Canada Pulls Extended Release Formulation of ADHD Drug Adderall From the Market, Action Raises Questions for FDA

The Canadian regulatory agency Health Canada on Wednesday suspended
sales of... Shire Pharmaceuticals Group's Adderall XR, the
extended release form of the drug, citing data -- previously reviewed by FDA -- indicating that the treatment for attention deficit hyperactivity disorder "may cause sudden
deaths," the Wall Street Journal reports. Health Canada took the action after examining safety data that showed
that since 1994, there have been 20 sudden deaths related to Adderall and Adderall XR. Adderall XR, which received Canadian
approval in January 2004, is the only approved version of Adderall in Canada. Many of the deaths, none of which occurred in
Canada, were in patients who had serious cardiac abnormalities. The agency advised patients to consult their doctors about
the use of the drug and selecting alternatives (Anand/Wilde Mathews, Wall Street Journal, 2/10). FDA reviewed
the same data last year and concluded that the drug required an additional warning stating that Adderall XR should not be
prescribed for people with "structural cardiovascular abnormalities" (AP/Washington
Post, 2/11). About 11,000 patients in Canada are currently prescribed Adderall XR. About 700,000 U.S. residents
take Adderall XR and another 300,000 take Adderall (AP/South Florida Sun-Sentinel, 2/10). Health Canada said in a press release that the
incidence of serious adverse reactions leading to death was higher in Adderall and Adderall XR combined than in any other
similar drugs (Wall Street Journal, 2/10). Health Canada said it is asking other drug manufacturers to "provide
a thorough review of their worldwide safety data" on other stimulants used to treat ADHD (AP/South Florida
Sun-Sentinel, 2/10). Other stimulants to treat ADHD include Novartis' Ritalin and Johnson & Johnson's Concerta. Eli Lilly's Strattera, a newer ADHD drug, is not a stimulant but has been
linked to serious liver side effects (Wall Street Journal, 2/10).

Canada Says Labeling Changes Would
Be Inadequate
Canadian regulators indicated that preliminary analyses found Adderall XR might be linked to two to
three times as many deaths as Ritalin and Concerta (Harris/Carey, New York Times, 2/11). In its
warning, Health Canada stated that the "identified risk of sudden death following the recommended doses cannot be managed by
label changes" (Wall Street Journal, 2/10). Robert Peterson, director general of the Therapeutic Products
Directorate at Health Canada, said, "It was not possible for us to determine wording that would caution individuals about
sudden death." He added that Canadian officials had found "instances where the sudden death occurred without underlying"
cardiac factors that would explain it (Wilde Mathews et al., Wall Street Journal, 2/11). Peterson also noted
that it would be difficult to warn patients about the risk of sudden death, adding, "It's very difficult to generate a
benefit-to-risk balance when the risk is sudden and unexpected death." Peterson added that some of the deaths had not been
previously reported to Health Canada and occurred years before Adderall XR received Canadian approval for sale. "We were
surprised to find these cases," he said. Shire officials said the company forwarded reports of deaths to Canadian officials
promptly (New York Times, 2/11). Shire said Health Canada learned about the deaths in November 2004, when the
company sought to add a warning label to Adderall XR (Kerr, Long Island Newsday,
2/11).

FDA Cites 'Complicating Factors' in Keeping Drug on Market
FDA on Thursday issued an alert to
doctors notifying them of Canada's action but saying the agency "cannot conclude that recommended doses of Adderall can cause
SUD (sudden unexplained death), but it is continuing to carefully evaluate these data" (Long Island Newsday,
2/11). According to the Journal, Canada's action "puts immediate pressure" on FDA, which in 2004 reviewed the
same data and determined that the drug required additional black box language warning about "sudden death and serious
cardiovascular adverse events." The "[e]merging safety concerns with Adderall" will "draw attention" to the class of drugs
and "likely create a headache for the FDA," the Journal reports. A senior FDA official said the agency does "not
believe [the data] is strong enough at the moment to merit an immediate change to the labeling or marketing status here in
the United States." The official added that the rate of sudden deaths and cardiovascular events associated with Adderall XR
"doesn't appear significantly different from the rate with other, similar drugs" or "from the background rate for people of
the same age groups who are not taking these products" (Wall Street Journal, 2/10). Peterson noted that Canadian
law allows regulators to suspend a drug while investigating safety questions; U.S. law does not permit such an action
(New York Times, 2/11).

FDA Provides 'Detailed' Safety Data
FDA officials on Thursday also
provided "unusually detailed descriptions of the causes behind the dozen deaths among U.S. young people" taking Adderall and
Adderall XR, citing "complicating factors" in the patients that could have contributed to their deaths, the
Journal reports. Five of the patients had heart defects, and others had various other risk factors, including
diabetes. According to FDA, the U.S. rate of sudden deaths among young people taking Adderall between 1999 and 2003 was 0.5
per 100,000, and the rate for young patients taking all such stimulant products -- known as methylphenidates -- was 0.19 per
100,000. However, the Journal reports, those rates are based on "spontaneous reports to the FDA" and could be
erroneous because they might comprise 10% or fewer of the true number of side effects, according to some estimates. Robert
Temple, director of the office of medical policy in FDA's drug center, said that such deaths are "extremely rare, and it's
hard to tell in any given case if it happens with the drug or just occurs spontaneously." Temple added that the deaths were
"difficult to interpret and ambiguous" (Wall Street Journal, 2/11). He said, "There is a tendency to believe
that sudden death doesn't occur in children. That is wrong." Temple also noted that the agency's decision to keep Adderall on
the market was not influenced by other recent long-term safety questions concerning Vioxx and other drugs. "It's still our
job to get as close as we can to the right answer and not panic and do things for the wrong reasons," Temple said, adding,
"Psychiatrists say that these drugs are needed. To get rid of them for something that may well be a background rate of death
is not responsible" (New York Times, 2/11).

Grassley Says FDA Pushed Canada to Keep Drug on Market

Senate Finance Committee Chair Chuck Grassley (R-Iowa) on
Thursday said that FDA officials had asked Canadian regulators to not suspend Adderall because the agency could not handle
another "drug safety crisis," the New York Times reports. Grassley, who has been investigating FDA for about a
year, said sources within the agency told him about the efforts to keep Adderall on the Canadian market. Grassley in a letter
written on Thursday asked FDA to answer questions about any discussions its officials may have held with Canadian regulators
about Adderall. Grassley stated in his letter that reports given to his staff suggested FDA was not acting with scientific
integrity, adding, "Unfortunately, such allegations raise additional concerns about the culture at the FDA." Peterson said
through a spokesperson that Grassley's allegations "are untrue," and he described the relationship between FDA and Health
Canada as "collegial." FDA spokesperson Brad Stone declined to respond directly to Grassley's letter but said the agency
believes Peterson's comment was "the correct one." According to the Times, Grassley's involvement in the matter
"promises to engulf the FDA in more questions about its oversight of the pharmaceutical industry" (New York
Times, 2/11).

Shire Reaction
A Shire spokesperson noted that more than 38 million prescriptions
have been written for Adderall and Adderall XR, and the "sudden deaths were extremely rare." Shire CEO Matthew Emmens said
the company strongly disputes Health Canada's claims, adding that the drug's suspension came as "an absolute, complete
surprise." He noted that the company on Wednesday refused a request from the agency to withdraw the drug from the market. "We
steadfastly disagree with their interpretation of this data," Emmens said. He added that the company will continue to market
the drug in the United States (Wall Street Journal, 2/10). The company on Thursday said, "In these cases, it was
not clear if the sudden death was caused by the medicine. There was no causal link confirmation" (Wall Street
Journal, 2/11).

Broadcast Coverage
NPR's "Morning Edition" on Friday reported
Canadian regulators' decision. The segment includes comments from Temple and psychiatrist James McGough, who directs ADHD
programs at the University of California-Los Angeles. (Neighmond, "Morning Edition," NPR, 2/11)

The complete version is available online in RealPlayer.


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View drug information on Adderall XR; Concerta; Ritalin LA.