Usual Adult Dose for Melanoma - Metastatic

60 mg orally once a day for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Comments:

• The presence of BRAF V600E or V600K mutation in tumor specimens should be confirmed with an FDA-approved test prior to therapy initiation; information on FDA-approved tests available at http://www.fda.gov/CompanionDiagnostics.

Usual Adult Dose for Histiocytic Neoplasm

60 mg orally once a day for first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Use: Treatment of adult patients with histiocytic neoplasms

Renal Dose Adjustments

• Mild (CrCl 60 to 89 mL/min) to moderate (CrCl 30 to 59 mL/min) renal impairment: No adjustment recommended.
• Severe (CrCl less than 30 mL/min) renal impairment or end-stage renal disease: Data not available

Liver Dose Adjustments

• Mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment: No adjustment in the starting dose recommended.

• Withhold treatment for up to 4 weeks.
• Resume at next lower dose if improved to Grade 0 or 1; permanently discontinue drug if not improved to Grade 0 or 1 within 4 weeks.
• Permanently discontinue drug for recurrent Grade 4 abnormalities/hepatotoxicity.

• First Dose Reduction: 40 mg orally once a day
• Second Dose Reduction: 20 mg orally once a day
• Permanently discontinue drug if patient unable to tolerate 20 mg orally once a day.

Dose Adjustments

MODERATE OR STRONG CYP450 3A INHIBITORS:

• Do not take moderate or strong CYP450 3A inhibitors while taking this drug.
• If concurrent short term (14 days or less) use of moderate CYP450 3A inhibitors is unavoidable for patients who are taking this drug at 60 mg, reduce the dose of this drug to 20 mg. After discontinuation of a moderate CYP450 3A inhibitor, resume previous dose of this drug at 60 mg.
• Use an alternative to a moderate or strong CYP450 3A inhibitor in patients who are taking a reduced dose of this drug (20 or 40 mg daily).

• First dose reduction: 40 mg orally once a day
• Second dose reduction: 20 mg orally once a day
• Permanently discontinue this drug if the patient unable to tolerate 20 mg orally once a day.

• No adjustment recommended.

• Grade 3: Withhold this drug for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• Grade 4: Permanently discontinue therapy.

• Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) from baseline of greater than 10% AND less than institutional lower limit of normal (LLN): Withhold therapy for 2 weeks; repeat LVEF. Resume at next lower dose if LVEF at or above LLN AND absolute decrease from baseline LVEF 10% or less. Permanently discontinue therapy if LVEF less than LLN OR absolute decrease from baseline LVEF is more than 10%.
• Symptomatic LVEF decrease from baseline: Withhold therapy for up to 4 weeks; repeat LVEF. Resume at next lower dose if symptoms resolve, LVEF at or above LLN, AND absolute decrease from baseline LVEF 10% or less. Permanently discontinue therapy if symptoms persist, LVEF less than LLN, OR absolute decrease from baseline LVEF more than 10%.

• Intolerable Grade 2 or Grade 3 or 4: Reduce dose or withhold therapy.

• Serious retinopathy: Withhold therapy for up to 4 weeks; if improved resume at the next lower dose level; if not improved or symptoms recur at the lower dose within 4 weeks, permanently discontinue therapy.
• Retinal vein occlusion: Permanently discontinue therapy.

• First occurrence Grade 4: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved to Grade 0 or 1 within 4 weeks, permanently discontinue therapy.
• Recurrent Grade 4: Permanently discontinue therapy.

• Grade 4 CPK elevation/any CPK elevation and myalgia: Withhold therapy for up to 4 weeks; if improved to Grade 3 or lower, resume at the next lower dose level: if not improved within 4 weeks, permanently discontinue therapy.

• Intolerable Grade 2 or Grade 3 or 4: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.

• Intolerable Grade 2 adverse reactions: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• Any Grade 3 adverse reactions: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• First occurrence of any Grade 4 adverse reaction: Withhold therapy until adverse reaction improves to Grade 0 or 1; resume at the next lower dose level, OR

• Recurrent Grade 4 adverse reaction: Permanently discontinue therapy.

Precautions

CONTRAINDICATIONS:

• None

Dialysis

Data not available

Other Comments

Administration advice:

• This drug may be taken with or without food.
• If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-daily regimen.
• In case of vomiting after administration of a dose, the patient should not take an additional dose on that day and therapy should be continued the following day.

• This drug should be stored at room temperature below 30C (86F).

• This drug is not indicated for patients with wild-type BRAF melanoma.
• Administration of this drug with vemurafenib results in increased apoptosis and reduced tumor growth in tumor cell lines harboring BRAF V600E mutations since these drugs target different kinases in the RAS/RAF/MEK/ERK pathway.
• This drug also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model.
• There is no information on overdosage with this drug.

• Cardiovascular: LVEF (prior to treatment initiation, 1 month after initiation, and every 3 months thereafter until treatment discontinuation); in patients restarting treatment after a dose reduction or interruption: LVEF (at 2, 4, 10, and 16 weeks during treatment and periodically as clinically indicated); ECG and electrolytes (before treatment initiation and routinely during treatment)
• Hepatic: Liver lab tests (before treatment initiation and at least monthly during treatment)
• Musculoskeletal: Baseline serum CPK and creatinine levels (prior to treatment initiation, and periodically during treatment)
• Ocular: Ophthalmological evaluation (at regular intervals and any time a patient reports new or worsening visual disturbances)
• Oncology: Cutaneous and non-cutaneous malignancies; dermatologic evaluations (prior to treatment initiation and every 2 months during therapy up to 6 months following last dose)

• Avoid grapefruit, grapefruit juice, and St. John's Wort during treatment.
• This drug can make your skin sensitive to sunlight. Wear clothes that protect your skin and use sunscreen and lip balm with SPF 30 or higher to help protect against sunburn.
• Use effective contraception during treatment and for 2 weeks after the last dose if you are a female patient with childbearing potential.
• Do not breastfeed during treatment and for 2 weeks after the final dose.