Health Canada's suspension of marketing authorization for Adderall XR
(mixed amphetamine salts extended release) surprised nearly all concerned and
shows how differently two regulatory agencies can interpret the same set of
The Therapeutic Products Directorate, Health Canada's equivalent of the
U.S. Food and Drug Administration (FDA), suspended all sales of Adderall XR on
February 9 after a routine review of safety information provided to regulatory
agencies worldwide by the drug's manufacturer, U.K.-based Shire
Pharmaceuticals Group Plc.
Health Canada said the 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 (sold in the United States, not in Canada) or Adderall XR (sold in
Canada). 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 deaths or
strokes occurred in Canada."
The Health Canada statement went on to say that the agency had determined
that the incidence of adverse events leading to death was "higher in
Adderall and Adderall XR combined than in the other drugs of this
The statement noted that the agency asked the manufacturers of other
related stimulants approved for the treatment of ADHD to provide a"
thorough review of their worldwide safety data." In addition,
Health Canada advised patients to consult their physicians immediately and
select an alternate treatment.
A Shire spokesperson said that there were approximately 11,000 patients on
the extended-release formulation of the drug in Canada, compared with more
than 750,000 patients in the United States.
The company's chief executive officer noted that the company was asked to
withdraw the product from the market voluntarily but declined to do so.
"We are surprised by this action from Health Canada," said CEO
Matthew Emmens. "Shire remains confident in the safety and efficacy of
In response to the Canadian action, the FDA posted an updated "Alert
for Healthcare Professionals" on its Web site, in addition to a health
advisory and fact sheets for the public.
The agency was put on the defensive by immediate Congressional inquiries as
well as questions from the public about why Canadian regulators had pulled the
drug when the FDA had seemingly not addressed the safety issue. In fact, the
FDA had reviewed exactly the same dataset and last October required Shire to
update the label of Adderall and Adderall XR immediately to include a strong
statement that "misuse of amphetamine may cause sudden death and serious
cardiovascular adverse events." It also required the company to include
information in the label about the known cases of sudden death.
While Health Canada officials noted that they "did not believe that
this adverse event—sudden death—could be dealt with through a
labeling change," the FDA responded that "[a]t this time, the FDA
cannot conclude that recommended doses of Adderall can cause [sudden death],
but is continuing to carefully evaluate these data."
After the Health Canada action, the FDA also posted within its health care
professionals alert a summary of the adverse events it has on file associated
with patients taking Adderall or Adderall XR. Twelve cases of sudden death
were reported between 1999 and 2003, all of which were males between ages 7
and 16. Five of the youngsters had significant cardiac risk factors, some of
which were identified only on autopsy, such as abnormal coronary artery
anatomy or abnormal valve structure. Seven of the youngsters had no
abnormality, but at least one had a family history of cardiac ventricular
arrhythmias. It also notes that several of the youngsters had unexplained and
unusually high levels of the drug in their system, in the absence of any
evidence indicating overdose.
The FDA concluded that "[sudden death] as a possible effect of
amphetamines should be considered in the assessment of benefit versus risk
during therapeutic decision making for individual patients. In the pediatric
population, potential risk factors include cardiac abnormalities that may be
undiagnosed, positive family history for ventricular arrhythmias, and as yet
unidentified factors that may cause excessive levels of stimulant to
accumulate in children who are apparently taking normal doses."