Table 1: Dose modification schedule based on the grade of any AEs

Grade (CTC-AE) (a)
 Recommended dose modification
 
1 or Grade 2 (tolerable)
 Maintain vemurafenib at a dose of 960 mg twice daily.
 
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 or persistence after treatment interruption
 Interrupt 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).
 
3rd occurrence of any grade 2 or 3 AE or persistence after 2nd dose reduction
 Discontinue permanently.
 
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 persistence of any grade 4 AE after 1st dose reduction
 Discontinue permanently.

(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 and >60 ms change from pre-treatment values
 Discontinue permanently.
 
1st occurrence of QTc>500 ms during treatment and change from pre-treatment value remains <60 ms
 Temporarily interrupt treatment until QTc decreases below 500 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 treatment and change from pre-treatment value remains <60 ms
 Temporarily interrupt treatment until QTc decreases below 500 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 treatment and change from pre-treatment value remains <60 ms
 Discontinue permanently.

Special population

Older people

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 impair