FDA Approves Vandetanib Tablets
Tuesday, April 12, 2011
In collaboration with the Food and Drug Administration (FDA), and as a service to our members, the Oncology Nursing Society will provide updates on recent FDA approvals and other important FDA actions (e.g., updated safety information, new prescribing information) pertaining to therapies for cancer patients. This will allow the agency to inform oncologists and professionals in oncology-related fields in a timely manner. Included in the email from the FDA will be a link to the product label or to other sites for additional relevant clinical information. In sending this information, ONS does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described. The following is a message from the FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur:
On April 6, 2011, the U. S. Food and Drug Administration approved vandetanib tablets (Vandetanib Tablets, AstraZeneca Pharmaceuticals LP), a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. The use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment-related risks of vandetanib.
The approval was based on an international, multicenter, randomized, double-blind trial conducted in patients with unresectable locally advanced or metastatic medullary thyroid carcinoma. Patients were randomized (2:1) to receive either vandetanib, 300 mg/day orally, (n=231) or placebo (n=100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared to placebo. Other endpoints included evaluation of overall survival (OS) and objective response rate (ORR). A central, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression by the investigator, patients were given the option of receiving open-label vandetanib.
An improvement in PFS was observed for patients randomized to receive vandetanib (HR=0.35; 95% CI: 0.24, 0.53; p<0.0001). Analyses in the subgroups who were either symptomatic or who had disease progression within 6 months prior to enrollment showed similar PFS results: hazard ratios of 0.31 (95% CI: 0.19, 0.53) and 0.41 (95% CI: 0.25, 0.66), respectively. At the primary PFS analysis, 15% of the patients had died; no significant OS difference was noted. The ORR was 44% versus 1% for patients randomized to receive vandetanib or placebo, respectively. All objective responses were partial responses.
QT prolongation, torsades de pointes, and sudden death are included in a boxed warning. Because of vandetanib’s prolonged half-life of 19 days, ECGs and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment and subsequently every 3 months. Electrolytes and ECGs may require more frequent monitoring in patients experiencing diarrhea. Only prescribers and pharmacies certified through the Vandetanib Risk Evaluation Mitigation Strategy Program, a restricted distribution program, are able to prescribe and dispense vandetanib.
The most common (≥ 20%) grade 1-4 adverse reactions included diarrhea/colitis, rash, dermatitis acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Laboratory abnormalities in > 20% of patients included decreased calcium, increased ALT, and decreased glucose. The most common (≥ 5%) grade 3-4 adverse reactions were diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Adverse reactions resulting in death in patients receiving vandetanib (n=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. In addition, two deaths in patients receiving vandetanib (one sudden death and one death from cardiopulmonary arrest) were noted after data cut-off.
The recommended daily dose of vandetanib is 300 mg orally. The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022405s000lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).