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Vemurafenib; Uses, Dosage, Side Effects, Interactions

Vemurafenib is a selective inhibitor of BRAF kinase that is used in the therapy of metastatic and advanced malignant melanoma. Vemurafenib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe cases of clinically apparent acute liver injury.

Vemurafenib is an orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation. Approximately 90% of BRAF gene mutations involve a valine-to-glutamic acid mutation at residue 600 (V600E); the oncogene protein product, BRAF(V600E) kinase, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway. The BRAF(V600E) gene mutation has been found to occur in approximately 60% of melanomas and in about 8% of all solid tumors, including melanoma, colorectal, thyroid, and other cancers.

Vemurafenib is a type of targeted cancer drug called a cancer growth blocker. It stops cells producing a protein called BRAF, which makes some cancer cells grow and divide. About half (about 50%) of all melanomas make too much BRAF proteins. This is due to a change in the BRAF gene. Vemurafenib is a competitive kinase inhibitor with activity against BRAF kinase with mutations like V600E. It exerts its function by binding to the ATP-binding domain of the mutant BRAF.

Mechanism of Action of Vemurafenib

Vemurafenib causes programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK stepon the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation. Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.BRAF is an intermediary molecule in MAPK whose activation depends on ERK activation, elevation of cyclin D1 and cellular proliferation. The mutation V600E produces a constitutive form of BRAF. Vemurafenib has been shown to reduce all activation markers related to BRAF; in clinical trials, vemurafenib treatment showed a reduction of cytoplasmic phosphorylated ERK and a cell proliferation driven by Ki-67. Studies also reported a decrease in MAPK-related metabolic activity. All the different reports indicate that Vemurafenib generates an almost complete inhibition of the MAPK pathway.

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Cutaneous squamous cell carcinoma (cuSCC) has been reported in patients with metastatic melanoma and CRC treated with vemurafenib. Clinical findings indicate that cuSCC may be related to treatment with vemurafenib. In order to understand the potential mechanism by which vemurafenib treatment contributes to the development of cuSCC, vemurafenib was tested in vivo in the A431 cuSCC xenograft model. There was dose-dependent tumor growth stimulation of the xenograft tumors at doses higher than 25 mg/kg bid. The optimal dose of 75 mg/kg bid of vemurafenib caused a 103% induction of growth compared to the control (p=0.002). Immunohistochemistry showed staining of pERK only in the tumor samples treated with vemurafenib (75 mg/kg) as compared to the vehicle-treated control group. Combination studies of vemurafenib and a MEK inhibitor, RO5068760, were performed to confirm the inhibition of pERK.

Indications of Vemurafenib

Metastatic Melanoma
Unresectable Melanoma
Refractory Erdheim-Chester disease
Refractory Non-small cell lung cancer
Vemurafenib is used for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation. Vemurafenib is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer

Contra Indication of Vemurafenib

Diabetes
High cholesterol
Low amount of magnesium in the blood
Low amount of phosphate in the blood
Low amount of calcium in the blood
Low amount of sodium in the blood
The high amount of potassium in the blood
Low amount of potassium in the blood
Anemia
Decreased Blood Platelets
Decreased Neutrophils a Type of White Blood Cell
High blood pressure
Very Rapid Heartbeat – Torsades de Pointes
prolonged QT interval on EKG
Abnormal EKG with QT changes from Birth
Hardening of the arteries due to plaque buildup
Liver problems
High Amount of Bilirubin in the Blood
High Blood Sugar
Abnormal liver function tests
Pregnancy
A mother who is producing milk and breastfeeding
Relapse of Hepatitis B Infection Symptoms
Pancreatitis

Dosages of Vemurafenib

Strengths: 240 mg

Melanoma – Metastatic

Maintenance dose: 960 mg orally every 12 hours with or without a meal
Duration of therapy: Treat patients until disease progression or unacceptable toxicity occurs.

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Side Effects of Vemurafenib

The most common

chest pain
certainly hair loss
headache
joint painPain
dizziness
nausea and vomiting
Severe stomach ache
epigastric pain,
diarrhoea,
anorexia,
flatulence,
headache,
dizziness,
fainting, fast or pounding heartbeats.

More common

Fast or irregular heartbeat
appetite loss
changes in nails
constipation
fatigue
fever
Back pain
dizziness
headache
increased cough
Acid or sour stomach
decreased appetite
Agitation
chest congestion
chest pain
cold sweats
confusion
decreased sexual ability or desire
stomach or abdominal cramps, gas, or pain
trouble sleeping

Less common

bleeding gums
blood in the urine or stools
chest pain
diarrhea
Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
difficulty in moving
muscle stiffness
redness of the face, neck, arms and occasionally, upper chest
lack or loss of strength
muscle spasm
difficult or labored breathing
dry mouth
headache
irritability
lack or loss of strength
loose stools
loss of interest or pleasure
muscle stiffness
night sweats
passing gas
stomach discomfort, upset, or pain
swollen joints
trouble concentrating
increased blood pressure

Drug Interactions of Vemurafenib

Vemurafenib may interact with following drugs, supplements & may change the efficacy of the drug

alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
“azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
beta-blockers (e.g., atenolol, propranolol, metoprolol)
barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine,)
carbamazepine
chloroquine
corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
cyclosporine
dantrolene
“gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delaviridine, efavirenz, etravirine, nevirapine)
losartan
macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
metronidazole
mirtazapine
montelukast
norfloxacin
ondansetron
carbamazepine
phenytoin
progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
sildenafil
“statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
tacrolimus
tadalafil
tamoxifen
tetracycline
theophylline
tocilizumab
tolterodine
tramadol
other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
5-HT3 antagonists (e.g., granisetron, ondansetron)
tamsulosin
tapentadol
thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
tramadol
tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
tetracycline
tocilizumab
vandetanib
vemurafenib
trimethoprim
vaccines
warfarin

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Pregnancy & Lactation

FDA Pregnancy Category C

Pregnancy

Vemurafenib may harm an unborn child. This medication should not be used during pregnancy unless the benefits outweigh the risks. Women who may become pregnant must use an effective birth control method while taking this medication and for at least 6 months after taking the last dose of medication. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if vemurafenib passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.