Posology : מינונים

4.2    Posology and method of administration

Treatment with vemurafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products.

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test (see sections 4.4 and 5.1).

Posology
The recommended dose of vemurafenib is 960 mg (4 tablets of 240 mg) twice daily (equivalent to a total daily dose of 1,920 mg). Vemurafenib may be taken with or without food, but consistent intake of both daily doses on an empty stomach should be avoided (see section 5.2).

Duration of treatment
Treatment with vemurafenib should continue until disease progression or the development of unacceptable toxicity (see tables 1 and 2 below).

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.

Vomiting
In case of vomiting after vemurafenib administration the patient should not take an additional dose of the medicinal product but the treatment should be continued as usual.

Posology adjustments
Management of adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation (see tables 1 and 2). Posology adjustments resulting in a dose below 480 mg twice daily are not recommended.

In the event the patient develops Cutaneous Squamous Cell Carcinoma (cuSCC), it is recommended to continue the treatment without modifying the dose of vemurafenib (see sections 4.4 and 4.8).

Table 1: Dose modification schedule based on the grade of any Adverse Events (AEs) 
Grade (CTC-AE) (a)                        Recommended dose modification Grade 1 or Grade 2 (tolerable)            Maintain vemurafenib at a dose of 960 mg twice daily.
Grade 2 (intolerable) or Grade 3
1st occurrence of any grade 2 or 3 AE     Interrupt treatment until grade 0 – 1. Resume dosing at 720 mg twice daily (or 480 mg twice daily if the dose has already been lowered).
2nd occurrence of any grade 2 or 3 AE     Interrupt treatment until grade 0 – 1. Resume dosing at or persistence after treatment            480 mg twice daily (or discontinue permanently if the interruption                              dose has already been lowered to 480 mg twice daily).
3rd occurrence of any grade 2 or 3 AE     Discontinue permanently.
or persistence after 2nd dose reduction
Grade 4
1st occurrence of any grade 4 AE          Discontinue permanently or interrupt vemurafenib treatment until grade 0 – 1.
Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily).
2nd occurrence of any grade 4 AE or       Discontinue permanently.
persistence of any grade 4 AE after
1st dose reduction
(a) The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE).

Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma. Management of QTc prolongation may require specific monitoring measures (see section 4.4).


Table 2: Dose modification schedule based on prolongation of the QT interval 
QTc value                                             Recommended dose modification QTc>500 ms at baseline                                Treatment not recommended.
QTc increase meets values of both >500 ms             Discontinue permanently.
and >60 ms change from pre-treatment values
1st occurrence of QTc>500 ms during                   Temporarily interrupt treatment until QTc treatment and change from pre-treatment value         decreases below 500 ms.
remains <60 ms                                        See monitoring measures in section 4.4.
Resume dosing at 720 mg twice daily (or
480 mg twice daily if the dose has already been lowered).
2nd occurrence of QTc>500 ms during                   Temporarily interrupt treatment until QTc treatment and change from pre-treatment value         decreases below 500 ms.
remains <60 ms                                        See monitoring measures in section 4.4.
Resume dosing at 480 mg twice daily (or discontinue permanently if the dose has already been lowered to 480 mg twice daily).
3rd occurrence of QTc>500 ms during                   Discontinue permanently.
treatment and change from pre-treatment value remains <60 ms

Special population

Elderly
No special dose adjustment is required in patients aged > 65 years old.
Renal impairment
Limited data are available in patients with renal impairment. A risk for increased exposure in patients with severe renal impairment cannot be excluded. Patients with severe renal impairment should be closely monitored (see sections 4.4 and 5.2).

Hepatic impairment
Limited data are available in patients with hepatic impairment. As vemurafenib is cleared by the liver, patients with moderate to severe hepatic impairment may have increased exposure and should be closely monitored (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of vemurafenib in children less than 18 years old have not been established.
Currently available data are described in sections 4.8, 5.1, and 5.2, but no recommendation on a posology can be made.

Non-Caucasian patients
The safety and efficacy of vemurafenib has not been established in non-Caucasian patients. No data are available.

Method of administration
Vemurafenib is for oral use. The tablets are to be swallowed whole with water. They should not be chewed or crushed.