Vemurafenib

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.

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.

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).

The most frequently observed adverse effects associated with vemurafenib are cutaneous in nature. These include, but are not limited to, nonspecific maculopapular eruptions, hyperkeratosis, and photosensitivity, particularly when used in conjunction with radiation therapy.

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).

/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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Vemurafenib

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

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).

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).

/LABORATORY ANIMALS: Acute Exposure/ ... Vemurafenib was administered as a single oral dose to male Sprague Dawley rats at doses of 0, 30, 100, or 1000 mg/kg (corn oil formulation). Animals were observed twice daily for mortality and moribundity. The positive control, chlorpromazine, produced the expected cascade of CNS depression. The NOAEL of vemurafenib was 1000 mg/kg with an estimated Cmax of 160 uM.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure 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.

/GENOTOXICITY/ Vemurafenib did not cause genetic damage when tested in in vitro assay (bacterial mutation (AMES Assay)), or in the in vivo rat bone marrow micronucleus test.

/GENOTOXICITY/

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.

Antineoplastic

MEDICATION