Names and pronunciation
Zelboraf
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Drug reference
Zelboraf
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Func. class.: Antineoplastic
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Chem. class.: Kinase inhibitor
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ACTION: Inhibitor of mutated forms of BRAF serine threonine kinase, blocking cellular proliferation in melanoma cells; inhibits kinases including CRAF, ARAF, wild-type BRAF, SRMA, ACK1, MAP4H5, and FGR
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USES: Unresectable or metastatic malignant melanoma with V600E mutation of the BRAF gene
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CONTRAINDICATIONS: Hyper sensitivity Precautions: Pregnancy, breastfeed ing, children, infants, neonates, hepatic disease, QT prolongation, secondary malignancy, torsades de pointes, hypo kalemia, hypomagnesemia, sunlight exposure
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SIDE EFFECTS CNS: Fatigue, fever, headache, dizziness, peripheral neuropathy, weakness CV: QT prolongation, atrial fibrillation, tor- sades de pointes EENT: Uveitis, blurred vision, iritis, photophobia GI: Nausea, diarrhea, dysgeusia, hepatotoxicity INTEG: Alopecia, pruritus, hyperkera tosis, maculopapular rash, actinic keratosis, xerosis/dry skin, papular rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), photosensitivity MS: Arthralgia, myalgias, extremity pain, musculoskeletal pain, back pain, arthritis V GU: Acute tubular necrosis, interstitial nephritis SYST: Secondary malignancy, anaphy- laxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia, anaphylaxis
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INTERACTIONS Increase: vemurafenib effect—CYP3A4/ CYP1A2 inhibitors (enoxacin, cimetidine, delavirdine, indinavir, isoniazid, itracon azole, dalfopristin, quinupristin, tiprana vir) Increase: QT prolongation, torsades de pointes—arsenic trioxide, certain pheno- thiazines (chlorproMAZINE, mesoridazine, thioridazine), grepafloxacin, pentamidine, probucol, sparfloxacin, troleandomycin, class IA antiarrhythmics (disopyramide, procainamide, quiNIDine), class III antiar- rhythmics (amiodarone, dofetilide, ibuti- lide, sotalol), clarithromycin, ziprasidone, pimozide, haloperidol, halofantrine, quiNI- Dine, chloroquine, dronedarone, droperidol, erythromycin, methadone, posaconazole, propafenone, saquinavir, abarelix, amoxapine, apomorphine, ase- napine, β-agonists, ofloxacin, eribulin, ezogabine, flecainide, gatifloxacin, gemi- floxacin, halogenated anesthetics, iloperi- done, levofloxacin, local anesthetics, mag- nesium sulfate, potassium sulfate, sodium, maprotiline, moxifloxacin, nilotinib, nor- floxacin, ciprofloxacin, OLANZapine, pali- peridone, some phenothiazines (fluPHEN- AZine, perphenazine, prochlorperazine, trifluoperazine), telavancin, tetrabenazine, tricyclic antidepressants, venlafaxine, vorinostat, citalopram, alfuzosin, cloZA Pine, cyclobenzaprine, dolasetron, palono- setron, QUEtiapine, rilpivirine, SUNItinib, tacrolimus, vardenafil, indacaterol, dasat- inib, fluconazole, lapatinib, lopinavir/rito- navir, mefloquine, octreotide, ondansetron, ranolazine, risperiDONE, telithromycin, vemurafenib Decrease: vemurafenib effect—CYP3A4 inducers (rifampin, barbiturates, carBA Mazepine, phenytoin, erythromycin, ketoconazole, fluvoxaMINE, alcohol, etravirine, ritonavir, bexarotene, rifabu tin, OXcarbazepine, nevirapine, moda- finil, metyraPONE) Drug/Lab Test: Increase: serum creatinine, LFTs, alkaline phosphatase, bilirubin
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DOSAGE AND ROUTES • Adult: PO 960 mg (4 tabs) bid q12hr, continue until unacceptable toxicity or disease progression, if strong CYP3A4 inducers are used increase dose to 1200 mg (5 tablets) Dose adjustments for toxicity from ad- verse reactions or QTc prolongation Grade 1 or tolerable grade 2: no dosage change; intolerable grade 2 or grade 3 (1st episode): interrupt treatment until toxicity resolves to grade ≤1, then reduce to 720 mg (3 tabs) bid; grade 2 or grade 3 (2nd episode): interrupt treatment until toxicity resolves to grade ≤1, then reduce to 480 mg (2 tabs) bid; grade 2 or grade 3 (3rd episode): discontinue treatment permanently; grade 4 (1st episode): dis- continue permanently or interrupt until toxicity resolves to grade ≤1, then reduce to 480 mg (2 tabs) bid; grade 4 (2nd episode): discontinue permanently
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Available forms: Tabs 240 mg
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Administer: • Continue until disease progresses or unacceptable toxicity occurs • Missed doses can be taken up to 4 hr before the next dose is due; take about 12 hr apart, take without regard to meals • Swallow whole with a full glass of wa ter; do not crush or chew • Store at room temperature in original container
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Assess: • Hepatotoxicity: liver function test (LFT) abnormalities, altered bilirubin levels may occur; monitor LFTs and bilirubin levels before treatment, then monthly; more fre- quent testing is needed in those with grade 2 or greater toxicities; laboratory alterations should be managed with dose reduction, treatment interruption, or discontinuation • Pancreatitis: Nausea, vomiting, severe abdominal pain • QT prolongation: avoid in patients with QT prolongation; monitor ECG and electrolytes in HF, bradycardia, electrolyte imbal- ance (hypokalemia, hypomagnesemia), or those taking concomitant medications known to prolong the QT interval; treat- ment interruption, dosage adjustment, treatment discontinuation may be needed in those who develop QT prolongation • Malignancy: New melanoma • Serum electrolytes, CCr, bilirubin, ECG • BRAF testing: obtain testing before use; do not use in wild-type BRAF; con firm BRAF V600E mutation • Skin reactions: assess for skin reaction • Pregnancy/breastfeeding: iden- tify whether pregnancy is planned or suspected; do not use in pregnancy; avoid breastfeeding
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Evaluate: • Decreased spread of malignancy
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CLINICAL CONSIDERATIONS
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Patient and caregiver information: • That missed doses can be taken up to 4 hr before the next dose is due to main tain the twice-daily regimen; that if vomit ing occurs, do not retake dose, take next dose as scheduled • Not to crush, chew tablets; use with water, take consistently with or without food • To notify prescriber of new skin lesions • To avoid sun exposure; to wear sun screen, protective clothing • Hepatotoxicity: To notify health care professional of yellow skin, eyes, dark urine, clay-colored stool, nausea/vomit- ing, pain in right side of abdomen • Allergic reactions: To report rash, trou- ble breathing; swelling of face, lips; blisters • To discuss with health care profes sional all RX, OTC, herbals, supplements taken • Pregnancy: to use reliable contracep- tion; that both women and men of child- bearing age should use adequate contra- ceptive methods during therapy and for at least 90 days after completing treatment HIGH ALERT
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PHARMACOKINETICS >99% protein binding (albumin and alpha-1 acid glycoprotein), an inhibitor of CYP1A2, 2A6, 2C9, 2C19, 2D6, 3A4/5 CYP1A2 inhibitor, a weak CYP2D6 inhibi tor, and a CYP3A4 inducer; elimination 94% in feces, 1% in urine, half-life 57 hr, peak 3 hr, duration up to 12 hr
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• Adult: PO 960 mg (4 tabs) bid q12hr, continue until unacceptable toxicity or disease progression, if strong CYP3A4 inducers are used increase dose to 1200 mg (5 tablets) Dose adjustments for toxicity from ad- verse reactions or QTc prolongation Grade 1 or tolerable grade 2: no dosage change; intolerable grade 2 or grade 3 (1st episode): interrupt treatment until toxicity resolves to grade ≤1, then reduce to 720 mg (3 tabs) bid; grade 2 or grade 3 (2nd episode): interrupt treatment until toxicity resolves to grade ≤1, then reduce to 480 mg (2 tabs) bid; grade 2 or grade 3 (3rd episode): discontinue treatment permanently; grade 4 (1st episode): dis- continue permanently or interrupt until toxicity resolves to grade ≤1, then reduce to 480 mg (2 tabs) bid; grade 4 (2nd episode): discontinue permanently
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