Mekinist

Warnings and Precautions ( 5.6 ) 5/2026

1 INDICATIONS AND USAGE MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. ( 1.1 , 2.1 ) MEKINIST is indicated, in combination with dabrafenib, for: the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. ( 1.1 , 2.1 ) the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. ( 1.2 , 2.1 ) the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. ( 1.3 , 2.1 ) the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options. ( 1.4 , 2.1 ) the treatment of adult and 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. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1.5 , 2.1 ) the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. ( 1.6 , 2.1 ) Limitations of Use : MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. ( 1.7 , 12.1 ) 1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST ® is indicated, as a single agent in BRAF-inhibitor treatment-naïve patients or in combination with dabrafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1)] . 1.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST is indicated, in combination with dabrafenib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection [see Dosage and Administration (2.1)]. 1.3 BRAF V600E Mutation-Positive Metastatic NSCLC MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and Administration (2.1)] . 1.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)] . 1.5 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors MEKINIST is indicated, in combination with dabrafenib, for the treatment of adult and 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 [see Dosage and Administration (2.1)] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.6)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a co …

2 DOSAGE AND ADMINISTRATION The recommended dosage of MEKINIST in adult patients is 2 mg orally once daily. The recommended dosage for MEKINIST in pediatric patients is based on body weight. ( 2 ) 2.1 Patient Selection Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as a single agent or in combination with dabrafenib [see Clinical Studies (14.1, 14.2)] . Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . NSCLC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.3)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.4)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in ATC is available at: http://www.fda.gov/CompanionDiagnostics . Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.6)] . An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available. Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.7)] . An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available. 2.2 Recommended Dosage MEKINIST Tablets Adult Patients The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily [see Dosage and Administration (2.3)] . Pediatric Patients The recommended dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)] . A recommended dosage of MEKINIST tablets has not been established in patients who weigh less than 26 kg. Table 1. Recommended Dosage for MEKINIST Tablets in Pediatric Patients (Weight-based) Body Weight Recommended Dosage 26 to 37 kg 1 mg orally once daily 38 to 50 kg 1.5 mg orally once daily 51 kg or greater 2 mg orally once daily MEKINIST for Oral Solution Adult and Pediatric Patients The recommended dosage for MEKINIST for oral solution for adult and pediatric patients is based on body weight (Table 2) [see Dosage and Administration (2.3)] . Table 2. Recommended Dosage for MEKINIST for Oral Solution in Adult and Pediatric Patients (Weight-based) Body Weight Recommended Dosage Total Volume of Oral Solution Once Daily (Trametinib Content) 8 kg 0.3 mg (6 mL) 9 kg 0.35 mg (7 mL) 10 kg 0.35 mg (7 mL) 11 kg 0.4 mg (8 mL) 12 to 13 kg 0.45 mg (9 mL) 14 to 17 kg 0.55 mg (11 mL) 18 to 21 kg 0.7 mg (14 mL) 22 to 25 kg 0.85 mg (17 mL) 26 to 29 kg 0.9 mg (18 mL) 30 to 33 kg 1 mg (20 mL) 34 to 37 kg 1.15 mg (23 mL) 38 to 41 kg 1.25 mg (25 mL) 42 to 45 kg 1.4 mg (28 mL) 46 to 50 kg 1.6 mg (32 mL) ≥ 51 kg 2 mg (40 mL) Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity. Combination Therapy with Dabrafenib Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.3 Administration Take MEKINIST at the same time each day, approx …

3 DOSAGE FORMS AND STRENGTHS MEKINIST tablets: 0.5 mg tablets: Yellow, ovaloid, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘TT’ on the other side. 2 mg tablets: Pink, round, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘LL’ on the other side. MEKINIST for oral solution: White to almost white powder containing 4.7 mg of trametinib per bottle. Each mL of reconstituted strawberry-flavored trametinib solution contains 0.05 mg of trametinib. MEKINIST Tablets: 0.5 mg, 2 mg ( 3 ) MEKINIST for Oral Solution: 4.7 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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 )] There are additional adverse reactions associated with dabrafenib. Refer to the dabrafenib prescribing information for additional information. Most common adverse reactions (≥ 20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema. ( 6.1 ) Most common adverse reactions (≥ 20%) for MEKINIST in combination with dabrafenib include: Unresectable or metastatic melanoma: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. ( 6.1 ) Adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. ( 6.1 ) NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. ( 6.1 ) Adult patients with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema. ( 6.1 ) Pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia. ( 6.1 ) Pediatric patients with LGG: pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054. Among these 329 patients who received MEKINIST as a single agent, 33% were exposed for 6 months or longer and 9% were exposed for greater than one year. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily, administered in combination with dabrafenib 150 mg orally, twice daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC. Among these 1087 patients who received MEKINIST administered with dabrafenib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year. Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based MEKINIST orally, once daily administered in combination with dabrafenib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refr …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS Lactation : Do not breastfeed. ( 8.2 ) Females and Males of Reproductive Potential : May impair fertility. Counsel patients on pregnancy planning and prevention. ( 8.3 ) 8.1 Pregnancy 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 a 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 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 Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating MEKINIST. Contraception Based on data from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 )]. Females Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. 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 4 months after the last dose. 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 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 wi …

12.1 Mechanism of Action Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo. Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation-positive tumor xenografts compared with either drug alone. In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.7)] .

11 DESCRIPTION Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C 26 H 23 FIN 5 O 4 •C 2 H 6 OS with a molecular mass of 693.53 g/mol. Trametinib dimethyl sulfoxide has the following chemical structure: Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media. MEKINIST (trametinib) tablets for oral use are supplied as 0.5 mg and 2 mg tablets for oral administration. Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent. The inactive ingredients of MEKINIST tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, and sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), and titanium dioxide. MEKINIST (trametinib) for oral solution is a white or almost white powder which produces a clear colorless solution when reconstituted with water. Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide. Each mL of reconstituted trametinib solution contains 0.05 mg of trametinib non-solvated parent. The inactive ingredients of MEKINIST for oral solution are betadex sulfobutyl ether sodium, citric acid monohydrate, dibasic sodium phosphate, methylparaben, potassium sorbate, sucralose, and strawberry flavor. Trametinib Structure-01

10 OVERDOSAGE The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of RPEDs for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

16 HOW SUPPLIED/STORAGE AND HANDLING MEKINIST Tablets : 0.5 mg tablets: Yellow, ovaloid, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘TT’ on the other side; available in bottles of 30 (NDC 0078-1105-15). 2 mg tablets: Pink, round, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘LL’ on the other side; available in bottles of 30 (NDC 0078-1112-15). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes. MEKINIST for Oral Solution : White or almost white powder in amber glass bottles, co-packaged with a press-in bottle adapter and an oral syringe. Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide. Each mL of reconstituted strawberry flavored trametinib solution contains 0.05 mg of trametinib non-solvated parent. (NDC 0078-1161-47). Store refrigerated at 2°C to 8°C (36°F to 46°F). Store in the original carton to protect from light and moisture. After reconstitution, store in the original bottle below 25°C (77°F) and do not freeze. Discard any unused solution 35 days after reconstitution.