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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

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

Treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation1 2 (designated an orphan drug by FDA for this use).3

Slideshow: Flashback: FDA Drug Approvals 2013

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 therapy.1 6

Not recommended for use in patients who have received prior therapy with a BRAF inhibitor.1 7

Mekinist Dosage and Administration

Administration

Oral Administration

Administer orally once daily. 1

Administer 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
Oral

2 mg once daily.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

If necessary, an initial dosage reduction by 0.5 mg (to 1.5 mg daily) is recommended.1 If further dosage modification necessary, dosage reduction by 0.5 mg (to 1 mg daily) may be considered.1 For patients unable to tolerate 1 mg daily, permanently discontinue the drug.1

Dosage Modification for Rash
Oral

Grade 2 rash: Reduce dosage by 0.5 mg daily.1 If rash is intolerable and does not improve within 3 weeks of dosage reduction, interrupt therapy for as long as 3 weeks.1 If rash improves within 3 weeks, resume drug at reduced dosage (decrease previous dosage by 0.5 mg daily).1 Permanently discontinue therapy in patients previously receiving 1 mg daily or in those with rash not improving within 3 weeks of treatment interruption.1

Grade 3 or 4 rash: Interrupt therapy for as long as 3 weeks.1 If rash improves within 3 weeks, resume drug at reduced dosage (decrease previous dosage by 0.5 mg daily).1 Permanently discontinue therapy in patients previously receiving 1 mg daily or in those with intolerable rash 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 limits of normal: Interrupt therapy for as long as 4 weeks.1 If LVEF improves to normal values within 4 weeks, resume drug at reduced dosage (decrease previous dosage by 0.5 mg daily).1 Permanently discontinue therapy in patients previously receiving 1 mg daily or 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 limits of normal: Permanently discontinue trametinib.1

Dosage Modification for Ocular Effects
Oral

Grade 2 or 3 retinal pigment epithelial detachments: Interrupt treatment for up to 3 weeks.1 If such retinal detachments improve to grade 0 or 1 within 3 weeks, resume drug at reduced dosage (decrease previous dosage by 0.5 mg daily).1 Permanently discontinue therapy in patients previously receiving 1 mg daily or in those with retinal pigment epithelial detachments not improving to at least grade 1 within 3 weeks.1

Retinal vein occlusion: Permanently discontinue trametinib.1

Dosage Modification for Pulmonary Effects
Oral

Interstitial lung disease or pneumonitis: Permanently discontinue trametinib.1

Dosage Modification for Other Toxicity
Oral

Grade 3 adverse reaction: Interrupt treatment for up to 3 weeks.1 If adverse reaction improves to grade 0 or 1 within 3 weeks, resume drug at reduced dosage (decrease previous dosage by 0.5 mg daily).1 Permanently discontinue therapy in patients previously receiving 1 mg daily.1 If adverse reaction does not improve to grade 0 or 1 within 3 weeks, permanently discontinue trametinib.1

Grade 4 adverse reaction: 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

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

Cardiac Effects

Cardiomyopathy (cardiac failure, left ventricular dysfunction, decreased LVEF) reported.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 Cardiac Effects under Dosage and Administration.)

Ocular Effects

Retinal pigment epithelial detachments and retinal vein occlusion reported.1 Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma.1

Perform ophthalmologic evaluation within 24 hours in patients reporting vision loss or visual disturbances and compare with baseline measurements, if available.1

If retinal pigment epithelial detachment is diagnosed, withhold trametinib.1 If resolution is confirmed within 3 weeks, resume trametinib at reduced dosage.1 (See Dosage Modification for Ocular Effects under Dosage and Administration.)

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

Pulmonary Effects

Interstitial lung disease or pneumonitis reported.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 Pulmonary Effects under Dosage and Administration.)

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.1

Monitor patients for dermatologic toxicity and secondary infections during treatment.1 (See Dosage Modification for Rash under Dosage and Administration.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Fertility

May impair fertility in female patients.1

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

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

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Rash; diarrhea; lymphedema; increased ALT, AST, or alkaline phosphatase concentrations; hypoalbuminemia; anemia.1

Interactions for Mekinist

Formal drug interaction studies not conducted.1

CYP3A4 inducer and CYP2C8 inhibitor in vitro.1

Not a substrate for CYP isoenzymes, P-glycoprotein (P-gp), or breast cancer resistance protein (BCRP).1

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

Not an inhibitor of organic anion transporter polypeptides (OATP) 1B1 or 1B3, P-gp, or BCRP.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

Comments

Everolimus

No clinically relevant effects on AUC and peak concentrations of everolimus1

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 has no clinically relevant effect on systemic exposure; not studied in patients with moderate or severe hepatic impairment.1

Mild or moderate renal impairment 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

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 confirming that patients have melanomas testing positive for the BRAF V600E or V600K mutation using an FDA-approved diagnostic test (e.g., THxID BRAF kit) prior to initiation of therapy.1 6

  • 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 dyspnea occurs.1

  • Risk of skin toxicities, including acneiform rash.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

  • 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 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.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.

Trametinib Dimethyl Sulfoxide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.5 mg (of trametinib)

Mekinist

GlaxoSmithKline

1 mg (of trametinib)

Mekinist

GlaxoSmithKline

2 mg (of trametinib)

Mekinist

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Mekinist(trametinib) tablets prescribing information. Research Triangle Park, NC; 2013 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. [PubMed 22663011]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.

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. [PubMed 23248257]

8. Salama AK, Kim KB. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013; 14:619-27. [PubMed 23432625]

9. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma?. Lancet Oncol. 2013; 14:e60-9. [PubMed 23369684]

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. [PubMed 23893461]

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. [PubMed 23922205]

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