Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to trametinib treatment initiation.
Melanoma, adjuvant treatment, with BRAF V600E or BRAF V600K mutation: Oral: 2 mg once daily (in combination with dabrafenib); continue until disease recurrence or unacceptable toxicity for up to 1 year (Long 2017).
Melanoma, metastatic or unresectable, with BRAF V600E or BRAF V600K mutation: Oral: 2 mg once daily (either as a single-agent or in combination with dabrafenib), continue until disease progression or unacceptable toxicity.
Non-small cell lung cancer, metastatic, with BRAF V600E mutation: Oral: 2 mg once daily (in combination with dabrafenib); continue until disease progression or unacceptable toxicity (Planchard 2016).
Thyroid cancer, anaplastic, locally advanced or metastatic, with BRAF V600E mutation: Oral: 2 mg once daily (in combination with dabrafenib); continue until disease recurrence or unacceptable toxicity (Subbiah 2018).
Missed doses: Do not take a missed dose within 12 hours of the next dose.
eGFR ≥15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, eGFR ≥15 mL/minute/1.73 m2 does not have a clinically significant effect on trametinib exposure.
eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.
Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.
Moderate (bilirubin >1.5 to 3 times ULN and any AST) to severe (bilirubin >3 to 10 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established).
In a small pharmacokinetic study, patients with moderate impairment who received either 1.5 or 2 mg once daily for up to 3 (28-day) cycles did not experience dose-limiting toxicities. Among patients with severe impairment who received either 1 or 1.5 mg once daily, no dose-limiting toxicities occurred at the 1 mg dose level, although 1 of the 2 patients who received 1.5 mg once daily experienced grade 3 acneiform rash (Voon 2022). According to the manufacturer, moderate or severe hepatic impairment had no significant effect on trametinib exposure or apparent clearance (compared to patients with normal hepatic function); based on the limited number of patients and doses studied, assess risks versus benefits with respect to dosing in patients with moderate or severe hepatic impairment.
Note: If using combination therapy, refer to Dabrafenib monograph for recommended dabrafenib dose reductions.
|
Usual (initial) dose |
2 mg once daily |
|
First dose reduction |
1.5 mg once daily |
|
Second dose reduction |
1 mg once daily |
|
If unable to tolerate 1 mg once daily, permanently discontinue trametinib. | |
|
Target organ |
Adverse reaction severity |
Trametinib dosage modification |
|---|---|---|
|
a LVEF = left ventricular ejection fraction; RPED = retinal pigment epithelial detachment; RVO = retinal vein occlusion; ILD = interstitial lung disease; DVT = deep vein thrombosis; PE = pulmonary embolism. | ||
|
Dermatologic |
Intolerable grade 2 toxicity or grade 3 or 4 toxicity |
Interrupt trametinib for up to 3 weeks. If toxicity improves within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
|
New primary cutaneous malignancy |
No trametinib dosage modification is necessary. | |
|
Severe cutaneous adverse reactions |
Permanently discontinue trametinib. | |
|
Cardiotoxicity |
Asymptomatic, absolute decrease in LVEF ≥10% from baseline and is below institutional LLN from pretreatment value |
Interrupt trametinib for up to 4 weeks. If LVEF improves to normal within 4 weeks, resume trametinib at a lower dose. If LVEF does not improve to normal, permanently discontinue trametinib. |
|
Symptomatic cardiomyopathy |
Permanently discontinue trametinib. | |
|
Absolute decrease in LVEF of >20% from baseline that is below institutional LLN | ||
|
Fever |
Fever of 38°C to 40°C (100.4°F to 104°F), or first symptoms in case of recurrence |
Interrupt trametinib therapy until fever resolves and then resume at the same or lower dose. |
|
Fever >40°C (104°F) or fever (any severity) complicated by rigors, hypotension, dehydration, or renal failure |
Interrupt trametinib therapy until febrile reaction resolves for at least 24 hours, then resume trametinib at a lower dose or permanently discontinue trametinib. Administer secondary prophylactic antipyretics upon trametinib resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episode of pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, hypotension, renal failure, severe chills/rigors with no evidence of active infection). | |
|
Hemorrhage |
Grade 3 hemorrhage |
Interrupt trametinib therapy. If hemorrhage improves, resume trametinib at a lower dose. If hemorrhage does not improve, permanently discontinue trametinib. |
|
Grade 4 hemorrhage |
Permanently discontinue trametinib. | |
|
Hyperglycemia |
Hyperglycemia may require initiation or optimization of insulin or oral hypoglycemic agent therapy (as clinically indicated). | |
|
Ocular |
Uveitis and iritis |
No trametinib dosage modification necessary. |
|
RPED |
Interrupt trametinib for up to 3 weeks. If RPED improves within 3 weeks, resume trametinib at the same or lower dose. If RPED does not improve, resume trametinib at a reduced dose or permanently discontinue trametinib. | |
|
RVO |
Permanently discontinue trametinib. | |
|
Pulmonary |
New or progressive pulmonary symptoms/findings (including cough, dyspnea, hypoxia, plural effusion, infiltrates) |
Withhold trametinib and assess for ILD. |
|
ILD/pneumonitis |
Permanently discontinue trametinib. | |
|
Venous thromboembolism |
Uncomplicated DVT or PE |
Interrupt trametinib therapy for up to 3 weeks. If toxicity improves to ≤ grade 1 within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
|
Life-threatening PE |
Permanently discontinue trametinib. | |
|
Other |
Intolerable grade 2 adverse reaction or any grade 3 adverse reaction |
Interrupt trametinib. If toxicity improves to ≤ grade 1, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
|
Grade 4 adverse reaction, first occurrence |
Interrupt trametinib therapy until toxicity improves to ≤ grade 1, then resume trametinib at a lower dose or permanently discontinue trametinib. | |
|
Grade 4 adverse reaction, recurrent |
Permanently discontinue trametinib. | |
|
New primary noncutaneous malignancy |
No trametinib dosage reduction is necessary. | |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mekinist: 0.5 mg, 2 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Mekinist: 0.5 mg, 2 mg
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204114s004lbl.pdf#page=32, must be dispensed with this medication.
Oral: Administer at least 1 hour before or 2 hours after a meal. Administer dose at the same time each day (trametinib doses should be administered ~24 hours apart), whether administered as a single agent or in combination with dabrafenib (when administered in combination with dabrafenib, take the once daily trametinib dose either with the morning or with the evening dabrafenib dose).
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Melanoma:
Adjuvant treatment of melanoma (in combination with dabrafenib) in patients with BRAF V600E or BRAF V600K mutations (as detected by an approved test), and lymph node involvement, following complete resection.
Treatment of unresectable or metastatic melanoma in patients with BRAF V600E or BRAF V600K mutations (as detected by an approved test), either as a single-agent (in BRAF inhibitor treatment-naive patients) or in combination with dabrafenib.
Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in patients with BRAF V600E mutation as detected by an approved test (in combination with dabrafenib).
Thyroid cancer, anaplastic, locally advanced or metastatic: Treatment of locally advanced or metastatic anaplastic thyroid cancer (in combination with dabrafenib) in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.
Trametinib may be confused with binimetinib, cobimetinib, dabrafenib, encorafenib, selumetinib, tepotinib, trilaciclib, tucatinib, vemurafenib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (including peripheral edema: ≤32%), hypertension (15%)
Dermatologic: Acneiform eruption (19%), skin rash (57%), xeroderma (11%)
Endocrine & metabolic: Hypoalbuminemia (42%)
Gastrointestinal: Abdominal pain (13%), diarrhea (43%), stomatitis (15%; grades 3/4: 2%)
Hematologic & oncologic: Anemia (38%; grades 3/4: 2%), hemorrhage (13%; grades 3/4: <1%), lymphedema (≤32%; grades 3/4: 1%)
Hepatic: Increased serum alanine aminotransferase (39%), increased serum alkaline phosphatase (24%), increased serum aspartate aminotransferase (60%)
1% to 10%:
Cardiovascular: Bradycardia
Dermatologic: Cellulitis, folliculitis, paronychia (10%), pruritus (10%), pustular rash
Gastrointestinal: Dysgeusia, xerostomia
Nervous system: Dizziness
Neuromuscular & skeletal: Rhabdomyolysis
Ophthalmic: Blurred vision, dry eye syndrome
Respiratory: Interstitial pulmonary disease (≤2%), pneumonitis (≤2%)
<1%:
Gastrointestinal: Colitis, gastrointestinal perforation
Ophthalmic: Retinal vein occlusion
Frequency not defined:
Cardiovascular: Decreased left ventricular ejection fraction
Ophthalmic: Retinal detachment
Renal: Renal failure syndrome
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to trametinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiac events: Cardiac events such as heart failure, left ventricular dysfunction, or decreased left ventricular ejection fraction were observed in clinical trials (for single-agent trametinib and when used in combination with dabrafenib).
• Dermatologic toxicity: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported; may be life-threatening or fatal.
• Febrile reactions: Serious febrile reactions and fever (any severity) accompanied by hypotension, rigors/chills, dehydration, or renal failure may occur when trametinib is used in combination with dabrafenib.
• GI events: Colitis and GI perforation, including fatal cases, have been reported with monotherapy and when administered concomitantly with dabrafenib.
• Hemorrhage: Hemorrhage, including symptomatic bleeding in a critical area/organ, may occur with trametinib, either as a single agent or in combination with dabrafenib. Major bleeding events (some fatal) included intracranial, subarachnoid, retroperitoneal, or GI hemorrhage.
• Hyperglycemia: Hyperglycemia may occur with trametinib/dabrafenib combination therapy.
• Hypertension: May cause hypertension.
• Malignancy: New primary cutaneous malignancies (which are associated with dabrafenib as single-agent therapy) may occur when trametinib is given in combination with dabrafenib. Basal cell carcinoma (BCC) occurred in 3% of patients. Cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthoma occurred in a small percentage of patients. New primary melanoma occurred rarely in patients receiving trametinib. There are case reports of noncutaneous malignancies with combination therapy.
• Ocular toxicity: Retinal pigment epithelial detachments and retinal vein occlusion were seen in clinical trials (rare). Detachments may be bilateral and multifocal, occurring in the central macular area of the retina or elsewhere in the retina. Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Uveitis and iritis have been reported when trametinib is used in combination with dabrafenib and are managed symptomatically with ophthalmic steroid and mydriatic drops (does not require alteration in trametinib therapy).
• Pulmonary toxicity: Interstitial lung disease and pneumonitis were observed in clinical trials; pulmonary symptoms may include cough, dyspnea, hypoxia, pleural effusion, and infiltrates.
• Venous thromboembolism: Venous thromboembolic events (some fatal) may occur (was observed when used in combination with dabrafenib). Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred at an increased incidence with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling).
Concurrent drug therapy issues:
• Combination therapy with dabrafenib: Serious adverse reactions (tumor promotion, hemolytic anemia), which occur with single-agent dabrafenib, may also occur when trametinib is administered in combination with dabrafenib. Refer to Dabrafenib monograph for further information.
Other warnings/precautions:
• Appropriate use: Prior to initiating therapy, confirm BRAF V600K and/or BRAF V600E mutation status (in tumor specimens) with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics. An approved test for BRAF V600E mutation detection in anaplastic thyroid cancer is not available.
None known.
Dabrafenib: Trametinib may enhance the adverse/toxic effect of Dabrafenib. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Administration of a single trametinib dose with a high-fat, high-calorie meal (~1,000 calories) decreased AUC by 24%, Cmax by 70%, and delayed Tmax by ~4 hours. Management: Administer 1 hour before or 2 hours after a meal.
Verify pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use effective contraceptive during trametinib therapy and for 4 months after the last trametinib dose. Males (including those with vasectomies) with pregnant partners or partners who could become pregnant should use condoms during trametinib treatment and for at least 4 months after the last trametinib dose.
Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to trametinib may cause fetal harm.
It is not known if trametinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during trametinib treatment and for 4 months after the last trametinib dose.
BRAF V600K or V600E mutation status (prior to treatment); liver function tests at baseline and periodically; assess left ventricular ejection fraction (LVEF) (by echocardiogram or MUGA scan) at baseline, 1 month after therapy initiation, and then at 2- to 3-month intervals. Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Perform ophthalmological evaluation (including retinal evaluation) periodically during treatment; if patient-reported loss of vision or other visual disturbances occur, urgently (within 24 hours) perform ophthalmological exam. Monitor for signs/symptoms of new or progressive pulmonary toxicity (eg, cough dyspnea, hypoxia, pleural effusion, or infiltrates). Monitor for new or worsening dermatologic toxicity and secondary skin infections. Monitor BP. Monitor for signs/symptoms of bleeding/hemorrhage, diarrhea, colitis, and GI perforations. Monitor adherence.
For patients receiving combination therapy with dabrafenib: Blood glucose (baseline and periodically in patients with preexisting diabetes or hyperglycemia). Monitor for signs/symptoms of fever or febrile reactions. Dermatologic exams should be performed prior to treatment initiation, every 2 months while receiving combination treatment, and for up to 6 months following combination therapy discontinuation. Monitor for signs/symptoms of venous thromboembolism, cutaneous and noncutaneous malignancies, and uveitis/iritis.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Trametinib reversibly and selectively inhibits mitogen-activated extracellular kinase (MEK) 1 and 2 activation and kinase activity. MEK is a downstream effector of the protein kinase B-raf (BRAF); BRAF V600 mutations result in constitutive activation of the BRAF pathway (including MEK1 and MEK2). Through inhibition of MEK 1 and 2 kinase activity, trametinib causes decreased cellular proliferation, cell cycle arrest, and increased apoptosis (Kim 2013). The combination of trametinib and dabrafenib allows for greater inhibition of the MAPK pathway, resulting in BRAF V600 melanoma cell death (Flaherty 2012a). Trametinib plus dabrafenib has been reported to synergistically inhibit cell growth in lung cancer cell lines which are BRAF V600E-mutant (Planchard 2016).
Absorption: Rapid; decreased with a high-fat, high-calorie meal (~1,000 calories).
Distribution: 214 L.
Protein binding: ~97% to plasma proteins.
Metabolism: Predominantly deacetylation (via hydrolytic enzymes) alone or with mono-oxygenation or in combination with glucuronidation.
Bioavailability: 72%.
Half-life elimination: ~4 to 5 days.
Time to peak: 1.5 hours; delayed with a high-fat, high-calorie meal (~1,000 calories).
Excretion: Feces (>80%); urine (<20% with <0.1% as unchanged drug).
Clearance: 4.9 L/hour.
Tablets (Mekinist Oral)
0.5 mg (per each): $156.24
2 mg (per each): $531.75
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