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Vemurafenib

Class: Antineoplastic Agents
Chemical Name: N - {3 - [5 - (4 - Chlorophenyl) - 1H - pyrrolo[2,3 - b]pyridin - 3 - carbonyl] - 2,4 - difluorophenyl}propane - 1 - sulfonamide
Molecular Formula: C23H18ClF2N3O3S
CAS Number: 918504-65-1
Brands: Zelboraf

Introduction

Antineoplastic agent; an inhibitor of b-Raf serine-threonine kinase with V600E mutation (BRAF V600E).1 2

Uses for Vemurafenib

Melanoma

Treatment of unresectable or metastatic melanoma with BRAF V600E mutation1 (designated an orphan drug by FDA for this use).3

FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 Mutation Test) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.1 6

Not indicated for use in patients with wild-type BRAF melanoma; safety and efficacy not established.1 (See Tumor Promotion in BRAF Wild-Type Melanoma under Cautions.)

Vemurafenib Dosage and Administration

General

  • Distribution of vemurafenib is restricted; drug is available only through designated specialty pharmacies.12 Specific information available from the manufacturer at or at 1-888-249-4918.12

  • Confirm presence of BRAF V600E mutation prior to initiation of therapy.1

Administration

Oral Administration

Administer orally twice daily without regard to meals.1

Do not crush or chew tablets.1

If a dose is missed, it may be taken up to 4 hours prior to next dose.1 Do not take 2 doses at the same time.1

If vomiting occurs following administration, do not take a replacement dose.1 Administer next dose at regularly scheduled time.1

Dosage

Adults

Melanoma
Oral

960 mg twice daily.1 Clinical studies continued therapy for as long as the patient derived clinical benefit or until unacceptable toxicity occurred.1

Dosage Modification for General Toxicity
Oral

If intolerable grade 2 or 3 toxicity occurs, temporarily interrupt vemurafenib therapy.1 When toxicity resolves or improves to grade 1 or less, resume therapy at a reduced dosage of 720 mg twice daily.1

If toxicity recurs at a dosage of 720 mg twice daily, temporarily interrupt therapy again until toxicity resolves to grade 1 or less, and resume therapy at a reduced dosage of 480 mg twice daily.1

If grade 4 toxicity occurs, permanently discontinue or temporarily interrupt therapy until toxicity resolves to grade 1 or less, and resume therapy at a reduced dosage of 480 mg twice daily if clinically appropriate.1

If toxicity recurs at a reduced dosage of 480 mg twice daily, permanently discontinue vemurafenib.1 Dosages <480 mg twice daily not recommended.1

Dosage Modification for Prolongation of QT Interval
Oral

If the corrected QT interval (QTc) is >500 msec, temporarily interrupt vemurafenib therapy.1

When QTc interval returns to ≤500 msec, resume therapy at a reduced dosage.1

If QTc interval >500 msec and increases >60 msec from baseline despite correction of electrolyte abnormalities and control of other risk factors (e.g., CHF, bradyarrhythmias), permanently discontinue vemurafenib.1

Dosage Modification for Development of New Primary Cutaneous Malignancies
Oral

No dosage adjustment necessary.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: No initial dosage adjustment required.1

Renal Impairment

Mild or moderate renal impairment: No initial dosage adjustment required.1

Geriatric Patients

No specific dosage adjustment recommendations at this time.1

Cautions for Vemurafenib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, generalized rash, erythema, hypotension, drug reaction with eosinophilia and systemic symptoms [DRESS syndrome]) reported during and upon reinitiation of therapy.1 Permanently discontinue vemurafenib in patients who experience a severe hypersensitivity reaction.1

Photosensitivity Reactions

Risk of photosensitivity reactions.1 Reduce dosage of vemurafenib in patients who experience intolerable grade 2 or greater reaction.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Other Warnings and Precautions

Development of New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma reported.1 2 5 10 17 18 First appearance of such skin lesions occurred within 7–8 weeks after initiating vemurafenib in clinical trials; patients with more than one occurrence reported time between occurrences of approximately 6 weeks.1 Possible risk factors include advanced age (i.e., ≥65 years of age), history of skin cancer, and chronic sun exposure.1 5 17

Non-cutaneous squamous cell carcinoma of the head and neck (e.g., oropharyngeal area) reported.1 Progression of a preexisting chronic myelomonocytic leukemia with NRAS mutation also reported during postmarketing experience.1

Perform dermatologic evaluation at baseline and every 2 months during therapy.1 May consider monitoring for 6 months following discontinuance of vemurafenib.1 Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.1 Closely monitor for signs and symptoms of development of new non-cutaneous squamous cell carcinoma or other primary malignancies.1

Tumor Promotion in BRAF Wild-Type Melanoma

In vitro, paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation observed in wild-type BRAF cells exposed to BRAF inhibitors.1 Confirm presence of BRAF V600E mutation prior to initiation of therapy.1

Dermatologic Effects

Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported.1 Permanently discontinue vemurafenib in patients who experience severe skin reactions.1

Prolongation of QT Interval

QT prolongation reported.1

Do not use in patients with congenital long QT syndrome, electrolyte disturbances unresponsive to corrective measures, or QTc intervals >500 msec.1 4

Avoid concomitant use with drugs known to prolong QT interval (e.g., class Ia and III antiarrhythmic agents).1 4 13 15 16 (See Specific Drugs under Interactions.)

Obtain ECG and serum electrolytes at baseline or following dosage modification for QT prolongation; monitor at 15 days after initiating vemurafenib, then monthly for the first 3 months, and every 3 months thereafter or more often as clinically indicated.1 4

Interruption or discontinuance of vemurafenib may be necessary if increases in the QTc interval occur.4 (See Dosage Modification for Prolongation of QT Interval under Dosage and Administration.)

Hepatic Effects

Hepatic injury may occur resulting in functional hepatic impairment, including coagulopathy or other organ dysfunction.1 Elevations in ALT, AST, bilirubin, and alkaline phosphatase concentrations of grade 3 or 4 severity reported in 0.9–2.9% of patients.1

Monitor serum aminotransferase, bilirubin, and alkaline phosphatase concentrations at baseline and then monthly thereafter.1

If laboratory abnormalities occur, reduce dosage, temporarily interrupt, or discontinue vemurafenib therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Safety and efficacy of vemurafenib used concomitantly with ipilimumab not established; however, grade 3 elevations in aminotransferase and bilirubin concentrations reported in patients receiving vemurafenib (720 or 960 mg twice daily) concurrently with ipilimumab (3 mg/kg).1

Ocular Effects

Uveitis (including iritis), blurry vision, and photophobia reported.1 Monitor patients for signs and symptoms of uveitis.1 If uveitis occurs, treatment with ophthalmic corticosteroid and mydriatic preparations may be required.1

Retinal vein occlusion also reported.1

Neutropenia

Neutropenia reported during postmarketing experience.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Advise men and women of childbearing potential to use effective contraception during and for ≥2 months after discontinuance of therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment; use with caution.1

Renal Impairment

Not studied in patients with severe renal impairment; use with caution.1

Common Adverse Effects

Arthralgia,1 2 5 7 rash,1 2 5 7 alopecia,1 2 5 fatigue,1 2 5 7 photosensitivity reaction,1 2 5 7 nausea,1 2 7 pruritus,1 2 5 7 cutaneous squamous cell carcinoma,1 2 5 7 skin papilloma.1 5

Interactions for Vemurafenib

Vemurafenib is a moderate inhibitor of CYP1A2, and a weak inhibitor of 2D6 in vivo.1 Vemurafenib inhibits CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 in vitro.1 The drug also is an inhibitor and substrate of CYP3A4.1

Vemurafenib is a substrate and inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of vemurafenib).1 Avoid concomitant use; selection of alternative drug with no or minimal CYP3A4 inhibition potential recommended.1

CYP3A4 inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of vemurafenib).1 Avoid concomitant use; selection of alternative drug with no or minimal CYP3A4 induction potential recommended.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2: Possible pharmacokinetic interaction (increased plasma concentrations of CYP1A2 substrate and possible toxicity).1 Concomitant use of vemurafenib and CYP1A2 substrates with a narrow therapeutic index not recommended.1 If concomitant use cannot be avoided, consider dosage reduction of the CYP1A2 substrate and closely monitor for adverse effects.1

Substrates of CYP2D6: Possible pharmacokinetic interaction (increased plasma concentrations of CYP2D6 substrate and possible toxicity).1

Substrates of CYP3A4: Possible pharmacokinetic interaction (decreased plasma concentrations of CYP3A4 substrate and possible decreased efficacy).1

Substrates of CYP2C9: Possible pharmacokinetic interaction (increased plasma concentrations of CYP2C9 substrate and possible toxicity).1

Substrates of CYP2C19: No clinically important interaction reported.1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT prolongation).1 Avoid concomitant use.1 4 (See Prolongation of QT Interval under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation13 15 16

Avoid concomitant use1

Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)

Possible increased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme inhibition potential1

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)

Possible decreased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme induction potential1

Antipsychotic agents that prolong QT interval (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)

Increased risk of QT-interval prolongation13 14 15 16

Avoid concomitant use1

Caffeine

Increased AUC of caffeine1

CYP1A2 substrates with a narrow therapeutic index: Concomitant use not recommended; if concomitant use cannot be avoided, consider dosage reduction of CYP1A2 substrate and closely monitor patient for adverse effects1

Carbamazepine

Possible decreased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme induction potential1

Dextromethorphan

Increased AUC of dextromethorphan1

Gatifloxacin

Increased risk of QT-interval prolongation13 15

Avoid concomitant use1

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme inhibition potential 1

Ipilimumab

Increased aminotransferase and bilirubin concentrations1

Macrolides (clarithromycin, telithromycin)

Possible increased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme inhibition potential 1

Midazolam

Decreased AUC of midazolam1

Moxifloxacin

Increased risk of QT-interval prolongation13 15 16

Avoid concomitant use1

Nefazodone

Possible increased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme inhibition potential1

Omeprazole

No change in systemic exposure of omeprazole1

Phenobarbital

Possible decreased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme induction potential1

Phenytoin

Possible decreased vemurafenib concentrations1

Avoid concomitant use; select alternative agent with no or minimal enzyme induction potential1

Tetrabenazine

Increased risk of QT-interval prolongation16

Avoid concomitant use1

Warfarin

Increased AUC of S-warfarin1

Vemurafenib Pharmacokinetics

Absorption

Food

Food increases systemic exposure.1 Administration of a single dose of vemurafenib with a high-fat meal increases AUC by approximately fivefold and increases peak concentrations by approximately 2.5-fold.1

Distribution

Extent

Not known whether vemurafenib is distributed into human milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

>99% (mainly albumin and α1-acid glycoprotein).1

Elimination

Elimination Route

Excreted in feces (94%) and urine (1%).1

Half-life

Approximately 57 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Potent inhibitor of the b-Raf serine-threonine kinase with V600E mutation (BRAF V600E).1 2 7

  • Approximately 40–60% of cutaneous melanomas carry a BRAF mutation;2 7 substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E) is the most common BRAF mutation.2 8

  • Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular-signal regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).8 9

  • Combination therapy with a BRAF inhibitor (i.e., dabrafenib, vemurafenib) and an MEK inhibitor (i.e., cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.20 21 22

  • Inhibits c-Raf, a-Raf, wild-type b-RaF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations in which inhibition of BRAF V600E occurs.1

Advice to Patients

  • Importance of advising patient to read the manufacturer’s medication guide before beginning treatment and each time the prescription is refilled.1

  • Instruct patients to take a missed dose as soon as it is remembered, but only if it can be taken at least 4 hours before the next scheduled dose.1

  • If vomiting occurs following administration, take the next dose at the regularly scheduled time.1 Do not take an additional dose.1

  • Importance of women informing clinicians if they are or plan to become pregnant.1 Vemurafenib may cause fetal harm.1 Necessity of advising men and women of childbearing potential to use effective contraception during therapy and for at least 2 months after discontinuance of therapy.1

  • Importance of women informing clinicians if they plan to breast-feed.1 Necessity of advising nursing women not to breast-feed during therapy with the drug.1

  • Importance of confirming that patients have melanomas testing positive for the BRAF V600E mutation using the cobas 4800 BRAF V600 Mutation Test or other FDA-approved diagnostic test prior to initiation of therapy.1 6

  • Risk of new primary cutaneous malignancies.1 Importance of contacting clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, or mole that changes in size or color) occur.1

  • Risk of mild to severe photosensitivity reactions.1 Importance of using sunscreen and lip balm (minimum SPF >30), wearing protective clothing, and avoiding sun exposure during therapy.1

  • Risk of severe adverse dermatologic effects.1 Importance of contacting clinician promptly if skin rash occurs with symptoms such as redness or swelling of face, hands, or soles of feet; blisters on skin or in mouth; peeling of skin; fever.1

  • Risk of QT-interval prolongation, which may result in ventricular arrhythmias.1 Importance of contacting clinician promptly if an abnormal heartbeat or feelings of dizziness or faintness occur.1

  • Risk of new primary malignant melanoma.1 Importance of contacting clinician promptly if skin changes occur.1

  • Risk of anaphylaxis or other serious hypersensitivity reactions during or upon reinitiation of therapy.1 Importance of advising patients to promptly notify their clinician if they develop any signs or symptoms of an allergic reaction during therapy (e.g., rash, angioedema, difficulty breathing, tachycardia, throat tightness, hoarseness).1

  • Risk of hepatic injury resulting in functional hepatic impairment.1 Importance of advising patients to schedule periodic laboratory monitoring for hepatotoxicity and to report clinically relevant symptoms to their clinician.1

  • Risk of adverse ocular effects.1 Importance of monitoring and contacting clinician promptly if ocular pain, swelling, redness, or blurred vision occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hepatic, renal, or cardiovascular diseases, electrolyte abnormalities) or planned surgical, dental, or other medical procedures.1

  • Importance of informing patients of other important precautionary information.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of vemurafenib is restricted.1 (See General under Dosage and Administration.)

Vemurafenib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

240 mg

Zelboraf

Genentech

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Genentech Inc. Zelboraf(vemurafenib) tablets prescribing information. South San Francisco, CA; 2014 Nov.

2. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364:2507-16. [PubMed 21639808]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.

4. Genentech Inc. South San Francisco, CA: Personal communication.

5. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366:707-14. [PubMed 22356324]

6. Roche Diagnostics. cobas 4800 BRAF V600 mutation test package insert. Indianapolis, IN. 2011 Aug.

7. Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363:809-19. [PubMed 20818844]

8. Russo AE, Torrisi E, Bevelacqua Y et al. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol. 2009; 34:1481-9. [PubMed 19424565]

9. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med. 2011; 364:2547-8. [PubMed 21639809]

10. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 2012; 18:263-72. [PubMed 22096025]

11. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464:427-30. [PubMed 20179705]

12. Genentech Inc. Overview of Access Solutions services. South San Francisco, CA. Accessed 2012 Mar 12.

13. Ortho-McNeil-Janssen Pharmaceuticals. Invega (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2011 Apr.

14. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005; 20:243-51. [PubMed 16096514]

15. Schering Corporation, a subsidiary of Merck & Co., Inc. Saphris (asenapine maleate) sublingual tablets prescribing information. Whitehouse Station, NJ; 2011 Oct.

16. Lundbeck Inc. Xenazine (tetrabenazine) tablets prescribing information. Deerfield, IL.; 2009 Sep.

17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366:207-15. [PubMed 22256804]

18. Weeraratna AT. RAF around the edges--the paradox of BRAF inhibitors. N Engl J Med. 2012; 366:271-3. [PubMed 22256810]

19. McArthur GA, Chapman PB, Robert C et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014; 15:323-32. [PubMed 24508103]

20. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367:1694-703. [PubMed 23020132]

21. Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371:1867-76. [PubMed 25265494]

22. Sanlorenzo M, Choudhry A, Vujic I et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014; 71:1102-1109.e1. [PubMed 25440439]

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