NCT01909453).
The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure of 98 patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer to MEKTOVI 45 mg twice daily and encorafenib 450 mg once daily until disease progression or unacceptable toxicity in PHAROS [see Clinical Studies (14.2)].
…
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
The safety of MEKTOVI in combination with encorafenib is described in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in an open-label, single-arm trial (PHAROS).
The PHAROS trial [see Clinical Studies (14.2)] excluded patients with abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for MEKTOVI and encorafenib was 8.4 and 9.2 months respectively.
The most common (greater than or equal to 25%) adverse reactions in patients receiving MEKTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.
Adverse reactions leading to dose interruptions of MEKTOVI occurred in 62% of patients receiving MEKTOVI; the most common (greater than or equal to 5%) were diarrhea (17%); nausea (15%); fatigue (9%); AST
increased (7%); ALT increased, anemia, musculoskeletal pain, vomiting (6% each); and acute kidney injury, hemorrhage, and LV dysfunction/cardiomyopathy (5% each). Adverse reactions leading to dose reductions of MEKTOVI occurred in 33% of patients receiving MEKTOVI; the most common (greater than or equal to 5%) were diarrhea (8%), nausea (6%), and AST increased (5%). A total of 17% of patients receiving MEKTOVI experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI; the most common (greater than or equal to 2%) were diarrhea (3.1%); musculoskeletal pain, LV dysfunction/cardiomyopathy, fatigue, nausea, rash, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of MEKTOVI occurred in more than 1 patient.
Serious adverse reactions occurred in 38% of patients who received MEKTOVI in combination with encorafenib. Serious adverse reactions in greater than or equal to 2% of patients included 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 MEKTOVI (45 mg twice-daily) in combination with encorafenib, including intracranial hemorrhage and myocardial infarction (1% each).
Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.
Please refer to label to view Table 5 and Table 6.
…
Other clinically important adverse reactions occurring in <10% of patients who received MEKTOVI in combination with encorafenib 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

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

… Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Based on animal data, MEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

…

8.5 Geriatric Use

Additions and/or revisions underlined:

…

Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received MEKTOVI in combination with encorafenib, 62 (63.2%) were 65 years of age and over and 20 (20.4%) were 75 years and over [see Clinical Studies (14.2)].

…

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 MEKTOVI administered with encorafenib can result in the development of 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 other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

…

Ocular Toxicities

Advise patients to contact their healthcare provider as soon as possible if they experience any changes in their vision [see Warnings and Precautions (5.4)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is MEKTOVI?

MEKTOVI is a prescription medicine used:

…

in combination with a medicine called encorafenib 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 MEKTOVI?
  MEKTOVI may cause serious side effects, including:
  …
  The most common side effects of MEKTOVI when taken with encorafenib 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
…