M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

**DATE:** September 27, 2000

**FROM:** Lois La Grenade, M.D., M.P.H., Epidemiologist

Parivash Nourjah, Ph.D., Epidemiologist

Division of Drug Risk Assessment I, HFD-430

Office of Post-Marketing Drug Risk Assessment (OPDRA)

**THROUGH:** Julie Beitz, M.D., Director

> Division of Drug Risk Assessment I, HFD-430

Office of Post-Marketing Drug Risk Assessment (OPDRA)

**SUBJECT: Review of study protocol, final study report and raw data
regarding the incidence of hemorrhagic stroke associated with the use of
phenypropanolamine.**

**TO:** Charles Ganley, M.D., Director,

Division of OTC Drug Products, HFD-560

PID \# D 000487

**Executive Summary**

This consult is in response to a request from the Division of OTC Drug
Products, HFD-560, to review the study report entitled
"Phenylpropanolamine & Risk of Hemorrhagic Stroke: Final Report of the
Hemorrhagic Stroke Project", the study protocol and raw data submitted
by Yale University. It was designed to test the association between
hemorrhagic stroke in young people and use of
phenylpropanolamine-containing products, a signal generated from
studying case reports in our spontaneous reporting system. Our overall
conclusion is that this study was well designed and executed. The
case-control design was best suited for this study since the outcome
under investigation was rare. All reasonable steps were taken to
minimize bias and confounding.

The study demonstrated a statistically significant increased risk of
hemorrhagic stroke among both appetite suppressant users and first time
users of PPA as a cough/cold remedy.

OPDRA concludes that the study provides compelling evidence of increased
risk of hemorrhagic stroke in young people who use PPA-containing
appetite suppressants. This finding, taken in association with evidence
provided by spontaneous reports and case reports published in the
medical literature, leads us to recommend that these products should no
longer be available for over-the-counter use.

The Yale investigators also found a statistically significant
association between first time PPA use in cough/cold remedies and
hemorrhagic stroke. OPDRA considers this association to be as important
as that for use of PPA as an appetite suppressant. FDA continues to
receive spontaneous reports of hemorrhagic stroke with high-dose
cough/cold remedies. Some reports indicate that only one dose was
administered. The doses of PPA delivered in cough/cold preparations
overlap those delivered in appetite suppressants, and there is evidence
to suggest that the risk of hemorrhagic stroke may be higher with PPA
doses at or above 75 mg/day. OPDRA concludes that high-dose PPA
cough/cold remedies are associated with an increased risk of hemorrhagic
stroke. These high doses may be achieved by exceeding the recommended
labeled dose of the low-dose products. OPDRA therefore recommends that
PPA-containing cough/cold remedies should no longer be available as
over-the-counter products.

**Introduction**

This consult is in response to a request from the Division of OTC Drug
Products, HFD-560, to review the study report entitled
"Phenylpropanolamine & Risk of Hemorrhagic Stroke: Final Report of the
Hemorrhagic Stroke Project", the study protocol and raw data submitted
by Yale University, as well as comments on the Hemorrhagic Stroke
Project Report, May 24, 2000, provided by the CHPA Phenylpropanolamine
Working Group. We were also requested to provide an update of cases of
hemorrhagic stroke associated with phenylpropanolamine (PPA) use,
reported to the Agency's Adverse Event Reporting System (AERS) since the
end of January 1991, the date of the last review.

The body of this memorandum contains the review of the study protocol
and final report. Appendix A contains an update of cases of hemorrhagic
stroke in AERS along with information on background incidence rates of
hemorrhagic stroke. Appendix B contains a response to CHPA's comments,
in the form of a consult to OPDRA prepared by Dr. Yi Tsong from the
Office of Biostatistics.

### Review of Study Protocol and Report

The Yale study demonstrated an increased risk of hemorrhagic stroke
associated with PPA use. The investigators found the increase in risk of
hemorrhagic stroke to be statistically significant among appetite
suppressant users and first time users of PPA as a cough/cold remedy.
Observational studies, particularly case-control studies, are
potentially subject to a number of biases, and this case-control study
is no exception. However, the hallmark of a good case-control study is
that these biases are anticipated and measures instituted in the design
and analysis stages to minimize them to the greatest extent possible. In
reviewing the design and analysis of this study we will attempt to
examine potential biases and the measures taken to minimize them. We
will also report on additional analyses undertaken by us to test the
consistency of the data and the results.

## Study Objectives

The objectives were clearly identified and articulated, and were
threefold:

1)  To estimate the association between PPA and hemorrhagic stroke among
    men and women aged 18 -- 49 years;

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2)  To estimate the association between PPA and hemorrhagic stroke by
    type of PPA exposure among the same target population;

3)  Among women aged 18-49 years to estimate (a) the association between
    first use of PPA and hemorrhagic stroke and (b) the association
    between PPA in appetite suppressants and hemorrhagic stroke.

We must point out that from the Agency's point of view, the third
hypothesis \[parts (a) and (b)\] was the most important, as this was
generated from studying case reports in our spontaneous reporting system
as well as those reported in the published literature (Heidi Jolson,
1991) and was the main stimulus for the performance of this study. It is
therefore pertinent that these were the hypotheses that were found to be
statistically significant.

### *Case Definition*

Strict diagnostic criteria were developed to ensure accurate
identification of hemorrhagic stroke cases in the target population.
Both clinical and diagnostic criteria had to be met. Clinical criteria
included signs and symptoms consistent with hemorrhagic stroke.
Diagnostic confirmatory criteria were either CT scan or MRI or lumbar
puncture in the absence of CT scan or MRI. One of the investigators
confirmed the disease status by reviewing the medical records of
suspected cases, without knowledge of the exposure status of the cases.
This served to minimize **misclassification bias** among cases.

### *Inclusion/Exclusion Criteria*

These were clearly defined for both cases and controls, again minimizing
**misclassification.**

### *Exposure Definition/Ascertainment*

Exposure was clearly defined and an exposure window was identified.
Ascertainment of exposure was undertaken by trained interviewers. It was
not possible to blind interviewers as to case/control status. To
minimize potential **interviewer bias**, interviewers were randomly
assigned to cases or controls, and questions were asked about multiple
medications, thus blinding them to the exact exposure under study. In
addition, subjects were only classified as "definitely exposed" if the
exposure was confirmed by one of several methods outlined in the
protocol. Both cases and controls were interviewed in-person. The
location of in-person interviews was determined by the subject\'s
preference. Cases were interviewed either in hospital (majority) or at
home. Controls were interviewed at home, physician's office, or other
convenient location. Since the choice of the location of the interview
was based on the subject\'s preference and convenience, it is highly
unlikely that the location of the interview would be related to the use
of PPA. Forty-four of the 1376 controls and three of 703 cases preferred
to complete the interview by telephone. Since telephone interviews only
were conducted on a very small fraction of cases and controls, any bias
due to differences in ascertainment methods should be minimal, and would
be expected to be non-differential with respect to the interviewing
methods.

## Opportunity of Exposure

Since the use of PPA might be seasonal, to ensure that cases and
controls had an equal opportunity of exposure, controls were identified
and interviewed within 30 days of the index date (e.g., date of stroke)
of their matched case subject. Controls were also matched to cases for
day of the week and time of day of the stroke. This matching strategy
ensured the probability of exposure to any medication or other
covariates (e.g., alcohol drinking or cigarette smoking) was similar
between cases and controls since their use could vary by time and by day
of the week.

***Recall Bias***

Recall bias reflects the greater likelihood of cases to recall events
prior to or surrounding the event of interest, in this case, the stroke.
Several strategies were used to minimize recall bias. First of all, case
subjects were interviewed within a short period of the index day (mean
13 days, range 0 -- 30 days). Another strategy to minimize recall bias
was to obtain information on **all** medications used, and by the use of
date prompts, such as birthdays or dates of other significant events.
For the purpose of ascertainment of PPA exposure, a focal time for
controls was established as one of the 7 days prior to their
identification as controls. The focal time was matched with the day and
time of day of the matched case\'s focal time -- the time of onset of
symptoms that led the cases to seek medical care. This was another
method of ensuring that controls were able to recall the events
accurately (a short period to the event). Further, by making the
\"exposure opportunity\" the same for cases and controls for those
variables that could vary by time of day, and day of the week, the
potential for **information bias** was also minimized. Information bias
refers to differences in data quality and completeness based on the
method used to obtain the information.

### *Independence of Association of Exposure to Cases or Controls*

Assessment of exposure was independent of the selection of cases and
controls. It is unlikely that participation in the study was related to
PPA use. First, more than 85% of cases were identified from 3 sites
which enrolled nearly all of the acute care hospitals in their
geographic location. Second, the reason why most eligible
non-participants did not participate in the study was that for logistic
reasons the interviewer was not able to contact these case subjects
within 30 days after the stroke, as specified in the protocol. There is
virtually no possibility that the interviewers' inability to contact
these individuals on time was related to the use of PPA, as the exposure
status of the cases was unknown. For controls, although we do not have
any information on how many eligible controls refused to participate,
nor what was the overall response rate, there is no reason to believe
that PPA use was related to participation of controls.

## Selection Bias

A potential bias in case-control studies is selection bias. This may
occur when groups of patients are selected into the study for whom risk
of disease is different from that of the whole group with the disease.
The possibility of selection bias exists in this study because the most
severe cases were excluded, i.e., those who died, were unconscious or
unable to speak up to 30 days after the stroke. This was considered by
the investigators in the planning stage but was weighed against the
exposure misclassification error that would result from the use of proxy
interviews for these cases. Sample calculations were done and the
results indicated that the error from proxy interviews greatly exceeded
that from any potential selection bias that might result from excluding
cases that were unable to speak. The investigators also calculated that
the impact of exposure misclassification error introduced by proxy
respondents would have been so great as to render the study incapable of
detecting an odds ratio as great as 10. In other words, there would have
been no point in conducting the study. In order to determine the impact
of excluding these cases on the estimate of the odds ratios we would
have to assume that PPA use was related to the survival or severity of a
stroke, and we have no reason to believe that this is true.

### *Selection of Controls*

The authors attempted to identify 2 controls per case by using random
digit dialing. This was a good strategy for two reasons. First, the
controls were chosen completely at random; second, the controls were
population-based, so that the results are generalizable to the source
population from which the cases and controls were drawn. To ensure
comparability between cases and controls with respect to some of the
risk factors (possible confounders), attempts were made to enroll
controls that were matched with cases on gender, age, race (black,
other), and telephone exchange (surrogate for socioeconomic status).
Although matching increases the complexity of a study, in case-control
studies, it is considered an excellent method for efficient controlling
of the confounding variables analytically. Although matching was largely
successful, matching on race and educational level was slightly unequal
between cases and controls. The authors further controlled for these
inequalities by adjustment during analysis. Since the use of PPA might
be seasonal, and to ensure that cases and controls had an equal
opportunity of exposure, controls were identified and interviewed within
30 days of the index date of their matched case subject. Finding
matching controls seems to have been difficult as the average number of
phone calls dialed to find matches for each case was 150.

***Temporal Precedence Bias***

To ensure that the exposure preceded the onset of stroke, the authors
used detailed accounts of subjects' onset of symptoms in relation to
diagnosis. This information was used to establish a focal time as
previously described. The focal time refers to the time of onset of
symptoms that led the patients to seek care. Only medication use prior
to the focal time was considered relevant to the study question. Since
headache may be a symptom of stroke, the authors also examined the
\"alternate focal time\" on the estimate of effect measurement to rule
out the possibility of temporal precedence bias. The "alternate focal
time" represented the earliest possible time that intracerebral bleeding
could have occurred and the onset of sentinel headache was chosen as the
"alternate focal time". Sub-analyses using the "alternative focal time"
yielded estimates of the odds ratio that were similar to that found with
the original focal time, leading the investigators to conclude that
temporal precedence bias in this study was minimal or not present.

## Misclassification Bias

The investigators reduced the possibility of misclassification of
exposure (PPA use) by using a highly structured questionnaire. Events
such as birthdays, holidays, and special events were used as memory
aids. The authors also verified each of the reported medications by
asking the subjects to present the actual container of the reported
medication or by picking out reported brand-name medications from a book
containing photographs (Product Identification Book). Verification for
medication use in the 3-day window prior to the focal time was 96% and
94% for cases and controls respectively. This verification was another
method of reducing misclassification of PPA use. Additionally, the
authors conducted two more steps to further ensure that the possibility
of exposure misclassification error was reduced to an absolute minimum.
One, they only considered the \"definite\" and \"possible\" exposure
responses in the analyses. Two, they compared the use of other
non-prescription medications between cases and controls to ensure that
the cases did not systematically have greater recall of the use of any
medications as a reason for their recent stroke. Based on their
analysis, there was no evidence of recall or misclassification bias.

### *Sample Size*

An essential step in the design of case-control studies is conducting
sample size and/or power calculations to ensure the study is large
enough to detect a difference if one really exists. Considerations are
given to the rarity of the outcome and of the exposure, as well as to
cost and time constraints. The authors did this in the protocol. They
took into account the rarity of hemorrhagic stroke in young people, the
problem of finding matched population controls and the prevalence of PPA
exposure in the population. They set up surveillance systems to detect
as many cases of stroke as possible, and estimated how long the study
would take. However, historical records indicate that the Agency was
concerned that the study might be underpowered to detect an association
since the original sample size calculation was based on an odds ratio of
5 for an association between hemorrhagic stroke and first use of PPA. We
must point out that the odds ratio of 5 was not determined by any public
health or clinical considerations, but on practical considerations
related to time and cost constraints. As often happens in epidemiologic
studies in the field, the investigators encountered practical problems
including difficulties in recruiting controls, which contributed to the
study taking longer than expected. Despite this, it should be noted that
this is a particularly large prospective case-control study, the largest
ever conducted on hemorrhagic stroke. In spite of the Agency's initial
reservations about inadequate sample size and power, the study still
identified an association between PPA use and hemorrhagic stroke in the
3-day period following initial use, the time period of greatest concern
and suspicion.

### Statistical Analysis

***Exposure Variables***

As outlined in the study protocol, the authors examined two
exposure-windows for PPA use: one was defined as "the index day prior to
the focal time and the preceding three calendar days", the other was
defined as PPA use on "the index day prior to the focal time or on the
preceding calendar day". In other words, the first exposure window
included the three days prior to the stroke date and the second window
-- defined as *current use* - included the day preceding the stroke. If
the latter exposure occurred without any use of PPA during the preceding
two-week period, that exposure was referred to as *first use*.
*Not-first use* is current use with other use in the two-week period
before the index date.

***Covariates***

The investigators collected a large amount of information on risk
factors for stroke by interviewing study participants. The confounding
effect of these variables was assessed analytically. The three most
important risk factors: race (black or non-black), history of
hypertension, and cigarette smoking, were included in the multivariate
analysis (basic adjusted model). The confounding effect of the other
covariates was examined if adding any of them to the basic model altered
the odds ratio estimate by 10%. High school education was the only
covariate determined to change the odds ratio by at least 10%.

***Statistical Method***

Appropriately, the conditional logistic regression model was used for
calculating both unadjusted and adjusted odds ratios, since the study
had a matched design. Since the number of exposures was small
particularly for analysis of appetite suppressant and first use, the
authors calculated the confidence interval of unadjusted odds ratio
based on an exact method. For the purpose of statistical testing, the
authors reported only the lower limit of the one-sided 95% C.I. as
pre-specified in the protocol.

## Additional Statistical Analyses of Raw Data Conducted by OPDRA

## Potential Confounding by Hypertension and Other Factors

Hypertension is the single most important risk factor for a stroke,
followed by smoking, body weight and alcohol consumption. Life-style
changes may lower hypertension and thus the risk for stroke. Therefore,
past history of hypertension may not be reflective of the hypertension
status of an individual at the time of a stroke. This misclassification
of hypertension status could result in residual confounding. Let us
therefore examine the possible effects of this residual confounding on
the results of the study. First, the odds ratio for appetite suppressant
use is 15.92, a substantial increase in risk. Its very magnitude makes
it difficult to explain by confounding alone. Second, in order for a
variable to be a confounder, the variable must in some way be associated
with the exposure. There is very little evidence to support the view
that PPA use/non-use is related to hypertension. Since the labels of
PPA-containing products advise that PPA use should be avoided in
hypertensive persons, the association of PPA use with hypertension
should be negative. Such a negative association would result in biasing
the result towards no association (OR=1) if the confounding factor is
not controlled for. Thirdly, in addition to the steps taken by the
investigators, we examined this further ourselves by additional analyses
restricted to subjects without a past history of hypertension as
described earlier, and the results did not change materially, thereby
providing additional evidence that confounding by hypertension is not
present.

We analyzed education and body mass index (BMI) as continuous rather
than categorical variables, and again the OR remained largely unchanged.
At our request, the Yale investigators explored the possible impact of
cigarette smoking and alcohol consumption in a more detailed way. The
following is an excerpt from their report.

With regard to cigarette smoking*: "The following measures of cigarette
smoking were examined for their effects on all PPA-stroke associations:
Current cigarette smoker (yes/no); average number of cigarettes per day
smoked in 3-day exposure period (continuous variable); average packs per
day smoked in 3-day exposure period (\<1, 1, 2+); cigarettes smoked in
3-day exposure period (any vs. none); average number of cigarettes per
day smoked in prior 6 months (continuous variable); average packs per
day smoked in prior 6 months (\<1, 1, 2+). Odds ratios for PPA and
stroke were essentially unchanged by inclusion of any of these
quantitative measures of smoking."*

With regard to alcohol consumption: *"The following measures of alcohol
consumption were examined for their effect on all PPA stroke
associations: Any positive response to history of alcohol abuse
screening questions; 3 or more positive responses to history of abuse
questions; average number of drinks per day in 3-day exposure period
(continuous variable); average of more than 2 drinks per day in 3-day
exposure period (yes/no); average number of drinks per week in prior 6
months (yes/no). Odds ratios for PPA and stroke were essentially
unchanged by inclusion of any of these measures of alcohol consumption
and final adjusted models were reported without adjustment for alcohol
use."*

In summary, the investigators examined the impact of all important
confounding factors on the estimates.

## Dose Response 

The investigators examined the association between current PPA dose and
risk for hemorrhagic stroke. Among 21 exposed control subjects, the
median current dose of PPA (i.e., the total amount taken on the index
day or preceding day) was 75 mg. The adjusted odds ratio was higher for
current doses above 75 mg than for lower doses. Among first dose users,
four of eight cases and two of five controls were exposed to \> 75 mg of
PPA.

Given that 75 mg is contained in a single dose of many over-the-counter
long-acting PPA cough/cold remedies, and that recommended adult dosing
is every 12 hours or 150 mg/day, OPDRA further evaluated the association
between risk of hemorrhagic stroke and a range of current PPA doses.
Exploratory analyses suggest that there may be an increased risk of
hemorrhagic stroke with labeled doses at or above 75 mg/day;
dose-ordering of odds ratios was seen.

***Sparse Data Bias***

The small number of exposed subjects (i.e., PPA users) limits the power
of the study and may also result in sparse data bias, particularly for
the results for appetite suppressant and first use of PPA. In order to
examine the impact of sparse data bias, we conducted three sensitivity
analyses. The results are displayed in Table 1. In each case we changed
the exposure status of only one subject. In the first analysis, we
changed the status of one case subject from non-exposed to exposed while
his/her matched control remained non-exposed. The odds ratio for PPA in
appetite suppressants and first time PPA use changed from 15.92 to 20.31
and from 3.14 to 3.45, respectively. In the second analysis, we changed
the status of one control subject from non-exposed to exposed, while
his/her matched case remained exposed. The odds ratio of PPA in appetite
suppressants and first use of PPA changed from 15.92 to 14.42 and from
3.14 to 3.07, respectively. In the third analysis, we changed the status
of one control subject from non-exposed to exposed, while his/her
matched case remained non-exposed. Under this condition, the odds ratio
of PPA in appetite suppressants and first use of PPA changed from 15.92
to 7.29 and 3.14 to 2.27, respectively. We consider these scenarios
unlikely because great care was taken to avoid misclassification error,
such that changes in excess of 10% are highly improbable. **The
association of appetite suppressants and first use of PPA still remains
even under these conditions.**

Further, we examined the impact of moving two control subjects from a
non-exposed to an exposed status. This analysis was only employed for
matched pairs in which both cases and controls were non-exposed. Under
this condition, the odds ratio of hemorrhagic stroke associated with PPA
in appetite suppressants changed from 15.92 to 3.22 and the odds ratio
of stroke associated with first use changed from 3.14 to 2.1. Again,
even under this extremely unlikely condition, the association of PPA
containing products with hemorrhagic stroke remains. We interpret this
to mean that the association between appetite suppressant and first use
of PPA with hemorrhagic stroke cannot be completely explained by the
sparse data bias alone.

### Discussion

This epidemiologic case-control study was designed to test specific
hypotheses generated by analysis of spontaneous reports received by the
Agency from 1977 to 1991. These reports strongly suggested an
association between hemorrhagic stroke and use of high-dose PPA as an
appetite suppressant. Additional evidence of an association was
suggested for use of PPA as a cough/cold remedy. Most of the reports
were associated with first use of these products. Domestic reports of
stroke in women aged 10-59 years topped the list of drugs with reports
of stroke in this population in the Agency's adverse event report
database (SRS). Additional details regarding these reports are
summarized in Dr. Tsong's review in Appendix B.

An updated search of spontaneous reports of hemorrhagic stroke in the
18-49 year age group in the Agency's adverse event reporting database
(encompassing 1991 -- 2000) revealed 16 additional cases, thirteen
occurring in women. In all cases, the suspect drug was a long-acting
preparation containing 75 mg of PPA per unit dose. Of eleven cases for
which the indication of use was provided, ten reported an indication for
respiratory symptoms. Further clinical details are provided in Appendix
A.

Case reports in the literature are consistent with spontaneous reports
received by the Agency in suggesting a possible association of PPA use
and hemorrhagic stroke.

The study conducted by Yale University was well designed and executed
and its findings merit serious attention. The strengths of the study lie
in the clarity of its objectives, the meticulous adherence to sound
epidemiology practices in its design and execution, and the consistency
of the findings, regardless of the analytic methods. Its only limitation
was in the power and sample size, which we discussed earlier. That the
study was nevertheless able to find a consistent association between PPA
use and hemorrhagic stroke, particularly in women, attests to its
overall high quality.

### The case-control design was best suited for this study since the outcome under investigation was rare. All reasonable steps were taken to minimize bias and confounding. Quality control measures were built into the design. Analysis was appropriate for the type of study. For the sub-sets of PPA use as an appetite suppressant and of first time PPA use as a cough/cold remedy, the association was statistically significant and was most striking in women. 

### Conclusion

The Yale study was a well-designed case-control study with prospectively
defined endpoints and appropriate statistical analyses. Study conduct
and analyses of results were done according to protocol. Specific
conclusions of OPDRA follow.

**Appetite Suppressants.** In the Yale study, for the association
between hemorrhagic stroke and PPA use in appetite suppressants within
the three-day exposure window, the adjusted odds ratio was 15.92 (lower
confidence limit=2.04, p=0.013). For the association between PPA in
appetite suppressants and risk for hemorrhagic stroke among women, the
adjusted odds ratio was 16.58 (lower confidence limit=2.22, p=0.011).
OPDRA believes that the weight of evidence from this epidemiologic
case-control study taken together with spontaneous reports and reports
in the published literature strongly suggests that PPA use as an
appetite suppressant is associated with hemorrhagic stroke.

**Cough/Cold Remedies.** In the Yale study, for the association between
hemorrhagic stroke and PPA use in cough/cold remedies within the
three-day exposure window, the adjusted odds ratio was 1.23 (lower
confidence limit=0.75, p=0.245). For first time PPA use among women, the
adjusted odds ratio was 3.13 (lower confidence limit=1.05, p=0.042). All
first dose PPA use involved cough/cold remedies. We note that the lower
odds ratio encountered with first time PPA use represents a wide range
of doses of PPA in the different preparations (e.g., 6.25 -- 75
mg/dose).

We consider the association with hemorrhagic stroke for cough/cold
remedies as important as that for use of PPA as an appetite suppressant.
FDA continues to receive spontaneous reports of hemorrhagic stroke with
high-dose PPA cough/cold remedies in recent years. Some reports indicate
that only one dose was administered. The doses of PPA delivered in
cough/cold preparations overlap those delivered in appetite
suppressants, and there is evidence to suggest that the risk of
hemorrhagic stroke may be higher with PPA doses at or above 75 mg/day.
We conclude that high-dose PPA cough/cold remedies are associated with
an increased risk of hemorrhagic stroke. These high doses may be
achieved by exceeding the recommended labeled dose of the low-dose
products.

### Recommendations

OPDRA recommends that over-the-counter use of PPA as an appetite
suppressant be reevaluated in light of its strong association with
hemorrhagic stroke. We recommend that PPA-containing appetite
suppressants should no longer be available as over-the-counter products.

OPDRA recommends that over-the-counter use of PPA as a cough/cold remedy
be reevaluated in light of its positive association with hemorrhagic
stroke. Although the odds ratio is less than that for PPA-containing
appetite suppressants, nonetheless it is clearly positive and
statistically significant. In addition, there was suggestive evidence
for a dose-related increase in the risk of hemorrhagic stroke. Thus, the
lower magnitude odds ratio with cough/cold remedies may well be
explained by diluting the effects of high-dose PPA products with
low-dose PPA products. In light of the potential for high dose exposure
from use of ***any*** of the PPA-containing cough/cold remedies, we
recommend that PPA-containing cough/cold remedies should no longer be
available as over-the-counter products. The use of PPA-containing
cough/cold remedies in the US population is undoubtedly greater than the
use of PPA-containing appetite suppressants, so the public health
implications of safe dosing for this indication are far-reaching.

Lois La Grenade, M.D., M.P.H. Parivash Nourjah, Ph.D

Copies: HFD 560 Ganley/Katz

> HFD 400 Honig/Himmel

HFD 430 Guinn (electronic copy/PID \# D 000487/Beitz/Trontell/division
files

### Table 1. Sensitivity Analyses for Addressing Bias due to Sparse Data

+-----------------------+-----------------------+-----------------------+
|                       | First Time PPA Use    | Appetite Suppressants |
|                       |                       |                       |
|                       | (Odds Ratio and 95%   | (Odds Ratio and 95%   |
|                       | C.I.)                 | C.I.)                 |
+-----------------------+-----------------------+-----------------------+
| From original study   | 3.14 (0.96 -- 10.28)  | 15.92 (1.37 --184.12) |
| report                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| One case subject      | 3.45 (1.09 -- 10.96)  | 20.31 (1.95 --        |
| moved from            |                       | 212.26)               |
| non-exposed to        |                       |                       |
| exposed while his/her |                       |                       |
| matched control       |                       |                       |
| remained non-exposed  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| One control subject   | 2.07 (0.93 --10.15)   | 14.42 (1.16 --178.09) |
| moved from            |                       |                       |
| non-exposed to        |                       |                       |
| exposed while his/her |                       |                       |
| matched case remained |                       |                       |
| exposed               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| One control subject   | 2.27 (0.73 -- 7.15)\* | 7.29 (1.14            |
| moved from            |                       | --46.31)\*\*          |
| non-exposed to        |                       |                       |
| exposed while his/her |                       |                       |
| matched case remained |                       |                       |
| non-exposed           |                       |                       |
+-----------------------+-----------------------+-----------------------+

\*We repeated this analysis 10 times, the average point estimate was 2.6

\*\*We repeated this analysis 10 times, the average point estimate was
6.9

(Note: Cases and controls were not matched on exposure)

**Appendix A**

**Update on Cases of Hemorrhagic Stroke Associated with PPA Use in
AERS**

On July 17, 2000, AERS was queried for cases reported since February 1,
1991, in association with PPA-containing medications, using the SOC
(System Organ Class) term Nervous system disorders and the PTs
(preferred terms) cerebrovascular accident NOS, hemorrhagic stroke,
intracranial hemorrhage NOS, subarachnoid hemorrhage NOS, and
intraventricular hemorrhage NOS. This yielded reports of 37 US cases.
Images were printed and reviewed for accuracy, duplications and
retrieval of relevant information. Cases of vascular malformations and
aneurysms were excluded, as also were cases over age 49 years, cases of
cerebrovascular accidents due to thrombosis or infarction, or reports
with no indication in the narrative or elsewhere of intracranial
hemorrhage.

The results are summarized in Table 1 A. After exclusions as listed
above there were 16 unduplicated cases of hemorrhagic stroke reported in
the 18-49 age group. The age range was 18-47 years, with a median of 35
years. Thirteen cases were female and three male. In all cases, the
suspect drug was a long-acting preparation containing 75 mg of PPA per
unit dose. There were 4 deaths, all in females, two due to overdose. The
diagnosis of hemorrhagic stroke was confirmed in 10 cases by CT scan or
autopsy. In 10 of the 11 cases for whom an indication for use was
provided, the indication was for respiratory symptoms. Information on
duration of treatment was provided for 8 cases and ranged from a single
dose to 7 days, with a median of 48 hours. The time to onset after the
last dose was only stated in 6 cases and ranged from 1-2 hours to less
than 24 hours, with a median of 4 hours. One case had a past history of
hypertension and another a past history of a previous infarct associated
with complicated migraine.

### Background Incidence of Hemorrhagic Stroke in Young People

Sacco and colleagues reported that the average annual age-specific
incidence of all strokes for ages 20-44 years was 20 per 100,000
population (1). They estimated that 23% of these were hemorrhagic
(intracerebral hemorrhage 17%, subarachnoid hemorrhage 6%). Combining
these estimates would give an average annual incidence of hemorrhagic
stroke in the 20 -- 44 age group of 4.6 per 100,000 per year. This
estimate is consistent with that of Petitti and colleagues who reported
the incidence of hemorrhagic stroke in women of childbearing age (15-44
years) as

5.2 per 100,000 (C.I.= 4.7-6.1) (2). The background incidence will be
used to assess the public health impact of the risk of hemorrhagic
stroke with PPA use in young people.

### References

1.  Sacco RL, et al. Stroke Incidence among White, Black and Hispanic
    Residents of an Urban Community. The Northern Manhattan Stroke
    Study. 1998 American Journal of Epidemiology. Vol 147, No.3,
    259-268.

2.  Petitti DB et al. Incidence of Stroke and Myocardial Infarction in
    Women of Reproductive Age. 1997 Stroke. Vol 28, No.2, 280-283.