E-drug: Halcion
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Below is the response of Sidney M. Wolfe, MD, Director of Public Citizen's
Health Research Group to the National Academy of Sciences Institute of
Medicine (IOM) report on triazolam (Halcion) released November 13, 1997.
The IOM was contracted by the US Food and Drug Administration (FDA) to
assess: (1) the adequacy of the study designs and quantitative endpoints
used in the major clinical trials of triazolam; (2) the quality and
quantity of postmarketing data with respect to adverse drug reactions; (3)
the overall confidence in the data on the effectiveness, adverse events,
and side effects of triazolam at different doses and for different
durations of use, including those specified in the current product
labeling; and (4) the need for additional studies to clarify and
characterize the risk and efficacy profiles of triazolam. The IOM found
triazolam safe and effective when used as recommended in the current
product labeling.
Some E-Drug subscribers may not be familiar with the almost 20 year
chronology and contentious issues surrounding triazolam. For those
subscribers some selected background comments follow. Subscribers
interested in an extensive treatment of the triazolam issue are directed to
the recent publication by Kales, Vgontzas and Bixler.(1)
Triazolam's safety was first questioned in 1979 when van der Kroef reported
a syndrome that included depression, amnesia, hallucinations, and anxiety
with the use triazolam(2) In 1991, as a result of a US court case, the
UK's Committee on Safety of Medicines (CSM) became aware that in the
product license application for triazolam, there were a number of omissions
of adverse events in Protocol 321. Protocol 321 was conducted in US prison
volunteers in 1972 and 1973 using a 1 mg dose of triazolam. Upjohn, now
Pharmacia & Upjohn, provided the CSM with the original clinical record
forms from Protocol 321 for review. The CSM's reappraisal of this protocol
and spontaneous adverse drug reaction reports from the UK and US led to the
conclusion: ". . . that triazolam is associated with an inadequate margin
of safety in relation to dose and that its risks outweigh its benefits in
relation to other benzodiazepines." An April 4, 1994 FDA memo revealed
that 30 percent of the serious adverse drug reactions seen in Protocol 321
subjects had not been reported to the FDA prior to the drug's approval in
the US.(3) Marketing approval for triazolam was ultimately withdrawn in
the UK, Brazil, Argentina, Norway, and Denmark.
In December 1991, the FDA Clinical Investigations Branch began an inquiry
of Upjohn that was suddenly suspended in March 1992. The final report of
this investigation was not released until 1994 with a recommendation that
the FDA establish another committee, The Halcion Task Force, to investigate
possible misconduct by Upjohn.
The FDA Psychopharmacology Drug Advisory Committee met in May 1992 to
review triazolam's safety. At this meeting further analysis of spontaneous
adverse drug reaction (ADR) reports were presented by the FDA Office of
Epidemiology and Biostatistics based on reports from the introduction of
temazepam in 1981 and triazolam in 1983 through December 1991. The
psychiatric and behavioral ADRs corrected for new prescriptions resulted in
reporting rates of 25 ADRs per million prescriptions for triazolam versus 2
ADRs per million for temazepam, a reporting rate ratio of 12.5. When
reporting rates were further corrected for drug usage, calendar year,
marketing year, secular trend, changing regulations, manufacturer reporting
patterns, publicity through literature and media, and data variation the
high reporting rate ratios persisted for triazolam
In July 1992, Public Citizen filed the second of its two petitions to the
FDA to withdraw marketing approval for triazolam.
The report of The Halcion Task Force was made available in 1996 with the
recommendation the Justice Department assess whether Upjohn committed
crimes by failing to report serious adverse events associated with the use
of triazolam.(4) The Halcion Task Force also recommended that an outside
reassessment of the safety and efficacy data for triazolam be conducted.
The FDA contracted with the IOM for this reassessment in April 1997 and
held its first meeting July 10 and 11, 1997. In August, the FDA denied
Public Citizen's petition to withdraw the marketing approval for triazolam
and November 13 the IOM issued its final report.
REFERENCES
1. Kales A, Vgontzas AN, Bixler EO. A reassessment of triazolam.
International Journal of Risk & Safety in Medicine 1996;9:7-27.
2. van der Kroef C. Reactions to triazolam. Lancet 1979;2:256.
3. Committee on the Safety of Medicines. Paper presented to the European
Community's Committee on Proprietary Medicinal Products as part of the
testimony of Sidney M. Wolfe, MD, Director, Public Citizen's Health
Research Group to the FDA Psychopharmacologic Drugs Advisory Committee May
18, 1992.
4. Eichenwald K, A Justice department review is sought on a sleeping pill's
side effects. New York Times, June 1, 1996.
Response of Sidney M. Wolfe, M.D.
Director, Public Citizen's Health Research Group
to the Institute of Medicine Report on Halcion
November 13, 1997
The Institute of Medicine (IOM) report, done in a hurried manner, is a
waste of taxpayers dollars in that many of the questions it was asked/paid
to answer by the Food and Drug Administration (FDA), had already been
answered by the FDA before the committee's process had barely begun.
Instead of waiting to respond to our 1992 petition to ban Halcion until the
report was finished, just as the IOM investigation was beginning, the FDA
issued a denial of our petition (August 19, 1997), concluding that the drug
was safe and effective enough to stay on the market. When asked why the
agency had preempted the IOM study, lead Deputy Commissioner Dr. Michael
Friedman is reported to have said that he was unaware of the IOM study
being underway.
The findings of the IOM study are a slap in the face to FDA's
epidemiologists who have raised serious questions about the drug's safety
for many years, having concluded that, in comparison to other sleeping
pills, Halcion has a much higher probability of causing extreme confusion
as well as memory loss. They are also at odds with the findings of an
Upjohn study in 1972-3 showing that people getting 1 milligram of Halcion,
compared to those getting a placebo, had a much higher incidence of serious
acute psychiatric symptoms, including paranoia and confusion. This dose is
only twice the current maximum dose (0.5 mg) on the U.S. label for Halcion
and, if it is being used by a small person, the 0.5 milligram dose, on a
dose per pound basis, may exceed the dose per pound of some of the large
subjects in the Upjohn study given 1 mg.
Based on a review of that study and all other available information, the
government in the U.K. banned the drug in late 1991, stating that the "CSM
[Committee on Safety of Medicines] have concluded that triazolam [Halcion]
is associated with an inadequate margin of safety in relation to dose and
that the risks outweigh its benefits in relation to other benzodiazepines."
The CSM concluded that "Considering all the information now available, it
has been concluded that triazolam can no longer be regarded as safe for the
purposes indicated in the licenses and that it should be withdrawn urgently
from the market."
Halcion is too dangerous to use and we advise anyone using it to ask their
doctor to help them slowly withdraw from the drug--it is addicting--or
switch to a safer sleeping pill. The market, as well as the U.K.
government, has also spoken loudly and clearly about the drug. Sales,
measured by retail prescriptions filled per year, have plummeted from a
peak of 11 million prescriptions a year in 1988 to 1.8 million in 1996, a
drop of 84%. Just as British people have not suffered, but rather have
benefitted, from the absence of Halcion there, so too will the increasing
number of Americans who do not use the drug. Unfortunately for Americans,
in this case the British government is doing a better job of thinking and
protection than the FDA or the IOM.
Larry D. Sasich, Pharm.D., M.P.H., FASHP
Research Analyst
Public Citizen Health Research Group
1600 20th Street, NW
Washington, DC, USA
Phone: 202-588-7782
FAX: 202-588-7796
Email: lsasich@citizen.org
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