Vemurafenib

Registered South African indications:

• Melanoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Moderate to severe hepatic impairment
• Patients with wild type BRAF malignant melanoma
• Radiation treatment or history thereof
• Patients with uncorrectable electrolyte abnormalities (including magnesium)
• Risk factors for QT prolongation
  - Long QT syndrome
  - Use of agents known to prolong QT interval
  - Congestive heart failure
  - Bradyarrhythmias
• Cancers associated with RAS mutations or history thereof 
• Exposure to sunlight or ultra-violet radiation
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Used for the treatment of

• BRAF V600E mutation-positive unresectable or metastatic melanoma

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Consult specialist for dosages and regimens

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Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test

Not established for use in children below 18 years

Pregnancy

• Caution
• There is no data regarding the use of vemurafenib in pregnant women
• Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses. In animal studies, vemurafenib was found to cross the placenta
• Based on its mechanism of action, vemurafenib could cause foetal harm when administered to a pregnant woman. Vemurafenib should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus
• Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after treatment
• Vemurafenib might decrease the efficacy of hormonal contraceptives

Breastfeeding

• Caution; not recommended
• It is not whether vemurafenib is excreted in human milk. A risk to the newborns/infants cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue vemurafenib therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings were noted in reproductive organs in males and females

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended 
  Limited data is available for patients with renal impairment. Patients with severe renal impairment should be closely monitored since a risk for increased exposure of vemurafenib cannot be excluded

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no dose adjustment recommended
  Limited data is available for patients with hepatic impairment. Patients with moderate to severe hepatic impairment should be closely monitored since vemurafenib is cleared by the liver thus increasing exposure to vemurafenib

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• 7th nerve paralysis
• Dizziness
• Peripheral neuropathy
• Fatigue

Cardiovascular Disorders

• Vasculitis
• QT prolongation

Respiratory Disorders

• Cough

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Pancreatitis

Hepatobiliary Disorders

• Hepatic injury
• Increased gamma-glutamyl transferase
• Increased alanine aminotransferase
• Increased alkaline phosphatase
• Increased bilirubin  
• Increased aspartate aminotransferase

Genitourinary Disorders

• Acute interstitial nephritis
• Acute tubular necrosis

Endocrine and Metabolic Disorders

• Decreased appetite
• Decreased weight  

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Pain in extremity
• Musculoskeletal pain
• Back pain
• Arthritis
• Plantar fascial fibromatosis
• Dupuytren's contracture

Skin and Subcutaneous Tissue Disorders

• Photosensitivity reaction
• Actinic keratosis
• Rash
• Maculopapular rash
• Papular rash
• Pruritus
• Hyperkeratosis
• Erythema
• Alopecia
• Dry skin
• Sunburn
• Palmar-plantar erythrodysaesthesia syndrome
• Panniculitis
• Erythema nodosum
• Keratosis pilaris
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Drug reaction with eosinophilia and systemic symptoms
• Peripheral oedema
• Folliculitis

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Sarcoidosis
• Fever
• Squamous cell carcinomas of the skin
• Keratoacanthoma
• Seborrheic keratosis
• Skin papilloma
• Basal cell carcinoma
• New primary melanoma
• Non-cu-Squamous cell carcinomas
• Chronic myelomonocytic leukaemia
• Pancreatic adenocarcinoma
• Increased blood creatinine
• Hypersensitivity reactions
  - Anaphylaxis
  - Stevens-Johnson syndrome
  - Generalised rash
  - Erythema
  - Hypotension

Sensory Disorders

• Uveitis
• Retinal vein occlusion
• Iridocyclitis
• Dysgeusia

Other

• Potentiation of radiation toxicity

• QT prolonging agents
• Aliskiren
• Ambrisentan
• Colchicine
• Dabigatran etexilate
• Digoxin
• Everolimus
• Fexofenadine
• Lapatinib
• Maraviroc
• Nilotinib
• Posaconazole
• Ranolazine
• Sirolimus
• Sitagliptin
• Talinolol
• Topotecan
• Breast cancer resistance protein inhibitors
• Gefitinib 
• Methotrexate
• Mitoxantrone
• Rosuvastatin
• Warfarin
• CYP3A4 substrates
• Oral contraceptives
• Midazolam
• CYP3A4 inhibitors
• Itraconazole
• Ritonavir
• Saquinavir
• Telithromycin
• Ketoconazole
• Voriconazole
• Nefazodone
• Atazanavir
• CYP3A4 inducers
• Rifampicin
• Rifabutin
• Carbamazepine
• Phenytoin
• Ipilimumab 
• CYP1A2 substrates
• Agomelatine
• Alosetron
• Duloxetine
• Melatonin
• Ramelteon
• Tacrine
• Tizanidine
• Theophylline
• Caffeine
• CYP2B6 substrates
• Bupropion
• CYP2C8 substrates
• P-glycoprotein substrates
• Verapamil 
• Cyclosporine
• Quinidine
• Radiation treatment
• St John's Wort (Hypericum perforatum)

• BRAF V600 mutation status
• Electrolytes
• ECG
• Renal function
• Hepatic function
• Ophthalmic examinations
• Chest Computerised Tomography (CT) scan
• Dermatological examination

None routine. Specific cases may require

• Anal examinations
• Pelvic examinations
• International normalised ratio

Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result in constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth factors.

Tablet 240mg

• Zelboraf (Roche) originator