Usual Adult Dose for Melanoma - Metastatic

Unresectable or Metastatic Melanoma:

• Single agent: 2 mg orally once a day
• Combination therapy: 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
• Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Adjuvant Treatment of Melanoma:

• Combination therapy: 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
• Duration of therapy: Until disease progression or unacceptable toxicity occurs for up to one year.

Comments:

• Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation.

Uses:

• As a single agent for the treatment of BRAF-inhibitor treatment-naive patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test
• In combination with dabrafenib for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test
• In combination with dabrafenib for patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection

Usual Adult Dose for Non-Small Cell Lung Cancer

2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.

Use: In combination with dabrafenib for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test

Usual Adult Dose for Thyroid Cancer

2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.

Use: In combination with dabrafenib for patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

Usual Adult Dose for Solid Tumors

2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.
• Approved for this indication under accelerated approval based on overall response rate and duration of response in clinical studies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Use: Indicated, in combination with dabrafenib, for the treatment of adults with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.

Usual Pediatric Dose for Solid Tumors

For pediatric patients with at least 26 kg of body weight:

• Body weight between 26 and 37 kg: 1 mg orally once a day
• Body weight between 38 and 50 kg: 1.5 mg orally once a day
• Body weight 51 kg or more: 2 mg orally once daily

Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.
• Approved for this indication under accelerated approval based on overall response rate and duration of response in clinical studies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Use: Indicated in combination with dabrafenib, for the treatment of pediatric patients 6 years of age and older who weight at least 26 kg, with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.

Renal Dose Adjustments

Mild (CrCl 60 to less than 90 mL/min) to Moderate (CrCl 30 to less than 60 mL/min): No adjustment recommended
Severe (CrCl 15 to less than 30 mL/min): Use with caution
End-stage renal disease (CrCl less than 15 mL/min): Data not available

Liver Dose Adjustments

Mild hepatic impairment: No adjustment recommended.
Moderate to severe hepatic impairment: Use with caution considering risks and benefits as dosage has not been established.

Dose Adjustments

Recommended Dose Reductions for Adverse Reactions in Adult Patients:

• First dose reduction: 1.5 mg orally once a day
• Second dose reduction: 1 mg orally once a day
• Subsequent modification: Permanently discontinue therapy if unable to tolerate 1 mg orally once a day

Recommended Dose Reductions for Adverse Reactions in Pediatric Patients:

• If dosage is 2 mg orally once daily: Same dose reductions as adult patients
• If dosage is 1.5 mg orally once daily:
• First dose reduction: 1 mg orally once daily
• Second dose reduction: 0.5 mg orally once daily
• Subsequent modification: Permanently discontinue if unable to tolerate a maximum of two dose reductions
• If dosage is 1 mg once daily:
• First dose reduction: 0.5 mg orally once daily
• Second dose reduction: Permanently discontinue

RECOMMENDED DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
Hemorrhage:

• Grade 3: Withhold treatment, if improved resume at lower dose, if not improved, permanently discontinue.
• Grade 4: Permanently discontinue

Venous Thromboembolism:

• Uncomplicated DVT or PE: Withhold therapy for up to 3 weeks; if improved to Grade 0 or 1, resume at a lower dose level; if not improved, permanently discontinue therapy.
• Life threatening PE: Permanently discontinue therapy.

Cardiac Toxicity:

• Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline that is below institutional lower limits of normal (LLN) from pretreatment value: Withhold therapy for up to 4 weeks; if improved to normal LVEF value, resume therapy at a lower dose; if not improved to normal LVEF value, permanently discontinue therapy.
• Symptomatic congestive heart failure or an absolute decrease in LVEF of greater than 20% from baseline that is below LLN: Permanently discontinue therapy.

Ocular Toxicity:

• Retinal pigment epithelial detachments (RPED): Withhold therapy for up to 3 weeks; if improved, resume therapy at same or lower dose level; if not improved, discontinue therapy or resume at a lower dose.
• Retinal vein occlusion: Permanently discontinue therapy.

Pulmonary Toxicity:
Interstitial lung disease/pneumonitis: Permanently discontinue therapy.

Febrile Drug Reactions:

• Fever higher than 104F or fever complicated by rigors, hypotension, dehydration or renal failure: Withhold therapy until fever resolves for at least 24 hours, then resume at a lower dose level; OR permanently discontinue.

Dermatologic Toxicity:

• Grade 3 or 4 or intolerable Grade 2: Withhold therapy for up to 3 weeks; if improved, resume therapy at a lower dose level; if not improved, permanently discontinue therapy.
• Severe cutaneous adverse reactions (SCARs): Permanently discontinue therapy.

Other Adverse Reactions (dose modifications are not recommended for this drug when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis; dose modification of this drug is not required for new primary cutaneous malignancies):

• Intolerable Grade 2 or any Grade 3 adverse reaction: Withhold therapy; if improved to Grade 0 to 1, resume therapy at a lower dose level, if not improved, permanently discontinue therapy.
• First occurrence of any Grade 4 adverse reaction: Withhold therapy until adverse reaction improves to Grade 0 to 1, then resume therapy at a lower dose level; if not improved, permanently discontinue therapy.
• Recurrent Grade 4 adverse reaction: Permanently discontinue therapy.

Refer to dabrafenib prescribing information for dose modifications for adverse reactions associated with this drug.

Precautions

CONTRAINDICATIONS:

• None

Limitations of use: This drug is not indicated for the treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition.

Safety and effectiveness of this drug in combination with dabrafenib in pediatric patients younger than 6 years old have not been established.
Safety and effectiveness as a single agent in pediatric patients have not been established.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug should be taken without food, at least 1 hour before or 2 hours after a meal.
• This drug should be taken with a full glass of water.
• When this drug and dabrafenib are taken in combination, the dose of this drug should be taken at the same time each day with either the morning or evening dose of dabrafenib.
• If a dose is missed, only take the dose if it is more than 12 hours until the next scheduled dose.

Storage requirements:

• Store refrigerated at 36F to 46F.
• Dispense in original container with desiccant intact.
• Protect from moisture and light.
• Do not place medication in pill boxes.

Monitoring:

• Monitor patients for new primary malignancies before treatment initiations, during treatment and after discontinuation.
• Monitor for signs and symptoms of bleeding.
• Monitor for signs of skin toxicity and secondary infections.
• Monitor blood glucose levels in patients with diabetes or hyperglycemia.
• Monitor closely for colitis and gastrointestinal perforations.
• Perform ophthalmological evaluations periodically.
• Monitor blood pressure and renal function.

Patient advice:

• Read the Patient Information and Instructions for Use.