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Trametinib: Drug information

(For additional information see "Trametinib: Patient drug information" and see "Trametinib: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Mekinist

Brand Names: Canada

Mekinist

Pharmacologic Category

Antineoplastic Agent, MEK Inhibitor

Dosing: Adult

Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to trametinib treatment initiation.

Melanoma, adjuvant treatment, with BRAF V600E or BRAF V600K mutation

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

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

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).

Ovarian carcinoma, serous, low-grade, recurrent

Ovarian carcinoma, serous, low-grade, recurrent (off-label use): Oral: 2 mg once daily until disease progression or unacceptable toxicity (Gershenson 2022). Refer to protocol for dosage adjustment details.

Solid tumors, unresectable or metastatic, with BRAF V600E mutation

Solid tumors, unresectable or metastatic, with BRAF V600E mutation: Oral: 2 mg once daily (in combination with dabrafenib) until disease progression or unacceptable toxicity.

Thyroid cancer, anaplastic, locally advanced or metastatic, with BRAF V600E mutation

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.

Dosing: Kidney Impairment: Adult

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 m²does 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.

Dosing: Hepatic Impairment: Adult

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.

Dosing: Pediatric

(For additional information see "Trametinib: Pediatric drug information")

Solid tumors; unresectable or metastatic

Solid tumors; unresectable or metastatic (with BRAF V600E mutation):

Note: For use in patients who have progressed following prior treatment and have no satisfactory alternative treatment options; approval from an accelerated process and subject to change as data evolves. Use in combination with dabrafenib and continue therapy until disease progression or unacceptable toxicity.

Children ≥6 years and Adolescents <18 years weighing ≥26 kg:

26 to <38 kg: Oral: 1 mg once daily.

38 to <51 kg: Oral: 1.5 mg once daily.

≥51 kg: Oral: 2 mg once daily.

Adolescents ≥18 years: Oral: 2 mg once daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for toxicity:

**Trametinib Dosage Level Reductions in Pediatric Patients**
Children ≥6 years and Adolescents <18 years weighing ≥26 kg: Oral
Patient Weight (Usual Dose)	First Dose Reduction	Second Dose Reduction	Subsequent Modifications
26 to <38 kg (1 mg/day)	0.5 mg once daily	Permanently discontinue if unable to tolerate 0.5 mg/day
38 to <51 kg (1.5 mg/day)	1 mg once daily	0.5 mg once daily	Permanently discontinue if unable to tolerate 2 trametinib dose reductions
≥51 kg (2 mg/day)	1.5 mg once daily	1 mg once daily	Permanently discontinue if unable to tolerate 2 trametinib dose reductions
Adolescents ≥18 years: Oral
Usual Dose	First Dose Reduction	Second Dose Reduction	Subsequent Modifications
2 mg/day	1.5 mg once daily	1 mg once daily	Permanently discontinue if unable to tolerate 2 trametinib dose reductions

**Trametinib Dosage Modifications for Adverse Reactions^a**
Adverse Reaction	Description/Severity	Trametinib Dosage Modification
^a LVEF = left ventricular ejection fraction; DVT = deep vein thrombosis; PE = pulmonary embolism.
Cardiomyopathy	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	Permanently discontinue trametinib.
Dermatologic toxicity	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.
Febrile reaction	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.
Febrile reaction	Fever >40°C (104°F) or fever (any severity) complicated by rigors, hypotension, dehydration, or kidney 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 antipyretics (as secondary prophylaxis) upon trametinib resumption if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, the equivalent of prednisone 10 mg daily in adults) 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, kidney 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.
Hemorrhage	Grade 4 hemorrhage	Permanently discontinue trametinib.
Hyperglycemia		Hyperglycemia may require initiation or optimization of insulin or oral hypoglycemic agent therapy (as clinically indicated).
Ocular toxicity	Uveitis	No trametinib dosage modification necessary.
	Retinal pigment epithelial detachment	Interrupt trametinib for up to 3 weeks. If improves within 3 weeks, resume trametinib at the same or lower dose. If not improved, resume trametinib at a reduced dose or permanently discontinue trametinib.
	Retinal vein occlusion	Permanently discontinue trametinib.
Pulmonary	New or progressive pulmonary symptoms/findings (including cough, dyspnea, hypoxia, plural effusion, infiltrates)	Withhold trametinib and assess.
Pulmonary	Interstitial lung disease/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.
Venous thromboembolism	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.

Dosing: Kidney Impairment: Pediatric

Children ≥6 years and Adolescents: Oral:

eGFR <15 mL/minute/1.73 m²: There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

Children ≥6 years and Adolescents: Oral:

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 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established). 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.

Dosing: Adjustment for Toxicity: Adult

Note: If using combination therapy, refer to Dabrafenib monograph for recommended dabrafenib dose modifications.

**Trametinib Dose Reduction Levels**
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.

**Trametinib Dosage Modifications for Adverse Reactions^a**
Adverse reaction	Description/severity	Trametinib dosage modification
^a LVEF = left ventricular ejection fraction; DVT = deep vein thrombosis; PE = pulmonary embolism.
Cardiomyopathy	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	Permanently discontinue trametinib.
Dermatologic toxicity	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.
Febrile reaction	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.
Febrile reaction	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 antipyretics (as secondary prophylaxis) upon trametinib resumption if patient had a prior episode of severe febrile reaction or fever associated with complications. 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.
Hemorrhage	Grade 4 hemorrhage	Permanently discontinue trametinib.
Hyperglycemia		Hyperglycemia may require initiation or optimization of insulin or oral hypoglycemic agent therapy (as clinically indicated).
Ocular toxicity	Uveitis	No trametinib dosage modification necessary.
	Retinal pigment epithelial detachment	Interrupt trametinib for up to 3 weeks. If improves within 3 weeks, resume trametinib at the same or lower dose. If not improved, resume trametinib at a reduced dose or permanently discontinue trametinib.
	Retinal vein occlusion	Permanently discontinue trametinib.
Pulmonary	New or progressive pulmonary symptoms/findings (including cough, dyspnea, hypoxia, plural effusion, infiltrates)	Withhold trametinib and assess.
Pulmonary	Interstitial lung disease/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.
Venous thromboembolism	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.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Mekinist: 0.5 mg, 2 mg

Generic Equivalent Available: US

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Mekinist: 0.5 mg, 2 mg

Medication Guide and/or Vaccine Information Statement (VIS)

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.

Administration: Adult

Oral: Administer at least 1 hour before or 2 hours after a meal. 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.

Administration: Pediatric

Oral: Administer at least 1 hour before or 2 hours after a meal. 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.

Missed doses: Do not take a missed dose within 12 hours of the next dose.

Hazardous Drugs Handling Considerations

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).

Use: Labeled Indications

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).

Solid tumors, unresectable or metastatic: Treatment (in combination with dabrafenib) of unresectable or metastatic solid tumors with a BRAF V600E mutation in adults and pediatric patients ≥6 years of age who have progressed following prior treatment and have no satisfactory alternative treatment options.

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.

Limitations of use: Trametinib is not indicated for treatment of colorectal cancer because of known intrinsic resistance to BRAF inhibition.

Use: Off-Label: Adult

Ovarian carcinoma, serous, low-grade, recurrent

Medication Safety Issues

Sound-alike/look-alike issues:

Trametinib may be confused with binimetinib, cobimetinib, dabrafenib, encorafenib, selumetinib, tepotinib, trilaciclib, tucatinib, vemurafenib.

High alert medication:

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.

Adverse Reactions

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

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to trametinib or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac events: Cardiomyopathy, including heart failure, may occur with trametinib (including 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 were intracranial hemorrhage (including fatal cerebral and brainstem hemorrhages) and GI hemorrhage.

• Hyperglycemia: Hyperglycemia may occur with trametinib/dabrafenib combination therapy, including some grade 3 or 4 events.

• 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 may occur with trametinib (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.

• 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 with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling).

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.

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Food Interactions

Administration of a single trametinib dose with a high-fat, high-calorie meal (~1,000 calories) decreased AUC by 24%, C_max by 70%, and delayed T_max by ~4 hours. Management: Administer 1 hour before or 2 hours after a meal.

Reproductive Considerations

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.

Pregnancy Considerations

Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to trametinib may cause fetal harm.

Breastfeeding Considerations

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.

Monitoring Parameters

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.

Mechanism of Action

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). Induction of EGFR-mediated MAPK pathway reactivation in the setting of BRAF-mutant colorectal cancer has been identified as a mechanism of intrinsic resistance to BRAF inhibitors.

Pharmacokinetics

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.

Pricing: US

Tablets (Mekinist Oral)

0.5 mg (per each): $159.36

2 mg (per each): $542.39

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International

Mekinist (AT, AU, BE, BM, CH, CL, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HR, HU, IE, IL, IS, JP, KR, LT, MT, NL, NO, NZ, PL, PT, RO, RU, SE, SI, SK, TW)

For country code abbreviations (show table)

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012a;367(18):1694-1703. [PubMed 23020132]
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012b;367(2):107-114. [PubMed 22663011]
Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9 [PubMed 35123694]
Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014;32(33):3697-3704. [PubMed 25287827]
Kim KB, Kefford R, Pavlick AC, et al, “Phase II study of the MED1/MEK2 Inhibitor Trametinib In Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With Or Without A BRAF Inhibitor,” J Clin Oncol, 2013, 31(4):482-9. [PubMed 23248257]
Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. [PubMed 28891408]
Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. [PubMed 26037941]
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888. [PubMed 25265492]
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