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.

MEKINIST (NDA-204114)

(TRAMETINIB DIMETHYL SULFOXIDE)

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

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05/07/2026 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Ocular Toxicities

Additions and/or revisions underlined:

. . .

Retinal Pigment Epithelial Detachment

MEKINIST Administered with Dabrafenib (Adult): In a clinical trial of 131 patients treated with MEKINIST in combination with dabrafenib that included ophthalmological monitoring with optical coherence tomography (OCT), RPED occurred in 5% of patients, including 1 patient with visual field defect symptoms.

MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, RPED events occurred in < 1% of patients.

Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at same or reduced dose. If no improvement after 3 weeks, resume MEKINIST at reduced dose or permanently discontinue MEKINIST [see Dosage and Administration (2.4)].

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 MEKINIST Plus Dabrafenib in Study BRF117019

…

Clinically relevant adverse reactions for MEKINIST in Study BRF117019 observed in less than 20% of patients who received MEKINIST in combination with dabrafenib 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)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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

…

Nervous System: Peripheral neuropathy, Guillain-Barré syndrome

…

Other clinically important adverse reactions for MEKINIST in the COMBI-AD study observed in less than 20% of patients who received MEKINIST in combination with dabrafenib 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 MEKINIST in combination with dabrafenib 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 MEKINIST in combination with dabrafenib 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)].

. . .

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Administration

Instruct patients to take MEKINIST tablets on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Dosage and Administration (2.3)].
When administering MEKINIST for oral solution as a single agent, instruct patients to take the oral solution with a low-fat meal or on an empty stomach [see Dosage and Administration (2.3)].
When coadministering with dabrafenib, instruct patients to take the MEKINIST oral solution 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)].

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

How should I take or give MEKINIST?

. . .

MEKINIST tablets:

Take MEKINIST 1 time each day, at the same time each day, about every 24 hours.
Take MEKINIST on an empty stomach (at least 1 hour before or 2 hours after a meal).
Take MEKINIST tablets whole. Do not crush or break MEKINIST tablets.
If MEKINIST tablets 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 MEKINIST tablets whole.

MEKINIST for oral solution:

MEKINIST for oral solution should only be given by a caregiver.
If MEKINIST for oral solution is prescribed for your child, your child’s healthcare provider will adjust their dose as your child grows.
See the “Instructions for Use” that comes with the medicine for instructions on how to correctly give a dose of MEKINIST.
MEKINIST for oral solution can be given using an oral syringe or feeding tube (4 French gauge or larger).
Give the MEKINIST oral solution 1 time each day, at the same time each day, about every 24 hours.
Give the MEKINIST oral solution with a low-fat meal or on an empty stomach when giving MEKINIST alone.
When giving MEKINIST in combination with dabrafenib, give the MEKINIST oral solution 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.

. . .

03/07/2025 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Cardiomyopathy

Additions and/or revisions underlined:

…

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the institutional LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN, permanently discontinue MEKINIST [see Dosage and Administration (2.4)].

10/01/2024 (SUPPL-27)

Approved Drug Label (PDF)

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

PATIENT INFORMATION

Additions and/or revisions underlined:

How should I store MEKINIST?

MEKINIST tablets:

Store MEKINIST tablets at room temperature between 68°F to 77°F (20°C to 25°C).

…

07/11/2024 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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

…

Nervous System: Dizziness, dysgeusia, peripheral neuropathy

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Nervous System: Peripheral neuropathy

…

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

Cardiac: Atrioventricular block

Nervous System: Peripheral neuropathy

…

03/29/2024 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Cardiac: Bradycardia, atrioventricular block, bundle branch block

Immune System: Sarcoidosis

Musculoskeletal and Connective Tissue: Rhabdomyolysis

Skin and Subcutaneous Tissue: Photosensitivity

…

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

Cardiac: Atrioventricular block

…

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

…

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

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Cardiac: Atrioventricular block complete. This adverse reaction was also observed with MEKINIST monotherapy.

Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.12)]

Skin and Subcutaneous Tissue: SCAR (including DRESS and SJS) [see Warnings and Precautions (5.9)]

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

PATIENT INFORMATION

Additions and/or revisions; please refer to label for complete information.

…

How should I take or give MEKINIST?

…

MEKINIST for oral solution:

…

MEKINIST for oral solution can be given using an oral syringe or feeding tube (4 French gauge or larger).
…
What are the possible side effects of MEKINIST?
MEKINIST may cause serious side effects, including:
…

heart problems, including heart failure. Your healthcare provider should check your heart function before and during treatment with MEKINIST. 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 and feet
feeling lightheaded
…
How should I store MEKINIST?
…
MEKINIST for oral solution:

Store MEKINIST for oral solution in the original amber bottle at room temperature below 77°F (25°C). Do not freeze.
Keep MEKINIST for oral solution in the carton it comes in and away from direct moisture and light.
Throw away unused MEKINIST for oral solution after the expiration or “discard after” date written on the amber bottle label.
…

02/27/2024 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

MEKINIST with Dabrafenib

…

Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients who received MEKINIST in combination with dabrafenib (N = 559) were:

…

Skin and Subcutaneous Tissue: Photosensitivity

…

08/31/2023 (SUPPL-29)

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 MEKINIST in combination with dabrafenib 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 MEKINIST in combination with dabrafenib 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 MEKINIST in combination with dabrafenib have not been established for these indications in pediatric patients less than 1 year old.

05/26/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Hemophagocytic Lymphohistiocytosis

(Newly added subsection)

Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when MEKINIST was administered with dabrafenib. 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)]

· Hemorrhage [see Warnings and Precautions (5.2)]

· Colitis and Gastrointestinal Perforation [see Warnings and Precautions (5.3)]

· Venous Thromboembolic Events [see Warnings and Precautions (5.4)]

· Cardiomyopathy [see Warnings and Precautions (5.5)]

· Ocular Toxicities [see Warnings and Precautions (5.6)]

· Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.7)]

· Serious Febrile Reactions [see Warnings and Precautions (5.8)]

· Serious Skin Toxicities [see Warnings and Precautions (5.9)]

· Hyperglycemia [see Warnings and Precautions (5.10)]

· Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.12)]

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 post approval use of MEKINIST in combination with dabrafenib. 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 (5.9)]

Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.12)]

7 Drug Interactions

(Additions and/or revisions underlined)

MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib prescribing information for additional risk information that applies to combination use treatment.

03/16/2023 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

Additions and/or revisions underlined:

Cutaneous Malignancies
MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthomas occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and < 1% of patients, respectively.
MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, new primary melanoma occurred in < 1% of patients.
Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination

Non-Cutaneous Malignancies

Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms; refer to the prescribing information for dabrafenib.

In the pooled safety population of MEKINIST administered with dabrafenib, non-cutaneous malignancies occurred in 1% of patients.

Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies.

5.2 Hemorrhage

Additions and/or revisions underlined:

Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. Fatal cases have been reported.

MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%) uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%) and epistaxis (0.6%).

Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

5.3 Colitis and Gastrointestinal Perforation

Additions and/or revisions underlined:

Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking

MEKINIST Monotherapy and Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], colitis occurred in < 1% of patients and gastrointestinal perforation occurred in < 1% of patients.

MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, colitis events occurred in <1% of patients.

Monitor patients closely for colitis and gastrointestinal perforations.

5.4 Venous Thromboembolic Events

Additions and/or revisions underlined:

MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.

MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, embolism events occurred in < 1% of patients.

…

5.5 Cardiomyopathy

Additions and/or revisions underlined:

Cardiomyopathy, including cardiac failure, can occur with MEKINIST.

MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ? 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 MEKINIST in 3% and < 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received MEKINIST administered with dabrafenib.

MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ? 10% from baseline and below the institutional LLN, occurred in 9% of patients.

…

5.6 Ocular Toxicities

Additions and/or revisions underlined:

Retinal Vein Occlusion

In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST administered with dabrafenib, there were no cases of RVO. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
…

Retinal Pigment Epithelial Detachment

Retinal pigment epithelial detachment (RPED) can occur with MEKINIST. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In melanoma and NSCLC trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.
MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, RPED events occurred in < 1% of patients.
…

5.7 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST administered with dabrafenib, ILD or pneumonitis occurred in 1% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment related ILD or pneumonitis [see Dosage and Administration (2.4)].

5.8 Serious Febrile reactions

Additions and/or revisions underlined:

…

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib.
MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], 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.
MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population [see Adverse Reactions (6.1)], pyrexia occurred in 66% of patients.
…

5.9 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 MEKINIST administered with dabrafenib [see Adverse Reactions (6.2)].

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

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

5.10 Hyperglycemia

Additions and/or revisions underlined:

MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], 15% of patients with a history of diabetes who had received MEKINIST with dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 2% of patients.
MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% of patients.

…

5.12 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment [see Use in Specific Populations (8.1, 8.3)]

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 its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose (see Data). Advise pregnant women of the potential risk to the fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day [approximately 0.3 times the human exposure at the recommended adult dose based on area under the curve (AUC)]. In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended adult dose, there was maternal toxicity and an increase in post-implantation loss.
In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended adult dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of trametinib in human milk, or the effects of trametinib 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 MEKINIST and for 4 months 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 MEKINIST may impair fertility. Increased follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3 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 MEKINIST in combination with dabrafenib have been established in pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAFV600E 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 MEKINIST in combination with dabrafenib 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 MEKINIST in combination with dabrafenib 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 mutations.

The safety and effectiveness of MEKINIST as a single agent in pediatric patients have not been established.
…

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

PATIENT INFORMATION

Additions and/or revisions underlined:

MEKINIST® (MEK-in-ist) (trametinib) tablets
MEKINIST® (MEK-in-ist) (trametinib) for oral solution

…

What is MEKINIST?

…

in combination with dabrafenib 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)

MEKINIST is not for use in treating people with colorectal cancer.

Your healthcare provider will perform a test to make sure that MEKINIST is right for you.

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

…

How should I take MEKINIST?

Take MEKINIST exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST tablets and MEKINIST for oral solution unless your healthcare provider tells you.

Your healthcare provider may change your dose of MEKINIST, temporarily stop, or completely stop your treatment with MEKINIST if you develop certain side effects.

MEKINIST tablets:

Take MEKINIST 1 time each day, at the same time each day, about every 24 hours.
Take MEKINIST at least 1 hour before or 2 hours after a meal.
Take MEKINIST tablets whole. Do not open, crush, or break MEKINIST tablets.
If MEKINIST tablets 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 MEKINIST tablets whole.
If you miss a dose of MEKINIST, take it as soon as you remember. Do not take a missed dose of MEKINIST if it is less than 12 hours before your next scheduled dose. Just skip the missed dose and take the next dose of MEKINIST at your regular time.
If you vomit after taking a dose of MEKINIST, do not take an additional dose. Take the next dose of MEKINIST at your regular time.

MEKINIST for oral solution:

MEKINIST for oral solution should only be given by a caregiver.
If MEKINIST for oral solution is prescribed for your child 1 year of age or older, your child’s healthcare provider will adjust their dose as your child grows.
See the “Instructions for Use” that comes with the medicine for instructions on how to correctly give a dose of MEKINIST.
MEKINIST for oral solution can be given using an oral dosing syringe or feeding tube.
Give MEKINIST for oral solution 1 time each day, at the same time each day, about every 24 hours.
Give MEKINIST for oral solution at least 1 hour before or 2 hours after a meal.
If you miss giving a dose of MEKINIST, give it as soon as you remember. Do not give a missed dose of MEKINIST if it is less than 12 hours before the next scheduled dose. Just skip the missed dose and give the next dose of MEKINIST at the regular time.
If vomiting happens after a dose of MEKINIST is given, do not give an additional dose. Give the next dose of MEKINIST at the regular time.

How should I store MEKINIST?

MEKINIST tablets:

Store MEKINIST in a refrigerator between 36°F to 46°F (2°C to 8°C).
Keep MEKINIST dry and away from moisture and light.
The bottle of MEKINIST contains a drying agent (desiccant packet) to help keep your medicine dry. Do not throw away the desiccant packet.
Keep MEKINIST in its original bottle. Do not place tablets in a pill box.

Safely throw away MEKINIST that is out of date or no longer needed.

MEKINIST for oral solution:

Store MEKINIST oral solution in the original bottle at room temperature below 77°F (25°C). Do not freeze the oral solution.

Throw away (dispose of) unused MEKINIST oral solution after the “discard after” date written on the bottle label.

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

General information about the safe and effective use of MEKINIST.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use MEKINIST for a condition for which it was not prescribed. Do not give MEKINIST to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about MEKINIST that is written for health professionals.
What are the ingredients in MEKINIST?
...
MEKINIST for oral solution:

Active ingredient: trametinib

Inactive ingredients: betadex sulfobutyl ether sodium, citric acid monohydrate, dibasic sodium phosphate, methylparaben, potassium sorbate, sucralose, and strawberry flavor.

01/28/2022 (SUPPL-21)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Hepatic Impairment

Additions and/or revisions underlined:

No dose adjustment is recommended in patients with mild (bilirubin ? upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment.

A recommended dosage of MEKINIST has not been established for patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) or severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment. Consider the risk-benefit profile of MEKINIST related to dosing prior to determining whether to administer MEKINIST to patients with moderate or severe hepatic impairment.

In patients with moderate hepatic impairment, 3 patients who received a starting dose of 1.5 mg orally once daily and two patients who received a starting dose of 2 mg orally once daily did not experience dose limiting toxicities (DLTs) during the first cycle of therapy.

In patients with severe hepatic impairment, 3 patients who received a starting dose of 1 mg orally once daily did not experience DLTs during the first cycle; one patient who received a starting dose of 1.5 mg orally once daily experienced a DLT (grade 3 acneiform rash).

Compared to patients with normal hepatic function, there was no increase in exposure of trametinib in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

12/03/2021 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Serious Febrile Reactions

Additions and/or revisions underlined:

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib.

Across clinical trials of MEKINIST administered with dabrafenib, 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 MEKINIST when used as monotherapy, and both MEKINIST and dabrafenib 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, MEKINIST, or both MEKINIST and dabrafenib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at same or lower dose [see Dosage and Administration (2.7)].

Administer antipyretics as secondary prophylaxis when resuming MEKINIST 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)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serious Febrile Reactions

Advise patients that MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop a fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

fever. Fever is common during treatment with MEKINIST and dabrafenib, but it may also be serious. When taking MEKINIST with dabrafenib, 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 MEKINIST.
Your healthcare provider may temporarily or permanently stop your treatment, or change your dose of MEKINIST with dabrafenib 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.
…

05/07/2021 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Other clinically important adverse reactions for MEKINIST observed in less than 10% of patients who received MEKINIST in combination with dabrafenib (N = 559) were:

Cardiac: Bradycardia

Immunologic: Sarcoidosis

Musculoskeletal: Rhabdomyolysis

…

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

…

06/23/2020 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Serious Febrile Reactions

(Additions and/or revisions underlined)

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib.

Withhold MEKINIST for fever higher than 104ºF or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Upon resolution, resume at same or lower dose [see Dosage and Administration (2.7)]. Administer antipyretics as secondary prophylaxis when resuming MEKINIST 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.

04/09/2020 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

(Extensive changes; please refer to label)

6 Adverse Reactions

Clinical Trials Experience

(Extensive changes; please refer to label)

Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during postapproval use of MEKINIST in combination with dabrafenib. 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)

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

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.

Patient Information

(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 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

10/06/2019 (SUPPL-12)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

Lactation

Additions and/or revisions underlined:

Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose.

07/16/2019 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Hyperglycemia

(additions underlined)

…

Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.

5.5 Cardiomyopathy

(additions and revisions underlined)

…

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below LLN, permanently discontinue MEKINIST.

5.6 Ocular Toxicities

(additions and revisions underlined)

…

Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at same or reduced dose. If no improvement after 3 weeks, resume at reduced dose or permanently discontinue MEKINIST.

5.8 Serious Febrile Reactions

(additions and revisions underlined)

…

Upon resolution, resume at same or lower dose.

…

5.9 Serious Skin Toxicity

(additions underlined)

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

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 MEKINIST.

…

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 MEKINIST and for at least 4 months after the last dose.

…

8.5 Geriatric Use

(additions underlined)

Of the 214 patients with melanoma who received single agent MEKINIST in the METRIC study, 27% were aged 65 years and older and 4% were over 75 years old . This study of single agent MEKINIST in melanoma did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adults.

…

Of the 93 patients with NSCLC received MEKINST in Study BRF113928, there were insufficient numbers of geriatric patients aged 65 and older to determine whether they respond differently from younger adults.

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

8.6 Renal Impairment

(additions underlined)

No dose adjustment is recommended in patients with mild (GFR 60 to 89 mL/min/1.73 m2) or moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2).

The appropriate dose of MEKINIST has not been established in patients with severe renal impairment (GFR ?30 mL/min/1.73 m2).

8.7 Hepatic Impairment

(additions underlined)

No dose adjustment is recommended in patients with mild (bilirubin ? ULN and AST > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment . A recommended dosage of MEKINIST has not been established in patients with moderate (bilirubin >1.5x to 3x ULN and any AST) or severe (bilirubin >3x to 10x ULN and any AST) hepatic impairment.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Embryo-Fetal Toxicity

Advise pregnant women and males of reproductive potential of the potential risk to a fetus .
InstructAdvise females to contact their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose.
Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for at least 4 months after the last dose.

Lactation

Advise women not to breastfeed during treatment with MEKINIST and for 1 month after the last dose.

…

PATIENT INFORMATION

(additions underlined)

Before you take MEKINIST, 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 MEKINIST and for at least 4 months after your last dose of MEKINIST.

...

05/04/2018 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Directly after Table 10, addition of the following:

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

The safety of MEKINIST when administered with dabrafenib 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 MEKINIST or dabrafenib. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity.

Among these 100 patients, 46 (46%) were exposed to MEKINIST and dabrafenib for > 6 months and 23 (23%) were exposed to MEKINIST and dabrafenib 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)

PATIENT INFORMATION

The most common side effects of MEKINIST when taken alone include:

Addition of the following:

rash

04/30/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

(Additions and/or revisions are underlined)

Cutaneous Malignancies

In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving MEKINIST and dabrafenib was 3.3%. Among the 7 patients receiving MEKINIST with dabrafenib who developed basal cell carcinoma, 2 experienced more than one occurrence (range: 1 to 3). Cutaneous squamous cell carcinomas and keratoacanthoma (cuSCC) and new primary melanoma occurred in 3% and 0.5% of patients receiving MEKINIST and dabrafenib, respectively.

In the COMBI-AD study in the adjuvant treatment of melanoma, cuSCC and new primary melanoma occurred in 1% and less than 1% of patients receiving MEKINIST plus dabrafenib, respectively.

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

Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST are recommended in patients who develop new primary cutaneous malignancies.

Non-Cutaneous Malignancies

Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In the COMBI-d, COMBI-AD, and BRF113928 studies, non-cutaneous malignancies occurred in 1.4%, 1%, and 1.1% of patients receiving MEKINIST plus dabrafenib, respectively.

5.11 Risks Associated with Combination Treatment

(Newly added subsection)

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

5.2 Hemorrhage

Additions and/or revisions are underlined)

…

In the COMBI-d study, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib was 19%. Gastrointestinal hemorrhage occurred in 6% of patients receiving MEKINIST in combination with dabrafenib. In the COMBI-d study, 1.4% of patients receiving MEKINIST and dabrafenib developed fatal intracranial hemorrhage. No fatal hemorrhagic events were observed in the COMBI-AD study.

…

5.4 Venous Thromboembolism

(Additions and/or revisions are underlined)

In the COMBI-d study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of patients receiving MEKINIST and dabrafenib. In the COMBI-AD study, DVT and PE occurred in 2% of patients receiving MEKINIST and dabrafenib.

...

5.5 Cardiomyopathy

(Additions and/or revisions are underlined)

Cardiomyopathy, including cardiac failure, can occur with MEKINIST.

In the METRIC study in patients with unresectable or metastatic melanoma, cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% of patients receiving MEKINIST; no chemotherapy-treated patient developed cardiomyopathy. Four percent of patients required discontinuation and/or dose reduction of MEKINIST. Cardiomyopathy resolved in 10 of 14 patients.

…

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 MEKINIST with dabrafenib 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 MEKINIST with dabrafenib.

In Study BRF113298, 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 MEKINIST with dabrafenib and resulted in dose interruption and permanent discontinuation of MEKINIST in 5% and 2.2% of patients, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving MEKINIST and dabrafenib.

…

5.7 Interstitial Lung Disease

(Additions and/or revisions are underlined)

In clinical trials of single-agent MEKINIST, ILD or pneumonitis occurred in 2% of patients. In the METRIC study, 2.4% of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. In the COMBI-d, COMBI-AD, and BRF113928 studies, 1.0%, less than 1%, and 2.2% of patients receiving MEKINIST and dabrafenib developed pneumonitis, respectively.

...

5.8 Serious Febrile Reactions

(Additions and/or revisions are underlined)

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib.

Fever (serious and non-serious) occurred in 57% of patients with unresectable or metastatic melanoma receiving MEKINIST and dabrafenib.1 Approximately one-half of the patients who received MEKINIST and dabrafenib and experienced pyrexia had three or more discrete episodes.

Across clinical trials of MEKINIST administered with dabrafenib in patients with unresectable or metastatic melanoma, serious febrile reactions or fever of any severity complicated by severe rigors/chills, hypotension, dehydration, renal failure, or syncope, occurred in 17% of patients receiving MEKINIST and dabrafenib. 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.

…

5.9 Serious Skin Toxicity

(Additions and/or revisions are underlined)

…

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

Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients with improvement or recovery from skin toxicity within 3 weeks.

6 Adverse Reactions

(Additions and/or revisions are underlined)

…

There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib 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 MEKINIST administered as a single agent in 329 patients with various solid tumors and exposure to MEKINIST administered with dabrafenib in 559 patients with unresectable or metastatic melanoma and 93 patients with NSCLC. MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) and in an open-label, randomized, active-controlled trial (N = 211; the METRIC study). The median age was 54 years, 60% were male, > 99% were White, and all patients had unresectable or metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST.

Unresectable or Metastatic BRAF V600E or V600K Mutation Positive Melanoma

MEKINIST Administered as a Single Agent

Table 3 presents adverse reactions identified from analyses of the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks).

…

Table 6. Laboratory Abnormalities Worsening from Baseline Occurring at greater than or equal to 10% (All Grades) of Patients Receiving MEKINIST with Dabrafenib and at a Higher Incidence* than in Patients Receiving Single-Agent Dabrafenib in the COMBI-d Study

…

Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

The safety of MEKINIST when administered with dabrafenib 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 MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice 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 MEKINIST in combination with dabrafenib 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 1. Patients receiving MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients receiving MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months.

The most commonly occurring adverse reactions (greater than or equal to 20%) in patients receiving MEKINIST in combination with dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most common for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most common were pyrexia and ejection fraction decrease.

Table 7 summarizes adverse reactions that occurred in at least 20% of the patients receiving MEKINIST in combination with dabrafenib

(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 Studya

(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

…

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

…

7 Drug Interactions

(Additions and/or revisions are underlined)

No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib.

MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib labeling for additional risk information that applies to combination use treatment.

8 Use in Specific Populations

8.4 Geriatric Use

(Additions and/or revisions are underlined)

Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Of the 994 patients with melanoma randomized to receive MEKINIST plus dabrafenib 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 MEKINIST plus dabrafenib 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%) 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, please refer to the label

Patient Information

(Additions and/or revisions have been underlined)

…

What is MEKINIST?

MEKINIST is a prescription medicine used:

alone or in combination with a medicine called dabrafenib to treat people with a type of skin cancer called melanoma:
- that has spread to other parts of the body or cannot be removed by surgery, and
- that has a certain type of abnormal “BRAF” gene.
in combination with a medicine called dabrafenib, to help prevent melanoma that has a certain type of abnormal “BRAF” gene from coming back after the cancer has been removed by surgery.
MEKINIST should not be used to treat people who already have received a BRAF inhibitor for treatment of their melanoma, and it did not work or is no longer working.
in combination with dabrafenib to treat a type of lung cancer called non-small cell lung cancer (NSCLC)
- that has spread to other parts of the body (metastatic NSCLC), and
- that has a certain type of abnormal “BRAF V600E” gene.
  Your healthcare provider will perform a test to make sure that MEKINIST is right for you.
  It is not known if MEKINIST alone or MEKINIST with dabrafenib is safe and effective in children.
  …
  How should I take MEKINIST?

Take MEKINIST exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST unless your healthcare provider tells you.
Take MEKINIST one time a day, about every 24 hours.
….

06/22/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

Cutaneous Malignancies

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 MEKINIST plus dabrafenib with a time to onset of the first occurrence of 25 days, 3.5 months, and 12.3 months.

Non-Cutaneous Malignancies

The 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 MEKINIST with dabrafenib.

5.2 Hemorrhage

The 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 MEKINIST with dabrafenib; these events were retroperitoneal hemorrhage and subarachnoid hemorrhage.

5.4 Venous Thromboembolism

The COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113928, DVT and PE occurred in 4.3% (4/93) of patients receiving MEKINIST and dabrafenib.

5.5 Cardiomyopathy

In the METRIC study in patients with melanoma replaces In Trial 1

The COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113298, 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 MEKINIST with dabrafenib. The median time to onset of cardiomyopathy was 6.7 months (range: 1.4 months to

14.1 months). Cardiomyopathy in patients receiving MEKINIST and dabrafenib resulted in dose interruption and permanent discontinuation of MEKINIST in 5% and 2.2%, respectively. Cardiomyopathy resolved in 4 of 8 patients receiving MEKINIST and dabrafenib.

5.6 Ocular Toxicities

Retinal Pigment Epithelial Detachment (RPED)

Additions and/or revisions underlined:

… In melanoma and NSCLC trials, routine monitoring of patients …

5.7 Interstitial Lung Disease

In the METRIC study in patients with melanoma replaces In Trial 1

The COMBI-d study replaces Trial 2

Addition of the following:

In Study BRF113928, 2.2% (2/93) of patients receiving MEKINIST and dabrafenib developed pneumonitis.

5.8 Serious Febrile Reactions

Additions and/or revisions underlined:

Fever (serious and non-serious) occurred in 57% (119/209) of patients with melanoma receiving MEKINIST and dabrafenib and in 33% (69/211) of patients receiving dabrafenib alone in the COMBI-d study. The median …

Across clinical trials of MEKINIST administered with dabrafenib in patients with melanoma, serious febrile …

5.9 Serious Skin Toxicity

In the METRIC study in patients with melanoma replaces In Trial 1

The COMBI-d study replaces Trial 2

Across clinical trials of MEKINIST administered with dabrafenib (N = 559) in patients with melanoma, serious skin toxicity occurred …

5.10 Hyperglycemia

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 MEKINIST administered as a single agent in 329 patients with various solid tumors and exposure to MEKINIST administered with dabrafenib in 559 patients with melanoma and 93 patients with NSCLC. MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) and in an open-label, randomized, active-controlled trial (N = 211; the METRIC study). The median age was 54 years, 60% were male, greater than 99% were White, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST.

Unresectable or Metastatic BRAF V600E Mutation Positive Melanoma

MEKINIST Administered as a Single Agent

Table 3 presents adverse reactions identified from analyses of the METRIC study, a randomized …

Addition of in the METRIC Study to the Table 3 and Table 4 table titles

MEKINIST Administered with Dabrafenib

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

COMBI-d Studya is added to the Table 5 title

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

Addition of the following:

Metastatic, BRAF V600E Mutation-Positive NSCLC

The safety of MEKINIST when administered with dabrafenib 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 MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice 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 MEKINIST and dabrafenib for greater than 6 months and 27 (29%) were exposed to MEKINIST and dabrafenib for greater than or equal to 1 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 MEKINIST occurred in 19% 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 MEKINIST occurred in 30% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients receiving MEKINIST plus dabrafenib; the most common were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and ejection fraction decreased (5%).

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

Newly Added:

Table 7. Adverse Reactions Occurring in greater than or equal to 20% (All Grades) of Patients Treated with MEKINIST plus Dabrafenib in Study BRF113928a

Table 8. Treatment-Emergent Laboratory Abnormalities Occurring in greater than or equal to 20% (All Grades) of Patients Receiving MEKINIST plus Dabrafenib in Study BRF113928

Please refer to label for full data

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

… Of the 559 patients with melanoma randomized …

Addition of the following:

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

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Serious skin reactions … other skin reactions can be severe or serious, and may …
Common side effects of MEKINIST when taken with dabrafenib in people with melanoma include:
Addition of the following:
fever
rash

Newly added:

Common side effects of MEKINIST when taken with dabrafenib in people with NSCLC include:

fever
fatigue
nausea
vomiting
diarrhea
dry skin
decreased appetite
rash
swelling of face, arms, and legs
chills
bleeding
cough
shortness of breath

02/24/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Colitis and Gastrointestinal Perforation

(Newly added subsection)

Colitis and gastrointestinal perforation can occur with MEKINIST.

Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking MEKINIST as a single-agent and when administered with dabrafenib. Across clinical trials of MEKINIST administered as a single agent (N = 329) and MEKINIST administered with dabrafenib (N = 559), colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients.

Monitor patients closely for colitis and gastrointestinal perforations.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are discussed in greater detail in another section of the label:

Colitis and Gastrointestinal Perforation

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Colitis and gastrointestinal perforation

MEKINIST can cause colitis and gastrointestinal perforation. Advise patients to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation.

Patient Information

(Additions and/or revisions are underlined)

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

inflammation of the colon and bleeding in the stomach or intestines. MEKINIST can cause inflammation of the colon and bleeding in the stomach or intestines that can lead to death. Tell your healthcare provider immediately if you have any of the following symptoms:
- diarrhea
- stomach or abdominal pain
- fever
- nausea