Shire Adderall XR Sales Suspended In Canada; FDA Stands By "Black Box"

Company plans a "Dear Doctor" letter informing U.S. physicians of Health Canada's decision. FDA says it "has not decided to take any further regulatory action at this time"; sudden death warnings were added to Adderall XR's labeling in August.

Shire plans to send a "Dear Health Care Professional" letter to U.S. physicians regarding Health Canada's decision to indefinitely suspend sales of the attention deficit/hyperactivity disorder agent Adderall XR (extended-release amphetamine).

Based on safety information concerning "sudden deaths, heart-related deaths, and strokes in children and adults taking usual recommended doses of Adderall and Adderall XR," Health Canada suspended Shire's marketing authorization for Adderall XR Feb. 9, an agency ¹ advisory says.

"Although Shire is complying with this request, the company strongly disagrees with the conclusions drawn by Health Canada and is considering appropriate responsive action," Shire said.

The company said it will educate U.S. physicians on Health Canada's decision and stress that Adderall XR continues to be available in the U.S.

Shire declined to voluntarily remove the drug from the Canadian market (see ² (Also see "Health Canada Requests Safety Data Profiles For ADHD Stimulant Drugs" - Pink Sheet, 10 Feb, 2005.)).

Although the company is not aware of a process by which to formally appeal Health Canada's decision, Shire is considering next steps to reinstate Adderall XR on the market. Immediate-release Adderall has never been marketed in Canada.

Health Canada suspended sales of Adderall XR in the process of a "routine label update," Shire said.

In November, Shire provided Health Canada with data on the rate of sudden deaths that had occurred in Adderall and Aderall XR patients, as well as language for warnings that could be included in Canadian labeling. The warnings were similar to language added to U.S. Adderall XR labeling in August, Shire stated.

FDA views the warnings added to Adderall XR labeling in August as sufficient, at this time, in addressing the risk of sudden death and cardiovascular adverse events associated with the drug.

"FDA does not feel that any immediate changes are warranted in the FDA labeling or approved use of this drug based upon its preliminary understanding of Health Canada's analyses of adverse event reports and FDA's own knowledge and assessment of the reports received by the agency," a Feb. 9 ³ statement by the agency says.

"FDA has not decided to take any further regulatory action at this time. However, because it appeared that patients with underlying heart defects might be at increased risk for sudden death, the labeling for Adderall XR was changed in August 2004," FDA said in a Feb. 9 public ⁴ health advisory.

In August, FDA strengthened Adderall XR's "black box" warning to include the statement: "Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events." The boxed warning previously included language on the abuse potential for amphetamines.

U.S. Adderall XR ⁵ labeling also added the warning, "Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalities. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities."

The labeling changes accompanied an FDA approval for use of Adderall XR to treat adult attention deficit/hyperactivity disorder (⁶ (Also see "Shire To Begin Promoting Adderall XR Adult Indication" - Pink Sheet, 12 Aug, 2004.)).

Immediate-release Adderall does not have the warnings, but Shire is expected to add them shortly following a Feb. 10 request by FDA.

"FDA is continuing to evaluate these and other post-marketing reports of serious adverse events in children, adolescents, and adults being treated with Adderall and related products," the FDA health advisory states.

The incidence of sudden deaths does not rise significantly above the rate reported in similar treated and untreated populations, the health advisory notes.

"The number of cases of sudden deaths reported for Adderall is only slightly greater, per million prescriptions, than the number reported for methylphenidate products, which are also commonly used to treat pediatric patients with ADHD," FDA said.

"When one considers the rate of sudden death in pediatric patients treated with Adderall products based on the approximately 30 mil. prescriptions written between 1999 and 2003 (the period of time in which these deaths occurred), it does not appear that the number of deaths reported is greater than the number of sudden deaths that would be expected to occur in this population without treatment."

Adderall XR cleared Health Canada for use in children in January 2004. Sales in the country totaled about $10 mil. from the February launch through the end of 2004, Shire said. In the U.S., the Adderall franchise topped $700 mil. in 2004 sales.

- Adam Eckstein