"The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved t"...
- Patient Information:
Details with Side Effects
New Primary Malignancies
Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see ADVERSE REACTIONS]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age ( ≥ 65 years), prior skin cancer, and chronic sun exposure.
In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.
Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.
Non-Cutaneous Squamous Cell Carcinoma
Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see ADVERSE REACTIONS]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC.
Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Tumor Promotion in BRAF Wild-Type Melanoma]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies.
Tumor Promotion In BRAF Wild-Type Melanoma
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION].
Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see ADVERSE REACTIONS].
Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see ADVERSE REACTIONS].
Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see CLINICAL PHARMACOLOGY]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.
Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation.
Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see DOSAGE AND ADMINISTRATION].
Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see ADVERSE REACTIONS]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see DOSAGE AND ADMINISTRATION].
Concurrent Administration with Ipilimumab
The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see INDICATIONS AND USAGE]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see DRUG INTERACTIONS].
Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see ADVERSE REACTIONS]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see DOSAGE AND ADMINISTRATION].
Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.
ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following:
- Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see DOSAGE AND ADMINISTRATION].
- ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately of any changes in their skin [see WARNINGS AND PRECAUTIONS].
- ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see WARNINGS AND PRECAUTIONS].
- ZELBORAF can cause mild to severe photosensitivity. Advise ZELBORAF-treated patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. ZELBORAF increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.
No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility; nevertheless, no histopathological findings were noted in reproductive organs in males and females in repeat-dose toxicology studies in rats at doses up to 450 mg/kg/day (approximately 0.6 and 1.6 times the human exposure based on AUC in males and females, respectively) and dogs at doses up to 450 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC in both males and females, respectively).
Use In Specific Populations
Pregnancy Category D
[see WARNINGS AND PRECAUTIONS].
ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3– 5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and efficacy in pediatric patients below the age of 18 have not been established.
Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see CLINICAL PHARMACOLOGY]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.
No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see CLINICAL PHARMACOLOGY]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment.
Last reviewed on RxList: 2/18/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Zelboraf Information
Report Problems to the Food and Drug Administration
Get the latest treatment options.