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Mekinist

Generic Name: Trametinib Dimethyl Sulfoxide
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. Last updated on May 27, 2019.

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.1 2

Uses for Mekinist

Melanoma

In combination with dabrafenib as adjuvant therapy following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement.1 4

Alone or in combination with dabrafenib for treatment of unresectable or metastatic melanoma in selected patients with BRAF V600E or V600K mutation1 2 5 (designated an orphan drug by FDA as monotherapy or when used in combination for this use).3

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.1 6

Not recommended for use in patients with melanoma who have experienced disease progression following treatment with a BRAF inhibitor.1 7

NSCLC

Used in combination with dabrafenib for treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation1 (designated an orphan drug by FDA when used in combination for this use).3

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.1

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 available1 (designated an orphan drug by FDA when used in combination for this use).3

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.1

Mekinist Dosage and Administration

General

  • Confirm presence of BRAF V600E or V600K mutation prior to initiation of monotherapy for the treatment of unresectable or metastatic melanoma or trametinib/dabrafenib combination therapy for the treatment of unresectable or metastatic melanoma or for the adjuvant treatment of melanoma.1

  • Confirm presence of BRAF V600E mutation prior to initiation of trametinib/dabrafenib combination therapy for the treatment of metastatic NSCLC or locally advanced or metastatic anaplastic thyroid cancer.1

Administration

Oral Administration

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

Dosage

Available as trametinib dimethyl sulfoxide; dosage expressed in terms of trametinib.1

Adults

Melanoma
Adjuvant Therapy for Melanoma
Oral

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

Monotherapy for Unresectable or Metastatic Melanoma
Oral

2 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Combination Therapy for Unresectable or Metastatic Melanoma
Oral

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

NSCLC
Oral

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

Anaplastic Thyroid Cancer
Oral

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

Dosage Modification for Toxicity
Oral

Dosage may be reduced or therapy temporarily interrupted in patients who develop adverse effects.1 Up to 2 dosage reductions for toxicity may be made.1

If necessary, an initial dosage reduction to 1.5 mg daily is recommended.1 If further dosage modification necessary, dosage reduction to 1 mg daily may be considered.1 For patients unable to tolerate 1 mg daily, permanently discontinue the drug.1

When used in combination with dabrafenib, dosage modification of dabrafenib for toxicity also may be required.1

Dosage Modification for New Primary Cutaneous Malignancies
Oral

If new cutaneous malignancies occur, dosage modification of trametinib not necessary.1

Dosage Modification for New Primary Noncutaneous Malignancies
Oral

If new noncutaneous malignancies occur in patients receiving trametinib/dabrafenib combination therapy, dosage modification of trametinib not necessary.1

Dosage Modification for Febrile Drug Reactions
Oral

Fever >40°C or fever with complications (e.g., rigors, hypotension, dehydration, renal failure): Interrupt trametinib therapy until fever resolves; may resume trametinib at same or reduced dosage.1

Dosage Modification for Dermatologic Effects
Oral

Intolerable grade 2 skin toxicity: Interrupt trametinib for up to 3 weeks.1 If improvement noted within 3 weeks, resume drug at reduced dosage.1 Permanently discontinue therapy in those with skin toxicity not improving within 3 weeks of treatment interruption.1

Grade 3 or 4 skin toxicity: Interrupt therapy for up to 3 weeks.1 If improvement observed within 3 weeks, resume drug at reduced dosage.1 Permanently discontinue therapy in those with intolerable skin toxicity not improving within 3 weeks of treatment interruption.1

Dosage Modification for Cardiac Effects
Oral

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.1 If LVEF improves to normal values within 4 weeks, resume drug at reduced dosage.1 Permanently discontinue therapy in those with decreased LVEF not improving within 4 weeks of treatment interruption.1

Symptomatic CHF or decrease in LVEF from baseline >20% and to a level below institution-specific lower limit of normal: Permanently discontinue trametinib.1

Dosage Modification for Hemorrhage
Oral

Grade 3 hemorrhagic events: Withhold trametinib therapy.1 If improvement observed, resume therapy at reduced dosage.1 If no improvement observed, permanently discontinue the drug.1

Grade 4 hemorrhagic events: Permanently discontinue trametinib.1

Dosage Modification for Venous Thromboembolism
Oral

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

Life-threatening PE: Permanently discontinue trametinib.1

Dosage Modification for Ocular Effects
Oral

Retinal pigment epithelial detachments: Interrupt trametinib for up to 3 weeks.1 If such retinal detachments improve within 3 weeks, resume drug at the same or a reduced dosage.1 Permanently discontinue therapy or resume therapy at a reduced dosage in those with retinal pigment epithelial detachments not improving within 3 weeks.1

Retinal vein occlusion: Permanently discontinue trametinib.1

Uveitis with trametinib/dabrafenib combination therapy: Dosage modification of trametinib not necessary.1

Dosage Modification for Pulmonary Effects
Oral

Interstitial lung disease or pneumonitis: Permanently discontinue trametinib.1

Dosage Modification for Other Toxicity
Oral

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

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

Grade 4 adverse reaction (recurrent): Permanently discontinue trametinib.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment required.1

Moderate or severe hepatic impairment: Appropriate dosage not established.1

Renal Impairment

Mild or moderate renal impairment: No dosage adjustment required.1

Severe renal impairment: Appropriate dosage not established.1

Geriatric Patients

No specific dosage recommendations in patients ≥65 years of age.1

Cautions for Mekinist

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Combination Therapy

When combination therapy with trametinib includes use of dabrafenib, cautions, precautions, and contraindications of dabrafenib also must be considered.1

Development of New Primary Malignancies

New primary cutaneous and noncutaneous malignancies are a known class effect of BRAF inhibitors (i.e., dabrafenib, encorafenib, vemurafenib).29 Cutaneous squamous cell carcinoma, new primary melanoma, basal cell carcinoma, and noncutaneous malignancies reported in patients receiving trametinib in combination with dabrafenib.1

Perform dermatologic evaluations prior to initiation of and every 2 months during therapy, then for up to 6 months following discontinuance of combination therapy.1 Monitor patients closely for signs or symptoms of new noncutaneous malignancies.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hemorrhage

Hemorrhage (sometimes fatal), including intracranial or GI hemorrhage, has occurred during trametinib/dabrafenib combination therapy.1

If hemorrhagic events occur, dosage modification and/or treatment discontinuance may be necessary.1 For grade 3 hemorrhagic events, interrupt trametinib therapy.1 If improvement observed, trametinib may be resumed at a reduced dosage.1 If no improvement observed, permanently discontinue trametinib.1 For grade 4 hemorrhagic events, permanently discontinue trametinib.1

Colitis and GI Perforation

Colitis and GI perforation, sometimes fatal, has occurred with monotherapy and trametinib/dabrafenib combination therapy.1

Monitor patients closely for manifestations of colitis and GI perforation.1

Venous Thromboembolism

Venous thromboembolism (VTE) has occurred during trametinib/dabrafenib combination therapy.1

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).1 Dosage modification or treatment discontinuance may be necessary if DVT or PE occurs.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Cardiac Effects

Cardiomyopathy, including cardiac failure, reported with monotherapy and trametinib/dabrafenib combination therapy.1

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.1

If cardiomyopathy occurs, treatment interruption, dosage reduction, or drug discontinuance is warranted.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Ocular Effects

Retinal pigment epithelial detachments and retinal vein occlusion reported with monotherapy or trametinib/dabrafenib combination therapy.1 Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma.1

Perform ophthalmologic evaluation periodically and as clinically indicated during therapy.1 In patients reporting vision loss or visual disturbances, perform ophthalmologic evaluations within 24 hours.1

If retinal pigment epithelial detachment is diagnosed, withhold trametinib.1 If resolution is confirmed within 3 weeks, resume trametinib at the same or a reduced dosage.1 If no improvement observed within 3 weeks, permanently discontinue or resume therapy at a reduced dosage.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Permanently discontinue trametinib in patients with confirmed retinal vein occlusion.1

Pulmonary Effects

Interstitial lung disease or pneumonitis reported with monotherapy or trametinib/dabrafenib combination therapy.1

In patients with new or progressive pulmonary manifestations (e.g., cough, dyspnea, hypoxia, pleural effusion, infiltrates), interrupt trametinib treatment pending results of clinical investigation.1

Permanently discontinue trametinib in patients diagnosed with treatment-related interstitial lung disease or pneumonitis.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Febrile Drug Reactions

Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure) reported during trametinib/dabrafenib combination therapy.1

If serious febrile reactions occur, interrupt trametinib therapy and evaluate the patient for manifestations of infection.1 Dosage modification or treatment discontinuance may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Use prophylactic antipyretics when resuming trametinib following serious febrile reactions or fever associated with complications.1 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.1

Dermatologic Effects

Rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), and erythema reported; severe cases with or without secondary bacterial infections (some requiring hospitalization) reported with monotherapy or trametinib/dabrafenib combination therapy.1

If dermatologic toxicity occurs, dosage modification or treatment discontinuance may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hyperglycemia

Hyperglycemia reported in patients receiving trametinib/dabrafenib combination therapy.1

Monitor serum glucose concentrations prior to initiation of therapy and as clinically appropriate in patients with preexisting diabetes mellitus or hyperglycemia.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and abortifacient in animals.1

Advise female patients of childbearing potential to use highly effective contraception during, and for 4 months following, treatment.1

If used during pregnancy, apprise of potential fetal hazard.1

Impairment of Fertility

May reduce female fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk.1 Effects on nursing infants and milk production also unknown.1 Discontinue nursing during therapy and for 4 months after the last dose.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Monotherapy: Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

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.1 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.1

Hepatic Impairment

Mild hepatic impairment did not substantially affect systemic exposure of trametinib.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with moderate or severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Mild to moderate renal impairment did not substantially affect systemic exposure of trametinib.1 (See Renal Impairment under Dosage and Administration.)

Not studied in patients with severe renal impairment.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Monotherapy in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation: Rash,1 diarrhea,1 lymphedema,1 elevated ALT/AST concentrations,1 hypoalbuminemia,1 anemia,1 elevated alkaline phosphatase concentrations.1

Combination therapy with dabrafenib in patients with previously untreated unresectable or metastatic melanoma with BRAF V600E or V600K mutation: Pyrexia,1 18 diarrhea,18 fatigue,18 nausea,18 rash,1 18 chills,1 18 headache,1 18 vomiting,18 arthralgia,1 18 hypertension,18 cough,1 hyperglycemia,1 elevated alkaline phosphatase concentrations,1 hypophosphatemia,1 hyponatremia.1

Combination therapy with dabrafenib for the adjuvant treatment of melanoma with BRAF V600E or V600K mutation: Pyrexia,1 4 fatigue,1 4 nausea,1 4 headache,1 4 chills,1 4 rash,1 4 diarrhea,1 4 arthralgia,1 4 vomiting,1 4 myalgia,1 hyperglycemia,1 elevated AST/ALT concentrations,1 neutropenia,1 hypophosphatemia,1 elevated alkaline phosphatase concentrations,1 lymphopenia,1 anemia,1 hypoalbuminemia.1

Combination therapy with dabrafenib in patients with metastatic NSCLC with BRAF V600E mutation: Pyrexia,1 fatigue,1 nausea,1 vomiting,1 diarrhea,1 dry skin,1 decreased appetite,1 edema,1 rash,1 chills,1 hemorrhage,1 cough,1 dyspnea,1 hyperglycemia,1 elevated alkaline phosphatase concentrations,1 elevated AST/ALT concentrations,1 hyponatremia,1 leukopenia,1 anemia,1 neutropenia,1 lymphopenia,1 hypophosphatemia,1 elevated Scr concentrations.1

Combination therapy with dabrafenib in patients with locally advanced or metastatic anaplastic thyroid cancer: Adverse effects similar to those in patients with melanoma or NSCLC.1

Interactions for Mekinist

Formal drug interaction studies not conducted.1

CYP3A inducer and CYP2C8 inhibitor in vitro.1

Substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP).1

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).1

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

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

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (decreased concentrations of substrate drug).1

Substrates of CYP2C8: Potential pharmacokinetic interaction (increased concentrations of substrate drug).1

Specific Drugs

Drug

Interaction

Dabrafenib

No clinically relevant effects on AUC of trametinib1

Mekinist Pharmacokinetics

Absorption

Bioavailability

72%.1

Onset

Following oral administration, peak plasma concentrations achieved 1.5 hours after dose.1 10

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.1 10

Distribution

Plasma Protein Binding

97.4%.1

Elimination

Metabolism

Principally metabolized by deacetylation with or without mono-oxygenation or in combination with glucuronidation.1

Elimination Route

Following oral administration of radiolabeled dose, >80% recovered in feces and <20% in urine.1

Half-life

3.9–4.8 days.1

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.1

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.1 Renal impairment not likely to have clinically important effect on systemic exposure; renal excretion of drug is low.1

Clinically important differences in pharmacokinetics based on age, gender, or weight not observed.1

Stability

Storage

Oral

Tablets

2–8°C; do not freeze.1

Dispense in original bottle; do not remove desiccant.1 Protect from moisture and light.1

Do not store in pill boxes.1

Actions

  • Selective inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and 2 activation and kinase activity in cells with BRAF V600E or V600K mutations.1 7

  • Inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo by decreasing cell proliferation, causing cell cycle arrest, and inducing apoptosis.1 7

  • MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1

  • Approximately 50% of cutaneous melanomas carry a BRAF mutation.1 2 8 9 11 Most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 (BRAF V600E); mutation involving substitution of lysine for valine at codon 600 (BRAF V600K) occurs less frequently.7 9

  • BRAF V600 mutations result in activation of BRAF pathway that includes MEK 1 and 2.1

  • BRAF V600E mutation activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).1 9

  • Combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.13 14 15

    Combination therapy with trametinib and dabrafenib resulted in greater growth inhibition of melanoma cell lines and prolonged inhibition of tumor growth in melanoma xenografts testing positive for BRAF V600 mutations in vitro.1

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information before beginning treatment and each time the prescription is refilled.1

  • Importance of taking trametinib at least 1 hour before or 2 hours after a meal.1

  • Importance of taking a missed dose as soon as it is remembered, but only if it can be taken at least 12 hours before the next scheduled dose.1

  • Importance of proper storage of trametinib (e.g., storing tablets in original bottle at 2–8°C).1 Importance of not removing desiccant from the bottle, and not storing tablets in pill boxes.1

  • Risk of new primary cutaneous and noncutaneous malignancies with trametinib/dabrafenib combination therapy.1 Importance of contacting clinician promptly if dermatologic changes (i.e., new lesions, changes to existing lesions) or signs and/or symptoms of other malignancies occur.1

  • Risk of intracranial and GI hemorrhage with trametinib/dabrafenib combination therapy.1 Importance of contacting clinician promptly if signs and/or symptoms of unusual bleeding or hemorrhage occur.1

  • Risk of colitis or GI perforation.1 Importance of contacting clinician promptly if unusual bleeding, diarrhea, abdominal pain or tenderness, fever, or nausea occurs.1

  • Risk of DVT and PE with trametinib/dabrafenib combination therapy.1 Importance of contacting clinician promptly if sudden onset of breathing difficulty, leg pain, or swelling occurs.1

  • Risk of cardiomyopathy.1 Importance of immediately contacting clinician if manifestations of heart failure occur.1

  • Risk of visual disturbances that may lead to blindness.1 Importance of contacting clinician if vision changes occur.1

  • Risk of interstitial lung disease (or pneumonitis).1 Importance of immediately contacting clinician if cough or dyspnea occurs.1

  • Risk of serious febrile reactions with trametinib/dabrafenib combination therapy.1 Importance of contacting clinician if fever develops.1

  • Risk of skin toxicities (possibly requiring hospitalization).1 Importance of contacting clinician if progressive or intolerable rash occurs.1

  • Risk of hypertension.1 Importance of monitoring BP regularly during therapy and of contacting clinician if manifestations of hypertension occur.1

  • Risk of diarrhea (sometimes severe).1 Importance of contacting clinician if severe diarrhea occurs.1

  • Risk of fetal harm if taken during pregnancy.1 Importance of female patients using highly effective contraception during treatment and for 4 months after discontinuance of trametinib.1 Importance of contacting clinician if pregnancy is suspected or confirmed during treatment.1

  • Risk of serious adverse reactions in nursing infants of women receiving trametinib.1 Importance of discontinuing breast-feeding during therapy and for 4 months after the last dose.1

  • Importance of advising women of reproductive potential that trametinib may reduce female fertility.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 2020, Selected Revisions May 27, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Novartis. Mekinist(trametinib) tablets prescribing information. East Hanover, NJ; 2018 May.

2. Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367:107-14. http://www.ncbi.nlm.nih.gov/pubmed/22663011?dopt=AbstractPlus

3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Jan 9. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

4. Long GV, Hauschild A, Santinami M et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017; 377:1813-1823. http://www.ncbi.nlm.nih.gov/pubmed/28891408?dopt=AbstractPlus

5. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367:1694-703. http://www.ncbi.nlm.nih.gov/pubmed/23020132?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3549295&blobtype=pdf

6. bioMerieux. THxID BRAF kit package insert. Durham, NC. 2013 May.

7. Kim KB, Kefford R, Pavlick AC et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013; 31:482-9. http://www.ncbi.nlm.nih.gov/pubmed/23248257?dopt=AbstractPlus

8. Salama AK, Kim KB. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013; 14:619-27. http://www.ncbi.nlm.nih.gov/pubmed/23432625?dopt=AbstractPlus

9. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma?. Lancet Oncol. 2013; 14:e60-9.

10. Cox DS, Papdopoulos K, Fang L et al. Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer. J Clin Pharmacol. 2013; 53:946-54. http://www.ncbi.nlm.nih.gov/pubmed/23893461?dopt=AbstractPlus

11. Bucheit AD, Syklawer E, Jakob JA et al. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer. 2013; 119:3821-9. http://www.ncbi.nlm.nih.gov/pubmed/23922205?dopt=AbstractPlus

12. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

13. Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371:1867-76. http://www.ncbi.nlm.nih.gov/pubmed/25265494?dopt=AbstractPlus

14. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367:1694-703. http://www.ncbi.nlm.nih.gov/pubmed/23020132?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3549295&blobtype=pdf

15. Sanlorenzo M, Choudhry A, Vujic I et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014; 71:1102-1109.e1. http://www.ncbi.nlm.nih.gov/pubmed/25440439?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4254519&blobtype=pdf

16. Hauschild A, Dummer R, Schadendorf D et al. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. J Clin Oncol. 2018; :JCO1801219. http://www.ncbi.nlm.nih.gov/pubmed/30343620?dopt=AbstractPlus

17. Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015; 372:30-9. http://www.ncbi.nlm.nih.gov/pubmed/25399551?dopt=AbstractPlus

18. Long GV, Stroyakovskiy D, Gogas H et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014; 371:1877-88. http://www.ncbi.nlm.nih.gov/pubmed/25265492?dopt=AbstractPlus

19. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366:707-14. http://www.ncbi.nlm.nih.gov/pubmed/22356324?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3724515&blobtype=pdf

20. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med. 2011; 364:2547-8. http://www.ncbi.nlm.nih.gov/pubmed/21639809?dopt=AbstractPlus

21. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 2012; 18:263-72. http://www.ncbi.nlm.nih.gov/pubmed/22096025?dopt=AbstractPlus

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