Novartis Pharmaceuticals Corporation

Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL POLYSORBATE 80 GS;TFC Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE GS;HMJ Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE YELLOW POLYETHYLENE GLYCOL TITANIUM DIOXIDE IMPRINT;TT biconvex, with beveled edges Mekinist trametinib TRAMETINIB DIMETHYL SULFOXIDE TRAMETINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE FERRIC OXIDE RED POLYETHYLENE GLYCOL POLYSORBATE 80 TITANIUM DIOXIDE IMPRINT;LL biconvex, with beveled edges

Dosage and Administration (2.7)	12/2021
Warnings and Precautions (5.8)	12/2021

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 and with no satisfactory locoregional treatment options. (1.4, 2.1)

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)].

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)].

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)].

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 and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)].

The recommended dosage of MEKINIST is 2 mg orally once daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal. (2)

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)]. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.

The recommended dosage of MEKINIST is 2 mg orally taken once daily, as a single agent or in combination with dabrafenib, until disease progression or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

The recommended dosage of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity for up to 1 year. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

The recommended dosage of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

The recommended dosage of MEKINIST is 2 mg orally taken once daily in combination with dabrafenib until disease recurrence or unacceptable toxicity. Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.

Take MEKINIST doses approximately 24 hours apart. Take MEKINIST at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST.

Dose reductions for adverse reactions associated with MEKINIST are presented in Table 1.

Table 1. Recommended Dose Reductions for MEKINIST for Adverse Reactions

Action	Recommended Dose
First Dose Reduction	1.5 mg orally once daily
Second Dose Reduction	1 mg orally once daily
Subsequent Modification	Permanently discontinue if unable to tolerate MEKINIST 1 mg orally once daily

Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 2.

Table 2. Recommended Dosage Modifications for MEKINIST for Adverse Reactions

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. bSee Table 1 for recommended dose reductions of MEKINIST. cDose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies.
Severity of Adverse Reactiona	Dosage Modification for MEKINISTb
Hemorrhage [see Warnings and Precautions (5.2)]
Grade 3	Withhold MEKINIST. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST.
Grade 4	Permanently discontinue MEKINIST.
Venous Thromboembolism [see Warnings and Precautions (5.4)]
Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE)	Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST.
Life threatening PE	Permanently discontinue MEKINIST.
Cardiomyopathy [see Warnings and Precautions (5.5)]
Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and is below institutional lower limit of normal (LLN) from pretreatment value	Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST.
Symptomatic cardiomyopathy Absolute decrease in LVEF of greater than 20% from baseline that is below LLN	Permanently discontinue MEKINIST.
Ocular Toxicities [see Warnings and Precautions (5.6)]
Retinal pigment epithelial detachments (RPED)	Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose. If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose.
Retinal vein occlusion (RVO)	Permanently discontinue MEKINIST.
Pulmonary [see Warnings and Precautions (5.7)]
Interstitial lung disease (ILD)/pneumonitis	Permanently discontinue MEKINIST.
Febrile Reactions [see Warnings and Precautions (5.8)]
Fever of 100.4°F to 104°F (or first symptoms in case of recurrence)	Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose.
Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure	Withhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST.
Skin Toxicities [see Warnings and Precautions (5.9)]
Intolerable Grade 2 Grade 3 or 4	Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue.
Severe cutaneous adverse reactions (SCARs)	Permanently discontinue MEKINIST.
Other Adverse Reactionsc
Intolerable Grade 2 Any Grade 3	Withhold MEKINIST. If improved to Grade 0-1, resume at lower dose. If not improved, permanently discontinue.
First occurrence of any Grade 4	Withhold MEKINIST until improves to Grade 0-1, then resume at lower dose. Or Permanently discontinue MEKINIST.
Recurrent Grade 4	Permanently discontinue MEKINIST.

Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.

Tablets: 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 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, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face. 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. Tablets: 0.5 mg, 2 mg (3)

None. None. (4)

New Primary Malignancies, Cutaneous, and Non-Cutaneous, can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of treatment. (5.1) Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. (5.2) Colitis and Gastrointestinal Perforation: Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. (5.3) Venous Thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST. (5.4, 2.7) Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every 2 to 3 months thereafter. (5.5, 2.7) Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. (5.6, 2.7) Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.7) Serious Febrile Reactions can occur when MEKINIST is used with dabrafenib. (5.8, 2.7) Serious Skin Toxicities: Monitor for skin toxicities and for secondary infections. Permanently discontinue MEKINIST for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. Permanently discontinue for severe cutaneous adverse reactions (SCARs). (5.9, 2.7) Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. (5.10) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.12, 8.1, 8.3)

Cutaneous Malignancies Across clinical trials of MEKINIST administered with dabrafenib, 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. 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. Across clinical trials 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.

Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. Fatal cases have been reported. Across clinical trials of MEKINIST administered with dabrafenib, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received MEKINIST administered with dabrafenib. Intracranial hemorrhage occurred in 0.6% of patients who received MEKINIST administered with dabrafenib. Fatal hemorrhage occurred in 0.5% of patients who received MEKINIST administered with dabrafenib. The fatal events were cerebral hemorrhage and brainstem hemorrhage. 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.

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, colitis occurred in < 1% of patients and gastrointestinal perforation occurred in < 1% of patients. Across clinical trials of MEKINIST administered with dabrafenib, colitis occurred in < 1% of patients and gastrointestinal perforation occurred in < 1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.

Across clinical trials of MEKINIST administered with dabrafenib, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level [see Dosage and Administration (2.7)].

Cardiomyopathy, including cardiac failure, can occur with MEKINIST. Across clinical trials of MEKINIST administered with dabrafenib, 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. Assess LVEF by echocardiogram or multi-gated 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 [see Dosage and Administration (2.7)].

Retinal Vein Occlusion Across clinical trials with MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. Across clinical trials of MEKINIST administered with dabrafenib, there were no cases of RVO. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO [see Dosage and Administration (2.7)]. 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. 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 [see Dosage and Administration (2.7)].

Across clinical trials of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. Across clinical trials 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 (2.7)].

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 ≥ 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.

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)]. Across clinical trials of MEKINIST administered with dabrafenib, other serious skin toxicity occurred in < 1% of patients. Monitor for new or worsening serious skin reactions. Permanently discontinue MEKINIST for SCARs [see Dosage and Administration (2.7)]. For other skin toxicities, 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 [see Dosage and Administration (2.7)].

Across clinical trials of MEKINIST administered with dabrafenib, 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. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.

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

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 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)].

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 Thromboembolism [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 )] 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 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) 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.

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. The pooled safety populations described in the WARNINGS and PRECAUTIONS reflect exposure to MEKINIST as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054, and to MEKINIST administered with dabrafenib in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among the 329 patients who received MEKINIST as a single agent, 33% were exposed for 6 months or longer and 9% were exposed for at least one year. Among the 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. Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST as a Single Agent The safety of MEKINIST was evaluated in the METRIC study, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1000 mg/m² every 3 weeks or paclitaxel 175 mg/m² every 3 weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded. The median duration of treatment with MEKINIST was 4.3 months. In this study, 9% of patients who received MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most frequent adverse reactions resulting in permanent discontinuation of MEKINIST were decreased LVEF, pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most frequent reasons cited for dose reductions of MEKINIST. Tables 3 and 4 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as a single agent in the METRIC study.

Table 3. Select Adverse Reactions Occurring in ≥ 10% of Patients Who Received MEKINIST and at a Higher Incidence (≥ 5%) Than in the Chemotherapy Arm or ≥ 2% (Grades 3 or 4) Adverse Reactions in METRIC

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bGrade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. cIncludes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. dIncludes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. eIncludes lymphedema, edema, and peripheral edema. fIncludes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.
Adverse Reactions	MEKINIST		Chemotherapy
	N = 211		N = 99
	All Gradesa (%)	Grades 3 and 4 b (%)	All Grades a (%)	Grades 3 and 4 b (%)
Skin and subcutaneous tissue
Rash	57	8	10	0
Acneiform dermatitis	19	< 1	1	0
Dry skin	11	0	0	0
Pruritus	10	2	1	0
Paronychia	10	0	1	0
Gastrointestinal
Diarrhea	43	0	16	2
Stomatitisc	15	2	2	0
Abdominal paind	13	1	5	1
Vascular
Lymphedemae	32	1	4	0
Hypertension	15	12	7	3
Hemorrhagef	13	< 1	0	0

Other clinically important adverse reactions observed in ≤ 10% of patients (N = 329) who received MEKINIST were: Cardiac: Bradycardia Gastrointestinal: Dry mouth Infections: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Dizziness, dysgeusia Ocular: Blurred vision, dry eye

Table 4. Laboratory Abnormalities Occurring at a Higher Incidence in Patients Who Received MEKINIST in the METRIC Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)^a]

aOnly Grade 3 adverse reactions were reported in either treatment arm.
Laboratory Abnormality	MEKINIST		Chemotherapy
	N = 211		N = 99
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Increased aspartate aminotransferase (AST)	60	2	16	1
Hypoalbuminemia	42	2	23	1
Increased alanine aminotransferase (ALT)	39	3	20	3
Anemia	38	2	26	3
Increased alkaline phosphatase	24	2	18	3

MEKINIST with Dabrafenib The safety of MEKINIST, administered with dabrafenib, was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received MEKINIST in two trials, the COMBI-d study (n = 209), a multicenter, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multicenter, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of glucose-6-phosphate dehydrogenase deficiency. Among these 559 patients, 197 (35%) were exposed to MEKINIST for > 6 months to 12 months, while 185 (33%) were exposed to MEKINIST for > 1 year. The median age was 55 years (range: 18 to 91), 57% were male, and 98% were white, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had a history of brain metastases. The most common adverse reactions (≥ 20%) for MEKINIST in patients who received MEKINIST plus dabrafenib were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies (14.1)]. Patients who received MEKINIST plus dabrafenib had a median duration of exposure of 11 months (range: 3 days to 30 months) to MEKINIST. Among the 209 patients who received MEKINIST plus dabrafenib, 26% were exposed to MEKINIST for > 6 months to 12 months while 46% were exposed to MEKINIST for > 1 year. In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (1.4%) and decreased ejection fraction (1.4%). Adverse reactions leading to dose reductions of MEKINIST occurred in 18% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (2.9%), neutropenia (1.9%), decreased ejection fraction (1.9%), and rash (1.9%). Adverse reactions leading to dose interruptions of MEKINIST occurred in 46% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (18%), chills (7%), vomiting (6%), and decreased ejection fraction (4.8%). Table 5 and Table 6 present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study.

Table 5. Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d^a

*≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. bIncludes peripheral edema, edema, lymphedema, localized edema, and generalized edema. cIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal discomfort. dIncludes rash, generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculo-papular, and folliculitis rash. eMost common events (≥ 1%) include epistaxis, hematochezia, decreased hemoglobin, purpura, and rectal hemorrhage. Grade 4 events were limited to hepatic hematoma and duodenal ulcer hemorrhage (each n = 1 in the pooled combination arm).
Adverse Reactions	Pooled MEKINIST plus Dabrafenib N = 559		COMBI-d Study
			MEKINIST plus Dabrafenib   N =   209		Dabrafenib N = 211
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
General
Pyrexia	54	5	57	7	33	1.9
Chills	31	0.5	31	0	17	0.5
Peripheral edemab	21	0.7	25	1.4	11	0.5
Gastrointestinal
Nausea	35	0.4	34	0.5	27	1.4
Diarrhea	31	1.3	30	1.4	16	0.9
Vomiting	27	1.1	25	1.0	14	0.5
Abdominal painc	18	0.9	26	1.0	14	2.4
Skin
Rashd	32	1.1	42	0	27	1.4
Vascular
Hypertension	26	11	25	6	16	6
Hemorrhagee	18	2.0	19	1.9	15	1.9
Nervous system
Dizziness	11	0.2	14	0	7	0

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

Table 6. Laboratory Abnormalities Worsening From Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received MEKINIST With Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. *≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. aFor these laboratory tests the denominator is 556. bFor these laboratory tests the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. cGrade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1), in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, hyperglycemia (each n = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm.
Laboratory Abnormality	Pooled MEKINIST plus Dabrafenib N = 559a		COMBI-d Study
			MEKINIST plus Dabrafenib   N =   209b		Dabrafenib N = 211b
	All Grades (%)	Grades 3 and 4c (%)	All Grades (%)	Grades 3 and 4c (%)	All Grades (%)	Grades 3 and 4c (%)
Chemistry
Hyperglycemia	60	4.7	65	6	57	4.3
Hypoalbuminemia	48	1.1	53	1.4	27	0
Hyponatremia	25	8	24	6	14	2.9
Hepatic
Increased AST	59	4.1	60	4.3	21	1.0
Increased blood alkaline phosphatase	49	2.7	50	1.0	25	0.5
Increased ALT	48	4.5	44	3.8	28	1.0
Hematology
Neutropenia	46	7	50	6	16	1.9
Anemia	43	2.3	43	2.4	38	4.3
Lymphopenia	32	8	38	9	28	7
Thrombocytopenia	21	0.7	19	0.5	10	0.5

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 [see Clinical Studies (14.2)]. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily for 12 months. The trial excluded patients with abnormal LVEF; 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 ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO. Patients who received MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients who received MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months. 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. The most common adverse reactions (≥ 20%) in patients who received 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 frequent for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most frequent were pyrexia and decreased ejection fraction. Table 7 summarizes adverse reactions that occurred in at least 20% of the patients who received MEKINIST in combination with dabrafenib.

Table 7. Adverse Reactions Occurring in ≥ 20% of Patients in COMBI-AD^a

aNCI CTCAE version 4.0. bIncludes pyrexia and hyperpyrexia. cIncludes fatigue, asthenia, and malaise. dIncludes headache and tension headache. eIncludes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. fIncludes myalgia, musculoskeletal pain, and musculoskeletal chest pain.
Adverse Reactions	MEKINIST plus Dabrafenib N = 435		Placebo N = 432
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
General
Pyrexiab	63	5	11	< 1
Fatiguec	59	5	37	< 1
Chills	37	1	4	0
Gastrointestinal
Nausea	40	< 1	20	0
Diarrhea	33	< 1	15	< 1
Vomiting	28	< 1	10	0
Nervous system
Headached	39	1	24	0
Skin
Rashe	37	< 1	16	< 1
Musculoskeletal
Arthralgia	28	< 1	14	0
Myalgiaf	20	< 1	14	0

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%). The laboratory abnormalities are summarized in Table 8.

Table 8. Laboratory Abnormalities Worsening From Baseline Occurring in ≥ 20% of Patients in COMBI-AD

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aThe incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: MEKINIST plus dabrafenib (range: 429 to 431) and placebo arm (range: 426 to 428).
Laboratory Abnormality	MEKINIST plus Dabrafeniba N = 435		Placeboa N = 432
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Chemistry
Hyperglycemia	63	3	47	2
Hypophosphatemia	42	7	10	< 1
Hypoalbuminemia	25	< 1	< 1	0
Hepatic
Increased AST	57	6	11	< 1
Increased ALT	48	5	18	< 1
Increased blood alkaline phosphatase	38	1	6	< 1
Hematology
Neutropenia	47	6	12	< 1
Lymphopenia	26	5	6	< 1
Anemia	25	< 1	6	< 1

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 ≥ 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. Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 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 LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of ILD or pneumonitis, or history or current RVO [see Clinical Studies (14.3)]. Among these 93 patients, 53 (57%) were exposed to MEKINIST and dabrafenib for > 6 months and 27 (29%) were exposed to MEKINIST and dabrafenib for ≥ 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 common adverse reactions (≥ 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 frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients who received MEKINIST plus dabrafenib; the most frequent 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 who received MEKINIST plus dabrafenib; the most frequent were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and decreased ejection fraction (5%). Table 9 and Table 10 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF113928.

Table 9. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated With MEKINIST plus Dabrafenib in Study BRF113928^a

aNCI CTCAE version 4.0. bIncludes fatigue, malaise, and asthenia. cIncludes peripheral edema, edema, and generalized edema. dIncludes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.
Adverse Reactions	MEKINIST plus Dabrafenib N =  93
	All Grades (%)	Grades 3 and 4 b (%)
General
Pyrexia	55	5
Fatigueb	51	5
Edemac	28	0
Chills	23	1.1
Gastrointestinal
Nausea	45	0
Vomiting	33	3.2
Diarrhea	32	2.2
Decreased appetite	29	0
Skin
Dry skin	31	1.1
Rashd	28	3.2
Vascular
Hemorrhagee	23	3.2
Respiratory system
Cough	22	0
Dyspnea	20	5

Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received MEKINIST Plus Dabrafenib in Study BRF113928

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. aFor these laboratory tests the denominator is 90. bFor these laboratory tests the denominator is 91.
Laboratory Abnormality	MEKINIST plus Dabrafenib N =  93
	All Grades (%)	Grades 3 and 4 (%)
Chemistry a
Hyperglycemia	71	9
Hyponatremia	57	17
Hypophosphatemia	36	7
Increased creatinine	21	1.1
Hepatica
Increased blood alkaline phosphatase	64	0
Increased AST	61	4.4
Increased ALT	32	6
Hematologyb
Leukopenia	48	8
Anemia	46	10
Neutropenia	44	8
Lymphopenia	42	14

Locally Advanced or Metastatic, BRAF V600E Mutation-Positive, Anaplastic Thyroid Cancer 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 ≥ 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.

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)

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

Lactation: Do not breastfeed. (8.2) Females and Males of Reproductive Potential: May impair fertility. Counsel patients on pregnancy planning and prevention. (8.3)

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 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 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 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 dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

Risk Summary There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with MEKINIST and for 4 months following the last dose.

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 at least 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 dose [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been established in pediatric patients. Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.

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 [see Clinical Studies (14.1)]. 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 994 patients with melanoma who received MEKINIST plus dabrafenib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.1, 14.2)], 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 geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in geriatric patients as compared to younger adults in these studies. Of the 93 patients with NSCLC who received MEKINIST in Study BRF113928, there were insufficient numbers of geriatric patients aged 65 and older to determine whether they respond differently from younger adults [see Clinical Studies (14.4)]. Of 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 [see Clinical Studies (14.4)]. This study did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

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)].

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.

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 C26H23FIN5O4•C2H6OS 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. Trametinib Structure-01

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.

Administration of 1 mg and 2 mg MEKINIST to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers, including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). Cardiac Electrophysiology The heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in a dedicated study in 32 patients who received placebo on Day 1 and MEKINIST 2 mg once daily on Days 2-14 followed by MEKINIST 3 mg on Day 15. No clinically relevant QTc prolongation was detected in the study. In clinical trials in patients who received MEKINIST with dabrafenib, QTc prolongation > 500 ms occurred in 0.8% of patients and QTc increased by > 60 ms from baseline in 3.8% of patients.

The pharmacokinetics of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma. Absorption After oral administration of MEKINIST, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single oral dose of MEKINIST 2 mg is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 mg (0.0625 times the approved recommended dosage) to 10 mg (5 times the approved recommended dosage) while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 mg to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively. Effect of Food Administration of a single dose of MEKINIST with a high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions. Distribution Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. Elimination The estimated elimination half-life of trametinib based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h. Metabolism Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and may also be mediated by other hydrolytic enzymes. Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥ 75% of drug-related material in plasma is the parent compound. Excretion Following oral administration of [14C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as parent. Specific Populations Age, sex, body weight, and renal impairment (eGFR 15 to 89 mL/min/1.73 m2) do not have a clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity. Patients with Hepatic Impairment: Based on results from a pharmacokinetic study in patients with mild to severe hepatic impairment defined by bilirubin and AST levels, mild, moderate, and severe hepatic impairment had no significant effect in trametinib exposure or apparent drug clearance compared with patients with normal hepatic function [see Use in Specific Populations (8.6)]. Drug Interaction Studies Effect of Dabrafenib on Trametinib : Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in no change in AUC of trametinib as compared with administration of trametinib. Effect of Trametinib on CYP Substrates: Based on in vitro studies, trametinib is an inhibitor of CYP2C8, but is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at a clinically relevant systemic concentration of 0.04 µM. Trametinib is an inducer of CYP3A in vitro. Based on cross-study comparisons, oral administration of MEKINIST 2 mg once daily with a sensitive CYP3A4 substrate had no clinically important effect on the AUC and Cmax of the sensitive CYP3A4 substrate. Effect of Transporters on Trametinib: Trametinib is a substrate of P-glycoprotein (P-gp) and BSEP. Inhibition of P-gp is unlikely to result in a clinically important increase in trametinib concentrations as trametinib exhibits high passive permeability and bioavailability. Trametinib is not a substrate of BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2, or MATE1 in vitro. Effect of Trametinib on Transporters: Based on in vitro studies, trametinib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, BSEP, MRP2, or MATE1 at a clinically relevant systemic concentration of 0.04 µM.

Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats. Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥ 0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues [see Use in Specific Populations (8.3)].

Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study Figure 2. Kaplan-Meier Curves of Overall Survival in the COMBI-d Study Figure 3. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma

MEKINIST as a Single Agent The safety and efficacy of MEKINIST were evaluated in an international, multicenter, randomized (2:1), open-label, active-controlled trial (the METRIC study; NCT01245062) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. In the METRIC study, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1000 mg/m² intravenously every 3 weeks or paclitaxel 175 mg/m² intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes vs. no) and LDH level (normal vs. greater than ULN). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID^®-BRAF assay. The major efficacy outcome measure was progression-free survival (PFS). The median age for randomized patients was 54 years, 54% were male, greater than 99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (less than 1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST. The METRIC study demonstrated a statistically significant increase in PFS in the patients treated with MEKINIST. Table 11 and Figure 1 summarize the PFS results.

Table 11. Efficacy Results in the METRIC Study

Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. aPike estimator.
Investigator - A ssessed Endpoints	MEKINIST N   =   214	Chemotherapy N   =   108
P rogression- F ree S urvival
Number of Events (%)	117 (55%)	77 (71%)
Progressive Disease	107 (50%)	70 (65%)
Death	10 (5%)	7 (6%)
Median, months (95% CI)	4.8 (4.3, 4.9)	1.5 (1.4, 2.7)
HRa (95% CI)	0.47 (0.34, 0.65)
P value (log-rank test)	< 0.0001
Confirmed Tumor Responses
Overall Response Rate (95% CI)	22% (17%, 28%)	8% (4%, 15%)
Complete Response, n (%)	4 (2%)	0
Partial Response, n (%)	43 (20%)	9 (8%)
Duration of Response
Median DoR, months (95% CI)	5.5 (4.1, 5.9)	NR (3.5, NR)

Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis. MEKINIST with Dabrafenib COMBI-d Study The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (the COMBI-d study; NCT01584648). The COMBI-d study compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by LDH level (greater than the ULN vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed PFS per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR). In the COMBI-d study, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, > 99% were white, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma.  The COMBI-d study demonstrated statistically significant improvements in PFS and OS. Table 12 and Figure 2 summarize the efficacy results.

Table 12. Efficacy Results in the COMBI-d Study

Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, overall response rate. aPFS and ORR were assessed by investigator. bBased on stratified log-rank test.
Endpoint	MEKINIST plus D abrafenib N   =   211	Placebo plus Dabrafenib N   =   212
Progression-Free Survivala
Number of Events (%)	102 (48%)	109 (51%)
Median, months (95% CI)	9.3 (7.7, 11.1)	8.8 (5.9, 10.9)
HR (95% CI)	0.75 (0.57, 0.99)
P valueb	0.035
Overall Survival
Number of Deaths (%)	99 (47%)	123 (58%)
Median, months (95% CI)	25.1 (19.2, NR)	18.7 (15.2, 23.1)
HR (95% CI)	0.71 (0.55, 0.92)
P valueb	0.01
Overall Response Ratea
ORR (95% CI)	66% (60%, 73%)	51% (44%, 58%)
P value	< 0.001
Complete Response	10%	8%
Partial Response	56%	42%
Median DoR, months (95% CI)	9.2 (7.4, NR)	10.2 (7.5, NR)

Figure 2. Kaplan-Meier Curves of Overall Survival in the COMBI-d Study COMBI-MB Study The activity of MEKINIST with dabrafenib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in a non-randomized, open-label, multicenter, multi-cohort trial (the COMBI-MB study; NCT02039947). Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least 5 mm in diameter, as assessed by independent review. The COMBI-MB study enrolled 121 patients with a BRAF V600E (85%) or V600K (15%) mutation. The median age was 54 years (range: 23 to 84 years), 58% were male, 100% were white, 8% were from the United States, 65% had a normal LDH value at baseline, and 97% had an ECOG performance status of 0 or 1. Intracranial metastases were asymptomatic in 87% and symptomatic in 13% of patients, 22% received prior local therapy for brain metastases, and 87% also had extracranial metastases. The intracranial response rate was 50% (95% CI: 40, 60), with a complete response rate of 4.1% and a partial response rate of 46%. The median duration of intracranial response was 6.4 months (range: 1 to 31 months). Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response.

The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, multicenter, randomized, double-blind, placebo-controlled trial (COMBI-AD; NCT01682083) that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the THxID^®-BRAF assay and pathologic involvement of regional lymph node(s). Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anticancer treatment, including radiotherapy. Patients were randomized (1:1) to receive MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for up to 1 year. Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7^th Edition) Stage (IIIa, IIIb, or IIIc). The major efficacy outcome measure was relapse-free survival (RFS) defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients underwent imaging for tumor recurrence every 3 months for the first two years and every 6 months thereafter. In COMBI-AD, a total of 870 patients were randomized: 438 to the MEKINIST in combination with dabrafenib and 432 to placebo. Median age was 51 years (range: 18 to 89), 55% were male, 99% were white, and 91% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIa (18%), Stage IIIb (41%), Stage IIIc (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic lymph nodes (65%); and tumor ulceration (41%). The median duration of follow-up (time from randomization to last contact or death) was 2.8 years. COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in combination with dabrafenib arm compared to those randomized to placebo. Efficacy results are presented in Table 13 and Figure 3.

Table 13. Efficacy Results in COMBI-AD in the Adjuvant Treatment of Melanoma

Abbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable. aPike estimator obtained from the stratified log-rank test. bLog-rank test stratified by disease stage – IIIa vs. IIIb vs. IIIc – and BRAF V600 mutation type – V600E vs. V600K.
	MEKINIST plus Dabrafenib N = 438	Placebo N = 432
Relapse-Free Survival
Number of Events (%)	166 (38)	248 (57)
Median, months (95% CI)	NE (44.5, NE)	16.6 (12.7, 22.1)
HR (95% CI)a	0.47 (0.39, 0.58)
P valueb	< 0.0001

Figure 3. Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma

The safety and efficacy of dabrafenib alone or administered with MEKINIST were evaluated in a multicenter, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928; NCT01336634). Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts A and B were required to have received at least one previous platinum-based chemotherapy regimen with demonstrated disease progression but no more than three prior systemic regimens. Patients in Cohort C could not have received prior systemic therapy for metastatic disease. Patients in Cohort A received dabrafenib 150 mg twice daily. Patients in Cohorts B and C received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response. There were a total of 171 patients enrolled, which included 78 patients enrolled in Cohort A, 57 patients enrolled in Cohort B, and 36 patients enrolled in Cohort C. The characteristics of the population were: a median age of 66 years; 48% male; 81% white, 14% Asian, 3% black, and 2% Hispanic; 60% former smokers, 32% never smokers, and 8% current smokers; 27% had ECOG performance status (PS) of 0, 63% had ECOG PS of 1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and 14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting, 58% of the 135 previously treated patients had only one line of prior systemic therapy for metastatic disease; 98% had non-squamous histology. Efficacy results are summarized in Table 14.

Table 14. Efficacy Results Based on Independent Review in Study BRF113928

Abbreviations: CI, confidence interval; DoR, duration of response; NE, not estimable.
Treatment	Dabrafenib	MEKINIST plus Dabrafenib
Population	Previously Treated N = 78	Previously Treated N = 57	Treatment Naïve N = 36
Overall Response Rate
ORR (95% CI)	27% (18%, 38%)	63% (49%, 76%)	61% (44%, 77%)
Complete Response	1%	4%	3%
Partial Response	26%	60%	58%
Duration of Response	n = 21	n = 36	n = 22
Median DoR, months (95% CI)	9.9 (4.2, NE)	12.6 (5.8, NE)	NE (6.9, NE)
% with DoR ≥ 6 months	52%	64%	59%

In a subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine^™ Dx Target Test, the ORR results were similar to those presented in Table 14.

The safety and efficacy of MEKINIST administered with dabrafenib was evaluated in an activity-estimating, nine-cohort, multicenter, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction. Patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome measure was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR). Thirty-six patients were enrolled and were evaluable for response in the ATC cohort. The median age was 71 years (range: 47-85); 44% were male, 50% white, 44% Asian; and 94% had ECOG performance status of 0 or 1. Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%). Efficacy results are summarized in Table 15.

Table 15. Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019

Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; ORR, overall response rate; NE, not estimable.
ATC Cohort Population	N = 36
Overall Response Rate
ORR (95% CI)	53% (35.5%, 69.6%)
Complete Response	6%
Partial Response	47%
Duration of Response	n = 19
Median DoR, months (95% CI)	13.6 (3.8, NE)
% with DoR ≥ 6 months	68%
% with DoR ≥ 12 months	53%

The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multicenter, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient achieved a confirmed partial or complete response as determined by the clinical investigators.

0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0078-0666-15). 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, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0078-0668-15). 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 refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes.

Advise the patient to read the FDA-approved patient labeling (Patient Information). New Cutaneous and Non-Cutaneous Malignancies Advise patients that MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. Hemorrhage Advise patients that MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)]. Colitis and Gastrointestinal Perforation Advise patients that MEKINIST can cause colitis and gastrointestinal perforation and to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)]. Venous Thrombosis Advise patients that MEKINIST administered with dabrafenib increases the risks of PE and DVT. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. Cardiomyopathy Advise patients that MEKINIST can cause cardiomyopathy and to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. Retinal Pigment Epithelial Detachment Advise patients that MEKINIST can cause severe visual disturbances that can lead to blindness and to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. Interstitial Lung Disease Advise patients that MEKINIST can cause ILD (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs, such as cough or dyspnea [see Warnings and Precautions (5.7)]. 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)]. Serious Skin Toxicities Advise patients that MEKINIST can cause serious skin toxicities, which may require hospitalization and to contact their healthcare provider for progressive or intolerable rash. Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of a severe skin reaction [see Warnings and Precautions (5.9)]. Hypertension Advise patients that MEKINIST can cause hypertension and that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension, such as severe headache, blurry vision, or dizziness. Diarrhea Advise patients that MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. Embryo-Fetal Toxicity Advise pregnant women and males of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.12), Use in Specific Populations (8.1, 8.3)]. Advise 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 4 months after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)]. Administration MEKINIST should be taken at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.6)]. THxID® BRAF assay is a trademark of bioMérieux. Oncomine™ Dx Target Test is a trademark of Life Technologies Corporation, a part of Thermo Fisher Scientific Inc. Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936 © Novartis T2022-06

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