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The following adverse reactions are discussed in greater detail in another section of the label:
- Cutaneous Squamous Cell Carcinoma [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
- Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see WARNINGS AND PRECAUTIONS]
- Liver Laboratory Abnormalities [see WARNINGS AND PRECAUTIONS]
- Photosensitivity [see WARNINGS AND PRECAUTIONS]
- Ophthalmologic Reactions [see WARNINGS AND PRECAUTIONS]
- New Primary Malignant Melanoma [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.
The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade ( ≥ 30% in either study) reported 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 2: 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 3 (%)||Grade 4 (%)||All Grades (%)||Grade 3 (%)||Grade 4 (%)||All Grades (%)||Grade 3 (%)||Grade 4 (%)|
|Skin and subcutaneous tissue disorders|
|Rash maculo-papular||9||2||-||< 1||-||-||21||6||-|
|Rash papular||5||< 1||-||-||-||-||13||-||-|
|Musculoskeletal and connective tissue disorders|
|Myalgia||13||< 1||-||1||-||-||24||< 1||-|
|Pain in extremity||18||< 1||-||6||2||-||9||-||-|
|Musculoskeletal pain||8||-||-||4||< 1||-||11||-||-|
|Back pain||8||< 1||-||5||< 1||-||11||< 1||-|
|General disorders and administration site conditions|
|Edema peripheral||17||< 1||-||5||-||-||23||-||-|
|Pyrexia||19||< 1||-||9||< 1||-||17||2||-|
|Asthenia||11||< 1||-||9||< 1||-||2||-||-|
|Diarrhea||28||< 1||-||13||< 1||-||29||< 1||-|
|Nervous system disorders|
|Neoplasms benign, malignant and unspecified (includes cysts and polyps)|
|Skin papilloma||21||< 1||-||-||-||-||30||-||-|
|Cutaneous SCC†#||24||22||-||< 1||< 1||-||24||24||-|
|Seborrheic keratosis||10||< 1||-||1||-||-||14||-||-|
|Gamma-glutamyltransferase increased||5||3||< 1||1||-||-||15||6||4|
|Metabolism and nutrition disorders|
|Decreased appetite||18||-||-||8||< 1||-||21||-||-|
|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
†Includes both squamous cell carcinoma of the skin and keratoacanthoma.
# All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.
Clinically relevant adverse events 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: dizziness, neuropathy peripheral, VIIth nerve paralysis
Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma
Infections and infestations: folliculitis
Investigations: weight decreased
Eye disorders: retinal vein occlusion, uveitis
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation
Table 3 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 3 Change From Baseline to Grade 3/4 Liver Laboratory
|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.|
Read the Zelboraf (vemurafenib tablet) Side Effects Center for a complete guide to possible side effects »
Effects of Vemurafenib on Drug Metabolizing Enzymes
Results from an in vivo drug-drug interaction study in patients with cancer demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer [see CLINICAL PHARMACOLOGY].
Coadministration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the AUC of dextromethorphan (CYP2D6 substrate) by 47%, while it decreased the AUC of midazolam (CYP3A4 substrate) by 39% [see CLINICAL PHARMACOLOGY]. Concomitant use of ZELBORAF with agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is not recommended as ZELBORAF may alter their concentrations. If Coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.
Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see CLINICAL PHARMACOLOGY]. Exercise caution and consider additional INR monitoring when ZELBORAF is used concomitantly with warfarin.
Drugs that Inhibit or Induce CYP3A4
Based on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfmavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with ZELBORAF.
Drug Abuse And Dependence
No studies on the potential for ZELBORAF to cause dependence have been performed. However, there is no evidence from the available data that ZELBORAF treatment can result in dependence.
Last reviewed on RxList: 8/29/2011
This monograph has been modified to include the generic and brand name in many instances.
Additional Zelboraf Information
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