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 MEKINIST™ (trametinib) tablets, for oral use

DESCRIPTION CLINICAL PHARMACOLOGY INDICATIONS AND USAGE
CONTRAINDICATIONS PRECAUTIONS ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION HOW SUPPLIED WARNINGS
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DRUG UPDATES:
Drug:  MEKINIST (trametinib) tablets, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013


WARNINGS  top of page

See warnings and precautions below.

DESCRIPTION  top of page

MEKINIST (trametinib) tablets, for oral use
Initial U.S. Approval: 2013

Trametinib dimethyl sulfoxide is a kinase inhibitor.
Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media.

MEKINIST (trametinib) tablets are supplied as 0.5-mg, 1-mg, and 2-mg tablets for oral administration. Each 0.5-mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2-mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent.

CLINICAL PHARMACOLOGY: top of page

Mechanism of Action:
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

INDICATIONS AND USAGE  top of page

INDICATIONS AND USAGE:
MEKINIST is a kinase inhibitor indicated as a single agent and in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with dabrafenib.

Limitation of use: MEKINIST as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy.

CONTRAINDICATIONS top of page

None.

PRECAUTIONS top of page

WARNINGS AND PRECAUTIONS:

  1. New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is used in combination with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy while on therapy, and following discontinuation of the combination treatment.
  2. Hemorrhage: Major hemorrhagic events can occur in patients receiving MEKINIST in combination with dabrafenib. Monitor for signs and symptoms of bleeding.
  3. Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST in combination with dabrafenib.
  4. Cardiomyopathy: Assess LVEF before treatment, after one month of treatment, then every 2 to 3 months thereafter.
  5. Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST.
  6. Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis.
  7. Serious Febrile Reactions can occur when MEKINIST is used in combination with dabrafenib.
  8. Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST.
  9. Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.
  10. Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus.

ADVERSE REACTIONS top of page

ADVERSE REACTIONS
Most common adverse reactions (GEQ20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema.

Most common adverse reactions (GEQ20%) for MEKINIST in combination with dabrafenib include pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS
Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8 when MEKINIST is used in combination with dabrafenib.

Avoid concurrent administration of strong inducers of CYP3A4 or CYP2C8 when MEKINIST is used in combination with dabrafenib.

Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents when MEKINIST is used in combination with dabrafenib.

USE IN SPECIFIC POPULATIONS
•Nursing Mothers: Discontinue drug or nursing.

•Females and Males of Reproductive Potential: Counsel female patients on pregnancy planning and prevention. May impair fertility.


See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

DOSAGE AND ADMINISTRATION  top of page

DOSAGE AND ADMINISTRATION:
 Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST.

The recommended dosage regimens of MEKINIST are 2 mg orally once daily as a single agent or in combination with dabrafenib 150 mg orally twice daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal.

HOW SUPPLIED top of page

DOSAGE FORMS AND STRENGTHS

Tablets: 0.5 mg, 1 mg, and 2 mg.

REFERENCE

Package insert data:   [Accessed: Jan 2014].

GlaxoSmithKline
Research Triangle Park, NC 27709
Revised: January 2014
MEKINIST is a registered trademark of the GlaxoSmithKline group of companies.
©2014, GlaxoSmithKline group of companies. All rights reserved.



DRUG UPDATES:
Drug:  MEKINIST (trametinib) tablets, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013
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