Differences between FDA and Health Canada's regulatory responses to adverse event reports for Adderall XR are likely to raise more questions about FDA's drug safety review process.

Health Canada has indefinitely suspended sales of the attention deficit/hyperactivity disorder product 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, a ¹ Health Canada advisory states. The immediate-release formulation, Adderall, has never been marketed in Canada.

FDA's early 2004 review of the same reports of sudden death in Adderall and Adderall XR patients that led to Health Canada's action resulted in a U.S. labeling change. FDA said that the rate of risk for sudden death with Adderall products does not warrant additional action.

The discrepancy in regulatory action by Health Canada and FDA on the same data will likely increase the already high level of scrutiny centered on FDA's drug safety monitoring abilities.

The differing regulatory actions could be the result of the authorities granted each agency; Health Canada can withdraw a product's market authorization upon being presented with data that raise safety concerns that were not included in the original marketing application.

While FDA can initiate a withdrawal if a product presents an immediate hazard, removing a drug over the manufacturer's objections requires a series of administrative procedures. In the interim, FDA can issue public alerts on the risk.

FDA suggested its authorities in this area are "more similar than it looks" to Health Canada's. "What seems somewhat different is the aspect of the Canadian procedure that looks like a 'pause' in marketing while the company makes arguments, submits data, etc."

Shire declined to voluntarily remove the drug from the Canadian market.

"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. "We are surprised by this action from Health Canada. Shire remains confident in the safety and efficacy of Adderall XR."

"The interpretation of the same data by the U.S. FDA led to a revised U.S. label for Adderall XR...clarifying that the drug generally should not be used in children or adults with structural cardiac abnormalities," Shire said.

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 ² FDA statement declares.

"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," the agency said in a Feb. 9 ³ FDA 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.

Adderall XR's ⁴ U.S. labeling also added the following 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 (⁵ 'The Pink Sheet' Aug. 16, 2004, In Brief). 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," FDA said.

Health Canada made the decision to indefinitely suspend Adderall XR sales during a "routine label updating," Shire said.

In November, Shire submitted the revised FDA-approved warning language and adverse event reports to Health Canada for consideration, the company said.

On Feb. 9, Canadian regulators requested that Shire remove Adderall XR from the market; Shire declined, the company said. The Canadian drug agency then issued a notice that it had decided to suspend Adderall's market authorization.

"Health Canada's decision comes as a result of a thorough review of safety information provided by the manufacturer, which indicated there were 20 international reports of sudden death in patients taking either Adderall...or Adderall XR," the Health Canada advisory states.

"These deaths were not associated with overdose, misuse, or abuse. Fourteen deaths occurred in children, and six deaths in adults. There were 12 reports of stroke, two of which occurred in children. None of the reported deaths or strokes occurred in Canada."

Health Canada is requesting that manufacturers of stimulants that treat ADHD submit "thorough" safety data reviews.

"A preliminary review of safety data for the other related stimulants authorized for use in the treatment of ADHD in Canada has been conducted," the Health Canada health advisory states.

"In that review, the incidence of serious adverse reactions leading to death was higher in Adderall and Adderall XR combined than in the other drugs in this class."

"Health Canada has asked manufacturers of other related stimulants approved for the treatment of ADHD to provide a thorough review of their worldwide safety data," the Health Canada health advisory states.

Specifically, Health Canada is requesting data on Novartis' Ritalin , Johnson & Johnson's Concerta and GlaxoSmithKline Dexedrine .

Health Canada does not suggest, however, that the adverse events associated with Adderall XR are a class effect.

"Patients taking drugs in the same class for the management of ADHD should not discontinue their medication, and should consult with their physician if they have any concerns or questions."

Although Shire is working with Health Canada to determine the next logistical steps of a withdrawal, the company said it is considering ways to appeal the agency's decision. Health Canada has no formal appeals process.

Shire plans to send a "Dear Healthcare Professional" letter to U.S. physicians regarding Health Canada's decision. Shire will stress that Adderall XR continues to be available in the U.S.

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., 2004 sales for the Adderall franchise topped $700 mil.

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

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