vemurafenib

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vemurafenib

(vem-u-raf-e-nib ) ,

Zelboraf

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: D

Indications

genetic implication Treatment of unresectable or metastatic melanoma with BRAF V600Emutation.

Action

Inhibits mutated forms of the enzyme kinase. Inhibits proliferation that occurs in conjunction with activated BRAF proteins.

Therapeutic effects

Decreased spread of melanoma.

Pharmacokinetics

Absorption: Some absorption follows oral administration, bioavailability is not known.
Distribution: Unknown.
Protein Binding: >99%.
Metabolism and Excretion: Mostly metabolized by the liver (mostly by the CYP3A4 enzyme system), 1% eliminated in urine.
Half-life: 57 hr (range 30–120 hr).

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POunknown3 hr12 hr

Contraindications/Precautions

Contraindicated in: Obstetric: Should not be used during pregnancy, may cause fetal harm; Lactation: Breast feeding should be avoided; None noted.
Use Cautiously in: Pre-existing severe hepatic or renal impairment; Geriatric: Increased risk of cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation;Concurrent use of stong inducers/inhibitors of the the CYP3A4 enzyme system or drugs that are substrates of CYP3A4, CYP1A2 or CYP2D6 enzyme systems; monitoring of effects and necessary dose adjustments may be necessary; Obstetric: Patients with child-bearing potential; Pediatric: safe and effective use in children <18 yr has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • fatigue (most frequent)
  • weakness (most frequent)
  • headache

Ear, Eye, Nose, Throat

  • iritis
  • retinal vein occlusion
  • uveitis

Respiratory

  • cough

Cardiovascular

  • QTc prolongation (life-threatening)
  • peripheral edema (most frequent)

Gastrointestinal

  • hepatotoxicity (life-threatening)
  • ↓ appetite
  • dysgeusia
  • nausea

Dermatologic

  • malignancy
  • stevens-johnson syndrome (life-threatening)
  • toxic epidermal necrolysis (life-threatening)
  • alopecia (most frequent)
  • dry skin (most frequent)
  • rash(↑ in females) (most frequent)
  • pruritus (most frequent)
  • rash (most frequent)
  • photosensitivity (↑ in females) (most frequent)
  • skin papilloma (most frequent)
  • keratocanthoma (↑ in males)

Genitourinary

  • ↑ creatinine (↑ in females)

Musculoskeletal

  • arthralgia(↑ in females) (most frequent)
  • myalgia (most frequent)
  • back pain
  • musculoskeletal pain

Miscellaneous

  • hypersensitivity reactions including anaphylaxis
  • fever (most frequent)

Interactions

Drug-Drug interaction

Concurrent use with agents with narrow therapeutic indices that are metabolized by the CYP1A2 enzyme systems not recommended. Consider dose ↓ of substrates.Strong CYP3A inhibitors, including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole may ↑ levels and effects; avoid concurrent use.Strong inducers of CYP3A4 including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine may ↓ levels and effectiveness; avoid concurrent use.May ↑ risk of bleeding with warfarin.Concurrent use with ipilimumab may ↑ risk of hepatotoxicity

Route/Dosage

Oral (Adults) 960 mg twice daily. Treatment should continue until unacceptable toxicity or disease progression occurs.

Availability

Tablets: 240 mg

Nursing implications

Nursing assessment

  • Perform dermatologic evaluation prior to initiation and every 2 mo during therapy. Excise any suspicious lesions, send for dermapathologic evaluation, and treat with standard care. Continue monitoring for 6 mo following discontinuation of therapy.
  • Monitor ECG 15 days after initiation of therapy, monthly during first 3 mo, every 3 mo thereafter, and more often if clinically indicated.
  • Monitor for hypersensitivity reactions (rash, erythema, hypotension). Permanently discontinue therapy if severe reaction occurs.
  • Monitor for signs and symptoms of uveitis periodically during therapy. May require treatment with steroid and mydriatic ophthalmic drops.
  • Assess patient for rash (mild to moderate rash usually occurs in the 2nd wk of therapy and resolves within 1–2 wk of continued therapy). If rash is severe (extensive erythematous or maculopapular rash with moist desquamation or angioedema) or accompanied by systemic symptoms (serum sickness-like reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis), therapy must be discontinued immediately.
  • Lab Test Considerations: Monitor serum potassium, magnesium, and calcium before starting therapy and after dose modification.
    • Monitor AST, ALT, alkaline phosphatase, and bilirubin before starting therapy, monthly during therapy, and as clinically indicated. May require dose reduction, treatment interruption or discontinuation.

Potential Nursing Diagnoses

Impaired skin integrity (Indications)

Implementation

  • Oral: Administer (four 240 mg tablets) twice daily, without regard to food. Take first dose in the morning with second dose about 12 hrs later. Swallow tablets whole, do not crush or chew.
    • Adverse reactions or QTc prolongation may occur requiring dose modification. If Grade 1 or 2 (tolerable) occur, maintain dose at 960 mg twice daily. If Grade 2 (Intolerable) or Grade 3, 1st appearance occurs, interrupt therapy until Grade 0–1. Resume dosing at 720 mg twice daily. If 2nd appearance, interrupt therapy until Grade 0–1. Resume dosing at 480 mg twice daily. If 3rd appearance, discontinue permanently. If Grade 4, 1st appearance occurs, discontinue permanently or interrupt therapy until Grade 0–1. Resume dosing at 480 twice daily. If 2nd appearance, discontinue permanently. Doses below 480 mg twice daily are not recommended.

Patient/Family Teaching

  • Instruct patient to take venurafenib as directed. Take missed doses as soon as remembered up to 4 hrs before next dose; do not double dose.
  • genetic implication Inform patient that assessment of BRAF mutation is required for selection of patients.
  • Instruct patient to stop taking vemurafenib and notify health care professional immediately if signs and symptoms of allergic reaction (rash or redness all over body; feeling faint; difficulty breathing or swallowing; throat tightness or hoarseness; fast heartbeat; swelling of face, lips, or tongue) or severe skin reactions (blisters on skin; blisters or sores in mouth; peeling of skin, fever, redness or swelling of face, hands, or soles of feet) occur.
  • Advise patient to wear broad spectrum UVA/UVB sunscreen, lip balm (SPF ≥30) and protective clothing, and to avoid sun exposure to prevent photosensitivity reactions. Severe photosensitivity reactions may require dose modifications.
  • Advise patient to notify health care professional if signs and symptoms of liver dysfunction (yellow skin or whites of eyes; feeling tired; urine turns dark or brown; nausea or vomiting; loss of appetite; pain on right side of stomach) or eye problems (eye pain, swelling, or redness; blurred vision; vision changes) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Inform patient that regular assessments of skin and assessments for signs and symptoms of other malignancies must be done during and for up to 6 mo after therapy. Advise patient to notify health care professional immediately if any changes in skin occur.
  • Advise women of childbearing potential and men to use appropriate contraceptive measures during and for at least 2 mo after discontinuation of vemurafenib, and to avoid breast feeding.

Evaluation/Desired Outcomes

  • Decreased spread of melanoma.

vemurafenib

An experimental drug which counters the V600E mutation of B-Raf in the B-Raf/MEK/ERK cell-signalling pathway, which controls cell division, differentiation and apoptosis. Vemurafenib disrupts V600E mutated B-Raf, which blocks apoptosis, allowing apoptosis to continue forward, which is effective for managing melanomas with the V600E mutation.
References in periodicals archive ?
PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors [abstract].
PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.
Differential Sensitivity of Melanoma Cell Lines with BRAFV600E Mutation to the Specific Raf Inhibitor PLX4032.
99) The company Plexxikon announced in 2010 that its drug PLX4032 had elicited positive response in more than 80 percent of melanoma patients in early-phase clinical trials.
Vemurafenib, also called PLX4032, is the first chemotherapy agent that targets a specific genetic mutation involved in the formation of skin tumors.
oncology product PLX4032 with the acquisition of Plexxikon.
The additional consideration is conditioned on near-term milestones related to the approval of Plexxikon's skin cancer treatment PLX4032, currently being tested, the target company said in a press release.
Plexxikon's lead program is PLX4032, a novel oral drug that targets melanoma cancers and solid tumors.
In a clinical trial, patients with BRAF-mutated metastatic melanoma have been responding very well to an experimental drug, PLX4032.
Patients whose melanoma lesions contain a mutation in the BRAF gene were successfully treated with a BRAF-specific inhibitor, PLX4032.
US researchers have uncovered several ways in which melanoma can outsmart a promising experimental cancer pill called PLX4032, a finding that could lead to new drugs to keep the deadly skin cancer at bay, the teams said.
Summary: Plexxikon today announced positive preliminary data from a pivotal Phase 2 clinical trial of PLX4032 (RG7204) in metastatic melanoma, showing significant tumor shrinkage in the majority of patients.