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MEKINIST (Trametinib) Label Snda 204114 S-001

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MEKINIST (Trametinib) Label Snda 204114 S-001 HIGHLIGHTS OF PRESCRIBING INFORMATION • Cardiomyopathy: Assess LVEF before treatment, after one month of These highlights do not include all the information needed to use treatment, then every 2 to 3 months thereafter. (5.4, 2.3) MEKINIST safely and effectively. See full prescribing information for • Ocular Toxicities: Perform ophthalmologic evaluation for any visual MEKINIST. disturbances. For Retinal Vein Occlusion (RVO), permanently MEKINIST (trametinib) tablets, for oral use discontinue MEKINIST. (5.5, 2.3). Initial U.S. Approval: 2013 • Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue ------------------------- RECENT MAJOR CHANGES --------------------------- MEKINIST for treatment-related ILD or pneumonitis. (5.6, 2.3) Indications and Usage (1) 01/2014 • Serious Febrile Reactions can occur when MEKINIST is used in Dosage and Administration (2.2-2.3) 01/2014 combination with dabrafenib. (5.7, 2.3) Warnings and Precautions (5-5.10) 01/2014 • Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not -------------------------- INDICATIONS AND USAGE ---------------------------- improving within 3 weeks despite interruption of MEKINIST. (5.8, 2.3) MEKINIST is a kinase inhibitor indicated as a single agent and in • Hyperglycemia: Monitor serum glucose levels in patients with pre- combination with dabrafenib for the treatment of patients with unresectable or existing diabetes or hyperglycemia. (5.9, 2.3) metastatic melanoma with BRAF V600E or V600K mutations as detected by • Embryofetal Toxicity: Can cause fetal harm. Advise females of an FDA-approved test. The use in combination is based on the demonstration reproductive potential of potential risk to the fetus. (5.10, 8.1, 8.6) of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with ------------------------------ ADVERSE REACTIONS ------------------------------ dabrafenib. (1, 14.1) • Most common adverse reactions (≥20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema. (6.1) Limitation of use: MEKINIST as a single agent is not indicated for treatment • Most common adverse reactions (≥20%) for MEKINIST in combination of patients who have received prior BRAF-inhibitor therapy. (1) with dabrafenib include pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. (6.1) ----------------------- DOSAGE AND ADMINISTRATION ----------------------- • Confirm the presence of BRAF V600E or V600K mutation in tumor To report SUSPECTED ADVERSE REACTIONS, contact specimens prior to initiation of treatment with MEKINIST. (2.1) GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or • The recommended dosage regimens of MEKINIST are 2 mg orally once www.fda.gov/medwatch. 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 ------------------------------- DRUG INTERACTIONS ------------------------ after a meal. (2.2) • Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8 when MEKINIST is used in combination with dabrafenib. (7.1) --------------------- DOSAGE FORMS AND STRENGTHS --------------------- • Avoid concurrent administration of strong inducers of CYP3A4 or Tablets: 0.5 mg, 1 mg, and 2 mg. (3) CYP2C8 when MEKINIST is used in combination with dabrafenib. (7.1) • Concomitant use with agents that are sensitive substrates of CYP3A4, ------------------------------- CONTRAINDICATIONS ------------------------------- CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy None. (4) of these agents when MEKINIST is used in combination with dabrafenib. (7.1) ------------------------ WARNINGS and PRECAUTIONS ------------------------ • New primary malignancies, cutaneous and non-cutaneous, can occur ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- when MEKINIST is used in combination with dabrafenib. Monitor • Nursing Mothers: Discontinue drug or nursing. (8.3) patients for new malignancies prior to initiation of therapy while on • Females and Males of Reproductive Potential: Counsel female patients on therapy, and following discontinuation of the combination treatment. pregnancy planning and prevention. May impair fertility. (8.6) (5.1, 2.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- • Hemorrhage: Major hemorrhagic events can occur in patients receiving approved patient labeling. MEKINIST in combination with dabrafenib. Monitor for signs and symptoms of bleeding (5.2, 2.3) Revised: 01/2014 • Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST in combination with dabrafenib. (5.3, 2.3). 6 ADVERSE REACTIONS FULL PRESCRIBING INFORMATION: CONTENTS* 6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS 2 DOSAGE AND ADMINISTRATION 7.1 Dabrafenib 2.1 Patient Selection 8 USE IN SPECIFIC POPULATIONS 2.2 Recommended Dosing 8.1 Pregnancy 2.3 Dose Modifications 8.3 Nursing Mothers 3 DOSAGE FORMS AND STRENGTHS 8.4 Pediatric Use 4 CONTRAINDICATIONS 8.5 Geriatric Use 5 WARNINGS AND PRECAUTIONS 8.6 Females and Males of Reproductive Potential 5.1 New Primary Malignancies 8.7 Hepatic Impairment 5.2 Hemorrhage 8.8 Renal Impairment 5.3 Venous Thromboembolism 10 OVERDOSAGE 5.4 Cardiomyopathy 11 DESCRIPTION 5.5 Ocular Toxicities 12 CLINICAL PHARMACOLOGY 5.6 Interstitial Lung Disease 12.1 Mechanism of Action 5.7 Serious Febrile Reactions 12.2 Pharmacodynamics 5.8 Serious Skin Toxicity 12.3 Pharmacokinetics 5.9 Hyperglycemia 13 NONCLINICAL TOXICOLOGY 5.10 Embryofetal Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 1 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 14.1 BRAF V600E or V600K Mutation-Positive 17 PATIENT COUNSELING INFORMATION Unresectable or Metastatic Melanoma *Sections or subsections omitted from the full prescribing information are not 14.2 Lack of Clinical Activity in Metastatic Melanoma listed. Following BRAF-Inhibitor Therapy 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE MEKINIST™ as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Clinical Studies (14.1)]. MEKINIST, in combination with dabrafenib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate [see Clinical Studies (14.1)]. 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 [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for treatment of unresectable or metastatic melanoma with MEKINIST based on presence of BRAF V600E or V600K mutation in tumor specimens [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosing The recommended dosage regimens of MEKINIST are: • 2 mg orally taken once daily as a single agent • 2 mg orally taken once daily in combination with dabrafenib 150 mg orally taken twice daily Continue treatment until disease progression or unacceptable toxicity occurs. Take MEKINIST as a single agent, or MEKINIST in combination with dabrafenib, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. When administered in combination with dabrafenib, take the once daily dose of MEKINIST at the same time each day with either the morning dose or the evening dose of dabrafenib. 2 2.3 Dose Modifications For New Primary Cutaneous Malignancies: No dose modifications are required. For New Primary Non-Cutaneous Malignancies: No dose modifications are required for MEKINIST. If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. Table 1. Recommended Dose Reductions Dose Reductions for MEKINIST When Administered as a Single Agent or in Combination With Dabrafenib First Dose Reduction 1.5 mg orally once daily Second Dose Reduction 1 mg orally once daily Subsequent Modification Permanently discontinue if unable to tolerate MEKINIST 1 mg orally once daily Dose Reductions for Dabrafenib When Administered in Combination With MEKINIST First Dose Reduction 100 mg orally twice daily Second Dose Reduction 75 mg orally twice daily Third Dose Reduction 50 mg orally twice daily Permanently discontinue dabrafenib if unable to tolerate Subsequent Modification 50 mg orally twice daily 3 Table 2. Recommended Dose Modifications for MEKINIST as a Single Agent and for MEKINIST and Dabrafenib Administered in Combination Dabrafenib Severity of Adverse b a MEKINIST (When Used in Reaction Combination)b,c Febrile drug reaction • Fever of 101.3°F to 104oF Do not modify the dose of Withhold dabrafenib until MEKINIST.
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