Psychiatric News April 15, 2005
Volume 40 Number 8
© 2005 American Psychiatric Association
p. 1
Zyprexa IM Caution Issued in Some Countries But Not U.S.
Mark Moran
One psychiatrist says the episode speaks to concern about the
FDA's postmarketing oversight of drug safety and suggests opening
pharmacovigilance data to clinicians.
At least 49 adverse events, some of which were related to cardiac and
respiratory depression and some of which have been fatal, have been associated
with inappropriate use of the intramuscular formulation of olanzapine,
marketed as Zyprexa IM.
If you are a psychiatrist in Canada, the United Kingdom, or Europe, that
may be old news: you might have read about these problems in "Dear
Healthcare Professional" letters requested by regulatory authorities in
Canada and Europe, distributed widely to prescribing psychiatrists, and signed
by Zyprexa manufacture Elli Lilly and Co.
A letter dated September 28, 2004, alerted European clinicians to eight
fatal adverse events, among 49 spontaneously reported adverse events,
associated with use of Zyprexa IM. Lilly sent the letter at the request of the
European Medications Evaluation Agency (EMEA), the European equivalent of the
U.S. Food and Drug Administration.
Lilly sent a similar letter, detailing clinical examples of inappropriate
use of the drug that resulted in death, to Canadian psychiatrists at the
request of the Canadian health ministry known as Health Canada. That letter,
which noted that 29 of the 49 adverse events were classified as
"serious," was dated September 7, 2004.
Yet Lilly has sent no such letter to American physicians, and the FDA has
not required it.
European psychiatrists who have seen the "Dear Healthcare
Professional" letters from Lilly told Psychiatric News that the
information warrants being made available to American clinicians. That it was
not disturbs at least one American psychiatrist who believes it underscores
widening concerns about the FDA's postmarketing oversight of drug safety.
"Why would fatalities be of less interest to U.S. physicians?"
asked emergency psychiatrist Michael Allen, M.D. "I can't understand why
we would receive less information than our European colleagues."
Allen was among the first to alert American physicians to the risks through
an article in Emergency Psychiatry, the newsletter of the American
Association of Emergency Psychiatrists. He believes the information about
cardiovascular risks associated with Zyprexa IM is important because the drug
has been marketed aggressively to American physicians who may be using it in
ways that could put patients at risk.
As an injectable, the intramuscular formulation quickly reaches much higher
blood levels than does the oral medication; it is also an alpha 1 antagonist
and as such might be expected to affect blood pressure.
Allen is director of psychiatric emergency services and an associate
professor of psychiatry at the University of Colorado Health Science Center in
Denver. He has ties to a number of pharmaceutical companies, including Lilly
and Pfizer, through research, consulting, and development of educational
materials.
Lilly representative Heather Lusk told Psychiatric News that the
company is "proactively discussing appropriate use and dosing" of
the medication with physicians through its sales representatives. "We
have no plans to do anything beyond what we are currently doing, which is to
educate physicians through our sales representatives."
Both American and European psychiatrists who spoke with Psychiatric
News agreed that it is not possible to attribute fatal adverse events to
Zyprexa IM alone; all of those events appear to have occurred in high-risk
subgroups and/or following concomitant use of Zyprexa IM with other
medications, including benzodiazepines.
Paul Andreason, M.D., team leader for psychopharmacology at the Division of
Neuropharmacologic Drug Products at the FDA, told Psychiatric News
that the agency was aware of the adverse events and of the European alert, but
had determined that the adverse events did not represent a safety signal.
Andreason said that of the eight deaths, one was the result of a fall from
a wheelchair, one was the result of a completed suicide, and one was the
result of a pulmonary embolism.
"That left five sudden and unexplained deaths," Andreason said.
"With more than 87,000 exposures, we didn't think that this represented
a safety signal above the expected background rate in this population.
However, we will continue to watch this."
Risks From Accumulating Doses
European psychiatrists who spoke with Psychiatric News questioned
why the FDA and Lilly had chosen not to inform American physicians about
adverse events associated with Zyprexa IM in an official, uniform fashion
similar to the way European and Canadian clinicians have been notified.
Robert Kerwin, M.B, D.Sc., a professor of clinical neuropharmacology at the
Institute of Psychiatry in London, said there are clear risks associated with
accumulating doses of Zyprexa IM in high-risk patients and in combination with
other medications.
"The question is why the same information was not given to American
physicians," said Kerwin.
Psychiatrist Wolfgang Fleischhacker, M.D., of the department of biological
psychiatry at Innsbruck University Clinics in Austria, reiterated the belief
that it is all but impossible to attribute the adverse events to Zyprexa IM
alone.
"Generally, the cases occurred in the context of polypharmacy, and
they were all in patients with concomitant medical disorders," he told
Psychiatric News. "From the information I have, in not a single
instance could I attribute the deaths to olanzapine alone. But I think our
American colleagues should have the same information we have. I am not sure
why the letter sent by Lilly in collaboration with EMEA was not also made
available in the United States."
Fleischhacker was also critical of Lilly's claim in the European letter
that the proportion of fatal events appeared to be similar to that reported
for other parenteral antipsychotics.
"I am not aware of any relevant comparative evidence, and I strongly
doubt that either the regulatory agencies or Lilly have information that would
lend scientific support to such a statement," he said.
When asked by Psychiatric News, Lusk said the claim in the letter
was based on data on competitors' products that was held by the EMEA and hence
could not be released by Lilly. "It is our understanding that the EMEA
was comfortable with that statement in the letter," she said.
Allen said some American "thought leaders" received a letter
from Lilly last October referencing eight deaths associated with use of
Zyprexa IM. But the letter made no mention of other nonfatal adverse events
reported to Canadian and European physicians, he said.
In general, Allen said he is concerned that the episode may reflect a
pattern of minimizing side effects associated with Zyprexa that goes back to
concerns about weight gain and metabolic effects in the oral formulation and
that now appears to be continuing with potentially more serious problems in
the intramuscular form.
In fact, a marketing war between Lilly and Pfizer Inc. focused attention on
the side effects of their respective competitive antipsychotic products:
metabolic and other effects associated with olanzapine, and QT prolongation
associated with ziprasidone, marketed by Pfizer as Geodon (Psychiatric
News, August 3, 2001).
In response to queries about the fatalities associated with Zyprexa IM,
Lusk suggested that similar problems may have turned up with ziprasidone
IM.
However, no equivalent regulatory warning has been issued with regard to
ziprasidone IM, either in the United States or in Europe. Antony Loebel, M.D.,
who is Pfizer's U.S. medical team leader for Geodon, denied that any of the
problems cited in the European letter about Zyprexa IM have been found to be
associated with Geodon IM.
"The bottom line is that there is no safety signal for Geodon IM
either alone or in combination with benzodiazepines," Loebel told
Psychiatric News. "There is no signal with respect to adverse
events such as bradycardia, cardiorespiratory depression, or hypotension, and
no letter has been requested to be sent out by Pfizer."
FDA Under Gun Again
Allen said he believes the episode speaks to concern about the FDA's
postmarketing oversight of drug safety.
"The history of the FDA is really about marketing of drugs, and its
roots go back to `snake oil' and preventing the promotion of drugs that had no
benefit," Allen said. "So its raison d'être was to require
people who were promoting drugs to show that they work so people weren't being
sold snake oil."
But once a company produces data that rise to a certain threshold of proof
that the drug is safe and effective, and the drug is on the market, the burden
then shifts.
"Prior to marketing, the burden is on the company to show a product
is generally safe and effective in certain populations," Allen said.
"After marketing, the product may be used in circumstances where it has
not been studied—for instance, in children—but the burden shifts
to others to prove the product is not safe, and that is difficult.
"There is a sense that the FDA is too focused on this narrow
definition of efficacy and that not enough attention is paid to safety of
medications once they are on the market," he continued. "That is
the difference between the United States and other countries, where there is
more of a consumer watchdog focus by regulatory agencies. If it's a good idea
to have a registry of clinical trials, perhaps it would be a good idea to open
the pharmacovigilance data." 
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American Psychiatric Association.
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