Mekinist

Small Molecule Antineoplastic Mitogen-Activated Protein Kinase (MEK) Inhibitors

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Take trametinib at the same time each day, approximately 24 hours apart.
Take at least 1 hour before or 2 hours after a meal.
If a dose is missed, take it as soon as possible. If it is less than 12 hours before the next scheduled dose, skip the missed dose and take the next dose at the regular time.
If vomiting occurs after a dose, do not take an additional dose and take the next dose at the regular time.

Swallow whole; do not open, crush, or break tablets.
Do not use in patients who weigh less than 26 kg or in children not able to swallow trametinib tablets whole.

Refer caregivers to the Instructions for Use provided with the medication on how to correctly prepare and give a dose of the oral suspension.
Reconstitution:
Tap the trametinib for oral solution bottle until the powder flows freely.
Add 90 mL of distilled or purified water to the powder in the bottle; invert or gently shake the bottle with re-attached cap for up to 5 minutes until the powder is fully dissolved and the solution is clear.
Separate the dosing adapter from the oral syringe; insert the dosing adapter into the bottle neck after reconstitution.
Storage: Store the oral solution in the original bottle below 25 degrees C (77 degrees F) for up to 35 days; do not freeze.
Administration:
Administer the appropriate dose orally using an oral dosing syringe; the reconstituted solution may also be given via a feeding tube.

hyponatremia / Delayed / 0-17.0
lymphopenia / Delayed / 1.4-14.0
hypertension / Early / 11.0-12.0
bradycardia / Rapid / 0-10.0
rhabdomyolysis / Delayed / 0-10.0
anemia / Delayed / 0-10.0
cardiomyopathy / Delayed / 0-9.0
hyperglycemia / Delayed / 0-9.0
rash / Early / 0-8.0
leukopenia / Delayed / 0-8.0
neutropenia / Delayed / 6.0-8.0
weight gain / Delayed / 0-8.0
hypophosphatemia / Delayed / 0-7.0
elevated hepatic enzymes / Delayed / 1.4-6.0
dyspnea / Early / 0-5.0
fever / Early / 5.0-5.0
fatigue / Early / 0-5.0
hypomagnesemia / Delayed / 0-4.1
hypocalcemia / Delayed / 0-4.1
vomiting / Early / 0-3.2
diarrhea / Early / 0-3.2
hyperkalemia / Delayed / 0-3.2
GI bleeding / Delayed / 0-3.0
bleeding / Early / 0-3.0
new primary malignancy / Delayed / 0-3.0
hyperbilirubinemia / Delayed / 0-2.1
hypokalemia / Delayed / 0-2.1
hypoalbuminemia / Delayed / 0-2.1
pruritus / Rapid / 0-2.0
oral ulceration / Delayed / 0-2.0
stomatitis / Delayed / 0-2.0
thrombosis / Delayed / 0-2.0
thromboembolism / Delayed / 2.0-2.0
pulmonary embolism / Delayed / 0-2.0
headache / Early / 0-1.5
xerosis / Delayed / 0-1.1
chills / Rapid / 0-1.1
peripheral edema / Delayed / 0-1.0
edema / Delayed / 0-1.0
acneiform rash / Delayed / 0-1.0
GI perforation / Delayed / 0-1.0
nausea / Early / 0-1.0
abdominal pain / Early / 0-1.0
renal failure (unspecified) / Delayed / 0-1.0
myalgia / Early / 0-1.0
arthralgia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-0.7
intracranial bleeding / Delayed / 0-0.6
dizziness / Early / 0-0.2
heart failure / Delayed / Incidence not known
visual impairment / Early / Incidence not known
retinal detachment / Delayed / Incidence not known
macular edema / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
ocular hemorrhage / Delayed / Incidence not known
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
hemophagocytic lymphohistiocytosis / Delayed / Incidence not known

lymphocytosis / Delayed / 0-224.0
hypermagnesemia / Delayed / 0-32.0
hypernatremia / Delayed / 0-27.0
constipation / Delayed / 0-23.0
blurred vision / Early / 0-10.0
sarcoidosis / Delayed / 0-10.0
peripheral neuropathy / Delayed / 0-7.0
QT prolongation / Rapid / 0.8-3.8
interstitial lung disease / Delayed / 1.0-2.0
pneumonitis / Delayed / 1.0-2.0
hypotension / Rapid / 0-2.0
colitis / Delayed / 0-1.0
dehydration / Delayed / 1.0-1.0
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
bullous rash / Early / Incidence not known
glossitis / Early / Incidence not known
hemoptysis / Delayed / Incidence not known
hematoma / Early / Incidence not known
hemorrhoids / Delayed / Incidence not known
vaginal bleeding / Delayed / Incidence not known
melena / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
bone pain / Delayed / Incidence not known

cough / Delayed / 0-44.0
musculoskeletal pain / Early / 0-36.0
anorexia / Delayed / 0-29.0
infection / Delayed / 0-23.0
epistaxis / Delayed / 0-16.0
xerophthalmia / Early / 0-10.0
panniculitis / Delayed / 0-10.0
xerostomia / Early / 0-10.0
folliculitis / Delayed / 0-10.0
dysgeusia / Early / 0-10.0
alopecia / Delayed / 0-3.0
anxiety / Delayed / 0-1.4
syncope / Early / 0-1.0
vesicular rash / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
cheilitis / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
purpura / Delayed / Incidence not known
vertigo / Early / Incidence not known
paresthesias / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
back pain / Delayed / Incidence not known

Mekinist

Rx

Mitogen-activated extracellular signal-regulated kinase (MEK)1 and MEK2 inhibitor
Used in adults as a single agent for advanced melanoma and in combination with dabrafenib for melanoma, NSCLC, and anaplastic thyroid cancer and for other BRAF V600 mutation-positive solid tumors (1 year and older); used in pediatric patients 1 year and older with low-grade glioma
Venous thromboembolism and interstitial lung disease have been reported

2 mg orally once daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372] Patients with BRAF V600E- or V600K-mutated unresectable stage IIIC or metastatic melanoma received daily oral trametinib (n = 214) or chemotherapy consisting of dacarbazine 1,000 mg/m2 IV every 3 weeks or paclitaxel 175 mg/m2 IV every 3 weeks (n = 108) in a multinational, randomized, phase 3 study. Patients who received up to 1 prior systemic therapy for advanced disease were eligible for enrollment; however, patients who had received prior BRAF- or MEK-inhibitor or ipilimumab therapy were ineligible. Approximately 66% of patients had received no prior chemotherapy for advanced disease before entering this study. Investigator assessed progression-free survival (PFS) time was significantly improved with trametinib compared with chemotherapy (4.8 months vs. 1.5 months; hazard ratio (HR) = 0.45; 95% CI, 0.33 to 0.63; p less than 0.001); PFS results were confirmed on independent radiologic review. Based on this significant PFS improvement and on initial overall survival (OS) results in an unplanned interim analysis, 51% of patients in the chemotherapy arm crossed over to the trametinib arm. Despite this high crossover rate, the 6-month OS rate was 81% in the trametinib arm and 67% in the chemotherapy arm (HR = 0.54; 95% CI, 0.32 to 0.92; p = 0.01).[54815]

2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372] Treatment with dabrafenib plus trametinib resulted in significantly improved median progression-free survival (PFS; 11.4 months vs. 7.3 months; hazard ratio (HR) = 0.56; 95% CI, 0.46 to 0.69; p less than 0.001) and overall survival (OS; median not reached vs. 17.2 months; HR = 0. 69; 95%CI, 0.53 to 0.89; p = 0.005) times compared with single-agent vemurafenib in previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K mutations in a planned interim analysis of a randomized, phase 3 study (n = 704; the COMBI-v study). This trial was stopped early based on the significantly improved OS data with combination therapy; cross-over from the vemurafenib to the combination arm was not allowed prior to the interim analysis.[58760] The median PFS (11 months vs. 8.8 months; HR = 0.67; 95% CI, 0.53 to 0.84; p = 0.0004) and OS (25.1 months vs. 18.7 months; HR = 0.71; 95% CI, 0.55 to 0.92; p = 0.0107) times were significantly improved with dabrafenib plus trametinib compared with dabrafenib plus placebo in previously untreated patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutations in a randomized, double-blind, phase 3 study (n = 423; the COMBI-d study). Cross-over from the dabrafenib plus placebo arm to the combination therapy arm was not permitted at the primary analysis.[59946] At a median follow-up time of 22 months (range, 0 to 76 months), the median PFS and OS times were 11.1 months and 25.9 months, respectively, in a pooled analysis of patients with advanced melanoma who received dabrafenib and trametinib in the COMBI-d and COMBI-v trials (n = 563); the 5-year PFS and OS rates were 19% and 37%, respectively.[64436]

2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression was evaluated in a cohort of 76 patients in a multicenter, phase 2 trial.[62027] Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372]

2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease recurrence or for up to 1 year was evaluated in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (n = 870; the COMBI-AD trial).  Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.

2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The investigator-assessed overall response rate (ORR) was 63.2% following treatment with dabrafenib and trametinib in a cohort of patients with previously treated stage IV BRAF V600E-mutant NSCLC (n = 57) in a multinational, nonrandomized, 3-cohort, phase II trial. At a median follow-up of 11.6 months, the median duration of response was 9 months and the median progression-free survival time was 8.6 months (evaluated by an independent review committee). Patients in this cohort (median age, 64 years; range, 58 to 71 years) had received up to 3 prior systemic therapies (1 prior therapy, 67%; 2 or 3 prior therapies, 33%) including at least 1 prior platinum-based chemotherapy regimen; patients who received prior BRAF or MEK inhibitor treatment were excluded from this study. The ORR was 61% in a cohort of patients with treatment-naive stage IV BRAF V600E-mutant NSCLC (n = 36) who received dabrafenib and trametinib

2 mg orally once daily plus dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity was evaluated in a subgroup of patients with ATC in a multicenter, nonrandomized phase 2 clinical trial.[62589] Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372]

NOTE: The recommended dosage of trametinib tablets has not been established in patients who weigh less than 26 kg.

2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with selected BRAF V600E mutation-positive tumors (n = 137) were treated with trametinib in 2 single-arm, open-label, clinical trials (BRF117019 and NCI-MATCH) were treated with trametinib plus dabrafenib. Response rates varied widely depending on indication including biliary tract cancer (n = 48; 46%); high grade gliomas (n = 48; 33%) including glioblastoma (n = 32; 25%), anaplastic pleomorphic xanthoastrocytoma (n = 6; 67%), anaplastic astrocytoma (n = 5; 20%), and astroblastoma (n = 2; 100%); low grade gliomas (n = 14; 50%); low grade serous ovarian cancer (n = 5; 80%); and others.

Dosage is based on weight as follows: 26 to 37 kg, give 1 mg PO once daily; 38 to 50 kg, give 1.5 mg PO once daily; and 51 kg or more, give 2 mg PO once daily. Administer in combination with dabrafenib until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. In 2 cohorts of a multicenter, multicohort, open-label clinical trial (Study X2101), pediatric patients with refractory or recurrent BRAF V600E mutation-positive solid tumors were treated with dabrafenib (n = 48), including 34 patients with low-grade glioma and 2 patients with high grade glioma. The objective response rate was 25%, with a duration of at least 6 months for 78% of patients and at least 24 months for 44% of patients.

2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with selected BRAF V600E mutation-positive tumors (n = 137) were treated with trametinib in 2 single-arm, open-label, clinical trials (BRF117019 and NCI-MATCH) were treated with trametinib plus dabrafenib. Response rates varied widely depending on indication including biliary tract cancer (n = 48; 46%); high grade gliomas (n = 48; 33%) including glioblastoma (n = 32; 25%), anaplastic pleomorphic xanthoastrocytoma (n = 6; 67%), anaplastic astrocytoma (n = 5; 20%), and astroblastoma (n = 2; 100%); low grade gliomas (n = 14; 50%); low grade serous ovarian cancer (n = 5; 80%); and others.

Dosage is based on weight as follows: 8 kg, give 0.3 mg (6 mL) once daily; 14 to 17 kg, give 0.55 mg (11 mL) once daily; 18 to 21 kg, give 0.7 mg (14 mL) once daily; 22 to 25 kg, give 0.85 mg (17 mL) once daily; 26 to 29 kg, give 0.9 mg (18 mL) once daily; 30 to 33 kg, give 1 mg (20 mL) once daily; 34 to 37 kg, give 1.15 mg (23 mL) once daily; 38 to 41 kg, give 1.25 mg (25 mL) once daily; 42 to 45 kg, give 1.4 mg (28 mL) once daily; 46 to 50 kg, give 1.6 mg (32 mL) once daily; and 51 kg or more, give 2 mg (40 mL) once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 cohorts of a multicenter, multicohort, open-label clinical trial (Study X2101), pediatric patients with refractory or recurrent BRAF V600E mutation-positive solid tumors were treated with dabrafenib (n = 48), including 34 patients with low-grade glioma and 2 patients with high grade glioma. The objective response rate was 25%, with a duration of at least 6 months for 78% of patients and at least 24 months for 44% of patients.

NOTE: A recommended dosage of trametinib tablets has not been established in pediatric patients who weigh less than 26 kg.

Dosage is based on weight as follows: 26 to 37 kg, give 1 mg PO once daily; 38 to 50 kg, give 1.5 mg PO once daily; and 51 kg or more, give 2 mg PO once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. The overall response rate (primary endpoint evaluated by an independent review committee) was significantly improved (46.6% vs. 10.8%; p-value less than 0.001) in pediatric patients aged 1 to less than 18 years (median age, 9.5 years) with WHO grades 1 and 2 LGG who received dabrafenib plus trametinib (n = 73) compared with carboplatin plus vincristine (n = 37) as first systemic therapy in a randomized (2:1), phase 2/3 (TADPOLE) trial. The complete response rate was 2.7% in each treatment arm. The median duration of response was 23.7 months in the dabrafenib plus trametinib arm and not estimable in the carboplatin plus vincristine arm. At the primary analysis when all patients had completed at least 32 weeks of therapy, the median progression-free survival time was significantly improved in patients who received dabrafenib plus trametinib compared with carboplatin plus vincristine (20.1 months vs. 7.4 months; hazard ratio = 0.31; 95% CI, 0.17 to 0.55).

Dosage is based on weight as follows: 8 kg, give 0.3 mg (6 mL) once daily; 9 to 10 kg, give 0.35 mg (7 mL) once daily; 11 kg, give 0.4 mg (8 mL) once daily; 12 to 13 kg, give 0.45 mg (9 mL) once daily; 14 to 17 kg, give 0.55 mg (11 mL) once daily; 18 to 21 kg, give 0.7 mg (14 mL) once daily; 22 to 25 kg, give 0.85 mg (17 mL) once daily; 26 to 29 kg, give 0.9 mg (18 mL) once daily; 30 to 33 kg, give 1 mg (20 mL) once daily; 34 to 37 kg, give 1.15 mg (23 mL) once daily; 38 to 41 kg, give 1.25 mg (25 mL) once daily; 42 to 45 kg, give 1.4 mg (28 mL) once daily; 46 to 50 kg, give 1.6 mg (32 mL) once daily; and 51 kg or more, give 2 mg (40 mL) once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. The overall response rate (primary endpoint evaluated by an independent review committee) was significantly improved (46.6% vs. 10.8%; p-value less than 0.001) in pediatric patients aged 1 to less than 18 years (median age, 9.5 years) with WHO grades 1 and 2 LGG who received dabrafenib plus trametinib (n = 73) compared with carboplatin plus vincristine (n = 37) as first systemic therapy in a randomized (2:1), phase 2/3 (TADPOLE) trial. The complete response rate was 2.7% in each treatment arm. The median duration of response was 23.7 months in the dabrafenib plus trametinib arm and not estimable in the carboplatin plus vincristine arm. At the primary analysis when all patients had completed at least 32 weeks of therapy, the median progression-free survival time was significantly improved in patients who received dabrafenib plus trametinib compared with carboplatin plus vincristine (20.1 months vs. 7.4 months; hazard ratio = 0.31; 95% CI, 0.17, 0.55).

Mild hepatic impairment (bilirubin at the upper limit of normal (ULN) or less and AST greater than ULN; OR bilirubin 1.1 to 1.5 times ULN and any AST): No dose adjustment necessary.
Moderate to severe hepatic impairment (bilirubin 1.6 to 10 times ULN and any AST): A recommended dose of trametinib has not been established. Consider the risks versus benefits of treatment.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Chloroquine: (Moderate) Concurrent use of chloroquine and trametinib is not recommended as there is an increased risk of retinal toxicity.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trametinib is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with trametinib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trametinib is a weak in vitro inhibitor of CYP2C8.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with trametinib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trametinib is a weak in vitro inhibitor of CYP2C8.

Mekinist Oral Tab: 0.5mg, 2mg
Trametinib Oral Pwd F/Recon: 0.05mg, 1mL

2 mg PO once daily.

2 mg PO once daily.

Tablets:
Less than 26 kg: Safety and efficacy have not been established.26 kg to 37 kg: 1 mg PO once daily.38 kg to 50 kg: 1.5 mg PO once daily.51 kg or more: 2 mg PO once daily.
Oral Solution:26 to 29 kg: 0.9 mg once daily.30 to 33 kg: 1 mg once daily.34 to 37 kg: 1.15 mg once daily.38 to 41 kg: 1.25 mg once daily.42 to 45 kg: 1.4 mg once daily.46 to 50 kg: 1.6 mg once daily.51 kg or more: 2 mg once daily.

Tablets:
Less than 26 kg: Safety and efficacy have not been established.26 kg to 37 kg: 1 mg PO once daily.38 kg to 50 kg: 1.5 mg PO once daily.51 kg or more: 2 mg PO once daily.
Oral Solution:
8 kg: 0.3 mg once daily.9 to 10 kg: 0.35 mg once daily.11 kg: 0.4 mg once daily.12 to 13 kg: 0.45 mg once daily.14 to 17 kg: 0.55 mg once daily.18 to 21 kg: 0.7 mg once daily.22 to 25 kg: 0.85 mg once daily.26 to 29 kg: 0.9 mg once daily.30 to 33 kg: 1 mg once daily.34 to 37 kg: 1.15 mg once daily.38 to 41 kg: 1.25 mg once daily.42 to 45 kg: 1.4 mg once daily.46 to 50 kg: 1.6 mg once daily.51 kg or more: 2 mg once daily.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Trametinib is a reversible inhibitor of mitogen-activated extracellular kinases (MEK)-1 and MEK-2 that has demonstrated activity against BRAF V600-mutated forms of BRAF kinases in melanoma cells in vitro and in vivo. MEK proteins belong to a family of enzymes that lie downstream of the BRAF kinase and upstream of the extracellular receptor kinase (ERK) signaling pathways. Approximately 50% of melanomas have BRAF mutations. Some BRAF mutations (e.g., BRAF V600 mutations) signal mitogen activated protein kinase (MAPK) pathways resulting in the hyperactivation of MEK and ERK leading to melanoma cell proliferation in the absence of growth factors that would normally be required for cell proliferation.
Potential mechanisms of resistance to trametinib include upregulation of MAPK signaling, phosphatase tensin homologue (PTEN) loss, hepatocyte growth factor (HGF)/MET signaling, amplified cyclin D1 (CCND1), and amplified receptor tyrosine kinase (RTK) signaling through PI3K and mTOR.
Induction of EGFR-mediated MAPK pathway reactivation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors in the setting of BRAF-mutant colorectal cancer.

Trametinib is administered orally. It is highly bound to plasma proteins (97.4%) and has an apparent volume of distribution of 214 L. In vitro, trametinib is metabolized by deacetylation alone (via hydrolytic enzymes such as carboxyl-esterases or amidases), mono-oxygenation, and/or glucuronidation pathways. The estimated trametinib elimination half-life is 3.9 to 4.8 days and the apparent clearance is 4.9 L/hour. The fecal route is the main route of trametinib excretion. Following a radioactive [14C]-trametinib dose, 50% of the radioactivity in the plasma is the parent compound; 80% of the radioactivity was recovered in the feces and less than 20% of the total reactivity was recovered in the urine (less than 0.1% as the parent drug). Following repeat trametinib dosing, 75% or more of the parent compound is found in the plasma.
 
Affected cytochrome P450 isoenzymes and drug transporters: None
In vitro, trametinib is a substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP) and an inhibitor of CYP2C8.

The mean absolute oral bioavailability is 72% for trametinib tablets and 81% for trametinib oral solution. Following oral administration, the median time to peak plasma concentration (Tmax) is 1.5 hours. Over a dosage range of 0.125 mg to 10 mg, trametinib tablets exhibit dose proportional Cmax following a single dose; however, the AUC is greater than dose proportional. Following repeat daily doses of 0.125 mg to 4 mg, trametinib exhibits dose proportional exposure; inter-subject steady-state Cmax and AUC variability was 28% and 22%, respectively.
Effects of food: Administering trametinib tablets with a high-fat, high-calorie meal decreases the Cmax by 70%, decreases the AUC by 24%, and delays the median Tmax by about 4 hours when compared to the fasted state. For both tablets and oral solution, take the trametinib dose at least 1 hour before or at least 2 hours after a meal.

Trametinib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and findings from animal studies. Advise females of reproductive potential to avoid pregnancy while taking trametinib. Discuss the potential hazard to the fetus if trametinib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weight (rats and rabbits), variations in bone ossification (rabbits), and increased post implantation loss (rabbits) were observed in pregnant animals that received trametinib at doses that resulted in drug exposures that were lower (about 0.3 times the human exposure or less) than those observed with the recommended human dose. An increase in post implantation loss was also seen in pregnant rats who received trametinib at doses that resulted in drug exposures that were 1.8-times higher than those observed with the recommended human dose.

Patients should discontinue breast-feeding during trametinib therapy and for 4 months after the last dose because of the potential for serious adverse reactions in the breastfed child. It is not known if trametinib is secreted in human milk or if it affects the breastfed child or milk production.