Health Canada has informed Shire BioChem Inc. that the company can resume
production and distribution of its medication for treatment of
attention-deficit/hyperactivity disorder (ADHD), mixed amphetamine
salts—extended release, sold under the brand name Adderall XR.
The decision was announced a little over six months after Canadian sales of
the stimulant were suspended out of concern about reports of serious adverse
events, including sudden cardiac death and stroke.
Canada's Health Products Directorate, equivalent to the U.S. Food and Drug
Administration (FDA), ordered Adderall XR off the Canadian market in February
after reviewing safety information voluntarily submitted by Shire. That
information included 20 international reports of sudden death in patients
taking mixed amphetamine salts. None of the deaths occurred in Canada. The
data indicated the deaths were not linked to overdose, misuse, or abuse.
Fourteen of the deaths occurred in children, six in adults.
The FDA, as well as other regulators around the world, reviewed the same
dataset. The Canadian agency was the only regulator to pull the drug off the
market (Psychiatric News, March 4).
Following the suspension of Canadian sales, Shire requested review of the
decision by a committee made up of independent outside consultants. Health
Canada formed the Adderall XR New Drug Committee, which included a pediatric
cardiologist, a physician specializing in pediatric developmental and
behavioral disorders, and a pharmacoepidemiologist.
The Adderall XR New Drug Committee reviewed extensive documentation
supplied by both Health Canada and Shire, ultimately concluding that "an
increased risk of sudden cardiac death and/or stroke with Adderall XR compared
to alternate active treatments has not been proven."
As a result, the committee recommended that Health Canada rescind its
suspension order and allow the the product to be returned to the market.
The committee also noted, however, that "such an increase [in risk of
sudden cardiac death associated specifically with Adderall XR use] has not
been ruled out due to limitations in the data currently available for
analysis." Therefore, the committee recommended several steps be taken
prior to the product's going back on pharmacy shelves.
In particular, the committee members stressed that, theoretically, an
increased risk of sudden cardiac death or stroke potentially exists with all
drugs used to treat ADHD. Thus, they recommended that Health Canada seek
expert consultation "on the appropriateness of potential additional
cautions (e.g., strenuous exercise, use of other stimulants, family history of
sudden cardiac death) in patients treated with any ADHD drug (stimulant or
non-stimulant) that might be considered in the assessment of benefit versus
risk for an individual patient."
The Adderall XR New Drug Committee also recommended that Health Canada
approve revised product labeling submitted by Shire in November 2004. That
proposed labeling (virtually identical to the approved labeling in the United
States) includes warnings regarding reports of sudden death in patients taking
therapeutic doses of amphetamines, particularly children with structural
cardiac abnormalities. The new Canadian labeling will also add myocardial
infarction, sudden death, and stroke to the list of potential adverse
Lastly, the label will include the statement, "Adderall XR generally
should not be used in patients with structural cardiac
The committee further recommended that Health Canada "enhance
postmarketing surveillance for all stimulant drugs used in the management of
ADHD," but did not list specific steps they thought should be taken. The
committee also noted that while an increased risk of adverse cardiac events
associated with stimulant medications "is lacking, even in the absence
of this information, it may still be prudent for a baseline EKG be obtained
prior to implementing drug therapy" for patients who are involved in
strenuous exercise, use more than one stimulant medication, or have a family
history of sudden cardiac death.