trametinib 0.5 MG (as trametinib dimethyl sulfoxide 0.5635 MG) Oral Tablet

Generic Name: TRAMETINIB
Brand Name: Mekinist
  • Substance Name(s):
  • TRAMETINIB DIMETHYL SULFOXIDE

DRUG INTERACTIONS

7 No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 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 retinal pigment epithelial detachments 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.

DESCRIPTION

11 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. 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 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, 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), titanium dioxide. Trametinib chemical structure

CLINICAL STUDIES

14 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic 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 (Trial 1) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. In Trial 1, 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. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 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 versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). 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 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. Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with MEKINIST. Table 7 and Figure 1 summarize the PFS results. Table 7. Investigator-Assessed Progression-Free Survival and Confirmed Objective Response Results in Trial 1 †CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. aPike estimator. Investigator-Assessed Endpoints† MEKINIST N = 214 Chemotherapy N = 108 Progression-Free Survival 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) P<0.0001 Confirmed Tumor Responses Objective Response Rate 22% 8% (95% CI) (17, 28) (4, 15) CR, n (%) 4 (2%) 0 PR, n (%) 43 (20%) 9 (8%) Duration of Response Median, 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 Trial 1 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 The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (Trial 2). Trial 2 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 lactate dehydrogenase (LDH) level (greater than the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR). In Trial 2, 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. Trial 2 demonstrated statistically significant improvements in PFS and OS (see Table 8 and Figure 2). Table 8. Efficacy Results in Trial 2 † CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached. a PFS and ORR were assessed by investigator. bBased on stratified log-rank test Endpoint† MEKINIST plus Dabrafenib N=211 Dabrafenib plus Placebo N=212 Progression-Free Survival (PFS) a 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 Rate (ORR) a ORR, % (95% CI) 66 (60, 73) 51 (44, 58) P value <0.001 CR, % 10 8 PR, % 56 42 Median duration of response, months (95% CI) 9.2 (7.4, NR) 10.2 (7.5, NR) Figure 2. Kaplan Meier Curves of Overall Survival in Trial 2 Kaplan-Meier Chart Figure 2 14.2 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy 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.

HOW SUPPLIED

16 /STORAGE AND HANDLING 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). 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). Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not place medication in pill boxes.

RECENT MAJOR CHANGES

Warnings and Precautions (5.3) 2/2017

GERIATRIC USE

8.5 Geriatric Use Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Of the 559 patients randomized to receive MEKINIST plus dabrafenib in clinical trials, 24% were aged 65 years and older and 6% patients aged 75 years and older. No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in elderly patients as compared to younger patients. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in elderly patients as compared to younger patients.

DOSAGE FORMS AND STRENGTHS

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

MECHANISM OF ACTION

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 BRAF V600 mutation-positive melanoma cell growth 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 melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

INDICATIONS AND USAGE

1 MEKINIST® is indicated, as a single agent 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 Clinical Studies (14.1)]. Limitation of use: MEKINIST is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy [see Clinical Studies (14.2)]. MEKINIST is a kinase inhibitor indicated, as a single agent 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. (1, 14.1) Limitation of use: MEKINIST is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy. (1)

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been established in pediatric patients. Juvenile Animal 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.

PREGNANCY

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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]. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient 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 2-4% and 15-20%, 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 based on AUC at the recommended dose). 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Review the Full Prescribing Information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib. 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, 2.3) Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. (5.2, 2.3) Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. (5.3). Venous thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST. (5.4, 2.3). Cardiomyopathy: Assess LVEF before treatment, after one month of treatment, then every 2 to 3 months thereafter. (5.5, 2.3) Ocular toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST. (5.6, 2.3). Interstitial lung disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.3) Serious febrile reactions: Can occur when MEKINIST is used with dabrafenib. (5.8, 2.3) Serious skin toxicity: Monitor for skin toxicities and for secondary infections. Discontinue MEKINIST for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. (5.9, 2.3) Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. (5.10, 2.3) Embryo-fetal toxicity: MEKINIST can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.11, 8.1, 8.3) 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is administered with dabrafenib. Cutaneous Malignancies In Trial 2, the incidence of basal cell carcinoma in patients receiving MEKINIST and dabrafenib was 3.3% (7/209) compared with 6% (13/211) in patients receiving single-agent dabrafenib. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the MEKINIST plus dabrafenib arm and was 4.4 months (range: 29 days to 16.5 months) in the dabrafenib arm. Among the 7 patients receiving MEKINIST with dabrafenib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3). Cutaneous squamous cell carcinomas (cuSCC) and keratoacanthoma occurred in 3% of patients receiving MEKINIST and dabrafenib and 10% of patients receiving single-agent dabrafenib. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the MEKINIST plus dabrafenib arm and was 2 months (range: 9 days to 20.9 months) in the dabrafenib arm. New primary melanoma occurred in 0.5% (1/209) of patients receiving MEKINIST and dabrafenib and in 1.9% (4/211) of patients receiving dabrafenib alone. Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST are recommended in patients who develop new primary cutaneous malignancies. Non-Cutaneous Malignancies Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving MEKINIST plus dabrafenib and in 2.8% (6/211) of patients receiving single-agent dabrafenib. 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 [see Dosage and Administration (2.3)]. 5.2 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. In Trial 2, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib was 19% (40/209) compared with 15% (32/211) of patients receiving dabrafenib alone. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving MEKINIST in combination with dabrafenib compared with 2.8% (6/211) of patients receiving single-agent dabrafenib. In Trial 2, 1.4% (3/209) of patients receiving MEKINIST and dabrafenib developed fatal intracranial hemorrhage compared with none of the patients receiving single-agent dabrafenib alone. Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level. 5.3 Colitis and Gastrointestinal Perforation Colitis and gastrointestinal perforation can occur with MEKINIST. Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking MEKINIST as a single-agent and when administered with dabrafenib. Across clinical trials of MEKINIST administered as a single agent (N = 329) and MEKINIST administered with dabrafenib (N = 559), colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients. Monitor patients closely for colitis and gastrointestinal perforations. 5.4 Venous Thromboembolism Venous thromboembolism can occur with MEKINIST. In Trial 2, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% (6/209) of patients receiving MEKINIST and dabrafenib compared with 0.9% (2/211) of patients receiving single-agent dabrafenib. 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 (2.3)]. 5.5 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST. In clinical trials of MEKINIST, all patients were required to have an echocardiogram at baseline to document normal LVEF and repeat echocardiograms at Week 4, Week 12, and every 12 weeks thereafter. In Trial 1, cardiomyopathy [defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF)] occurred in 7% (14/211) of patients receiving MEKINIST; no chemotherapy-treated patient in Trial 1 developed cardiomyopathy. The median time to onset of cardiomyopathy in patients receiving MEKINIST was 2.1 months (range: 16 days to 5.1 months); cardiomyopathy was identified within the first month of receiving MEKINIST in five of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/211) and/or dose reduction (7/211) of MEKINIST. Cardiomyopathy resolved in 10 of these 14 (71%) patients. Across clinical trials of MEKINIST as a single agent (N = 329), 11% of patients developed evidence of cardiomyopathy [decrease in LVEF below institutional lower limits of normal (LLN) with an absolute decrease in LVEF ≥10% below baseline] and 5% demonstrated a decrease in LVEF below institutional LLN with an absolute decrease in LVEF of ≥20% below baseline. In Trial 2, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline) occurred in 6% (12/206) of patients receiving MEKINIST and dabrafenib and in 2.9% (6/207) of patients receiving single-agent dabrafenib. The median time to onset of cardiomyopathy in patients receiving MEKINIST and dabrafenib was 8.2 months (range: 28 days to 24.9 months); cardiomyopathy was identified within the first month of receiving MEKINIST and dabrafenib in 2 of these 12 patients. In patients receiving MEKINIST and dabrafenib, cardiomyopathy resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Cardiomyopathy resolved in 10 of 12 patients receiving MEKINIST and dabrafenib. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold MEKINIST for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction of >20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST [see Dosage and Administration (2.3)]. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO) Across all clinical trials with MEKINIST, the incidence of RVO was 0.2% (4/1,749). 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 (2.3)]. Retinal Pigment Epithelial Detachment (RPED) Retinal pigment epithelial detachment (RPED) can occur with MEKINIST administration. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In Trial 1 and Trial 2, 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. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks [see Dosage and Administration (2.3)]. 5.7 Interstitial Lung Disease In clinical trials of single-agent MEKINIST (N = 329), ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2.4% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 5.3 months (range: 2 to 5.7 months). In Trial 2, 1.0% (2/209) of patients receiving MEKINIST and dabrafenib developed pneumonitis compared with none of the patients receiving single-agent dabrafenib. 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 (2.3)]. 5.8 Serious Febrile Reactions Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib. Fever (serious and non-serious) occurred in 57% (119/209) of patients receiving MEKINIST and dabrafenib and in 33% (69/211) of patients receiving dabrafenib alone. The median time to initial onset of fever was 1.2 months (range: 1 day to 23.5 months) with a median duration of fever of 3 days (range: 1 day to 1.7 months) on the MEKINIST plus dabrafenib arm compared with a median time to initial onset of fever of 20 days (range: 1 day to 22.9 months) and median duration of fever of 3 days (range: 1 day to 1.9 months) on the dabrafenib arm. Approximately one-half of the patients who received MEKINIST and dabrafenib and experienced pyrexia had three or more discrete episodes. Across clinical trials of MEKINIST administered with dabrafenib, serious febrile reactions or fever of any severity complicated by severe rigors/chills hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving MEKINIST and dabrafenib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients. Withhold MEKINIST for fever higher than 104ºF or for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. 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. 5.9 Serious Skin Toxicity Serious skin toxicity can occur with MEKINIST. In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients receiving MEKINIST and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with MEKINIST. Skin toxicity requiring hospitalization occurred in 6% of patients treated with MEKINIST, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to initial onset of skin toxicity in patients treated with MEKINIST was 15 days (range: 1 day to 7.3 months) and median time to resolution of skin toxicity was 1.6 months (range: 1 day to 9.3 months). Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was required in 1% of patients with skin toxicity. In Trial 2, the overall incidence of any skin toxicity was 55% for patients receiving MEKINIST and dabrafenib compared with 55% for patients receiving single-agent dabrafenib. No serious or severe cases of skin toxicity occurred in patients treated with MEKINIST and dabrafenib. The median time to initial onset of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.9 months (range: 1 day to 22.1 months) and median time to resolution of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.2 months (range: 1 day to 24.4 months). Reductions in the dose of MEKINIST were required in 5% of patients receiving MEKINIST and dabrafenib and no patients required permanent discontinuation of MEKINIST for skin toxicity. Across clinical trials of MEKINIST administered with dabrafenib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients. Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)]. 5.10 Hyperglycemia Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy can occur when MEKINIST is administered with dabrafenib. In Trial 2, 27% (4/15) of patients with a history of diabetes who received MEKINIST and dabrafenib and 13% (2/16) of patients with a history of diabetes who received single-agent dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients receiving MEKINIST and dabrafenib, respectively, compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent dabrafenib. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia. 5.11 Embryo-Fetal Toxicity 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. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1, 8.3)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the following: Confirmation of BRAF V600E or V600K mutation Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary to identify patients for whom treatment with MEKINIST is indicated [see Dosage and Administration (2.1)]. New cutaneous and non-cutaneous malignancies 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 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 MEKINIST can cause colitis and gastrointestinal perforation. Advise patients to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)]. Venous thrombosis MEKINIST administered with dabrafenib increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. Cardiomyopathy MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. Retinal Pigment Epithelial Detachment MEKINIST can cause severe visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. Interstitial lung disease MEKINIST can cause interstitial lung disease (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 MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)]. Serious skin toxicities MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.9)]. Hypertension MEKINIST can cause hypertension. Advise patients 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 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 MEKINIST can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Females and males of reproductive potential Instruct females of reproductive potential to use highly effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. 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 males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)]. Instructions for taking MEKINIST MEKINIST should be taken at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.2)].

DOSAGE AND ADMINISTRATION

2 Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST. (2.1) The recommended dosage regimen of MEKINIST is 2 mg orally once daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal. (2.2) 2.1 Patient Selection Select patients for treatment of unresectable or metastatic melanoma with MEKINIST based on the presence of BRAF V600E or V600K mutation in tumor specimens [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosing The recommended dosage regimen is MEKINIST 2 mg orally taken once daily at the same time each day as a single agent or with dabrafenib. Continue treatment until disease progression or unacceptable toxicity occurs. 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. 2.3 Dose Modifications Review the Full Prescribing Information for dabrafenib for recommended dose modifications. Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. For New Primary Cutaneous Malignancies No dose modifications are required. Table 1. Recommended Dose Reductions Dose Reductions for MEKINIST 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 Table 2. Recommended Dose Modifications for MEKINIST aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. bSee Table 1 for recommended dose reductions of MEKINIST. Severity of Adverse Reactiona MEKINISTb Febrile Drug Reaction •Fever higher than 104°F •Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until fever resolves. Then resume MEKINIST at same or lower dose level. Cutaneous •Intolerable Grade 2 skin toxicity •Grade 3 or 4 skin toxicity Withhold MEKINIST for up to 3 weeks. •If improved, resume at a lower dose level. •If not improved, permanently discontinue. Cardiac •Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and is below institutional lower limits of normal (LLN) from pretreatment value Withhold MEKINIST for up to 4 weeks. •If improved to normal LVEF value, resume at a lower dose level. •If not improved to normal LVEF value, permanently discontinue. •Symptomatic congestive heart failure •Absolute decrease in LVEF of greater than 20% from baseline that is below LLN Permanently discontinue MEKINIST. Venous Thromboembolism •Uncomplicated DVT or PE Withhold MEKINIST for up to 3 weeks. •If improved to Grade 0-1, resume at a lower dose level. •If not improved, permanently discontinue. •Life threatening PE Permanently discontinue MEKINIST. Ocular Toxicities •Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. •If improved, resume MEKINIST at same or lower dose level. •If not improved, discontinue or resume at a lower dose. •Retinal vein occlusion Permanently discontinue MEKINIST. Pulmonary •Interstitial lung disease/pneumonitis Permanently discontinue MEKINIST. Other •Intolerable Grade 2 adverse reactions •Any Grade 3 adverse reactions Withhold MEKINIST •If improved to Grade 0-1, resume at a lower dose level. •If not improved, permanently discontinue. •First occurrence of any Grade 4 adverse reaction •Withhold MEKINIST until adverse reaction improves to Grade 0-1. Then resume at a lower dose level. Or •Permanently discontinue. •Recurrent Grade 4 adverse reaction Permanently discontinue MEKINIST.