"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"...
The following adverse reactions are discussed in greater detail in other sections of the label:
- New Primary Malignancies [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Photosensitivity [see WARNINGS AND PRECAUTIONS]
- Ophthalmologic Reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m² intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily.
Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade ( ≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common ( ≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.
Table 1 : Adverse Reactions Reported in ≥ 10% of
Patients Treated with ZELBORAF*
|ADRs||Trial 1: Treatment Naive Patients||Trial 2: Patients with Failure of at Least One Prior Systemic Therapy|
|All Grades (%)||Grade 3a (%)||All Grades (%)||Grade 3 (%)||All Grades (%)||Grade 3a (%)|
|Skin and subcutaneous tissue disorders|
|Rash maculo-papular||9||2||< 1||0||21||6|
|Rash papular||5||< 1||0||0||13||0|
|Musculoskeletal and connective tissue disorders|
|Myalgia||13||< 1||1||0||24||< 1|
|Pain in extremity||18||< 1||6||2||9||0|
|Musculoskeletal pain||8||0||4||< 1||11||0|
|Back pain||8||< 1||5||< 1||11||< 1|
|General disorders and administration site conditions|
|Edema peripheral||17||< 1||5||0||23||0|
|Pyrexia||19||< 1||9||< 1||17||2|
|Asthenia||11||< 1||9||< 1||2||0|
|Diarrhea||28||< 1||13||< 1||29||< 1|
|Nervous system disorders|
|Neoplasms benign, malignant and unspecified (includes cysts and polyps)|
|Skin papilloma||21||< 1||0||0||30||0|
|Cutaneous SCCt#||24||22||< 1||< 1||24||24|
|Seborrheic keratosis||10||< 1||1||0||14||0|
|Metabolism and nutrition disorders|
|Decreased appetite||18||0||8||< 1||21||0|
|Respiratory, thoracic and mediastinal disorders|
|Injury, poisoning and procedural complications|
|*Adverse drug reactions, reported using MedDRA and graded
using NCI-CTC-AE v 4.0 (NCI common toxicity criteria) for assessment of
aGrade 4 adverse reactions limited to gamma-glutamyltransferase increased ( < 1% in Trial 1 and 4% in Trial 2).
† Includes both squamous cell carcinoma of the skin and keratoacanthoma.
#Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.
Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:
Musculoskeletal and connective tissue disorders: arthritis
Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma
Infections and infestations: folliculitis
Eye disorders: retinal vein occlusion
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation
Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.
Table 2 : Change From
Baseline to Grade 3/4 Liver Laboratory Abnormalities*
|Parameter||Change From Baseline to Grade 3/4|
|ZELBORAF (%)||Dacarbazine (%)|
|* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm.|
The following adverse reactions have been identified during postapproval use of ZELBORAF because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation.
Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Read the Zelboraf (vemurafenib) Side Effects Center for a complete guide to possible side effects
Effect Of Strong CYP3A4 Inhibitors Or Inducers On Vemurafenib
Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see CLINICAL PHARMACOLOGY]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.
Effect Of Vemurafenib On CYP1A2 Substrates
Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see CLINICAL PHARMACOLOGY]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.
Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see WARNINGS AND PRECAUTIONS].
Read the Zelboraf Drug Interactions Center for a complete guide to possible interactions
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
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options.