Vemurafenib

489.9221264

489.92

207SMY3FQT

761431

DTXSID50238710

C64768

White to off-white crystalline solid

L01EC01|L01XE15|L - Antineoplastic and immunomodulating agents

2935009090

100

5

1.46

272°C

384.0±35.7 °C

1.653

H2O: <1 mg/mL;Practically insoluble in aqueous media

Store at room temperature 20 deg C - 25 degC (68 deg F - 77 deg F); excursions permitted between 15 deg C and 30 deg C (59 deg F and 86 deg F), See USP Controlled Room Temperature. Store in the original container with the lid tightly closed.

8.21X10-15 mm Hg at 25 deg C (est)

7.1None

Henry's Law constant = 1.23X10-17 atm-cu m/mol at 25 °C (est)

7.1|pKa = 7.2 (amine) (est)

Stable if stored as directed; avoid strong oxidizing agents

P201, P202, P260, P264, P270, P273, P281, P301+P312, P308+P313, P314, P330, P405, P501

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vemurafenib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H410 (100%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]|P273, P391, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Personal protective equipment as follows: Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles.

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/.

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing; material may be an irritant.|Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.

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.

In large clinical trials of vemurafenib, abnormalities in routine liver tests were common and serum aminotransferase elevations occurred in up to one third of patients. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 3% of patients, and rare instances of clinically apparent liver injury were reported, but the clinical features of the injury have not been described. The onset of liver test abnormalities was typically within 3 to 6 weeks of starting vemurafenib, and the abnormalities resolved rapidly either spontaneously or with temporary drug discontinuation. Vermurafenib has also been linked to instances of drug related rash with eosinophilia and systemic manifestations (DRESS) as well as Stevens Johnson syndrome, both of which can be accompanied by liver dysfunction and in some cases jaundice with clinically apparent liver injury.

Concomitant use of vemurafenib with drugs known to prolong the QT interval, including class Ia (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol) antiarrhythmic agents, some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine is not recommended by the manufacturer.|Concomitant use of vemurafenib with CYP2C9 substrates may result in increased plasma concentrations of the CYP2C9 substrate and possible toxicity. When the CYP2C9 substrate warfarin was administered concomitantly with vemurafenib, the systemic exposure of S-warfarin increased by 18%. Vemurafenib and warfarin should be used concomitantly with caution and additional monitoring of the international normalized ratio (INR) should be considered.|Concomitant use of vemurafenib with CYP3A4 substrates may result in decreased plasma concentrations of the CYP3A4 substrate and possible decreased efficacy. When the CYP3A4 substrate midazolam was administered concomitantly with vemurafenib, the systemic exposure of midazolam decreased by 39%. Concomitant use of vemurafenib with CYP3A4 substrates that have a narrow therapeutic index should be avoided.|Concomitant use of vemurafenib with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and possible toxicity. When the CYP2D6 substrate dextromethorphan was administered concomitantly with vemurafenib, the systemic exposure of dextromethorphan increased by 47%. Concomitant use of vemurafenib with CYP2D6 substrates that have a narrow therapeutic index should be avoided. If concomitant use cannot be avoided, dosage reduction of the CYP2D6 substrate should be considered, and the drugs should be used concomitantly with caution.|For more Interactions (Complete) data for Vemurafenib (9 total), please visit the HSDB record page.

The manufacturer does not recommend initiation of vemurafenib in patients with electrolyte abnormalities unresponsive to corrective measures or congenital long QT syndrome.|In a population pharmacokinetic analysis, the clearance of vemurafenib was not affected in patients with mild or moderate renal impairment. Pharmacokinetic data in patients with severe renal impairment are limited; therefore, the drug should be used with caution in these patients.|In a population pharmacokinetic analysis, the clearance of vemurafenib was not affected in patients with mild or moderate hepatic impairment. Pharmacokinetic data in patients with severe hepatic impairment are limited; therefore, the drug should be used with caution in these patients.

Vemurafenib highly binds to plasma proteins where >99% of the administered dose will be found protein bound to serum albumin and alpha-1 acid glycoprotein.

Vernurafenib's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6.8X10+5(SRC), determined from a structure estimation method(2), indicates that the neutral species of vernurafenib is expected to be immobile in soil(SRC). The estimated pKa of vernurafenib is 7.1(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of vernurafenib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Vernurafenib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2013).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6.8X10+5(SRC), determined from a structure estimation method(2), indicates that vernurafenib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 310(SRC), from an estimated log Kow of 5.17(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2013).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), vernurafenib, which has an estimated vapor pressure of 8.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase vernurafenib may be removed from the air by wet and dry deposition(SRC). Vernurafenib does not contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Vernurafenib is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Vernurafenib does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 310 was calculated in fish for vernurafenib(SRC), using an estimated log Kow of 5.17(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of vernurafenib can be estimated to be 6.8X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that the neutral species of vernurafenib is expected to be immobile in soil. The estimated pKa of vernurafenib is 7.1(3), indicating that this compound will exist partially in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for vernurafenib is estimated as 1.2X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that vernurafenib is expected to be essentially nonvolatile from water and moist soil surfaces(2). Vernurafenib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.2X10-15 mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to vernurafenib may occur through inhalation and dermal contact with this compound at workplaces where vernurafenib is produced or used. Exposure to vernurafenib among the general population may be limited to those administered the drug, an antineoplastic. (SRC)

Vemurafenib is approved since 2011 for the treatment of metastatic melanoma with a mutation on BRAF in the valine located in the exon 15 at codon 600, this mutation is denominated as V600E. The 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.|FDA Label|Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF-V600-mutation-positive unresectable or metastatic melanoma.|Treatment of melanoma|Drug: Vemurafenib

Vemurafenib is a selective inhibitor of BRAF kinase that is used in the therapy of patients with metastatic and advanced malignant melanoma. Vemurafenib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe cases of clinically apparent acute liver injury.

Antineoplastic Agents

Vemurafenib is used for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation. Vemurafenib is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer. An FDA-approved diagnostic test (e.g., cobas 4800 BRAF V600 Mutation Test) is required to confirm the presence of the BRAF V600E mutation prior to initiation of therapy. /Included in US product label/|Zelboraf is not recommended for use in patients with wild-type BRAF melanoma.

Serious hypersensitivity reactions (e.g., anaphylaxis, generalized rash and erythema, hypotension) have been reported in patients receiving vemurafenib. Vemurafenib should be permanently discontinued in patients who experience a severe hypersensitivity reaction.|Photosensitivity reactions (mild to severe) have been reported in 33-49% of patients receiving vemurafenib in clinical trials. If intolerable grade 2 (i.e., tender erythema covering 10-30% of body surface area) or greater reaction occurs, the dosage of vemurafenib should be reduced.|Vemurafenib prolongs the QT interval in a concentration-dependent manner. In a multicenter, open-label, phase 2 study, QT interval prolongation was evaluated in patients with BRAF V600E mutation-positive, metastatic melanoma who were receiving vemurafenib (960 mg twice daily). A maximum mean corrected QT (QTc) interval change from baseline of 12.8 msec during the first month of treatment and 15.1 msec during the first 6 months of treatment was observed in these patients. The manufacturer does not recommend initiation of vemurafenib in patients with electrolyte abnormalities unresponsive to corrective measures or congenital long QT syndrome. In addition, concomitant use of vemurafenib with drugs known to prolong the QT interval (e.g., class Ia and III antiarrhythmic agents) is not recommended. ECGs and serum electrolyte concentrations, including concentrations of potassium, magnesium, and calcium, should be obtained prior to initiation of therapy or following dosage modification, and monitored 15 days following initiation of therapy, then monthly for the first 3 months of treatment, and then every 3 months thereafter or more often as clinically indicated. Interruption or discontinuance of vemurafenib may be necessary if increases in the QTc interval occur during therapy with the drug.|Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported with vemurafenib. If severe skin reactions occur, vemurafenib therapy should be permanently discontinued.|For more Drug Warnings (Complete) data for Vemurafenib (18 total), please visit the HSDB record page.

Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the extracellular signal-regulated kinases, ERK1/2. In many cases tumor cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumor-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, whilst clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress it is apparent that tumor cells adapt quickly to these new, targeted agents so that tumors with acquired resistance can emerge within 6-9 months of primary treatment. One of the major reasons for this is that tumor cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumor cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here /the investigators/ discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic.|BRAF-mutated melanomas with RAF inhibitors (either vemurafenib or dabrafenib) results in rapid and dramatic responses in most patients-results that are associated with improved progression-free survival (PFS) and in the case of vemurafenib, overall survival (OS). However, resistance develops at a median time of approximately 6 months. Understanding the mechanisms of resistance is critical to develop strategies to prolong PFS and OS. Negative feedback mechanisms inherent in the MAPK pathway serve to modulate responses to these drugs. However, genetic changes develop within the tumor, which lead to reactivation of the MAPK and resistance to these drugs. The mechanisms that have been demonstrated in many patients by multiple investigators are (1) development of an activating mutation in NRAS, and (2) appearance of a BRAFV600E splice variant that encourages RAF dimerization. Several other mechanisms of resistance have also been described in individual patients or in preclinical models of resistance. In addition, there is evidence that activation of parallel pathways, such as the PI3K/AKT pathway, may represent another mechanism of resistance. Understanding the various mechanisms of resistance will inform our attempts to prevent resistance to RAF inhibitors.|Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. /The investigators/ identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. ... Findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.|Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with?=50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumor regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here /the researchers/ investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors show continued dependency on BRAF(V600E)?MEK?ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, /the researchers/ demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. /The researchers/ further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.

BRAF 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.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

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. It is unknown how food affects the absorption of vemurafenib. It presents an accumulation ratio of 7.36 after repeating doses of 960 mg|Analysis showed that 94% of administered Vemurafenib is excreted via feces and 1% is excreted by urine.|The estimation of the volume of distribution for Vemurafenib is 106 L.|The total body clearance is 31 L/day.|Following oral administration of (14)C-vemurafenib 960 mg in the tablet formulation, plasma samples were analyzed over 48 hours for vemurafenib and its metabolites. Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively.|Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 106 L (with 66% inter-patient variability).|The bioavailability of vemurafenib has not been determined. Following oral administration of vemurafenib at 960 mg twice daily for 15 days to patients with metastatic melanoma, the median Tmax was approximately 3 hours. Following 15 days of dosing at 960 mg twice daily, the mean (+ or - SD) Cmax and AUC0-12 were 62 ug/mL + or - 17 and 601 + or - 170 ug*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.36, with steady state achieved at approximately 15 to 22 days following dosing at 960 mg twice daily. At steady state, the mean vemurafenib exposure in plasma is stable (concentrations before and 2-4 hours after the morning dose) as indicated by the mean ratio of 1.13. The potential effect of food on vemurafenib absorption has not been studied. In clinical trials, vemurafenib was administered without regard to food.|Following oral administration of (14)C-vemurafenib 960 mg in the tablet formulation, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 31 L/day (with 32% inter-patient variability).|For more Absorption, Distribution and Excretion (Complete) data for Vemurafenib (6 total), please visit the HSDB record page.

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%.|The results from in vitro studies indicate that CYP3A4 was the major enzyme responsible in the metabolism of vemurafenib. The formation of mono-hydroxyl metabolites were inhibited for approximately 82% using the CYP inhibitor ketoconazole. No significant inhibition in the metabolism was observed in human liver microsomes in the presence of quinidine (CYP2D6 inhibitor), sulfaphenazole (CYP2C9 inhibitor), tranylcypromine (CYP2A6 inhibitor) and (-)-N-3-benzyl-phenobarbital (CYP2C19 inhibitor). In addition, CYP3A4 was responsible for the formation of the mono-hydroxylation metabolites.|In vitro metabolism was analyzed for rat, mouse, dog, cynomolgus and human. The metabolism of vemurafenib was investigated both in vitro using microsomes and hepatocytes of various species and in vivo in rat, dog and human. In vitro analysis of vemurafenib metabolism in liver hepatocytes at the concentration of 10 uM, humans, dogs, and cynomolgus monkeys did not metabolize vemurafenib extensively (unchanged vemurafenib > or = 89%).|In study /of patients/, identification of vemurafenib and metabolites in plasma, feces and urine was made for the first 96 hr, with a total collection period of 432 hrs (18 days). Mean data from the 7 patients indicated that over the period investigated (0 to 96 hours), potential metabolites each accounted for < 0.5% of the total administered dose in urine and .6% of the total administered dose in feces. In pooled fecal samples up to 48 hours post post-dose, parent compound accounted for at least 94% of total radioactivity (37% of the dose). In fecal samples taken 48-96 hr post-dose, the amount of metabolites increased, with M6, M3, and M8 representing approximately 19%, 14% and 12%, of the total chromatographic peak area, respectively (mean values) or 3%, 5% and 4% of the dose, respectively. Over the 0-96 hr collection period, potential metabolites M3 (mono-hydroxy) and M6 (glucosylation) each accounted for <0.5% of the total administered dose in urine. Vemurafenib accounted for approximately 1% of the total dose in urine.

The elimination half-life of Vemurafenib is estimated to be 57 hours (range of 30-120 hours).|Single dose studies to determine pharmacokinetics were conducted in mouse, rat, rabbit, dog and monkey. In all pre-clinical species, half-lifes were between 2 and 5 hours ... . Only after intraperitoneal (IP) administration in mice, the half-life was much longer (20.6 h). Compared with other species, rabbits showed higher plasma exposure levels with a longer mean terminal half-life between 12 and 18 hours.|The median of the individual elimination half-life estimates for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).

Vemurafenib is an orally available inhibitor of mutated BRAF-serine-threonine kinase. Vemurafenif is a small molecule that interacts as a competitive inhibitor of the mutated species of BRAF. It is especially potent against the BRAF V600E mutation. Vemurafenib blocks downstream processes to inhibit tumour growth and eventually trigger apoptosis. Vemurafenib does not have antitumour effects against melanoma cell lines with the wild-type BRAF mutation.|Cutaneous squamous cell carcinoma (cuSCC) has been reported in patients with metastatic melanoma and CRC treated with vemurafenib. Clinical findings indicate that cuSCC may be related to treatment with vemurafenib. In order to understand the potential mechanism by which vemurafenib treatment contributes to development of cuSCC, vemurafenib was tested in vivo in the A431 cuSCC xenograft model. There was dose-dependent tumour growth stimulation of the xenograft tumours at doses higher than 25 mg/kg bid. The optimal dose of 75 mg/kg bid of vemurafenib caused a 103% induction of growth compared to the control (p=0.002). Immunohistochemistry showed staining of pERK only in the tumour samples treated with vemurafenib (75 mg/kg) as compared to the vehicle treated control group. Combination studies of vemurafenib and a MEK inhibitor, RO5068760, were performed to confirm inhibition of pERK.|The effect of vemurafenib on RAF-MEK-ERK pathway inhibition was investigated in a panel of cancer cell lines, including melanoma cell lines expressing BRAFV600E, BRAFV600D, BRAFV600R, or BRAFWT. MEK and ERK phosphorylation (pMEK and pERK respectively) immunoassays were conducted to measure the levels of pMEK and pERK in various cancer cells treated with vemurafenib compared to vehicle control In cells expressing mutated BRAF (Colo829,WM2664 and WM1341D), vemurafenib inhibited both pERK and pMEK in a dose dependent manner. However, cells expressing BRAF WT vemurafenib induced rather than inhibited ERK or MEK phosphorylation in the cells expressing BRAFWT, such as HCT116, CHL-1 and SK-MEL-2 cells.|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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ The BRAF inhibitor vemurafenib can cause severe cutaneous reactions, including Stevens-Johnson syndrome, particularly when administered after ipilimumab, which usually prevents further drug administration. /The investigators/ report the case of a patient with Stevens-Johnson syndrome due to vemurafenib, who was retreated with vemurafenib with a program of slow desensitization with dexamethasone and diphenhydramine. Vemurafenib was tolerated at a 50% dose after a 3-week desensitization. Desensitization may be possible in patients who develop Stevens-Johnson syndrome after vemurafenib treatment.|/CASE REPORTS/ Vemurafenib is a targeted therapy, used in patients with metastatic cutaneous melanoma who carry the BRAF V600E mutation, with a relative reduction of 63% in the risk of death. Several adverse events have been described previously, such as photosensitivity or squamous-cell carcinomas. Two cases of panniculitis have been reported recently with two different selective BRAF inhibitors. /The reseaerchers/ report two cases of neutrophilic panniculitis in patients treated by vemurafenib for a metastatic melanoma. Clinical and biological examinations showed no indications for an immune nor an infectious cause of neutrophilic panniculitis. Thus, /the researchers/ believe that vemurafenib caused this panniculitis. Treatment with vemurafenib was maintained in both patients because of the clinical and radiological tumoral responses. One patient showed spontaneous recovery, whereas the other patient presented several recurrences of panniculitis. We believe that physicians should be aware of this cutaneous side effect of vemurafenib, but it should not lead to discontinuation of this treatment.|/CASE REPORTS/ The BRAF inhibitor vemurafenib is state of the art in therapy of patients with malignant melanoma in non-resectable stage III or stage IV and evidence of oncogenetic BRAF mutation. Multiple cutaneous side effects like rash and keratoacanthoma-like lesions have been described so far./The researchers/ report a patient who presented multiple wart-like lesions under therapy with vemurafenib. Histologically we have seen multiple melanocytic nevi with a wart-like appearance. One melanoma in situ developed on the left forearm. Eruptive nevi and induction of melanoma may be a further side effect in patients undergoing a therapy with BRAF inhibitors|/CASE REPORTS/ Treatment with vemurafenib, a small-molecule BRAF inhibitor, has led to dramatic regression of metastatic melanomas harboring a V600E BRAF mutation. As with other kinase inhibitors, the use of vemurafenib has been accompanied by several dermatologic adverse effects. We describe a patient who experienced exacerbation of preexisting acantholytic dyskeratosis in a dose-dependent manner shortly after starting vemurafenib treatment. This was subsequently complicated by Kaposi varicelliform eruption and cessation of the drug treatment owing to progression of the disease.|For more Human Toxicity Excerpts (Complete) data for Vemurafenib (9 total), please visit the HSDB record page.

PLX 4032

Oral: Tablets, film-coated: 240 mg, Zelboraf (Genentech).

Human drugs -> Zelboraf -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients