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Trametinib Dimethyl Sulfoxide (Monograph)

Brand name: Mekinist
Drug class: Antineoplastic Agents
Chemical name: N-[3-[3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-acetamide compd. with 1,1′-sulfinylbis[methane] (1:1)
Molecular formula: C26H23FIN5O4•C2H6OS
CAS number: 1187431-43-1

Medically reviewed by Drugs.com on Jan 30, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2 in cells with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutations.

Uses for Trametinib Dimethyl Sulfoxide

Melanoma

In combination with dabrafenib as adjuvant therapy following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement.

Alone or in combination with dabrafenib for treatment of unresectable or metastatic melanoma in selected patients with BRAF V600E or V600K mutation (designated an orphan drug by FDA as monotherapy or when used in combination for this use).

FDA-approved in vitro diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of monotherapy or combination therapy.

Not recommended for use as a single agent in patients with melanoma who have experienced disease progression following treatment with a BRAF inhibitor.

NSCLC

Used in combination with dabrafenib for treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation (designated an orphan drug by FDA when used in combination for this use).

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.

Anaplastic Thyroid Cancer

Used in combination with dabrafenib for treatment of locally advanced or metastatic anaplastic thyroid cancer in patients with BRAF V600E mutation when no satisfactory locoregional treatment options are available (designated an orphan drug by FDA when used in combination for this use).

Testing required to confirm presence of BRAF V600E mutation prior to initiation of therapy; no FDA-approved diagnostic test currently available for detection of BRAF V600E in anaplastic thyroid cancer.

BRAF V600E-mutant Solid Tumors

Used in combination with dabrafenib for treatment of adult and pediatric patients ≥6 years of age with unresectable or metastatic solid tumors (excluding colorectal cancer) with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment. Designated an orphan drug by FDA when used in combination for malignant glioma.

Accelerated approval for this indication is based on response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory studies.

Testing required to confirm presence of BRAF V600E mutation prior to initiation of therapy; no FDA-approved diagnostic test currently available for detection of BRAF V600E in solid tumors other than melanoma and NSCLC.

Trametinib Dimethyl Sulfoxide Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Premedication and Prophylaxis

Other General Considerations

Administration

Oral Administration

Administer orally once daily, approximately every 24 hours, at least 1 hour before or 2 hours after a meal.

Dosage

Available as trametinib dimethyl sulfoxide; dosage expressed in terms of trametinib.

Pediatric Patients

BRAF V600E-mutant Solid Tumors
Oral

Recommended dosage in pediatric patients ≥6 years of age and weighing at least 26 kg is described in Table 1 (use in combination with dabrafenib). Continue therapy until disease progression or unacceptable toxicity occurs.

Table 1. Trametinib Dosing in Pediatric Patients ≥6 Years of Age

Body Weight

Recommended Dosage

26 kg to 37 kg

1 mg (two 0.5-mg tablets) once daily

38 kg to 50 kg

1.5 mg (three 0.5-mg tablets) once daily

51 kg or greater

2 mg once daily

Adults

Melanoma
Adjuvant Therapy for Melanoma
Oral

2 mg once daily (use in combination with dabrafenib). Continue therapy for up to 1 year or until disease progression or unacceptable toxicity occurs.

Monotherapy for Unresectable or Metastatic Melanoma
Oral

2 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Combination Therapy for Unresectable or Metastatic Melanoma
Oral

2 mg once daily (use in combination with dabrafenib). Continue therapy until disease progression or unacceptable toxicity occurs.

NSCLC
Oral

2 mg once daily (use in combination with dabrafenib). Continue therapy until disease progression or unacceptable toxicity occurs.

Anaplastic Thyroid Cancer
Oral

2 mg once daily (use in combination with dabrafenib). Continue therapy until disease progression or unacceptable toxicity occurs.

BRAF V600E-mutant Solid Tumors
Oral

2 mg once daily (use in combination with dabrafenib). Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Dosage may be reduced or therapy temporarily interrupted in patients who develop adverse effects (Tables 2 and 3). Up to 2 dosage reductions for toxicity may be made. When used in combination with dabrafenib, dosage modification of dabrafenib for toxicity also may be required.

Table 2. Trametinib Dose Modifications for Toxicity in Adults

Action

Recommended Dosage

First dose reduction

1.5 mg (three 0.5-mg tablets) once daily

Second dose reduction

1 mg (two 0.5-mg tablets) once daily

Subsequent modification

Permanently discontinue trametinib

Table 3. Trametinib Dose Modifications for Toxicity in Pediatric Patients 6–17 Years of Age

Action

Current dosage of 1 mg once daily

Current dosage of 1.5 mg once daily

Current dosage of 2 mg once daily

First dose reduction

0.5 mg once daily

1 mg (two 0.5-mg tablets) once daily

1.5 mg (three 0.5-mg tablets) once daily

Second dose reduction

Not applicable, see below

0.5 mg once daily

1 mg (two 0.5-mg tablets) once daily

Subsequent modification

Permanently discontinue trametinib if unable to tolerate a maximum of 2 dose reductions

Dosage Modification for New Primary Cutaneous Malignancies

If new cutaneous malignancies occur, dosage modification of trametinib not necessary.

Dosage Modification for New Primary Noncutaneous Malignancies

If new noncutaneous malignancies occur in patients receiving trametinib/dabrafenib combination therapy, dosage modification of trametinib not necessary.

Dosage Modification for Febrile Drug Reactions

Fever (temperature of 38–40°C) or any initial symptom of fever recurrence: Interrupt trametinib therapy until the adverse reaction resolves. Once fever resolves, may resume trametinib at same or reduced dosage.

Fever >40°C or fever with complications (e.g., rigors, hypotension, dehydration, renal failure): Interrupt trametinib therapy until fever resolves for ≥24 hours; may resume trametinib at same or reduced dosage or permanently discontinue.

Dosage Modification for Dermatologic Effects

Intolerable grade 2 skin toxicity: Interrupt trametinib for up to 3 weeks. If improvement noted within 3 weeks, resume drug at reduced dosage. Permanently discontinue therapy in those with skin toxicity not improving within 3 weeks of treatment interruption.

Grade 3 or 4 skin toxicity: Interrupt therapy for up to 3 weeks. If improvement observed within 3 weeks, resume drug at reduced dosage. Permanently discontinue therapy in those with intolerable skin toxicity not improving within 3 weeks of treatment interruption.

Severe cutaneous adverse reactions (SCARs): Permanently discontinue trametinib.

Dosage Modification for Cardiac Effects

Asymptomatic decrease in left ventricular ejection fraction (LVEF) from baseline of ≥10% and to a level below institution-specific lower limit of normal: Interrupt trametinib for up to 4 weeks. If LVEF improves to normal values within 4 weeks, resume drug at reduced dosage. Permanently discontinue therapy in those with decreased LVEF not improving within 4 weeks of treatment interruption.

Symptomatic cardiomyopathy or an absolute decrease in LVEF from baseline >20% and to a level below institution-specific lower limit of normal: Permanently discontinue trametinib.

Dosage Modification for Hemorrhage

Grade 3 hemorrhagic events: Withhold trametinib therapy. If improvement observed, resume therapy at reduced dosage. If no improvement observed, permanently discontinue the drug.

Grade 4 hemorrhagic events: Permanently discontinue trametinib.

Dosage Modification for Venous Thromboembolism

Uncomplicated DVT or PE: Interrupt trametinib for up to 3 weeks. If improvement to grade 0 or 1 observed within 3 weeks, resume therapy at lower dosage. If no improvement observed within 3 weeks, permanently discontinue trametinib.

Life-threatening PE: Permanently discontinue trametinib.

Dosage Modification for Ocular Effects

Retinal pigment epithelial detachments: Interrupt trametinib for up to 3 weeks. If such retinal detachments improve within 3 weeks, resume drug at the same or a reduced dosage. Permanently discontinue therapy or resume therapy at a reduced dosage in those with retinal pigment epithelial detachments not improving within 3 weeks.

Retinal vein occlusion: Permanently discontinue trametinib.

Uveitis with trametinib/dabrafenib combination therapy: Dosage modification of trametinib not necessary.

Dosage Modification for Pulmonary Effects

Treatment-related interstitial lung disease or pneumonitis: Permanently discontinue trametinib.

Dosage Modification for Other Toxicity

Intolerable grade 2 or any grade 3 adverse reaction: Interrupt treatment. If adverse reaction improves to grade 0 or 1, resume drug at reduced dosage. If adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.

Grade 4 adverse reaction (first occurrence): Interrupt treatment until adverse reaction improves to grade 0 or 1, then resume therapy at reduced dosage. If the grade 4 adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.

Grade 4 adverse reaction (recurrent): Permanently discontinue trametinib.

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment required.

Moderate (bilirubin concentration >1.5–3 times the ULN and any AST concentration) or severe (bilirubin concentration 3–10 times the ULN and any AST concentration) hepatic impairment: Appropriate dosage not established. Consider the potential risks and benefits of the drug when initiating trametinib therapy or determining the appropriate dosage.

Renal Impairment

Estimated glomerular filtration rate (GFR) 15–89 mL/minute per 1.73 m2: No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations in patients ≥65 years of age.

Cautions for Trametinib Dimethyl Sulfoxide

Contraindications

Warnings/Precautions

Combination Therapy

When combination therapy with trametinib includes use of dabrafenib, cautions, precautions, and contraindications of dabrafenib also must be considered.

Development of New Primary Malignancies

New primary cutaneous and noncutaneous malignancies are a known class effect of BRAF inhibitors (i.e., dabrafenib, encorafenib, vemurafenib). Cutaneous squamous cell carcinoma, keratoacanthomas, new primary melanoma, basal cell carcinoma, and noncutaneous malignancies reported in patients receiving trametinib in combination with dabrafenib.

Perform dermatologic evaluations prior to initiation of and every 2 months during therapy, then for up to 6 months following discontinuance of combination therapy. Monitor patients closely for signs or symptoms of new noncutaneous malignancies.

Hemorrhage

Hemorrhage (sometimes fatal), including intracranial or GI hemorrhage, has occurred during trametinib/dabrafenib combination therapy.

If hemorrhagic events occur, dosage modification and/or treatment discontinuance may be necessary. For grade 3 hemorrhagic events, interrupt trametinib therapy. If improvement observed, trametinib may be resumed at a reduced dosage. If no improvement observed, permanently discontinue trametinib. For grade 4 hemorrhagic events, permanently discontinue trametinib.

Colitis and GI Perforation

Colitis and GI perforation, sometimes fatal, has occurred with monotherapy and trametinib/dabrafenib combination therapy.

Monitor patients closely for manifestations of colitis and GI perforation.

Venous Thromboembolism

Venous thromboembolism (VTE) has occurred during trametinib/dabrafenib combination therapy.

Advise patients to immediately seek medical care if they develop symptoms of DVT or PE (e.g., shortness of breath, chest pain, arm or leg swelling). Dosage modification or treatment discontinuance may be necessary if DVT or PE occurs.

Cardiac Effects

Cardiomyopathy, including cardiac failure, reported with monotherapy and trametinib/dabrafenib combination therapy.

Assess LVEF by echocardiogram or multigated radionuclide angiography (MUGA) prior to initiation and after 1 month of therapy, then every 2–3 months during therapy.

If cardiomyopathy occurs, treatment interruption, dosage reduction, or drug discontinuance is warranted.

Ocular Effects

Retinal pigment epithelial detachments and retinal vein occlusion reported with trametinib therapy. Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Perform ophthalmologic evaluation periodically and as clinically indicated during therapy. In patients reporting vision loss or visual disturbances, perform ophthalmologic evaluations within 24 hours.

If retinal pigment epithelial detachment is diagnosed, withhold trametinib. If resolution is confirmed within 3 weeks, resume trametinib at the same or a reduced dosage. If no improvement observed within 3 weeks, permanently discontinue or resume therapy at a reduced dosage.

Permanently discontinue trametinib in patients with confirmed retinal vein occlusion.

If uveitis occurs in patients receiving combination therapy with trametinib and dabrafenib, no dosage modification of trametinib required.

Pulmonary Effects

Interstitial lung disease or pneumonitis reported with monotherapy or trametinib/dabrafenib combination therapy.

In patients with new or progressive pulmonary manifestations (e.g., cough, dyspnea, hypoxia, pleural effusion, infiltrates), interrupt trametinib treatment pending results of clinical investigation.

Permanently discontinue trametinib in patients diagnosed with treatment-related interstitial lung disease or pneumonitis.

Febrile Drug Reactions

Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure) reported during trametinib/dabrafenib combination therapy.

If patient’s temperature ≥100.4°F (38.0°C), interrupt trametinib (and dabrafenib, if used in combination); evaluate for signs and symptoms of infection and monitor renal function (e.g., serum creatinine) during and following severe pyrexia. May resume trametinib (and dabrafenib, if used in combination) ≥24 hours after recovery at same or reduced dosage.

Use prophylactic antipyretics when resuming trametinib following serious febrile reactions or fever associated with complications. Use corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent occurrences of prolonged fever (lasting >3 days) or fever associated with complications (e.g., dehydration, hypotension, renal failure, severe chills/rigors) without evidence of an active infection.

Dermatologic Effects

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms, reported in postmarketing surveillance during therapy with trametinib in combination with dabrafenib.

Monitor for new or worsening serious skin toxicities. If dermatologic toxicity occurs, dosage modification or treatment discontinuance may be necessary. Permanently discontinue trametinib if SCARs occur.

Hyperglycemia

Hyperglycemia reported in patients receiving trametinib/dabrafenib combination therapy.

Monitor serum glucose concentrations prior to initiation of therapy and as clinically appropriate in patients with preexisting diabetes mellitus or hyperglycemia.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and abortifacient in animals.

Advise female patients of childbearing potential to use effective contraception during, and for 4 months following, treatment.

If used during pregnancy, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether distributed into human milk. Effects on breast-fed infants and milk production also unknown. Discontinue breast-feeding during therapy and for 4 months after the last dose.

Females and Males of Reproductive Potential

May reduce female fertility.

Advise females of reproductive potential to use effective contraception during and for 4 months following treatment.

Advise males with female partners of reproductive potential to use condoms during trametinib therapy and for at least 4 months after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients <6 years of age, or when used as monotherapy in pediatric patients.

Geriatric Use

Monotherapy: Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Combination therapy: No overall differences in efficacy of trametinib/dabrafenib combination therapy relative to younger adults with melanoma; some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma. Insufficient experience with trametinib/dabrafenib combination therapy in patients ≥65 years of age with NSCLC to determine whether geriatric patients respond differently than younger adults. Insufficient experience in younger adults with anaplastic thyroid cancer to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Mild hepatic impairment did not substantially affect systemic exposure of trametinib.

Appropriate dosage not established in patients with moderate to severe hepatic impairment. Moderate or severe hepatic impairment did not substantially increase systemic exposure compared with patients with normal hepatic function.

Renal Impairment

Estimated GFR 15–89 mL/minute per 1.73 m2 did not substantially affect systemic exposure of trametinib.

Not studied in patients with severe renal impairment.

Common Adverse Effects

The most common adverse reactions (≥20%) in adults receiving trametinib monotherapy are rash, diarrhea, and lymphedema.

The most common adverse reactions (≥20%) in adults receiving trametinib in combination with dabrafenib for adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

The most common adverse reactions (≥20%) in adults receiving trametinib in combination with dabrafenib for unresectable or metastatic melanoma include pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.

The most common adverse reactions (≥20%) in adults receiving trametinib in combination with dabrafenib for metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

The most common adverse reactions (≥20%) in adults receiving trametinib in combination with dabrafenib for other solid tumors include pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.

The most common adverse reactions (≥20%) in pediatric patients receiving trametinib in combination with dabrafenib for solid tumors include pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.

Drug Interactions

Formal drug interaction studies not conducted.

CYP3A inducer and CYP2C8 inhibitor in vitro.

Substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP).

Not a substrate for CYP isoenzymes, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, or multidrug and toxic compound extrusion 1 (MATE1).

Not an inhibitor of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.

Not an inhibitor of organic anion transporter polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, OCT2, P-gp, BCRP, BSEP, MRP2, or MATE1.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (decreased concentrations of substrate drug).

Substrates of CYP2C8: Potential pharmacokinetic interaction (increased concentrations of substrate drug).

Specific Drugs

Drug

Interaction

Dabrafenib

No clinically relevant effects on AUC of trametinib

Trametinib Dimethyl Sulfoxide Pharmacokinetics

Absorption

Bioavailability

72%.

Onset

Following oral administration, peak plasma concentrations achieved 1.5 hours after dose.

Food

High-fat, high-calorie meal decreased AUC by 24% and peak plasma concentrations by 70%; also delayed time to peak plasma concentrations by approximately 4 hours.

Distribution

Plasma Protein Binding

97.4%.

Elimination

Metabolism

Principally metabolized by deacetylation with or without mono-oxygenation or in combination with glucuronidation.

Elimination Route

Following oral administration of radiolabeled dose, >80% recovered in feces and <20% in urine.

Half-life

3.9–4.8 days.

Special Populations

Mild hepatic impairment (total bilirubin concentration at or below ULN with AST concentration exceeding ULN or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration) has no clinically relevant effect on systemic exposure; not studied in patients with moderate or severe hepatic impairment.

Mild or moderate renal impairment (GFR 30–89 mL/minute per 1.73 m2) has no clinically relevant effect on systemic exposure; not studied in patients with severe renal impairment. Renal impairment not likely to have clinically important effect on systemic exposure; renal excretion of drug is low.

Clinically important differences in pharmacokinetics based on age, gender, or weight not observed.

In pediatric patients, exposures at recommended weight-adjusted dosage were within ranges observed in adults.

Stability

Storage

Oral

Tablets

2–8°C; do not freeze.

Dispense in original bottle; do not remove desiccant. Protect from moisture and light.

Do not store in pill boxes.

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Trametinib Dimethyl Sulfoxide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg (of trametinib)

Mekinist

Novartis

2 mg (of trametinib)

Mekinist

Novartis

AHFS DI Essentials™. © Copyright 2024, Selected Revisions January 30, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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