Mekinist

2 DOSAGE AND ADMINISTRATION The recommended dosage of MEKINIST in adult patients is 2 mg orally once daily. The recommended dosage for MEKINIST in pediatric patients is based on body weight. ( 2 ) 2.1 Patient Selection Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as a single agent or in combination with dabrafenib [see Clinical Studies (14.1, 14.2)] . Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics . NSCLC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.3)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics . ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.4)] . Information on FDA-approved tests for the detection of BRAF V600E mutations in ATC is available at: http://www.fda.gov/CompanionDiagnostics . Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.6)] . An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available. Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.7)] . An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available. 2.2 Recommended Dosage MEKINIST Tablets Adult Patients The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily [see Dosage and Administration (2.3)] . Pediatric Patients The recommended dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)] . A recommended dosage of MEKINIST tablets has not been established in patients who weigh less than 26 kg. Table 1. Recommended Dosage for MEKINIST Tablets in Pediatric Patients (Weight-based) Body Weight Recommended Dosage 26 to 37 kg 1 mg orally once daily 38 to 50 kg 1.5 mg orally once daily 51 kg or greater 2 mg orally once daily MEKINIST for Oral Solution Adult and Pediatric Patients The recommended dosage for MEKINIST for oral solution for adult and pediatric patients is based on body weight (Table 2) [see Dosage and Administration (2.3)] . Table 2. Recommended Dosage for MEKINIST for Oral Solution in Adult and Pediatric Patients (Weight-based) Body Weight Recommended Dosage Total Volume of Oral Solution Once Daily (Trametinib Content) 8 kg 0.3 mg (6 mL) 9 kg 0.35 mg (7 mL) 10 kg 0.35 mg (7 mL) 11 kg 0.4 mg (8 mL) 12 to 13 kg 0.45 mg (9 mL) 14 to 17 kg 0.55 mg (11 mL) 18 to 21 kg 0.7 mg (14 mL) 22 to 25 kg 0.85 mg (17 mL) 26 to 29 kg 0.9 mg (18 mL) 30 to 33 kg 1 mg (20 mL) 34 to 37 kg 1.15 mg (23 mL) 38 to 41 kg 1.25 mg (25 mL) 42 to 45 kg 1.4 mg (28 mL) 46 to 50 kg 1.6 mg (32 mL) ≥ 51 kg 2 mg (40 mL) Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity. Combination Therapy with Dabrafenib Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information. 2.3 Administration Take MEKINIST at the same time each day, approximately 24 hours apart. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. If vomiting occurs after MEKINIST administration, do not take an additional dose. Take the next dose at its scheduled time. MEKINIST Tablets Take MEKINIST tablets on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)] . Do not crush or break MEKINIST tablets. MEKINIST for Oral Solution MEKINIST powder for oral solution must be reconstituted by a pharmacist or other healthcare provider prior to dispensing to the patient. MEKINIST for oral solution is intended for administration by a caregiver. Prior to use of the oral solution, ensure caregivers receive training on proper dosing and administration of MEKINIST for oral solution. When administering MEKINIST for oral solution as a single agent, take the oral solution with a low-fat meal or on an empty stomach [see Clinical Pharmacology (12.3)] . When coadministering with dabrafenib, take the MEKINIST oral solution on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions [see Clinical Pharmacology (12.3)] . Preparation and Administration To prepare MEKINIST for oral solution, tap the bottle until powder flows freely. Add 90 mL distilled or purified water to the powder in the bottle and invert or gently shake the bottle with re-attached cap for up to 5 minutes until powder is fully dissolved yielding a clear solution. Separate the bottle adapter from the oral syringe. Insert bottle adapter into bottle neck after reconstitution of the solution. Write the discard after date. Once reconstituted, MEKINIST for oral solution can be used for 35 days. The final concentration of the solution is 0.05 mg/mL. Administer MEKINIST for oral solution from an oral syringe or feeding tube (4 French gauge or larger). After reconstitution, store in original bottle below 25°C (77°F) and do not freeze. 2.4 Dosage Modifications for Adverse Reactions Dose reductions for adverse reactions associated with MEKINIST are presented in Tables 3 and 4. Table 3. Recommended Dosage Reductions for MEKINIST Tablets for Adverse Reactions Recommended Dosage 1 mg orally once daily 1.5 mg orally once daily 2 mg orally once daily First dose reduction 0.5 mg orally once daily 1 mg orally once daily 1.5 mg orally once daily Second dose reduction N/A 0.5 mg orally once daily 1 mg orally once daily Subsequent modification Permanently discontinue MEKINIST tablets if unable to tolerate a maximum of two dose reductions. Table 4. Recommended Dosage Reductions for MEKINIST for Oral Solution for Adverse Reactions Body Weight (Recommended dosage once daily) First Dose Reduction (Administer once daily) Second Dose Reduction (Administer once daily) 8 kg [0.3 mg (6 mL)] 0.25 mg (5 mL) 0.15 mg (3 mL) 9 kg [0.35 mg (7 mL)] 0.25 mg (5 mL) 0.2 mg (4 mL) 10 kg [0.35 mg (7 mL)] 0.25 mg (5 mL) 0.2 mg (4 mL) 11 kg [0.4 mg (8 mL)] 0.3 mg (6 mL) 0.2 mg (4 mL) 12 to 13 kg [0.45 mg (9 mL)] 0.35 mg (7 mL) 0.25 mg (5 mL) 14 to 17 kg [0.55 mg (11 mL)] 0.4 mg (8 mL) 0.3 mg (6 mL) 18 to 21 kg [0.7 mg (14 mL)] 0.55 mg (11 mL) 0.35 mg (7 mL) 22 to 25 kg [0.85 mg (17 mL)] 0.65 mg (13 mL) 0.45 mg (9 mL) 26 to 29 kg [0.9 mg (18 mL)] 0.7 mg (14 mL) 0.45 mg (9 mL) 30 to 33 kg [1 mg (20 mL)] 0.75 mg (15 mL) 0.5 mg (10 mL) 34 to 37 kg [1.15 mg (23 mL)] 0.85 mg (17 mL) 0.6 mg (12 mL) 38 to 41 kg [1.25 mg (25 mL)] 0.95 mg (19 mL) 0.65 mg (13 mL) 42 to 45 kg [1.4 mg (28 mL)] 1.05 mg (21 mL) 0.7 mg (14 mL) 46 to 50 kg [1.6 mg (32 mL)] 1.2 mg (24 mL) 0.8 mg (16 mL) ≥ 51 kg [2 mg (40 mL)] 1.5 mg (30 mL) 1 mg (20 mL) Permanently discontinue MEKINIST for oral solution if unable to tolerate a maximum of two dose reductions. Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 5. Table 5. Recommended Dosage Modifications for MEKINIST for Adverse Reactions a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of MEKINIST. c Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies. Severity of Adverse Reaction a Dosage Modification for MEKINIST b Hemorrhage [see Warnings and Precautions (5.2)] Grade 3 Withhold MEKINIST. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Grade 4 Permanently discontinue MEKINIST. Venous Thromboembolic Events [see Warnings and Precautions (5.4)] Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Life-threatening PE Permanently discontinue MEKINIST. Cardiomyopathy [see Warnings and Precautions (5.5)] Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline that is below the institutional lower limit of normal (LLN) Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST. Symptomatic cardiomyopathy Absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN Permanently discontinue MEKINIST. Ocular Toxicities [see Warnings and Precautions (5.6)] Retinal pigment epithelial detachments (RPED) Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose. If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose. Retinal vein occlusion (RVO) Permanently discontinue MEKINIST. Pulmonary [see Warnings and Precautions (5.7)] Interstitial lung disease (ILD)/pneumonitis Permanently discontinue MEKINIST. Febrile Reactions [see Warnings and Precautions (5.8)] Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose. Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure Withhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. Skin Toxicities [see Warnings and Precautions (5.9)] Intolerable Grade 2 Grade 3 or 4 Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. Severe cutaneous adverse reactions (SCARs) Permanently discontinue MEKINIST. Other Adverse Reactions c Intolerable Grade 2 Any Grade 3 Withhold MEKINIST. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. First occurrence of any Grade 4 Withhold MEKINIST until improves to Grade 0-1, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. Recurrent Grade 4 Permanently discontinue MEKINIST. Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.

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1 INDICATIONS AND USAGE MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.