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Label Changes for:

Zelboraf (vemurafenib) Tablets

August 2015

Changes have been made to the WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

August 2015

WARNINGS AND PRECAUTIONS

Radiation Sensitization and Radiation Recall
  • Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to vemurafenib treatment [see Adverse Reactions (6.2)]. Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment

ADVERSE REACTIONS

Postmarketing Experience
  • Injury, poisoning and procedural complications: Radiation sensitization and recall
  • Gastrointestinal Disorders: Pancreatitis

DRUG INTERACTIONS

Effect of Vemurafenib on P-gp Substrates
  • Coadministration of ZELBORAF with digoxin, a sensitive P-glycoprotein (P-gp) substrate, increased digoxin systemic exposure by 1.8-fold. Avoid concurrent use of P-gp substrates known to have narrow therapeutic indices. If use of these medications is unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices.

 

November 2014

WARNINGS AND PRECAUTIONS

Hepatotoxicity
  • Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF

ADVERSE REACTIONS

  • panniculitis and neutropenia

 

February 2014

WARNINGS AND PRECAUTIONS

5.3 Hypersensitivity Reactions
  • addition of DRESS Syndrome

ADVERSE REACTIONS

  • addition of Hypersensitivity Reactions
6.2 Postmarketing Experience
  • addition of… progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation. 

 

July 2013

WARNINGS AND PRECAUTIONS

New Primary Malignancies

Cutaneous 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 (6.1)]. 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, …
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 speci
Hepatotoxicity
  • Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. 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 (2.3)].
Concurrent Administration with Ipilimumab
  • The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. 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 (7.3)].

ADVERSE REACTIONS

DRUG INTERACTIONS

Ipilimumab
  • Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF

 

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