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4.9 Overdose
 There is no specific antidote for overdose of vemurafenib. Patients who develop adverse reactions should receive appropriate symptomatic treatment. No cases of overdose have been observed with vemurafenib in clinical trials. In case of suspected overdose, vemurafenib should be withheld and supportive care initiated.

5. Pharmacological properties
  
5.1 Pharmacodynamic properties
 Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15

Mechanism of action and pharmacodynamic effects

Vemurafenib is a low molecular weight, orally available, inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation.

Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit BRAF kinases with activating codon 600 mutations (table 4).

Table 4: Kinase inhibitory activity of vemurafenib against different BRAF kinases

Kinase
 Anticipated frequency in V600 mutation-positive melanoma (f)
 Inhibitory Concentration 50 (nM)
 
BRAFV600E
 93.2%
 10
 
BRAFV600K
 5.6%
 7
 
BRAFV600R
 1%
 9
 
BRAFV600D
 <0.1%
 7
 
BRAFV600G
 <0.1%
 8
 
BRAFV600M
 <0.1%
 7
 
BRAFV600A
 0
 14
 
BRAFWT
 NA
 39

(f) Estimated from 2099 melanomas with annotated BRAF codon 600 mutations in the public COSMIC database, release 54 (July 2011).

This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays the IC50 against V600 mutated cell lines (V600E, V600R, V600D and V600K mutated cell lines) ranged from 0.016 to 1.131 μM whereas the inhibitory concentration 50 against BRAF wild type cell lines were 12.06 and 14.32 μM, respectively.

Determination of BRAF mutation status

Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the phase II and phase III clinical trials, eligible patients were identified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation Test). This test has CE marking and is used t