Vemurafenib is a protein kinase inhibitor that blocks the mutated gene protein BRAFV600E so that the cascade of messages that drive cell division and prevent apoptosis is stopped, resulting in tumor shrinkage.
Approved Drug:Vemurafenib (Zelboraf)
Treatment of patients with unresectable or metastatic BRAFV600Emutation.
Mechanism of Action
BRAF (v-raf murine sarcoma viral oncogene homolog B1) is a gene that gives the cell instructions to make a protein that helps send messages from outside the cell to the cell’s nucleus. It is part of the RAS/MAPK pathway which helps to regulate the growth, maturation, and proliferation of cells, as well as cell movement and cell death (apoptosis). When mutated, the gene can cause malignant transformation and tumor growth. In particular, 50% of patients with melanoma carry the BRAFV600E mutation. Vemurafenib is a protein kinase inhibitor that blocks the mutated gene protein BRAFV600E so that the cascade of messages that drive cell division and prevent apoptosis is stopped, resulting in tumor shrinkage.
Following oral administration, the drug is well absorbed, with a median Tmax (maximal concentration) of about 3 hours. Steady state is reached in about 15–22 days. Vemurafenib is highly protein-bound (> 99%) and is excreted primarily via the feces (94%), with 1% excreted in the urine. Elimination half-life is 57 hours (range 30–120 hrs). Drug pharmacokinetics are not markedly changed in patients with mild to moderate hepatic or renal dysfunction, but they have not been studied in patients with severe dysfunction. Vemurafenib appears to cross the placenta; it is unknown if it is excreted in breast milk.
• BRAFV600E mutation status of tumor must be confirmed by an FDA- approved test in order for a patient to receive vemurafenib.
• Dosage is 960 mg orally twice daily, 12 hours apart, without regard to meals. Teach patient to swallow pills whole and not to crush them. Available in 240-mg tablets in a bottle of 120 tablets.
• Grade 2 (intolerable) or Grade 3: At first appearance, interrupt therapy until grade 0–1, resume at 720 mg twice daily; at second appearance, interrupt therapy until grade 0–1, then resume dosing at 480 mg twice daily; at third appearance, discontinue permanently.
• Grade 4: At first appearance, discontinue permanently or interrupt until grade 0–1, resume dosing at 480 mg twice daily; at second appearance, discontinue permanently.
• Drug dose below 480 mg twice daily is not recommended.
• Drug has been shown to work only in patients with a special gene mutation (BRAFV600E).
• Take the pills twice a day, 12 hours apart. If you forget, you can take the dose when you remember up until 4 hours before the next dose. Do not take the missed dose if it is within 4 hours of your next dose. Take the pills with water, and you may take them with food if you want.
• You may have an allergic reaction to the drug. Stop taking the drug and get medical help right away if you have any of these symptoms: rash or redness all over your body, feeling faint, trouble breathing or swallowing, throat tightness or hoarseness, a fast heartbeat, or swelling of the face, lips, or tongue.
• Stop taking the drug if you get a severe skin reaction: blisters on your skin, blisters or sores in your mouth, peeling of your skin, fever, or redness or swelling of your face, hands, or soles of your feet. Tell your doctor right away.
• Drug may cause a skin cancer that usually does not spread, called cutaneous squamous cell carcinoma. You should check your skin regularly, and let your doctor know if you see any skin changes such as a new wart, a sore or reddish bump that bleeds or does not heal, or a change in size or color of a mole. Your doctor will check your skin before you start the drug, and every 2 months while you take the drug, then for 6 months after you stop treatment with the drug. Rarely, new melanomas may form, so the doctor will check for these also.
• The drug may cause you to get a sunburn. It increases your sensitivity to the sun (photosensitivity), so you should avoid being in the sun. When you go outside, wear protective clothing, a hat, and sunglasses, and use broad-spectrum UVA/UVB sunscreen (SPF 30 and higher) and lip balm.
• Most common side effects are joint pain (arthralgia), rash, hair loss (alopecia), fatigue, photosensitivity reactions, itching (pruritus), and skin papilloma.
• Tell your doctor if you have any heart problems, including a condition called QT syndrome; if you have kidney or liver problems; if you plan to have surgery, dental, or other medical procedures; or if you are pregnant or plan to become pregnant. In addition, tell your doctor all the medicines you take, including herbal supplements. Most importantly, tell your doctor if you are taking warfarin (Coumadin), drugs to treat a fungal infection, HIV medicines, seizure drugs, an antidepressant, or medicines for an irregular heartbeat.
• You should use an effective birth-control method, as the drug may harm the fetus. In addition, you should not breastfeed an infant while receiving the drug.
ADVERSE REACTIONS TO VEMURAFENIB BY BODY SYSTEM
(boldface type indicates more common events, with 25% or higher incidence)
atrial fibrillation, vasculitis
headache, VII cranial nerve paralysis, retinal vein occlusion, uveitis
vomiting, constipation, decreased appetite, weight loss, dysgeusia
myalgia, pain in extremity, musculoskeletal pain, back pain, arthritis
dizziness, peripheral neuropathy
Drug presumed to be harmful to fetus
Skin: rash, photosensitivity reaction, alopecia,
pruritus, hyperkeratosis, maculopapular rash, actinic keratosis, dry skin, erythema, squamous cell carcinoma, basal cell carcinoma folliculitis, palmar-plantar erythrodysesthesia (hand-foot) syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, skin papilloma, seborrheic keratosis
peripheral edema, pyrexia, asthenia
Vemurafenib is an inhibitor of CYP1A2 (moderate), 2A6, 2C9, 2C19, 2D6 (weak), and 3A4/5; the drug is an CYP3A4 inducer as well as a substrate.
• Warfarin(CYP2C9 substrate): 18% increase in warfarin AUC when coadministered; monitor INR closely and discuss dose modification with MD/midlevel practitioner.
• Drugs with a narrow therapeutic window that are metabolized by CYP3A4, CYP1A2, or CYP2D6: avoid concomitant use; if used together, consider a dose reduction of the CYP1A2 or CYP3A4, or CYP2D6 substrate drug.
• Caffeine (CYP2D6): increases caffeine AUC 2.6-fold; decrease caffeine intake until effect has been determined.
• Dextromethorphan (CYP2D6 substrate): decreases dextromethorphan AUC by 39%; consider lower dose of dextromethorphan if needed.
• Vemurafenib as a substrate of CYP3A4:
– strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir [Reyataz], nefazodone, saquinavir, telithromycin [Ketek], ritonavir, indinivir, nelfinavir [Viracept], voriconazole [Vfend]): use together cautiously.
– strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine [Priftin], phenobarbital): use together cautiously.
• Patient should have a full dermatologic exam at baseline, every 2 months while on therapy, and for 6 months after treatment has ended. If cutaneous superficial squamous cell carcinomas are found, they should be managed with excision and the drug continued without dose change. Likewise, if new primary malignant melanoma is found, it should be excised, and the drug continued without dose adjustment.
• Patient may experience a severe hypersensitivity reaction (HSR) characterized by symptoms along a spectrum from generalized body rash and erythema, to hypotension, to frank anaphylaxis. This has occurred during and upon reinitiation of treatment. Provide symptomatic care and discontinue drug permanently.
• Rarely, patients may develop severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The drug should be discontinued if this occurs.
• Drug can prolong the QT-interval (called QTc), increasing the risk of ventricular arrhythmias. The patient should have an ECG and electrolytes (especially potassium, magnesium and calcium) assessed at baseline, at day 15 of treatment, then monthly for the first 3 months of treatment, then every 3 months during treatment, and more frequently if clinically indicated. If the QTc > 500 ms (grade III or higher), temporarily hold the drug, correct electrolyte abnormalities, and control cardiac risk factors that may prolong QTc (eg, congestive heart failure, bradyarrhythmias). Once the QTc is < 500 ms, resume the drug at a lower dose. If the QTc again becomes prolonged > 500 ms, and there is a > 60 ms change from pretreatment value, the drug must be discontinued.
• Monitor LFTs (transaminases, alkaline phosphatase, bilirubin) at baseline, then monthly during treatment, or as clinically indicated. Manage abnormalities with dose reduction, treatment interruption, or drug discontinuation. Use cautiously, if at all, in patients with severe liver or renal impairment.
• Patients may develop mild to severe photosensitivity. Teach the patient to avoid sun exposure; to wear protective clothing, sunglasses, and a hat; and to use a broad spectrum UVA/UVB sunscreen (SPF 30 or higher) and lip balm. If the patient develops intolerable tender erythema covering 10%–30% of body surface (grade 2) or greater photosensitivity, drug dose should be modified.
• Teach patient to report any changes in eye appearance or function. Uveitis (inflammation of the middle layer of the eye, uvea) may occur rarely, and steroid and mydriatic ophthalmic drop treatment may be required. Additionally, iritis, photophobia, retinal vein occlusion, or blurry vision may occur.
• Drug appears to cross the placenta, and may be harmful to the fetus. It is unknown if the drug or its metabolites are found in breast milk. Thus, teach patient to use effective birth control measures during treatment and for at least 2 months after drug therapy is stopped, and not to breastfeed while taking the drug.
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase;
GGT = gamma-glutamyltransferase; LFTs = liver function tests; ms = millisecond
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.