FDA Approves Vandetanib

FDA Approves Orphan Drug Vandetanib for Advanced Medullary Thyroid Cancer

WILMINGTON, Del.--(BUSINESS WIRE)--Apr 6, 2011 - AstraZeneca today announced that the U.S. Food and Drug Administration (FDA) approved the orphan drug vandetanib for the treatment of medullary thyroid cancer that cannot be removed by surgery or that has spread to other parts of the body.

Vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable (non-operable) 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.

"Vandetanib is the only medicine to receive FDA approval specifically for use in patients with advanced medullary thyroid cancer and is the first treatment that AstraZeneca has developed and brought to market under orphan drug designation in the US," said Howard Hutchinson, Chief Medical Officer, AstraZeneca.

The approval of vandetanib is based on the results of the ZETA study, a Phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). In the study, patients randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (Hazard Ratio [HR]=0.35; 95% Confidence Interval [CI]=0.24-0.53; p<0.0001).This difference reflects a 65% reduction in risk for disease progression. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted. QT prolongation, Torsades de pointes, and sudden death are included in the boxed warning for vandetanib. The most common adverse drug reactions (>20%) seen in the ZETA trial with vandetanib were diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%).

A Risk Evaluation and Mitigation Strategy (REMS) is required for vandetanib due to the risks of QT prolongation, Torsades de pointes, and sudden death. Only prescribers and pharmacies who are certified through the vandetanib REMS program, a restricted distribution program, will be able to prescribe and dispense vandetanib.

AstraZeneca will work to make vandetanib available to patients as soon as possible. Vandetanib will be dispensed exclusively through the pharmacy business unit of Biologics, Inc., an integrated oncology management company.

Vandetanib received orphan drug designation in medullary thyroid cancer in 2005. Vandetanib is also under regulatory review in the European Union and Canada.

Important Safety Information, including boxed WARNING

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH

  • Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib.
  • Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia and/or hypomagnesemia must be corrected prior to vandetanib administration and should be periodically monitored.
  • Drugs known to prolong the QT interval should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended.
  • Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above.
  • Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately.
  • Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense vandetanib.
  • Do not use vandetanib in patients with congenital long QT syndrome.
  • Because of the risk of QT prolongation, ECGs and levels of serum potassium, calcium, magnesium, and TSH should be monitored at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib, and every 3 months thereafter and following dose adjustments.
  • Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported and may prompt permanent discontinuation of vandetanib.
  • Interstitial lung disease (ILD) has been observed with vandetanib and deaths have been reported. Interrupt vandetanib treatment and investigate unexplained dyspnea, cough, and fever.
  • Ischemic cerebrovascular events, serious hemorrhagic events, and heart failure have been observed with vandetanib and some cases have been fatal.
  • Diarrhea has been observed with vandetanib. Serum electrolytes and ECGs should be carefully monitored in cases of diarrhea because of the risk of QT prolongation with vandetanib. If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves.
  • Hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome (RPLS) have been observed with vandetanib.
  • The concomitant use of known strong CYP3A4 inducers may reduce drug levels of vandetanib and should be avoided. The administration of vandetanib with antiarrhythmic drugs and other drugs that may prolong the QT interval should be avoided.
  • Vandetanib exposure is increased in patients with impaired renal function. The starting dose of vandetanib should be reduced to 200 mg in patients with moderate to severe renal impairment and the QT interval should be monitored closely.
  • Vandetanib is not recommended for patients with moderate and severe hepatic impairment, since safety and efficacy have not been established.
  • Vandetanib can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving vandetanib and for at least 4 months following treatment.
  • The most common adverse drug reactions (>20%) seen with vandetanib are diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%). The most common laboratory abnormalities (>20%) were decreased calcium (57%), increased ALT (51%), and decreased glucose (24%).
  • Vandetanib REMS Program: Because of the risks of QT prolongation, Torsades de pointes and sudden death, vandetanib is available only through the Vandetanib REMS Program. Only prescribers and pharmacies certified with the restricted program are able to prescribe and dispense vandetanib. To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236-9933 or visit www.vandetanibrems.com.

For further information on vandetanib, please see the full Prescribing Information including boxed WARNING, at http://www1.astrazeneca-us.com/pi/vandetanib.pdf.

About the ZETA Study

The approval of vandetanib is based on the results of the ZETA study, a Phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). In the study, patients randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (Hazard Ratio [HR]=0.35; 95% Confidence Interval [CI]=0.24-0.53; p<0.0001). This difference reflects a 65% reduction in risk for disease progression. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm.

At the primary PFS analysis, no significant overall survival difference was noted.The objective response rate (ORR) was 44% versus 1% for patients randomized to receive vandetanib or placebo, respectively. All objective responses were partial responses. QT prolongation was reported in 14% of patients in the vandetanib arm and 1% of patients in the placebo arm. The most common adverse drug reactions (>20%) seen with vandetanib were diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%).

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information about AstraZeneca in the U.S. or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363).

The statements contained herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report and Form 20-F Information 2010. Nothing contained herein should be construed as a profit forecast.

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Posted: April 2011

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