ZELBORAF

What it is

Zelboraf is a film coated tablet containing 240 mg vemurafenib. Zelboraf is a protein kinase inhibitor, selective for the activating mutation of the oncogenic BRAF serine-threonine kinase enzyme. Vemurafenib is an inhibitor of BRAF serine-threonine kinase, and other kinases, such as CRAF, ARAF, SRMS, ACK1, MAP4K5 and FGR.

Approved indications

— Unresectable stage IIIC or stage IV metastatic melanoma positive for a BRAF V600 mutation.

Dosing overview

The recommended dose of Zelboraf is 960 mg (four 240 mg tablets) twice daily (equivalent to a total daily dose of 1920 mg). The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Both doses of Zelboraf should be taken either at least 1 hour before or at least 2 hours after a meal.

Key safety warnings

Cases of cutaneous squamous cell carcinoma (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with Zelboraf, usually occurring early in the course of treatment. Potential risk factors associated with cutaneous squamous cell carcinoma in Zelboraf clinical trials included age (≥ 65 years old), prior skin cancer, and chronic sun exposure. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and be monitored routinely while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per local standard of care. Severe dermatologic reactions have been reported in patients receiving Zelboraf, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with Zelboraf. In patients who experience a severe dermatologic reaction, Zelboraf treatment should be permanently discontinued. Mild to severe photosensitivity was reported in patients who were treated with Zelboraf in clinical trials. All patients should be advised to avoid sun exposure while taking Zelboraf. While taking Zelboraf, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sun screen and lip balm (SPF ≥ 30+) when outdoors to help protect against sunburn. Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II QT sub-study in previously treated patients with metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de Pointes. Treatment with Zelboraf is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes should be monitored before treatment with Zelboraf and after dose modification. Further monitoring should occur monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Pancreatitis has been reported in Zelboraf-treated subjects, generally occurring within two weeks after initiation of Zelboraf treatment. Unexplained abdominal pain should be promptly investigated, including appropriate diagnostic tests for pancreatitis. Liver injury, including cases of severe liver injury, has been reported with Zelboraf. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be measured before initiation of treatment and monitored monthly during treatment, or as clinically indicated.

Contraindications

Zelboraf is contraindicated in patients with hypersensitivity to vemurafenib or to any of its excipients.

PBS listing

The 240 mg tablet is listed on the PBS with streamlined restriction at an ex-manufacturer price of A$1632.22.

Regulatory history

Zelboraf was first listed on the Australian Register of Therapeutic Goods on 10 May 2012. The AusPAR approval date was 1 April 2012 for the indication of treatment of unresectable Stage IIIC or Stage IV metastatic melanoma positive for a BRAF V600 mutation.