Vemurafenib


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO BRAF V600 mutation-positive, including BRAF V600E mutation-positive unresectable or metastatic melanoma 960 mg bid, continue until disease progression or unacceptable toxicity. BRAF V600 mutation Erdheim-Chester disease 960 mg bid, continue until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Dosage Details
Oral
Erdheim-Chester disease
Adult: In patients with BRAF V600 mutation: 960 mg bid, continue until disease progression or unacceptable toxicity. Missed dose can be taken up to 4 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Metastatic melanoma, Unresectable melanoma
Adult: In patients with BRAF V600 mutation-positive, including BRAF V600E mutation-positive cases: 960 mg bid, continue until disease progression or unacceptable toxicity. Missed dose can be taken up to 4 hours prior to the next dose, administer the next dose as scheduled. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Special Patient Group
Patients taking strong CYP3A4 inducers: Increase dose by 240 mg as tolerated. Return to usual dosing after 2 weeks of discontinuing treatment with CYP3A4 inducers.

BRAF, a member of rapidly growing fibrosarcoma (RAF) family of serine/threonine kinase, is a part of the mitogen-activated protein kinase (MAPK) pathway involved in the regulation of important cell functions (e.g. cell growth, division, differentiation, apoptosis). The RAS family contains 3 genes (HRAS, KRAS, NRAS) that serve as essential transducers of signaling pathways in the transmission of extracellular growth signals to cell nucleus via the MAPK pathway. Variations in RAS genes lead to the resistance of RAS proteins to GTPase wherein GTP remains permanently bound and the receptors remain switched on to provide continuous cell growth stimulus. Research indicated that BRAF and RAS (HRAS, KRAS, NRAS) gene mutations may contribute to the ability of melanoma cells to aberrantly proliferate, survive, invade tissues, evade immune system surveillance, and alter the pharmacodynamics of vemurafenib. BRAF V600E, the most common BRAF mutation variant, is detected in approx 50% of melanomas while NRAS variants are found in approx 15-20% of melanomas and up to 30% of all malignancies. These variants are also associated with acquired resistance to BRAF inhibitors.

According to in vitro studies, vemurafenib can enhance MAPK pathway activity in cells with wild-type BRAF which may indicate the growth acceleration of some tumours with wild-type BRAF. Therefore, vemurafenib should not be used in patients with wild-type BRAF melanoma. FDA label also states that vemurafenib may promote malignancies associated with the activation of RAS (HRAS, KRAS, NRAS).

EMA and FDA drug labels for vemurafenib recommend performing approved and validated genetic testing to confirm the presence of BRAF V600E mutation status prior to initiating therapy in patients with unresectable or metastatic melanoma.
Administration
May be taken with or without food. Swallow whole, do not chew/crush.
Special Precautions
Patient with history of skin cancer, chronic sun exposure, co-existing myeloid malignancies, electrolyte abnormalities, risk factors for QT prolongation. Patients taking strong CYP3A4 inducers. Concomitant or sequential radiation treatment. Not indicated for treatment in patients with wild-type BRAF melanoma. Renal and hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Significant: Dupuytren’s contracture, plantar fascial fibromatosis, generalised rash, erythema, hypotension, hepatotoxicity, malignancies (e.g. squamous cell carcinomas, keratoacanthomas, melanoma), interstitial nephritis, acute tubular necrosis, serum creatine elevation, uveitis, blurred vision, photophobia; pancreatitis, photosensitivity, QT prolongation.
Blood and lymphatic system disorders: Neutropenia.
Cardiac disorders: Atrial fibrillation.
Eye disorders: Retinal vein occlusion.
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, constipation, dysgeusia.
General disorders and administration site conditions: Fatigue, weakness.
Immune system disorders: Panniculitis.
Investigations: Weight loss; increased gamma-glutamyl transferase, ALT, bilirubin, alkaline phosphatase.
Metabolism and nutrition disorders: Peripheral oedema, decreased appetite.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, back or limb pain, musculoskeletal pain, arthritis.
Neoplasms benign, malignant and unspecified: Cutaneous papilloma.
Nervous system disorders: Peripheral sensory neuropathy, headache, cranial nerve palsy, dizziness.
Respiratory, thoracic and mediastinal disorders: Cough.
Skin and subcutaneous tissue disorders: Maculo-papular/papular rash, alopecia, hyperkeratosis, keratosis (e.g. seborrhoeic, pilaris, actinic); xeroderma, palmar-plantar erythrodysaesthesia, pruritus, nevus, sunburn.
Vascular disorders: Hypertension, vasculitis.
Potentially Fatal: Steven-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), radiation sensitisation and recall.
Patient Counseling Information
This drug may cause fatigue and blurred vision, if affected, do not drive or operate machinery. Avoid sun exposure or utilise adequate sun protection (e.g. clothing, sunscreen).
MonitoringParameters
Perform confirmatory test for the presence of BRAF V600E mutation in melanoma tumour and dermatologic evaluation prior to initiation of treatment. Monitor transaminases, alkaline phosphatase, and bilirubin prior to therapy and monthly thereafter; CBC, serum creatinine, electrolytes (Ca, Mg, K); ECG at baseline, then monthly for 3 months, then every 3 months thereafter. Monitor for signs and symptoms of skin lesions, ocular toxicity, hypersensitivity reactions, and other malignancies.
Drug Interactions
Decreased serum concentration with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin). Increased serum concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin). Enhanced QT-prolonging effect with hydroxychloroquine, mifepristone, mizolastine. May increase serum concentration of digoxin, and CYP1A2 substrate (e.g. tizanidine). Increased serum transaminases and bilirubin with ipilimumab.
Food Interaction
Increased concentration with grapefruit juice. Decreased serum concentration with St John’s wort.
Action
Description: Vemurafenib is a BRAF serine threonine kinase inhibitor, which prevents tumour growth of melanomas with BRAF V600 mutation by inhibiting kinase activity, thereby blocking cellular proliferation in mutated melanoma cells.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: Approx 3-4 hours.
Distribution: Volume of distribution: Approx 106 L. Plasma protein binding: >99%, to albumin and α1-acid glycoprotein.
Metabolism: Metabolised mainly by CYP3A4 enzyme.
Excretion: Mainly via faeces (approx 94%); urine (approx 1%). Elimination half-life: Approx 57 hours.
Chemical Structure

Chemical Structure Image
Vemurafenib

Source: National Center for Biotechnology Information. PubChem Database. Vemurafenib, CID=42611257, https://pubchem.ncbi.nlm.nih.gov/compound/Vemurafenib (accessed on Jan. 23, 2020)

Storage
Store between 20-25°C. Protect from moisture.
This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01XE15 - vemurafenib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
References
Dean, L. Vemurafenib Therapy and BRAF and NRAS Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). 2017 Aug:1-6. Accessed 11/12/2019. PMID: 28809522

Annotation of EMA Label for Vemurafenib and BRAF. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/12/2019.

Annotation of FDA Label for Vemurafenib and BRAF. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/12/2019.

Annotation of FDA Label for Vemurafenib and HRAS, KRAS, NRAS. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/12/2019.

Annotation of PMDA Label for Vemurafenib and BRAF. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 11/12/2019.

Anon. V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) - Pharmacogenomics. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/12/2019.

Anon. Vemurafenib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/12/2019.

Buckingham R (ed). Vemurafenib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 11/12/2019.

Joint Formulary Committee. Vemurafenib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 06/12/2017.

McEvoy GK, Snow EK, Miller J et al (eds). Vemurafenib. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 06/12/2017.

Zelboraf Tablet, Film-Coated (Genentech, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 06/12/2017.

Disclaimer: This information is independently developed by MIMS based on Vemurafenib from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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