Vemurafenib is a selective inhibitor of BRAF kinase that is used in the therapy of patients with 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 (vem’ ue raf” e nib) is an orally available inhibitor of mutated forms of BRAF, a serine/threonine kinase that is a component of the mitogen-activated pathway (MAP) kinases which are important intracellular signals involved in control of cell growth and proliferation. BRAF kinase is an early step in the cascade of MAP kinases (RAS-RAF-MEK-ERK) and is frequently mutated in malignant conditions, including at least half of cases of melanoma. Vemurafenib was shown to be active against the V600E mutants of BRAF in vitro and in animal models. Furthermore, in clinical trials vemurafenib therapy was associated with an improvement in overall survival in patients with metastatic malignant melanoma with V600E mutations. Vemurafenib was approved for use in the United States in 2011 and current indications are for unresectable or metastatic melanoma with the BRAF V600E mutation and Langerhans-cell histiocytosis with BRAF V600 mutations. Vemurafenib is available in tablets of 240 mg under the brand name Zelboraf. The typical dose is 960 mg (4 tablets) twice daily. Common side effects include fatigue, nausea, arthralgias, rash, alopecia, photosensitivity, pruritus, and skin papilloma. Uncommon, but potentially severe side effects include severe skin and hypersensitivity reactions (including Stevens Johnson syndrome), cutaneous squamous cell carcinoma, ocular toxicity, and prolonged QTc intervals.


In large clinical trials of vemurafenib, abnormalities in routine liver tests were common and serum aminotransferase elevations occurred in up to one third of patients. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 3% of patients, and rare instances of clinically apparent liver injury were reported, but the clinical features of the injury have not been described. The onset of liver test abnormalities was typically within 3 to 6 weeks of starting vemurafenib, and the abnormalities resolved rapidly either spontaneously or with temporary drug discontinuation. Vermurafenib has also been linked to instances of drug related rash with eosinophilia and systemic manifestations (DRESS) as well as Stevens Johnson syndrome, both of which can be accompanied by liver dysfunction and in some cases jaundice with clinically apparent liver injury.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury.

Mechanism of Injury

The mechanism of injury accounting for serum enzyme elevations during vemurafenib therapy is not known. Vemurafenib is metabolized in the liver largely through the CYP 1A2 pathway and liver injury may be related to production of a toxic intermediate. The rare cases of liver injury accompanying severe skin reactions are likely related to hypersensitivity. Vemurafenib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 1A2 activity.

Outcome and Management

In using kinase inhibitors in the therapy of cancer, monitoring of routine liver tests before starting and during therapy is warranted. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to temporary cessation. Restarting vemurafenib after temporary cessation should be done with caution and only after the liver test abnormalities have resolved or improved significantly. There does not appear to be cross reactivity in risk for hepatic injury between vemurafenib and other kinase inhibitors and, in some situations, switching to another BRAF inhibitor may be appropriate.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors



Vemurafenib – Zelboraf®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 28 June 2018

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