P Substrates: Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP1A2 or CYP2D6 is not recommended. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 or CYP2D6 substrate drug. (7.1)
ZELBORAF may increase exposure to concomitantly administered warfarin. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin. (7.1)
Use In Specific Populations
Nursing Mothers: Discontinue nursing when receiving ZELBORAF (8.3)
1 INDICATIONS AND USAGE
ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dose of ZELBORAF is 960 mg (four 240 mg tablets) twice daily. The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Each dose can be taken with or without a meal.
ZELBORAF tablets should be swallowed whole with a glass of water. ZELBORAF tablets should not be chewed or crushed.
Duration of treatment
It is recommended that patients are treated with ZELBORAF until disease progression or unacceptable toxicity occurs.
Missed doses
If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time.
2.2 Dose Modifications
Management of symptomatic adverse drug reactions or prolongation of QTc may require dose reduction, treatment interruption, or treatment discontinuation of ZELBORAF (Table 1). Dose modifications or interruptions are not recommended for cutaneous squamous cell carcinoma (cuSCC) adverse reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Dose reductions resulting in a dose below 480 mg twice daily are not recommended.
Table 1 Dose Modification Information Grade (CTC-AE)* Recommended ZELBORAF Dose Modification
Grade 1 or Grade 2 (tolerable) Maintain ZELBORAF at a dose of 960 mg twice daily.
Grade 2 (Intolerable) or Grade 3
1st Appearance Interrupt treatment until grade 0 – 1. Resume dosing at 720 mg twice daily.
2nd Appearance Interrupt treatment until grade 0 – 1. Resume dosing at 480 mg twice daily.
3rd Appearance Discontinue permanently
Grade 4
1st Appearance Discontinue permanently or interrupt ZELBORAF treatment until grade 0 – 1.
Resume dosing at 480 mg twice daily.
2nd Appearance Discontinue permanently
*The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)
3 DOSAGE FORMS AND STRENGTHS
Film-coated tablet: 240 mg
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approx |
