Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater
Health Risks for Women (19-JAN-01, GAO-01-286R).
The Food and Drug Administration (FDA) approves drugs for sale in
the United States when it determines that the clinical benefits
of a drug outweigh its potential health risks. To make this
decision, FDA reviews supporting data collected from several
thousand patients during the drug's development. Once a drug is
approved for marketing and used by potentially thousands of
patients, however, the type, rate, and severity of adverse events
caused by the drug can be much different than those seen during
the drug's development. In some cases, FDA or drug manufacturers
have removed from the market drugs that have been shown to have
unacceptable health risks once they were in widespread use. GAO
found that 10 prescription drugs have been withdrawn from the
U.S. market since January 1, 1997. Eight of the 10 prescription
drugs posed greater health risks for women than for men: four of
these may have led to more adverse events in women because they
were prescribed more often to women than to men, while the other
four had more adverse events in women even though they were
widely prescribed to both men and women. Of the two remaining
withdrawn drugs, one belongs to a class of drugs known to pose a
greater health risk for women, but GAO was unable to find direct
evidence that the adverse events that contributed to its
withdrawal occurred predominantly in women. GAO found no evidence
that the health risks for the remaining withdrawn drug differed
for women and men.
-------------------------Indexing Terms-------------------------
REPORTNUM: GAO-01-286R
ACCNO: 577746
TITLE: Drug Safety: Most Drugs Withdrawn in Recent Years Had
Greater Health Risks for Women
DATE: 01/19/2001
SUBJECT: Consumer protection
Controlled substances
Drugs
Health hazards
Pharmacological research
Safety standards
Women
Health hazards
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GAO-01-286R
Drugs Withdrawn From Market United States General Accounting
Office
Washington, DC 20548
January 19, 2001 The Honorable Tom Harkin The Honorable Olympia J. Snowe The
Honorable Barbara A. Mikulski United States Senate
The Honorable Henry A. Waxman House of Representatives
Subject: Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater
Health Risks for Women
The Food and Drug Administration (FDA) approves drugs for sale in the United
States based on its determination that the clinical benefits of a drug
outweigh its potential health risks. To make this decision, FDA reviews
supporting data collected from several thousand patients during the drug's
development. Once a drug is approved for marketing and used by potentially
hundreds of thousands of patients, however, the type, rate, and severity of
adverse events caused by the drug can be much different than those detected
during the drug's development. In some cases, FDA or drug manufacturers have
acted to remove from the market drugs that have been shown to have
unacceptable health risks once they were in widespread use.
You requested that we identify drug products withdrawn from the market in
the United States since January 1, 1997, and that we note which of the
withdrawn drugs posed greater health risks for women than for men. We
collected this information from publicly available sources, primarily FDA
documents and research articles from the medical literature. We also
consulted drug safety experts. We looked only at prescription
pharmaceuticals, not at vaccines or over- the- counter medicines. 1 We
conducted our work from December 2000 to January 2001 in accordance with
generally accepted government auditing standards.
1 Although not included in our sample of withdrawn drugs, ingredients are
occasionally removed from nonprescription drugs because they are proven to
pose serious health risks. For example, on Nov. 6, 2000, FDA took steps to
remove phenylpropanolamine (PPA) from all drug products and requested that
all drug companies discontinue marketing products containing PPA. PPA, which
could be found in many over- the- counter (OTC) and prescription cough and
cold medications and OTC weight loss products, was reported to increase the
risk of hemorrhagic stroke (bleeding into the brain or tissue around the
brain) in women but not in men. See W. N. Kernan and others,
“Phenylpropanolamine and the Risk of Hemorrhagic Stroke,” New
England Journal of Medicine, Vol. 343, No. 25 (2000), pp. 1826- 32.
2 GAO- 01- 286R Drugs Withdrawn From Market
In summary, we found that 10 prescription drugs have been withdrawn from the
U. S. market since January 1, 1997. Eight of the 10 prescription drugs posed
greater health risks for women than for men: four of these may have led to
more adverse events in women because they were prescribed more often to
women than to men, while the other four had more adverse events in women
even though they were widely prescribed to both women and men. Of the two
remaining withdrawn drugs, one belongs to a class of drugs known to pose a
greater health risk for women, but we were unable to find direct evidence
that the adverse events that contributed to its withdrawal occurred
predominantly in women. We found no direct evidence that the health risks
for the remaining withdrawn drug differed for women and men. In comments on
a draft of this letter, FDA generally agreed with our analysis.
Eight of the 10 prescription drugs withdrawn since January 1, 1997, posed
greater health risks for women than for men (see table 1). For four of the
withdrawn drugs, the greater health risk may have been due to a higher level
of use among women. For example, the appetite suppressants Pondimin and
Redux were withdrawn from the U. S. market because they caused valvular
heart disease in some patients. Although the majority of the reported cases
were in women, most of the users were women, so the apparent gender- related
effects could be a reflection of the products' usage patterns. 2 Similarly,
women accounted for more than two- thirds of the deaths due to liver failure
in patients taking Rezulin, but women also were prescribed Rezulin more
often than men. 3 Finally, it is likely that Lotronex posed a greater health
risk for women because the drug was approved to treat irritable bowel
syndrome in women only. 4
Four other withdrawn drugs posed greater health risks for women even though
they were widely prescribed to both women and men. Posicor, which was
approved for the treatment of hypertension and angina, slowed or stopped the
heart rate in otherwise healthy people, especially elderly women, and
interacted with 26 different drugs. 5 Greater health risks for women may be
due to physiological differences that
2 See FDA, Center for Drug Evaluation and Research (CDER), Questions and
Answers About the Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine
(Redux), http:// www. fda. gov/ cder/ news/ phen/ fenphenqa2. htm
(downloaded Dec. 20, 2000); H. M. Connolly and others, “Valvular Heart
Disease Associated with Fenfluramine- Phentermine,” New England
Journal of Medicine, Vol. 337, No. 9 (1997), pp. 581- 88; D. J. Graham, and
L. Green, “Further Cases of Valvular Heart Disease Associated with
Fenfluramine- Phentermine,” New England Journal of Medicine, Vol. 337,
No. 9 (1997), p. 635.
3 See J. Kohlroser and others, “Hepatotoxicity Due to Troglitazone:
Report of Two Cases and Review of Adverse Events Reported to the United
States Food and Drug Administration,” American Journal of
Gastroenterology, Vol. 95, No. 1 (2000), pp. 272- 76; FDA, CDER,
presentation of D. Graham, Endocrinologic and Metabolic Drugs Advisory
Committee Meeting No. 72 (Mar. 26, 1999), pp. 94- 95.
4 See FDA talk paper, Glaxo Wellcome Decides to Withdraw Lotronex From the
Market (Nov. 28, 2000), http:// www. fda. gov/ bbs/ topics/ answers/
anhs01058. html (downloaded Dec. 20, 2000); FDA, CDER, Lotronex Questions
and Answers, http:// www. fda. gov/ cder/ drug/ infopage/ lotronex/
lotronex- qa. htm (downloaded Dec. 20, 2000).
5 See Medwatch: The FDA Medical Products Reporting Program, Background:
Posicor Labeling Changes (Dec. 18, 1997), http:// pharminfo. com/ medwatch/
mwrpt31. html (downloaded Nov. 29, 2000).
3 GAO- 01- 286R Drugs Withdrawn From Market
Table 1: Prescription Drugs Withdrawn From the United States Market, Jan. 1,
1997 Through Dec. 31, 2000
Drug Type of Drug Date Approved Date
Withdrawn Primary Health Risk Prescription Drugs With Evidence of Greater
Health Risks in Women
Pondimin (fenfluramine hydrochloride)
Appetite suppressant 6/ 14/ 1973 9/ 15/ 1997 Valvular heart disease
Redux (dexfenfluramine hydrochloride)
Appetite suppressant 4/ 29/ 1996 9/ 15/ 1997 Valvular heart disease
Seldane a (terfenadine) Antihistamine 5/ 8/ 1985 2/ 27/ 1998 Torsades de
Pointes (potentially
fatal irregular heartbeat) Posicor (mibefradil dihydrochloride)
Cardiovascular 6/ 20/ 1997 6/ 8/ 1998 Lowered heart rate in elderly women
and adverse interactions
with 26 other drugs Hismanal (astemizole) Antihistamine 12/ 19/ 1988 6/ 18/
1999 Torsades de Pointes
Rezulin (troglitazone) Diabetic 1/ 29/ 1997 3/ 21/ 2000 Liver failure
Propulsid b (cisapride monohydrate) Gastrointestinal 7/ 29/ 1993 7/ 14/ 2000
Torsades de Pointes
Lotronex (alosetron hydrochloride) Gastrointestinal 2/ 9/ 2000 11/ 28/ 2000
Ischemic colitis (intestinal
inflammation due to lack of blood flow)
Prescription Drugs Without Evidence of Greater Health Risks in Women
Raxar (grepafloxacin hydrochloride) Antibiotic 11/ 6/ 1997 11/ 1/ 1999
Torsades de Pointes
Duract (bromfenac sodium)
Analgesic and anesthetic 7/ 15/ 1997 6/ 22/ 1998 Liver failure
a Seldane- D was also withdrawn from the market Feb. 27, 1998. Terfenadine
was the active ingredient in both Seldane and Seldane- D; Seldane- D also
contained the decongestant pseudoephedrine. b Propulsid remains minimally
available on a patient- by- patient basis for those with severely
debilitating conditions.
Source: GAO analysis.
4 GAO- 01- 286R Drugs Withdrawn From Market
make women differentially more susceptible to some drug- related health
risks. Seldane, Hismanal, and Propulsid can in some circumstances prolong
the interval between the heart muscle's contractions and induce Torsades de
Pointes (TdP), a potentially fatal cardiac arrhythmia. Women have a higher
incremental risk of suffering an arrhythmia after taking these drugs than do
men probably because (1) the interval between heart muscle contractions is
naturally longer for women than for men and (2) male sex hormones moderate
the heart muscle's sensitivity to these drugs. 6
The remaining two withdrawn drugs have not demonstrated a greater health
risk for women. The first, Raxar, belongs to a class of drugs
(fluoroquinolone antibiotics) known to pose a greater health risk for women.
Since the early 1990s, there has been mounting evidence that fluoroquinolone
antibiotics, antiarrhythmic drugs, antihistamines (for example, Seldane and
Hismanal), and gastrointestinal prokinetics (for example, Propulsid) prolong
heart muscle contractions and induce TdP. 7 However, there is no conclusive
evidence that the adverse events that contributed to Raxar's withdrawal
occurred primarily in women. For the second, Duract, we found no evidence
that the risk of adverse events differed for women and men.
It is important to note that an examination of drug withdrawals, by itself,
does not provide a complete picture of drug safety. First, drug withdrawals
do not reflect a judgment concerning the absolute safety of a drug but
reflect a judgment about the risks and rewards of a drug in the context of
alternative treatments. For instance, despite the documented deaths from
liver failure among patients taking Rezulin, the drug was not withdrawn from
the market until FDA approved new, safer medications with similar benefits.
On the other hand, Raxar was withdrawn from the market on the basis of
relatively few adverse event reports because alternative treatments were
readily available.
Second, drug withdrawals may occur because the drugs are used incorrectly by
health professionals and patients, not because the drugs are inherently
dangerous
6 See Georgetown Center for Education and Research on Therapeutics , Drugs
That Prolong the QT Interval and/ or Induce Torsades de Pointes (Sept. 1,
2000), http:// www. torsades. org (downloaded Dec. 20, 2000); R. L. Woosley,
“From Bench to Bedside: Role of Gender- Based Therapeutics in the
Clinical Care of Women,” Journal of Women's Health, Vol. 7, No. 1
(1998), pp. 21- 23; S. N. Ebert and others, “Female Gender as a Risk
Factor for Drug- Induced Cardiac Arrhythmias: Evaluation of Clinical and
Experimental Evidence,” Journal of Women's Health, Vol. 7, No. 5
(1998), pp. 547- 57; C. Hart, “Monitoring Medications in the
Marketplace,” Modern Drug Discovery, Vol. 3, No. 5 (2000), pp. 40- 41,
43- 44, http:// pubs. acs. org/ hotartcl/ mdd/ oo/ jun/ mddhart. html
(downloaded Dec. 18, 2000); W. Haverkamp, “The Potential for QT
Prolongation and Proarrhythmia by Non- Antiarrhythmic Drugs: Clinical and
Regulatory Implications,” Report on a Policy Conference of the
European Society of Cardiology 2000, European Heart Journal, http:// www.
idealibrary. com (downloaded Dec. 12, 2000); J. T. Barbey and others,
“Spontaneous Adverse Event Reports of Serious Ventricular Arrhythmias,
QT Prolongation, Syncope, and Sudden Death in Patients Treated with
Cisapride” (obtained from J. T. Barbey Jan. 5, 2000, submitted for
publication).
7 See Woosley, pp. 21- 23; Ebert and others, pp. 547- 57; Hart, pp. 40- 41,
43- 44; L. Patmore and others, “Effects of Sparfloxacin,
Grepafloxacin, Moxifloxacin, and Ciprofloxacin on Cardiac Action Potential
Duration,” European Journal of Pharmacology, Vol. 406, No. 3 (2000),
pp. 449- 52.
5 GAO- 01- 286R Drugs Withdrawn From Market
when used correctly. For example, Duract was approved by FDA only for short-
term use (less than 10 days) for acute pain, but some physicians continued
to prescribe it for longer periods despite efforts by FDA and the
manufacturer to educate physicians about the dangers of doing so. Similarly,
the health risks associated with Seldane occurred when the drug was taken in
combination with medications that were contraindicated on Seldane's label.
Third, the off- label use of drugs also can be problematic because such use
may not have been shown to be safe and effective. For example, while
Pondimin (fenfluramine) was approved for short- term use as an appetite
suppressant, it was increasingly prescribed and used in combination with the
appetite suppressant phentermine as a part of a long- term weight loss and
management program. The offlabel use of this combination known as
“fen- phen” posed serious health risks for women. 8
AGENCY COMMENTS We received written comments from FDA on a draft of this
letter (see enclosure). FDA generally agreed with our description of the
issues and provided technical comments, which we have incorporated where
appropriate. FDA also suggested that we distinguish more clearly between
withdrawn drugs that led to more adverse events in women because they were
prescribed more often to women and those that caused more adverse events in
women even though the drugs were roughly prescribed on an equal basis to
women and men. We have revised the letter to clarify this distinction. FDA
also suggested that we include Raxar in the list of drugs with greater
health risks for women because it belongs to a class of drugs with known
risks for women. We did not do so because, as FDA's comments acknowledge, it
has not been shown that the adverse events that led to Raxar's withdrawal
occurred primarily in women.
- - - - 8 The use of phentermine alone has not been associated with valvular
heart disease.
6 GAO- 01- 286R Drugs Withdrawn From Market
We plan no further distribution of this correspondence until 30 days after
the date of this letter. At that time, we will send copies of this letter to
the Commissioner of FDA and to others who request it. The letter will also
be available on GAO's home page at http:// www. gao. gov.
Major contributors to this letter were Martin T. Gahart, Emily J. Rowe, and
Lisanne Bradley. Please contact me at (202) 512- 7119 if you have any
questions.
Janet Heinrich, Director Health Care- Public Health Issues
Enclosure
ENCLOSURE ENCLOSURE 7 GAO- 01- 286R Drugs Withdrawn From Market
ENCLOSURE ENCLOSURE 8 GAO- 01- 286R Drugs Withdrawn From Market
(290023)
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