from only three patients with pre-existing severe hepatic impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. ZELBORAF should be used with caution in patients with pre-existing severe hepatic impairment [see Clinical Pharmacology (12.3)].
8.8 Renal Impairment
No adjustment to the starting dose is needed for patients with pre-existing mild and moderate renal impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data from one patient with pre-existing severe renal impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. ZELBORAF should be used with caution in patients with pre-existing severe renal impairment [see Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
No studies on the potential for ZELBORAF to cause dependence have been performed. However, there is no evidence from the available data that ZELBORAF treatment can result in dependence.
10 OVERDOSAGE
There is no specific antidote for overdosage of ZELBORAF. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, ZELBORAF should be withheld and supportive care instituted.
11 DESCRIPTION
ZELBORAF (vemurafenib) is a kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure:
Vemurafenib is a white to off-white crystalline solid. It is practically insoluble in aqueous media.
Tablets of ZELBORAF are for oral administration. Each tablet contains 240 mg of vemurafenib.
The inactive ingredients of ZELBORAF are: Tablet Core: hypromellose acetate succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and hydroxypropyl cellulose. Coating: pinkish white: poly(vinyl alcohol), titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.
Chemical Structure
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E.
12.3 Pharmacokinetics
The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of dosing at 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. A one-compartment disposition model with first-order absorption |
