FDA Approval for Vandetanib
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
• Approved for unresectable, locally advanced, or metastatic medullary thyroid cancer.
On April 6, 2011, the Food and Drug Administration (FDA) 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 considered carefully 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 with 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 assessment of disease progression by the investigator, patients were given the option of receiving open-label vandetanib.
An improvement in PFS was observed for patients who received vandetanib compared with patients who received placebo (HR=0.35; 95 percent CI: 0.24, 0.53; p<0.0001). In subgroup analyses, similar improvements in PFS were seen among patients who were symptomatic (HR=0.31, 95 percent CI: 0.19, 0.53) and among patients who had disease progression within 6 months prior to enrollment (HR=0.41, 95 percent CI: 0.25, 0.66). At the primary PFS analysis, 15 percent of the patients had died; no significant OS difference was noted. The ORR was 44 percent among patients who received vandetanib, compared with 1 percent among patients who received placebo. 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 every 3 months thereafter. 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 (at least 20 percent) grade 1-4 adverse reactions included diarrhea/colitis, rash, dermatitis acneiform, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Laboratory abnormalities in at least 20 percent of patients included decreased calcium, increased ALT, and decreased glucose. The most common (at least 5 percent) 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 between 30 and 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.