Mekinist

Mekinist

trametinib

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Trametinib.
Description
0.5 mg film-coated tablets: Each film-coated tablet contains trametinib-dimethylsulfoxide (1:1) equivalent to 0.5 mg trametinib.
2 mg film-coated tablets: Each film-coated tablet contains trametinib-dimethylsulfoxide (1:1) equivalent to 2 mg trametinib.
Excipients/Inactive Ingredients:
Tablet core: Mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (vegetable source), sodium laurilsulfate, colloidal silicon dioxide.
Tablet film coat:
Hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow (for 0.5-tablets), polysorbate 80 and iron oxide red (for 2 mg tablets).
Action
Pharmacotherapeutic Group: Protein kinase inhibitor.
Pharmacology: Pharmacodynamics:
Mechanism of Action: Mekinist Monotherapy - Melanoma and NSCLC: Trametinib (Mekinist) is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases 1 (MEK1) and 2 (MEK2) activation and kinase activity. MEK proteins are critical components of the extracellular signal-regulated kinase (ERK) pathway. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activate MEK and stimulate tumor cell growth. Trametinib inhibits MEK kinase activity, suppresses growth of BRAF V600 mutant melanoma and non-small cell lung cancer (NSCLC) cell lines in vitro and demonstrates anti-tumor effects in BRAF V600 mutant melanoma xenograft models.
Mekinist in combination with dabrafenib - Melanoma and NSCLC: Dabrafenib (Tafinlar) is a potent, selective, ATP-competitive inhibitor of the BRAF (both wild-type and V600 variants) and wild type CRAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumor cell growth. Because, co-treatment with Mekinist and dabrafenib results in concomitant inhibition of two kinases in this pathway, BRAF and MEK, the combination provides superior pathway suppression relative to either agent alone. The combination of trametinib with dabrafenib is synergistic/additive in BRAF V600 mutation positive melanoma and NSCLC cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation positive melanoma xenografts.
Pharmacodynamics: Trametinib suppressed levels of phosphorylated ERK in BRAF V600 mutant melanoma and NSCLC tumor cell lines and melanoma xenografts models.
In patients with BRAF and NRAS mutant melanoma, administration of Mekinist 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). The mean trametinib concentrations observed following repeat dose administration of 2 mg once daily exceeds the preclinical target concentration over the 24-hr dosing interval, thereby providing sustained inhibition of the MEK pathway.
Cardiac electrophysiology: Study MEK111054: Initially the QT prolongation potential of trametinib was assessed as part of the first time in human study to determine the relationship between the independently manually-read QTc interval and plasma concentrations of trametinib using a nonlinear mixed effects model. Data were available in 50 patients with a total of 498 matched QTc values. Based on the concentration-QTc analysis, Mekinist showed no apparent potential to alter the QTc interval. At the mean Cmax value observed at the recommended dose of 2 mg once daily, the median increase in QTc is 2.2 msec (90 % CI: 0.2, 4.0).
To confirm the lack of effect on QTc, the QT prolongation potential of Mekinist was further assessed in a dedicated, stand-alone Phase I study in 35 patients (32 patients completed the study) with solid tumors. Patients received 3 mg matched placebo on study day 1 followed by a 2 mg once daily dose of trametinib and 2 tablets of 0.5 mg matched placebo on study days 2 to 14. On study day 15, all patients received a single dose of 3 mg Mekinist (supratherapeutic dose). The study showed no potential for Mekinist to alter the QTcF interval after repeat dose administration of 2 mg trametinib, including at the supratherapeutic dose of 3 mg on day 15. At a dose 1.5 times the maximum recommended dose, Mekinist does not prolong the QT interval to any clinically relevant extent.
Clinical Studies: Unresectable or metastatic melanoma: Mekinist monotherapy: Study MEK114267: The efficacy and safety of Mekinist in patients with BRAF mutant unresectable or metastatic melanoma (V600E and V600K) were evaluated in a randomized open label study. Measurement of patients BRAF V600 mutation status was required. Screening included central testing of BRAF mutation (V600E and V600K) using a BRAF mutation assay conducted on the most recent tumor sample available.
Patients (N = 322) who were treatment naïve or may have received one prior chemotherapy treatment in the metastatic setting [Intent to Treat (ITT) population] were randomized 2:1 to receive trametinib 2 mg once daily or chemotherapy (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Treatment for all patients continued until disease progression, death or withdrawal.
The primary endpoint of the study was to evaluate the efficacy of trametinib compared to chemotherapy with respect to progression-free survival (PFS) in patients with advanced (unresectable or metastatic) BRAF V600E mutation-positive melanoma without a prior history of brain metastases (N = 273) which is considered the primary efficacy population. The secondary endpoints were progression-free survival in the ITT population and overall survival (OS), overall response rate (ORR), and duration of response (DoR) in the primary efficacy population and ITT population. Patients in the chemotherapy arm were allowed to cross-over to the trametinib arm after independent confirmation of progression. Fifty one (47 %) patients with confirmed disease progression in the chemotherapy arm crossed over to receive trametinib.
Baseline characteristics were balanced between treatment groups in the primary efficacy population and the ITT population. In the ITT population, the majority of patients were male (54 %) and all were Caucasians (100 %). The median age was 54 years (22 % were ≥ 65 years), most patients (64%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 11 patients (3 %) had a history of brain metastases. Most patients (87 %) in the ITT population had a BRAF V600E mutation and 12 % of patients had a BRAF V600K mutation. Most patients (66 %) had received no prior chemotherapy for advanced or metastatic disease.
The efficacy results in the primary efficacy population were consistent with those in the ITT population; therefore, only the efficacy data for the ITT population are presented in Table 2 and Figure 1. (See Table 2 and Figure 1.)

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The PFS result was consistent in the subgroup of patients with V600K mutation positive melanoma (HR = 0.50; [95 % CI: 0.18, 1.35], p=0.0788).
In a single arm Phase II study, Mekinist did not demonstrate clinical activity in patients who progressed on a prior BRAF inhibitor therapy in one of the cohorts (see Indications).
Mekinist in combination with dabrafenib: The efficacy and safety of the recommended dose of Mekinist (2 mg once daily) in combination with dabrafenib (150 mg twice daily) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation were studied in two pivotal Phase III studies.
MEK115306 (COMBI-d): MEK115306 (COMBI-d) was a Phase III, randomized, double-blind study comparing the combination of Mekinist and dabrafenib to dabrafenib and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of the study was investigator assessed progression-free survival (PFS) with a key secondary endpoint of overall survival (OS). Patients were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ULN) and BRAF mutation (V600E versus V600K).
A total of 423 patients were randomized 1:1 to either the combination therapy arm (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily) (N = 211) or dabrafenib monotherapy arm (150 mg twice daily) (N = 212). Baseline characteristics were balanced between treatment groups. Males constituted 53 % of patients and the median age was 56 years. The majority of patients had an ECOG performance score of 0 (72%) and had Stage IVM1c disease (66%). Most patients (85%) had the BRAF V600E mutation; the remaining 15% of patients had the BRAF V600K mutation.
At the time of final OS analysis, a total of 222 deaths (52.5%) [combination 99 deaths (47%) and dabrafenib 123 deaths (58%)] out of the randomized (or ITT) population were reported. The median follow up time on study treatment was 20 months in the combination therapy arm and 16 months in the dabrafenib monotherapy arm. Study MEK115306 showed a statistically significant 29% reduction in the risk of death for the combination therapy arm compared with the dabrafenib monotherapy arm (HR=0.71, 95% CI: 0.55, 0.92; p=0.011). The median OS was 25.1 months for the combination therapy arm and 18.7 months for the dabrafenib monotherapy arm. The 12-month (74%) and 24-month (51.4%) OS estimates for the combination were also greater than those for dabrafenib monotherapy (67.6 and 42.1%, respectively).
Extended follow-up found the 36-month OS estimate to be 44% for patients who received Mekinist in combination with Tafinlar and 32% for patients who received Tafinlar monotherapy. (See Figure 2.)

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Efficacy Results of PFS, ORR and Duration of Response are summarized in Table 2. (See Table 2.)

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MEK116513 (COMBI-v): Study MEK116513 was a two-arm, randomized, open-label, Phase III study comparing Mekinist and dabrafenib combination therapy with vemurafenib monotherapy in BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of the study was overall survival. patients were stratified by lactate dehydrogenase (LDH) level (> the upper limit of normal (ULN) versus ≤ ULN) and BRAF mutation (V600E versus V600K).
A total of 704 patients were randomized 1:1 to either the combination therapy arm (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily) or the vemurafenib monotherapy arm (960 mg twice daily). Most patients were Caucasians (>96%) and male (55%), with a median age of 55 years (24% were ≥ 65 years). The majority of patients had Stage IV M1c disease (61%). Most patients had LDH ≤ULN (67%), ECOG performance status of 0 (70%), and visceral disease (78%) at baseline. Overall, 54% of patients had <3 disease sites at Baseline. The majority of patients had a BRAF V600E mutation (89%).
The OS analysis was conducted when 222 total deaths (77% of the required events for the final analysis) occurred. The Independent Data Monitoring Committee (IDMC) recommended stopping the study since the OS results crossed the pre-specified efficacy boundary. As a consequence the interim OS summary was considered the final comparative OS analysis.
The OS analysis for Study MEK116513 was based on 222 deaths (32%) [combination;100 deaths (28%) and vemurafenib 122 deaths (35%)]. The median follow up time on study treatment was 11 months for the combination arm and 9 months in the vemurafenib arm. Study MEK116513 showed a statistically significant 31% reduction in the risk of death for the combination therapy compared with vemurafenib (HR=0.69, 95% CI: 0.53, 0.89; p=0.005). The median OS was not yet reached for the combination arm, and was 17.2 months for vemurafenib monotherapy.
Extended follow-up found the 36-month OS estimate to be 45% for patients who received Mekinist in combination with Tafinlar and 31% for patients who received vemurafenib monotherapy. (See Figure 3.)

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Results of the endpoints for PFS, ORR and Duration of response are summarized in Table 3. (See Table 3.)

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Adjuvant treatment of melanoma: Study BRF115532 / CDRB436F2301 (COMBI-AD): The efficacy and safety of Mekinist in combination with Tafinlar was studied in a Phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
Patients were randomized 1:1 to receive either dabrafenib and trametinib combination therapy (Mekinist 2 mg once daily and Tafinlar 150 mg twice daily) or two placebos for a period of 12 months. Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. Any prior systemic anticancer treatment, including radiotherapy, was not allowed. Patients with a history of prior malignancy, if disease free for at least 5 years, were eligible. Patients presenting with malignancies with confirmed activating RAS mutations were not eligible. Patients were stratified by BRAF mutation status (V600E or V600K) and stage of disease prior to surgery (by Stage III sub-stage, indicating different levels of lymph node involvement and primary tumor size and ulceration). The primary endpoint was investigator-assessed relapse-free survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Radiological tumor assessment was conducted every 3 months for the first two years and every 6 months thereafter, until first relapse was observed. Secondary endpoints include overall survival (OS; key secondary endpoint) and distant metastasis-free survival (DMFS).
A total of 870 patients were randomized to the combination therapy (n=438) and placebo (n=432) arms. Most patients were Caucasian (99%) and male (55%), with a median age of 51 years (18% were ≥65 years). The study included patients with all sub-stages of Stage III disease prior to resection; 18% of these patients had lymph node involvement only identifiable by microscope and no primary tumor ulceration. The majority of patients had a BRAF V600E mutation (91%). The median duration of follow-up (time from randomization to last contact or death) was 2.83 years in the dabrafenib and trametinib combination arm and 2.75 years in the placebo arm.
Results for the primary analysis of RFS are presented in Figure 4 and in Table 4. The study showed a statistically significant difference for the primary outcome of RFS between treatment arms, with an estimated 53% risk reduction in the dabrafenib and trametinib combination arm as compared to the placebo arm (HR=0.47; 95% CI: 0.39, 0.58; p=1.53×10-14). Results were consistent across subgroups, including stratification factors for disease stage and BRAF V600 mutation type. Median RFS was 16.6 months for the placebo arm, and has not yet been reached for the combination arm. (See Table 4 and Figure 4.)

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Based on 153 events (60 (14%) in the combination arm and 93 (22%) in the placebo arm) corresponding to a 26% information fraction of the total target of 597 OS events, the estimated hazard ratio for OS was 0.57 (95% CI: 0.42, 0.79; p=0.0006). These results did not meet the pre-specified boundary to claim statistical significance at this first OS interim analysis (HR=0.50; p=0.000019). Survival estimates at 1 and 2 years from randomization were 97% and 91% in the combination arm and 94% and 83% in the placebo arm, respectively. The Kaplan-Meier curve for this OS interim analysis is shown in Figure 5. (See Figure 5.)

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Advanced NSCLC: Study E2201 BRF113928: The efficacy and safety of Mekinist in combination with dabrafenib was studied in a Phase II, three-cohort, multicenter, non-randomized, open-label study enrolling patients with Stage IV BRAF V600E mutant NSCLC.
The primary endpoint was the investigator-assessed overall response rate ORR using the 'Response Evaluation Criteria In Solid Tumors' (RECIST 1.1 assessed by the investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and population pharmacokinetics. ORR, DoR and PFS were also assessed by an Independent Review Committee (IRC) as a sensitivity analysis.
Cohorts were enrolled sequentially: Cohort A: Monotherapy (dabrafenib 150 mg twice daily): 84 patients enrolled. 78 patients had previous systemic treatment for their metastatic disease (see prescribing information for dabrafenib on results from Cohort A).
Cohort B (n=57): Combination therapy (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily): 59 patients enrolled. 57 patients had previously received one to three lines of systemic treatment for their metastatic disease. Two patients did not have any previous systemic treatment and were included in the analysis for patients enrolled in Cohort C.
Cohort C (n=36): Combination therapy (Mekinist 2 mg once daily and dabrafenib 150 mg twice daily): 34 patients enrolled (note: the two patients from Cohort B that did not have any previous systemic treatment were included in the analysis for patients enrolled in Cohort C for a total of 36 patients. All patients received study medication as first-line treatment for metastatic disease.
Among the total of 93 patients who were enrolled in the combination therapy in Cohorts B and C most patients were Caucasians (n=79, 85%). There was a similar female to male ratio (54% vs 46%). The median age was 64 years in patients who had at least one prior therapy and 68 years in patients who were treatment naïve for their advanced disease. Most patients (n=87, 94%) enrolled in the combination therapy treated Cohorts had an ECOG performance status of 0 or 1. Twenty-six (26) patients (28%) had never smoked. Ninety-one (91%) patients had a non-squamous histology. In the pre treated population, 38°patients (67%) had one line of systemic anti-cancer therapy for metastatic disease.
For the primary endpoint the investigator-assessed ORR, was 61.1% (95% CI, 43.5, 76.9) in the first-line population and 66.7% in the previously treated population. These results met the statistical significance to reject the null hypothesis that the ORR of Mekinist in combination with Tafinlar for both NSCLC populations was less than or equal to 30%.
The ORR results assessed by IRC were consistent to the investigator assessment (see Table 2).
The response was durable with median DoR in the previously treated population reaching 9.8 months (95% CI, 6.9, 16.0) by investigator assessment. For the first-line population, the median DoR and PFS could not yet be estimated (Table 5), and 68% of patients with confirmed response were still ongoing in follow-up for duration of response. (See Table 5.)

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Pharmacokinetics: Absorption: Trametinib is absorbed orally with median time to achieve peak concentrations of 1.5 hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72 % relative to an intravenous (IV) microdose. The increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. Following administration of 2 mg once daily, geometric mean Cmax, AUC(0-τ) and pre dose concentration were 22.2 ng/ml, 370 ng*hr/ml and 12.1 ng/ml, respectively with a low peak:trough ratio (1.8). Inter-subject variability was low (< 28 %).
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70 % and 10 % decrease in Cmax and AUC, respectively compared to fasted conditions (see Dosage & Administration).
Distribution: Binding of trametinib to human plasma proteins is 97.4 %. Trametinib has a volume of distribution of 1,060 L determined following administration of a 5 microgram IV microdose.
Biotransformation/Metabolism: In vitro and in vivo studies demonstrated that trametinib is metabolized predominantly via deacetylation alone or in combination with mono-oxygenation. The deacetylated metabolite was further metabolized by glucuronidation. The deacetylation is mediated by the carboxy-lesterase 1b, 1c and 2) and may also be mediated by other hydrolytic enzymes.
Elimination: Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 following a 2 mg once daily dose. Mean terminal half-life is 127 hours (5.3 days) after single dose administration. Steady-state was achieved by Day 15. Trametinib plasma IV clearance is 3.21 l/hr.
Total dose recovery is low after a 10-day collection period (< 50 %) following administration of a single oral dose of radiolabeled trametinib as a solution, due to the long half-life. Drug-related material was excreted predominantly in the feces (≥81% of recovered radioactivity) and to a small extent in urine (≤19%). Less than 0.1% of the excreted dose was recovered as parent in urine.
In Vitro evaluation of drug interaction potential: Effects of other drugs on trametinib: In vitro and in vivo data suggest that the pharmacokinetics (PK) of trametinib are unlikely to be affected by other drugs. Trametinib is deacetylated via carboxylesterases and possibly other hydrolytic enzymes. There is little evidence from clinical studies for drug interactions mediated by carboxylesterases. CYP enzymes play a minor role in the elimination of trametinib and the compound is not a substrate of the following transporters: breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, and the multidrug and toxin extrusion protein (MATE) 1. Trametinib is an in vitro substrate of the efflux transporter P-glycoprotein (Pgp), but is unlikely to be significantly affected by inhibition of this transporter given its high passive permeability and high bioavailability.
Special Patient Populations: Pediatric population (below 18 years): No studies have been conducted to investigate the pharmacokinetics of Mekinist in pediatric patients.
Geriatric population (65 years of age or older): Based on the population pharmacokinetic analysis, age had no relevant clinical effect on Mekinist pharmacokinetics.
Gender/Weight: Based on the population pharmacokinetic analysis, gender and weight were found to influence trametinib oral clearance. Although smaller female subjects are predicted to have higher exposure than heavier male subjects, these differences are unlikely to be clinically relevant and no dose adjustment is warranted.
Race/Ethnicity: There are insufficient data to evaluate the potential effect of race on trametinib pharmacokinetics.
Hepatic Impairment: The pharmacokinetics of trametinib were characterized in 64 patients enrolled in clinical trials with trametinib who had mild hepatic impairment (defined by National Cancer Institute classification) using a population pharmacokinetic analysis. Trametinib oral clearance was not significantly different in these patients relative to patients with normal hepatic function. No data are available in patients with moderate or severe hepatic impairment (see Dosage & Administration).
Renal Impairment: Renal impairment is unlikely to have a clinically relevant effect on trametinib pharmacokinetics given the low renal excretion of trametinib. The pharmacokinetics of trametinib were characterized in 223 patients enrolled in clinical trials with trametinib who had mild renal impairment and 35 patients with moderate renal impairment using a population pharmacokinetic analysis. Mild and moderate renal impairment had no effect on trametinib exposure (< 6 % for either group). No data are available in patients with severe renal impairment (see Dosage & Administration).
Toxicology: Non-Clinical Safety Data: Safety pharmacology and repeat dose toxicity: In mice, lower heart rate, heart weight and left ventricular function were observed without cardiac histopathology after 3 weeks at ≥ 0.25 mg/kg/day trametinib (approximately three times human clinical exposure based on AUC) for up to three weeks. In adult rats, myocardial mineralization and necrosis associated with increased serum phosphorus were seen at doses ≥1 mg/kg/day (approximately 12 times human clinical exposure based on AUC). In juvenile rats, increased heart weight with no histopathology was observed at 0.35 mg/kg/day (approximately 2 times adult human clinical exposure based on AUC).
Trametinib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay at significantly higher concentrations than clinical exposures (IC50 at 2.92 microgram/mL, ≥ 130 times the clinical exposure based on Cmax), indicating that there is low risk for phototoxicity to patients taking trametinib.
In repeat-dose studies in rats, hepatocellular necrosis and transaminase elevations were seen after 8 weeks at ≥ 0.062 mg/kg/day (approximately 0.8 times human clinical exposure based on AUC).
Carcinogenicity and mutagenicity: 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 micrnuclei in the bone marrow of rats.
Reproductive Toxicity: Embryofetal development and fertility: Trametinib may impair female fertility in humans. In adult and juvenile rat repeat dose studies with trametinib, alterations in follicular maturation, consisting of increases in cystic follicles and decreases in cystic corpora lutea, were observed at ≥ 0.016 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC).
Additionally, in juvenile rats given trametinib, decreased ovarian weights, slight delays in hallmarks of female sexual maturation (vaginal opening and increased incidence of prominent terminal end buds within the mammary gland) and slight hypertrophy of the surface epithelium of the uterus were observed. All of these effects were reversible following an off-treatment period and attributable to pharmacology. However, in rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues.
Juvenile animal studies: In a juvenile rat toxicity study, the principal toxicities in juvenile rats were on growth (bodyweight and long bone length), adverse microscopic findings included changes in the bone, mineralization and/or degeneration in various organs, primarily stomach at all doses. Adverse findings at the higher doses included in eye, kidney, aortic arch and/or nasal cavity/sinuses, heart, liver and in skin, and higher heart weights and the delay in a physical landmark of sexual maturity in females (vaginal opening).
The majority of findings are reversible with the exception of the bone, serum phosphorus and soft tissue mineralization which progressed/worsened during the off-drug period. Also, kidney tubular basophilia and higher heart weights were still present at end of recovery period.
With the exception of corneal mineralization/dystrophy and increased heart weight, similar effects have been observed in adult animals given trametinib. At the lowest combined dose level evaluated, the systemic exposure is approximately 0.3 times the human exposure at clinical dose of 2 mg/day based on AUC.
Non-fixed dose combination therapy: Trametinib in combination with dabrafenib: Dogs given trametinib and dabrafenib in combination for 4 weeks demonstrated similar toxicities to those observed in comparable monotherapy studies. Refer to the full prescribing information for dabrafenib.
Indications/Uses
Unresectable or metastatic melanoma: Mekinist in combination with dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Mekinist as a monotherapy is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Mekinist as monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Adjuvant treatment of melanoma: Mekinist in combination with Tafinlar, is indicated for the adjuvant treatment of patients with Stage III melanoma with a BRAF V600E or V600K mutation, and involvement of lymph node(s), following complete resection.
Advanced non-small cell lung cancer: Mekinist in combination with dabrafenib is indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.
Dosage/Direction for Use
Treatment with Mekinist should be initiated by a physician experienced in the use of anticancer therapies.
General target population: Adults:
Confirmation of BRAF V600 mutation using an approved/validated test is required for selection of patients appropriate for treatment with Mekinist as monotherapy and in combination with dabrafenib (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
When Mekinist is used in combination with dabrafenib, please refer to the full dabrafenib prescribing information (see Dosage & Administration).
The recommended dose of Mekinist either as monotherapy or in combination with dabrafenib is 2 mg given orally once daily with a full glass of water.
Mekinist should be taken without food, at least one hour before or two hours after a meal (see Pharmacology under Actions).
When Mekinist and dabrafenib are taken in combination, the once-daily dose of Mekinist should be taken at the same time each day with either the morning dose or the evening dose of dabrafenib.
If a dose of Mekinist is missed, it should only be taken if it is more than 12 hours until the next scheduled dose.
Dose adjustments: Mekinist as Monotherapy and in combination with dabrafenib: The management of adverse events/adverse drug reactions may require treatment interruption, dose reduction, or treatment discontinuation (see Tables 6 and 7).

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Dose adjustment for Mekinist below 1 mg once daily is not recommended, whether used as monotherapy or in combination with Tafinlar. (See Table 7.)

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When an individual's adverse reactions are under effective management, dose re-escalation following the same dosing steps as de-escalation may be considered. The Mekinist dose should not exceed 2 mg once daily.
If treatment related toxicities occur when Mekinist is used in combination with dabrafenib then both treatments should be simultaneously dose reduced, interrupted or discontinued with the exceptions shown below.
Exceptions where dose modifications are necessary for Mekinist only: Left ventricular ejection fraction (LVEF) reduction.
Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED).
Pneumonitis and Interstitial Lung Disease (ILD).
LVEF Reduction/Left Ventricular Dysfunction management: Mekinist should be interrupted in patients who have an asymptomatic, absolute decrease of > 10% in LVEF compared to baseline and the ejection fraction below the institution's lower limit of normal (LLN) (see Precautions). If Mekinist is being used in combination with dabrafenib then therapy with dabrafenib may be continued at the same dose. If the LVEF recovers, treatment with Mekinist may be restarted, but the dose should be reduced by one dose level with careful monitoring. Mekinist should be permanently discontinued with Grade 3 or 4 left ventricular cardiac dysfunction or if repeatedly reduced LVEF does not recover.
Retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED) management: If RPED is diagnosed, the dose modification schedule (intolerable) in Table 7 for Mekinist should be followed and, if Mekinist is being used in combination with dabrafenib, dabrafenib should be continued at the same dose (see Precautions).
Pneumonitis and Interstitial Lung Disease (ILD) management: For events of pneumonitis, follow dose modification guidelines in Table 7 for Mekinist only; no modification of dabrafenib is required when taken in combination with Mekinist.
Refer to the full prescribing information of dabrafenib for dose modification guidelines (see Dosage & Administration).
Special populations: Renal impairment: No dose adjustment required in patients with mild or moderate renal impairment. Mild or moderate renal impairment had no significant effect on the population pharmacokinetics of Mekinist (see Pharmacology: Pharmacokinetics under Actions). There are no clinical data in patients with severe renal impairment; therefore, the potential need for starting dose adjustment cannot be determined. Mekinist should be used with caution in patients with severe renal impairment.
Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. In a population pharmacokinetic analysis, Mekinist oral clearance and thus exposure was not significantly different in patients with mild hepatic impairment compared to patients with normal hepatic function (see Pharmacology: Pharmacokinetics under Actions). There are no clinical data in patients with moderate or severe hepatic impairment; therefore, the potential need for starting dose adjustment cannot be determined. Mekinist should be used with caution in patients with moderate or severe hepatic impairment.
Overdosage
No cases of overdose have been reported. There were no cases of Mekinist dose above 4 mg once daily reported from the clinical trials. Doses of up to 4 mg orally once daily and loading doses of 10 mg orally once daily administered on two consecutive days, have been evaluated in clinical trials.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of Mekinist. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Hemodialysis is not expected to enhance the elimination as Mekinist is highly bound to plasma proteins.
Contraindications
Trametinib is contraindicated in patients with hypersensitivity to any of the ingredients.
Pediatric patients (below the age of 18 years): The safety and efficacy of Mekinist in pediatric patients have not been established. Mekinist is not recommended in this age group.
Geriatric patients (65 years of age or older): No dose adjustment is required in patients over 65 years of age (see Pharmacology: Pharmacokinetics under Actions).
Special Precautions
When Mekinist is used together with dabrafenib read the full prescribing information for dabrafenib precautions section.
LVEF Reduction/Left Ventricular Dysfunction:
Mekinist has been reported to decrease LVEF (see Adverse Reactions). In clinical trials, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease in patients treated with Mekinist as monotherapy or in combination with dabrafenib was between two to five months. Mekinist should be used with caution in patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Mekinist with a recommendation of periodic follow-up within eight weeks of initiating therapy, as clinically appropriate. LVEF should continue to be evaluated during treatment with Mekinist as clinically appropriate (see Dosage & Administration).
Hemorrhage: Hemorrhagic events, including major hemorrhagic events have occurred in patients taking Mekinist as monotherapy and in combination with dabrafenib (see Adverse Reactions). Out of the 559 unresectable or metastatic melanoma patients treated with Mekinist in combination with dabrafenib, there were six fatal intracranial hemorrhagic cases (1%). Three cases were from study MEK115306 (COMBI-d) and three cases were from study MEK116513 (COMBI-v). No fatal hemorrhagic events occurred in the Phase III study in the adjuvant treatment of melanoma. Two out of 93 patients (2%) receiving Mekinist in combination with dabrafenib in a Phase II NSCLC trial had fatal hemorrhagic events. If patients develop symptoms of hemorrhage they should immediately seek medical care.
Visual Impairment: Disorders associated with visual disturbances, including chorioretinopathy or retinal pigment epithelial detachment (RPED) and Retinal Vein Occlusion (RVO) have been observed with Mekinist. Symptoms such as blurred vision, decreased acuity, and other visual phenomena have been reported in the clinical trials with Mekinist (see Adverse Reactions). Mekinist is not recommended in patients with a history of RVO. A thorough ophthalmological evaluation should be performed at baseline and during treatment with Mekinist, if clinically warranted. If patients report visual disturbances at any time while on Mekinist therapy, additional ophthalmological evaluation should be undertaken. If a retinal abnormality is noted, treatment with Mekinist should be interrupted immediately and referral to a retinal specialist should be considered. If RPED is diagnosed, the dose modification schedule (intolerable) in Table 7 should be followed (see Dosage & Administration). In patients who experience RVO, treatment with Mekinist should be permanently discontinued.
Rash: In clinical studies, rash has been observed in about 60 % of patients receiving Mekinist as monotherapy and 20 to 30% receiving Mekinist in combination with dabrafenib (see Adverse Reactions). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Deep vein thrombosis (DVT)/Pulmonary embolism (PE): DVT and PE can occur on Mekinist monotherapy and when Mekinist is used in combination with dabrafenib. Patients should be advised to immediately seek medical care if they develop symptoms of pulmonary embolism or deep vein thrombosis.
Pyrexia: Pyrexia was reported in the clinical trials with Mekinist. The incidence and severity of pyrexia are increased when Mekinist is used in combination with dabrafenib (see Adverse Reactions). In patients with unresectable or metastatic melanoma who received the combination dose of Mekinist 2 mg once daily and Tafinlar 150 mg twice daily developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy. About one-third of the patients receiving combination therapy who experienced pyrexia had three or more events. Pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in some cases can lead to acute renal insufficiency. Serum creatinine and other evidence of renal function should be monitored during and following severe events of pyrexia. Serious non-infectious febrile events have been observed. These events responded well to dose interruption and/or dose reduction and supportive care in clinical trials.
For management of pyrexia see the full prescribing information for dabrafenib (see Dosage & Administration).
Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking Mekinist as monotherapy and in combination with dabrafenib (Adverse Reactions). Treatment with Mekinist monotherapy or in combination with dabrafenib should be used with caution in patients with risk factors for gastrointestinal perforation, including a history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognised risk of gastrointestinal perforation.
If patients develop symptoms of colitis and gastrointestinal perforation they should immediately seek medical care.
Females and males of reproductive potential: Contraception: Females of reproductive potential should be advised that animal studies have been performed showing Mekinist to be harmful to the developing fetus. Sexually-active females of reproductive potential are recommended to use effective contraception (methods that result in less than 1% pregnancy rates) when using Mekinist during treatment and for four months after stopping treatment with Mekinist.
Females of reproductive potential receiving Mekinist in combination with dabrafenib should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternative method of contraception, such as barrier methods, should be used.
Infertility: There is no information on the effect of Mekinist on human fertility. In animals, no fertility studies have been performed, but adverse effects were seen on female reproductive organs (see Pharmacology: Toxicology under Actions). Mekinist may impair fertility in humans.
Use In Pregnancy & Lactation
Use in Pregnancy: Risk summary: Mekinist can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Mekinist in pregnant women. Reproductive studies in animals have demonstrated that trametinib induces maternal and developmental toxicity.
In rats decreased fetal weight and increased incidences of post implantation loss were observed following maternal exposure to trametinib at concentrations 0.3 and 1.8 times the exposure in humans at the highest recommended dose of 2 mg once daily. In rabbits, decreased fetal weight and increased incidence of variations in ossification and post implantation loss were observed following maternal exposure to trametinib at concentrations 0.09 and 0.3 times the exposure in humans at the highest recommended dose of 2 mg once daily. Pregnant women the patient should be informed advised of the potential hazard risk to the fetus.
Animal data: In embryo-fetal development studies, rats and rabbits received oral doses of trametinib up to 0.125 mg/kg/day and 0.31 mg/kg/day, respectively, during the period of organogenesis. In rats at ≥0.031 mg/kg/day and 0.125 mg/kg/day, maternal systemic exposures (AUC) were 110 ng*h/mL and 684 ng*h/mL, respectively, corresponding to approximately 0.3 and 1.8 times the exposure in humans at the highest recommended dose of 2 mg once daily. At doses ≥0.031 mg/kg/day developmental toxicity consisted of decreased fetal weights. At a dose of 0.125 mg/kg/day there was maternal toxicity and increases in post implantation loss. In rabbits at ≥0.039 mg/kg/day and 0.15 mg/kg/day, maternal systemic exposures (AUC) were 31.9 ng*h/mL and 127 ng*h/mL, respectively corresponding to approximately 0.09 and 0.3 times the exposures in humans at the highest recommended dose of 2 mg once daily. At doses ≥0.039 mg/kg/day developmental toxicity consisted in decreased fetal body weight and increased incidence of variations in ossification. At doses 0.15 mg/kg/day there were increases in post-implantation loss, including total loss of pregnancy, compared with control animals.
Lactation: Risk summary: There are no data on the effect of Mekinist on the breast-fed child, or the effect of Mekinist on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Mekinist, a nursing woman should be advised on the potential risks to the child. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mekinist and any potential adverse effects on the breast-fed child from Mekinist or from the underlying maternal condition.
Adverse Reactions
Summary of the safety profile: Unresectable or metastatic melanoma: Mekinist monotherapy: he safety of Mekinist monotherapy was evaluated in an integrated population of 329 patients with BRAF V600 mutant unresectable or metastatic melanoma treated with Mekinist 2 mg orally once daily. Of these patients, 211 patients were treated with Mekinist for BRAF V600 mutant melanoma in a randomized open-label study (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The most common adverse events (≥ 20 %) for Mekinist were rash, diarrhea, fatigue, edema peripheral, nausea, and dermatitis acneiform. In clinical trials with Mekinist, adverse events of diarrhea and rash were managed with appropriate supportive care (see Dosage & Administration).
Mekinist and dabrafenib combination therapy: The safety of Mekinist and dabrafenib combination therapy was evaluated in two randomized Phase III studies of patients with BRAF V600 mutant unresectable or metastatic melanoma treated with Mekinist 2 mg orally once daily and dabrafenib 150 mg orally twice daily (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The most common adverse events (≥20%) for Mekinist and dabrafenib combination therapy were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, hypertension, vomiting, peripheral edema and cough.
Tabulated summary of adverse events from clinical trials in unresectable metastatic melanoma: Adverse events from clinical trials in patients with unresectable or metastatic melanoma are listed by MedDRA system organ class in Table 8 and Table 9 for Mekinist monotherapy and Mekinist in combination with Tafinlar, respectively. Within each system organ class, the adverse events are ranked by frequency, with the most frequent adverse events first. In addition, the corresponding frequency category for each adverse event is based on the following convention (CIOMS III): Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 8.)

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Table 9 lists adverse events when Mekinist was used in combination with dabrafenib from the randomized double-blind Phase III study MEK115306 (N=209), and integrated safety data from MEK115306 (N=209) and from the randomized open-label Phase III study MEK 116513 (N=350). (See Table 9a and 9b.)

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Adjuvant treatment of melanoma: Mekinist in combination with Tafinlar: The safety of Mekinist in combination with Tafinlar was evaluated in a Phase III, randomized, double-blind study of Mekinist in combination with Tafinlar versus two placebos in the adjuvant treatment of Stage III BRAF V600 mutation-positive melanoma after surgical resection (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
In the Mekinist 2 mg once daily and Tafinlar 150 mg twice daily arm, the most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.
Table 10 lists the adverse drug reactions in study BRF115532 (COMBI-AD) occurring at an incidence ≥10% for all grade adverse reactions or at an incidence ≥2% for Grade 3 and Grade 4 adverse drugs reactions or adverse events that are medically significant in the Mekinist in combination with Tafinlar arm.
Adverse drug reactions are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent adverse drug reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 10.)

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Advanced non-small cell lung cancer (NSCLC): Mekinist in combination with dabrafenib: The safety of Mekinist in combination with dabrafenib was evaluated in a Phase II, multicenter, multi-cohort, non-randomized, open label study of patients with BRAF V600E mutation positive metastatic NSCLC (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
In the Mekinist 2 mg orally once daily and dabrafenib 150 mg orally twice daily arms (Cohorts B and C) the most common adverse events (≥20%) reported for Mekinist and dabrafenib combination therapy were pyrexia, nausea, vomiting, peripheral edema, diarrhea, decreased appetite, asthenia, dry skin, chills, cough, fatigue, rash and dyspnea.
Table 11 lists the adverse drug reactions for Mekinist in combination with dabrafenib occurring at an incidence ≥10% for all adverse drug reactions or at an incidence ≥2% for Grade 3 and Grade 4 adverse drug reactions or events which are medically significant in Cohorts B and C of study BRF113928.
Adverse drug reactions are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent adverse drug reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 11.)

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Drug Interactions
Monotherapy: As trametinib is metabolized predominantly via deacetylation mediated by hydrolytic enzymes (including carboxylesterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions. Trametinib repeat-dose exposure was not affected by co-administration with a cytochrome P450 (CYP) 3A4 inducer.
Based on in vitro and in vivo data, Mekinist is unlikely to significantly affect the pharmacokinetics of other medicinal products via interactions with CYP enzymes or transporters (see Pharmacology: Pharmacokinetics under Actions). Repeat dose administration of Mekinist 2 mg once daily had no clinically relevant effect on the single dose Cmax and AUC of dabrafenib, a CYP2C8/CYP3A4 substrate.
Combination therapy and non-fixed dose combination therapy: Combination with dabrafenib: Co-administration of repeat dosing of Mekinist 2 mg once daily and dabrafenib 150 mg twice daily resulted in a 16% increase in dabrafenib Cmax and a 23% increase in dabrafenib AUC. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when Mekinist is administered in combination with dabrafenib using a population pharmacokinetic analysis. These changes in dabrafenib or trametinib Cmax and AUC are considered not clinically relevant. See the full prescribing information for dabrafenib for guidelines on drug interactions associated with dabrafenib monotherapy.
Caution For Usage
Instructions for Use and Handling: There are no special requirements for use or handling of this product.
Incompatibilities:
Not applicable.
Storage
Store refrigerated, 2 to 8°C. Do not freeze. Protect from moisture and light. Store in the original container. Keep the bottle tightly closed. Contains dessicant, do not remove or eat.
ATC Classification
L01EE01 - trametinib ; Belongs to the class of mitogen-activated protein kinase (MEK) inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 0.5 mg (yellow, modified oval, biconvex with 'GS' debossed on one face and 'TFC' on the opposing face) x 7's. 2 mg (pink, round, biconvex with 'GS' debossed on one face and 'HMJ' on the opposing face) x 7's.
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