ZELBORAF

Vemurafenib is a competitive kinase inhibitor with activity against BRAF kinase with mutations like V600E.

It exerts its function by binding to the ATP-binding domain of the mutant BRAF.

Vemurafenib was co-developed by Roche and Plexxikon and it obtained its FDA approval on August 17, 2011, under the company Hoffmann La Roche.

After approval, Roche in collaboration with Genentech launched a broad development program.

Vemurafenib is approved since for the treatment of metastatic melanoma with a mutation on BRAF in the valine located in the exon at codon 600, this mutation is denominated as V600E.

V600E mutation, a substitution of glutamic acid for valine, accounts for 54% of the cases of cutaneous melanoma.

Vemurafenib approval was extended in 2017, for its use as a treatment of adult patients with Erdheim-Chester Disease whose cancer cells present BRAF V600 mutation.

Erdheim-Chester disease is an extremely rare histiocyte cell disorder that affects large bones, large vessels, central nervous system, as well as, skin and lungs.

It is reported an association of Erdheim-Chester disease and V600E mutation.

activation results in cell growth, proliferation, and metastasis.

BRAF is an intermediary molecule in MAPK whose activation depends on ERK activation, elevation of cyclin D1 and cellular proliferation.

The mutation

V600E produces a constitutively form of BRAF.

Vemurafenib has been shown to reduce all activation markers related to BRAF; in clinical trials, vemurafenib treatment showed a reduction of cytoplasmic phosphorylated ERK and a cell proliferation driven by Ki-67.

Studies also reported decrease in

MAPK-related metabolic activity.

All the different reports indicate thet

Vemurafenib generates an almost complete inhibition of the MAPK pathway.

Vemurafenib is well absorbed after oral administration.

Peak concentrations are reached in 3 hours when an oral dose of 960 mg twice daily for 15 days has been given to patients.

In the same conditions, Vemurafenib presents a Cmax of 62 mcg/ml and AUC of 601 mcg h/ml. Label It is unknown how food affects the absorption of vemurafenib.

It presents an accumulation ratio of 7.36 after repeating doses of 960 mg 10.

The estimation of the volume of distribution for Vemurafenib is 106 L.

Vemurafenib is metabolized by

CYP3A4 and the metabolites make up 5% of the components in plasma.

The parent compound makes up for the remaining 95%.

Hover over products below to view reaction partners Vemurafenib vemurafenib intermediary metabolite secondary metabolite of vemurafenib alternative secondary metabolite of vemurafenib.

Analysis showed that 94% of administered Vemurafenib is excreted via feces and 1% is excreted by urine.

The elimination half-life of

Vemurafenib is estimated to be 57 hours (range of 30-120 hours).

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In the few toxicity reports, it has been shown an increased in the development of cutaneous squamous cell carcinomas or acceleration in pre-existant tumor growth.

Confirm the presence of BRAF

V600E mutation in tumor specimens prior to initiation of treatment with ZELBORAF.

Recommended dose: 960 mg orally twice daily taken approximately 12 hours apart with or without a meal. 2.1 Patient Selection for Treatment of Melanoma Confirm the presence of BRAF V600E mutation in melanoma tumor specimens prior to initiation of treatment with ZELBORAF.

Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at 2.2 Recommended Dose The recommended dose of ZELBORAF is 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal.

A missed dose can be taken up to 4 hours prior to the next dose.

Treat patients with

ZELBORAF until disease progression or unacceptable toxicity occurs.

Do not take an additional dose if vomiting occurs after ZELBORAF administration, but continue with the next scheduled dose.

Do not crush or chew the tablets. 2.3 Dose Modifications For New Primary Cutaneous Malignancies: No dose modifications are recommended.

Permanently discontinue ZELBORAF for any of the following: Grade 4 adverse reaction, first appearance (if clinically appropriate) or second appearance QTc prolongation > 500 ms and increased by > 60 ms from pre-treatment values Withhold ZELBORAF for NCI-CTCAE (v4.0) intolerable Grade 2 or greater adverse reactions.

Upon recovery to

Grade 0–1, restart ZELBORAF at a reduced dose as follows: 720 mg twice daily for first appearance of intolerable Grade 2 or Grade 3 adverse reactions 480 mg twice daily for second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate) Do not dose reduce to below 480 mg twice daily. 2.4 Dose Modification for Strong CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers during treatment with ZELBORAF.

If concomitant use of a strong

CYP3A4 inducer is unavoidable, increase the dose of ZELBORAF by 240 mg (one tablet) as tolerated.

After discontinuation of a strong

CYP3A4 inducer for two weeks, resume the ZELBORAF dose that was taken prior to initiating the strong CYP3A4 inducer.

(vemurafenib) is supplied as 240 mg film-coated tablets with VEM debossed on one side.

The following packaging configurations are available

NDC 50242-090-01 single bottle of 120 count NDC 50242-090-02 single bottle of 112 count Storage and Stability: Store at room temperature 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F), See USP Controlled Room Temperature.

Store in the original container with the lid tightly closed.

Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized.

Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.

Use established "collection systems," if available in your location.

Store at room temperature 20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and 86°F), See USP Controlled Room Temperature.

Store in the original container with the lid tightly closed.

Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman.

There are no available data on the use of ZELBORAF in pregnant women to determine the drug-associated risk; however, placental transfer of vemurafenib to a fetus has been reported.

Exposure to vemurafenib could not be achieved in animals at levels sufficient to fully address its potential toxicity in pregnant women.

Advise pregnant women of the potential harm to a fetus.

The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Vemurafenib showed no evidence of developmental toxicity in rat fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the clinical exposure at 960 mg twice daily based on AUC) or rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the clinical exposure at 960 mg twice daily based on AUC).

Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus.

The safety and effectiveness of

ZELBORAF in pediatric patients have not been established.

Vemurafenib was studied in 6 adolescent patients to 17 years of age with unresectable or metastatic melanoma with BRAF V600 mutation.

A maximum tolerated dose was not reached with doses up to vemurafenib 960 mg twice daily.

No new safety signals were observed.

Vemurafenib steady-state exposure in these 6 adolescent patients was generally similar to that in adults.

Clinical studies of

ZELBORAF did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.