[Federal Register Volume 66, Number 157 (Tuesday, August 14, 2001)]
[Notices]
[Pages 42665-42671]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-20300]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01N-0196]


Phenylpropanolamine; Proposal to Withdraw Approval of New Drug 
Applications and Abbreviated New Drug Applications; Opportunity for a 
Hearing

AGENCY: Food and Drug Administration, HHS.

[[Page 42666]]


ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
withdraw approval of 16 new drug applications (NDAs) and 8 abbreviated 
new drug applications (ANDAs). These are the approved applications for 
prescription and over-the-counter (OTC) drug products containing 
phenylpropanolamine. FDA is offering the holders of the applications an 
opportunity for a hearing on the proposal. All other drug products 
containing phenylpropanolamine that are considered new drugs (e.g., 
extended-release products and any prescription product) are also 
subject to this notice. FDA is taking this action because of the 
association of phenylpropanolamine with increased risk of hemorrhagic 
stroke.

DATES: Submit written requests for a hearing by September 13, 2001. 
Submit data and information in support of the hearing request by 
October 15, 2001. An applicant planning to withdraw or reformulate a 
product covered by the applications listed in this notice should inform 
the agency as early as possible, preferably on or before October 15, 
2001.

ADDRESSES: A request for a hearing, supporting data, and other comments 
are to be identified with Docket No. 01N-0196 and submitted to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852.
    Communications pertaining to withdrawal or reformulation of 
products covered by applications listed in this notice should be 
directed to the Division of Pulmonary and Allergy Drug Products (HFD-
570), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, rm. 10B-45, Rockville, MD 20857, or 
the Office of Generic Drugs (HFD-600), 7500 Standish Pl., Rockville, MD 
20855.

FOR FURTHER INFORMATION CONTACT:
    For information on medical/scientific issues: Gerald M. Rachanow or 
Robert L. Sherman, Center for Drug Evaluation and Research (HFD-560), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-2222.
    For general information concerning this notice: Mitchell Weitzman, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Phenylpropanolamine is an ingredient used in prescription and OTC 
drug products as a nasal decongestant to relieve stuffy nose or nasal 
congestion and in OTC weight control drug products to control appetite. 
Phenylpropanolamine was included in the agency's OTC drug review. 
Although phenylpropanolamine was regarded as effective for weight 
control and as a nasal decongestant, final classification of the 
ingredient was deferred pending the resolution of issues pertaining to 
its safety.

II. Products Subject to This Notice

    This notice applies to all OTC and prescription immediate-release 
and extended-release drug products containing phenylpropanolamine that 
are marketed under approved applications. The agency is aware that a 
number of prescription products and some OTC extended-release products 
containing phenylpropanolamine, all of which are considered new drugs, 
have been marketed without an approved application. This notice also 
applies to all of these products. This notice does not apply to 
immediate-release OTC drug products marketed under the OTC drug 
monograph system; FDA intends to address these products in a separate 
document to be published in a future issue of the Federal Register.
    The following applications are affected by this notice:

----------------------------------------------------------------------------------------------------------------
           Application Number                         Drug                             Applicant
----------------------------------------------------------------------------------------------------------------
NDA 11-694..............................  Dimetane-DC Syrup..........  A. H. Robins Co., P.O. Box 8299,
                                                                        Philadelphia, PA 19101.
NDA 12-152..............................  Ornade Extended-Release      SmithKline-Beecham, 1250 South
                                           Capsule.                     Collegeville Rd., P.O. Box 5089,
                                                                        Collegeville, PA 19426.
NDA 12-436..............................  Dimetapp Extended-Release    Whitehall-Robins, 5 Giralda Farms,
                                           Tablet.                      Madison, NJ 07940.
NDA 13-087..............................  Dimetapp Elixir............  Do.
NDA 18-050..............................  Corsym Extended-Release      Medeva Americas, Inc., 755 Jefferson Rd.,
                                           Suspension.                  P.O. Box 1710, Rochester, NY 14603.
NDA 18-099..............................  Contac Extended-Release      SmithKline Beecham Consumer Health, L.
                                           Capsule.                     P., 1500 Littleton Rd., Parsippany, NJ
                                                                        07054.
NDA 18-298..............................  Tavist-D Extended-Release    Novartis Consumer Health, Inc., 560
                                           Tablet.                      Morris Ave., Summit, NJ 07901.
NDA 18-556..............................  Demazin Extended-Release     Schering-Plough HealthCare Products,
                                           Tablet.                      Three Oak Way, P.O. Box 603, Berkeley
                                                                        Heights, NJ 07922.
NDA 18-809..............................  Phenylpropanolamine          Schwarz Pharma, 6140 West Executive Dr.,
                                           Hydrochloride (HCL)          Mequon, WI 53092.
                                           Chlorpheniramine Maleate
                                           Extended-Release Capsule.
NDA 19-410..............................  Hycomine Syrup.............  Endo Pharmaceuticals, Inc., 500 Endo
                                                                        Blvd., Garden City, NY 11530.
NDA 19-411..............................  Hycomine Pediatric Syrup...  Do.
NDA 19-613..............................  Contac Extended-Release      Novartis Consumer Health, Inc.
                                           Tablet.
NDA 20-640..............................  Tavist-D Extended-Release    Do.
                                           Tablet.
ANDA 71-099.............................  Bromatapp Extended-Release   Teva Pharmaceuticals, USA, 1090 Horsham
                                           Tablet.                      Rd., P.O. Box 1090, North Wales, PA
                                                                        19454.
ANDA 88-359.............................  Drize Extended-Release       B. F. Ascher & Co., Inc., 15501 West
                                           Capsule.                     109th St., Lenexa, KS 66219.
ANDA 88-681.............................  Chlorpheniramine Maleate     Chelsea Laboratories, 896 Orlando Ave.,
                                           and Phenylpropanolamine      West Hempstead, NY 11552.
                                           HCL Extended-Release
                                           Capsule.
ANDA 88-687.............................  Biphetap Elixir............  Morton Grove Pharmaceuticals, Inc., 6451
                                                                        Main St., Morton Grove, IL 60053.
ANDA 88-688.............................  Bromanate Elixir...........  Alpharma, U.S. Pharmaceuticals Division,
                                                                        333 Cassell Dr., suite 3500, Baltimore,
                                                                        MD 21224.
ANDA 88-723.............................  Bromanate DC Syrup.........  Do.
ANDA 88-904.............................  Myphetane DC Syrup.........  Morton Grove Pharmaceuticals, Inc.

[[Page 42667]]

 
ANDA 88-940.............................  Chlorpheniramine Maleate     Geneva Pharmaceuticals, Inc., 2555 West
                                           and Phenylpropanolamine      Midway Blvd., P.O. Box 446, Broomfield,
                                           HCL Extended-Release         CO 80038.
                                           Capsule.
----------------------------------------------------------------------------------------------------------------

III. Recent Data on the Safety of Phenylpropanolamine

A. Introduction and Rationale for Developing a Study

    Spontaneous case reports and published case series, accumulated 
from 1969 to 1991, suggested a possible association between 
phenylpropanolamine use and an increased risk of hemorrhagic stroke. At 
that time, however, it was not possible to prove or disprove an 
association. In an effort to resolve this issue, representatives of the 
manufacturers of products containing phenylpropanolamine and agency 
staff met in 1991 to plan a study that could further examine whether 
there was an association between phenylpropanolamine use and the risk 
of hemorrhagic stroke. An epidemiologic case-control study was 
determined to be the most feasible study design to evaluate the 
possible association between exposure to phenylpropanolamine and a rare 
outcome such as hemorrhagic stroke. The industry sponsors of the study 
selected investigators at Yale University School of Medicine to conduct 
the study. The following discussion is based on the study report (Ref. 
1) submitted to FDA.

B. The Yale Hemorrhagic Stroke Project

1. Study Design
    The Yale Hemorrhagic Stroke Project (Ref. 1) was designed as a 
case-control study. Because several case reports had described strokes 
in young women who took phenylpropanolamine as an appetite suppressant, 
often after the first dose, the study examined three questions: (1) 
Whether all users of phenylpropanolamine (the study cohort included men 
and women aged 18 to 49 years), compared with nonusers, had an 
increased risk of hemorrhagic stroke; (2) the possible association 
between phenylpropanolamine use and hemorrhagic stroke by type of 
exposure (appetite suppressant or cough-cold product); and (3) among 
women age 18 to 49 years, the possible association between first use of 
phenylpropanolamine and hemorrhagic stroke and the possible association 
between use of phenylpropanolamine-containing appetite suppressants and 
hemorrhagic stroke.
    The study was performed between December 1994 and July 1999 and 
involved men and women 18 to 49 years old who were hospitalized with a 
primary subarachnoid hemorrhage (SAH) or a primary intracerebral 
hemorrhage (ICH). Eligible case subjects had no prior history of stroke 
and were able to be interviewed within 30 days of their event. The 
subjects were recruited from hospitals in four geographic regions of 
the United States.
    Both SAH and ICH were determined by clinical symptoms and specific 
diagnostic information from computed tomography (CT). Magnetic 
resonance imaging was accepted for the diagnosis of SAH or ICH only if 
other studies were not diagnostic. Subjects were ineligible for 
enrollment if they died within 30 days, were not able to communicate 
within 30 days of their stroke, had a previously diagnosed brain lesion 
predisposing to hemorrhage risk (e.g., arteriovenous malformation, 
vascular aneurysm, or tumor), or had a prior history of stroke. 
Subjects who first experienced stroke symptoms after being in the 
hospital for 72 hours (e.g., for an unrelated matter) were also 
excluded.
    For each case subject, random digit dialing (matched to the first 
three digits of the case subject) was used to identify two control 
subjects who were matched on: (1) Gender, (2) race (African-American 
versus non-African-American), (3) age (within 3 years for case subjects 
less than 30 years old and within 5 years for subjects 30 years or 
over), and (4) telephone exchange. Cases and control subjects were 
interviewed to ascertain medical history, medication use, and habits 
affecting health, such as use of tobacco and alcohol. Interviews of 
control subjects were completed within 30 days of the subject's stroke 
event to minimize seasonal differences in the likelihood of exposure to 
cough-cold drug products. Eligibility criteria for control subjects 
were the same as for case subjects except for the stroke event. During 
the consent procedure, all subjects (cases and controls) were told that 
the study was designed to examine causes of hemorrhagic stroke in young 
persons without specific mention of phenylpropanolamine or other 
potential risk factors. Case and control subjects were interviewed by a 
trained interviewer using a structured questionnaire developed for this 
study. Subjects were classified as exposed to phenylpropanolamine if 
they reported use within 3 days of the stroke event for case subjects 
or a corresponding date for control subjects. Reported exposures were 
verified by the study investigators, who documented the actual 
product(s) used and their ingredients.
    The exposure window refers to the interval before the focal time 
when the subject's exposure to phenylpropanolamine was assessed. For 
all analyses except first-dose use, the exposure window was defined as 
the index day before focal time and the preceding 3 calendar days. For 
first-dose use, a subject was considered exposed if phenylpropanolamine 
use occurred on the index day before the focal time or on the preceding 
calendar day, with no other phenylpropanolamine use during the 
preceding 2 weeks. To maintain a consistent reference group for all 
analyses, nonexposure was defined as no use of phenylpropanolamine 
within the 2 weeks preceding the focal time. Exposure windows were 
defined similarly in the matched case controls, based on the focal time 
for the corresponding case.
2. Statistical Analysis
    Case and control subjects were compared on a variety of clinical 
and demographic features, including those used in matching. Statistical 
comparisons were made using chi-square tests and the Fisher's exact 
test (where appropriate) for categorical variables, and the Student t-
test for continuous variables. For the analyses of the primary 
endpoints, conditional logistic models for matched sets (with a 
variable number of controls per case) were used to estimate odds 
ratios, lower limits of the one-sided 95 percent confidence intervals, 
and p-values for the risk factors under investigation. One-tailed 
statistical results were reported because the focus of the study was 
whether phenylpropanolamine use increases the risk of stroke. Each 
logistic model was estimated with two mutually exclusive binary 
exposure terms: (1) The subject's primary exposure status as defined by 
the specific aim (e.g., phenylpropanolamine use in the 3-day window; 
yes/no), and (2) phenylpropanolamine users who were not exposed within 
the 3-day window

[[Page 42668]]

(but with some exposure within 2 weeks of the focal time).
    In multivariate conditional logistic models (using asymptotic 
methods), adjustments were made for race (African-American compared 
with non-African-American), history of hypertension (yes/no), and 
current cigarette smoking (current compared with never or ex-smoker) as 
these are major risk factors for stroke. Other underlying diseases and/
or conditions were also examined to determine if any of these, when 
added to this basic adjusted model, altered the matched odds ratio by 
at least 10 percent.
3. Study Results
    There were 702 case subjects, including 425 subjects (60 percent) 
with an SAH and 277 (40 percent) with an ICH, and 1,376 control 
subjects. Hemorrhage was associated with an aneurysm in 307 subjects 
(44 percent), an arteriovenous malformation in 50 subjects (7 percent), 
and a tumor in one subject (0.1 percent). Two control subjects were 
located for each of 674 case subjects (96 percent) and one control 
subject for each of 28 case subjects (4 percent). All control subjects 
were matched to their case subjects on gender and telephone exchange. 
Age matching was successful for 1,367 controls (99 percent) and race 
matching was achieved for 1,321 controls (96 percent). Twenty-seven 
case subjects and 33 control subjects reported phenylpropanolamine use 
within the 3-day exposure window.
    Compared with control subjects, case subjects were significantly 
more likely to be African-American (21 percent compared with 17 
percent). Case subjects were also more likely to report lower 
educational achievement (20 percent did not graduate from high school 
compared with 9 percent of control subjects), current cigarette smoking 
(51 percent compared with 30 percent), a history of hypertension (39 
percent compared with 20 percent), family history of hemorrhagic stroke 
(9 percent compared with 5 percent), heavy alcohol use (14 percent 
compared with 7 percent), and recent cocaine use (2 percent compared 
with less than 1 percent). For all other clinical variables examined, 
case and control subjects were not dissimilar. Case subjects were 
significantly (p0.05) less likely to report use of nonsteroidal anti-
inflammatory drugs and significantly more likely to report use of 
caffeine and nicotine in the 3 days before their event. Of the factors 
examined, only education was found to change the adjusted odds ratio 
for the association between phenylpropanolamine and hemorrhagic stroke 
by more than 10 percent, and this demographic factor was included in 
all subsequent models.
    Analyses of the study results were consistent with an association 
between hemorrhagic stroke and use of phenylpropanolamine (in a nasal 
decongestant or weight control drug product) in the 3 days prior to the 
event. Such use of phenylpropanolamine, compared with no use in the 
prior 2 weeks, was associated with a relative risk for hemorrhagic 
stroke of 1.67 (unadjusted odds ratio) (p=0.040). The corresponding 
adjusted odds ratio was 1.49 (lower limit of the one-sided 95 percent 
confidence interval (LCL)=0.93, p=0.084).
    The relative risks of hemorrhagic stroke observed with use of the 
two types of phenylpropanolamine-containing products (in the 3-day 
exposure window, compared with no use in the prior 2 weeks) were as 
follows. For cough-cold products, the unadjusted odds ratio was 1.38 
(p=0.163) and the adjusted odds ratio was 1.23 (LCL=0.75, p=0.245). For 
weight control products, the unadjusted odds ratio was 11.98 (p=0.007) 
and the adjusted odds ratio was 15.92 (LCL=2.04, p=0.013).
    To analyze the relation between recency of phenylpropanolamine 
exposure and risk for hemorrhagic stroke, odds ratios were also 
calculated according to the timing of the most recent 
phenylpropanolamine use. The prespecified definition for current use 
was use of any phenylpropanolamine-containing product on the day of the 
event (before focal time) or the preceding calendar day. Prior use was 
defined as use 2 or 3 calendar days before the focal time. The odds 
ratio was slightly higher for current use (adjusted odds ratio 
(AOR)=1.61, LCL=0.93, p=0.078) than for prior use (AOR=1.16, LCL=0.47, 
p=0.393). Within current use, odds ratios were then calculated 
according to first use or nonfirst use. First use was defined as 
current use with no other use within the prior 2 weeks. Nonfirst use 
included other uses within the 2-week interval. The odds ratio was 
higher for first use (AOR=3.14, LCL=1.16, p=0.029) than for nonfirst 
use (AOR=1.20, LCL=0.61, p=0.329). All first uses of 
phenylpropanolamine (n=13) reported in these data were in cough-cold 
drug products.
    In women using phenylpropanolamine in weight control drug products 
(3-day exposure window, versus no use in the prior 2 weeks), the 
unadjusted odds ratio for hemorrhagic stroke was 12.19 (p=0.006) and 
the adjusted odds ratio was 16.58 (LCL=2.22, p=0.011). Among the 
Hemorrhagic Stroke Project subjects, all hemorrhagic stroke events that 
occurred within the 3-day exposure window were in women. In the 
analyses of the possible association between hemorrhagic stroke and 
first day use of phenylpropanolamine, 11 of the 13 first day use events 
were in women (7 cases compared with 4 controls). The unadjusted odds 
ratio was 3.50 (p=0.039) and the adjusted odds ratio was 3.13 
(LCL=1.05, p=0.042).
    Based on the findings that risk for hemorrhagic stroke seemed to be 
concentrated among current users, the association between current 
phenylpropanolamine dose and risk for hemorrhagic stroke was examined. 
Among 21 exposed control subjects, the median current dose of 
phenylpropanolamine (i.e., total amount taken on the index day or 
preceding day) was 75 milligrams (mg). Analysis according to dose shows 
that the odds ratio was higher for current doses above the median 
(greater than 75 mg) (AOR=2.31, LCL=1.10, p=0.031) than for 1ower doses 
(AOR=1.01, LCL=0.43, p=0.490). Among first-dose users, four of eight 
cases and two of five controls were exposed to greater than 75 mg of 
phenylpropanolamine. To examine the potential effect of ambiguity in 
the correct focal time, the odds ratios were recalculated after 
excluding all 154 case subjects who were classified as having a 
definite (n=76) or uncertain (n=78) sentinel symptom preceding the 
stroke event. The magnitude of the adjusted odds ratios did not change 
substantially.
4. Study Conclusions
    According to the investigators, several features of the study 
supported the validity of the study findings regarding an association 
between phenylpropanolamine use and risk for hemorrhagic stroke in 
subjects between 18 and 49 years of age. First, in addition to the 
finding of elevated odds ratios that reached statistical significance, 
the magnitude of the odds ratios for phenylpropanolamine use as an 
appetite suppressant (15.92) and as a first-dose use (3.14) remained 
large even after adjustment for important clinical features. Second, 
the data showed an association between both types of 
phenylpropanolamine drug products (nasal decongestants and weight 
control products) and hemorrhagic stroke. Because so few men were 
exposed to phenylpropanolamine in this study (n=19), it was not 
possible to determine whether their risk for hemorrhagic stroke (in 
association with use of phenylpropanolamine) is different from that of 
women.

[[Page 42669]]

5. FDA's Evaluation of the Study
    Observational studies, particularly case-control studies, are 
potentially subject to a number of biases, and this case-control study 
is no exception. The hallmark of a good case-control study is that 
biases are anticipated and measures are instituted in the design and 
analysis stages to minimize biases to the greatest extent possible.
    Strict diagnostic criteria, as described in section III.B.1 of this 
document, were developed to ensure accurate identification of 
hemorrhagic stroke cases in the target population. A number of steps 
were taken to minimize misclassification bias. One of the investigators 
confirmed the stroke by reviewing the medical records of suspected 
cases, without knowledge of the exposure status. Inclusion and 
exclusion criteria were clearly defined for both cases and controls. 
Exposure was clearly defined, an exposure window was identified, and 
exposure was ascertained by trained interviewers. Interviewers were 
randomly assigned to cases or controls, and questions were asked about 
multiple medications, thus blinding subjects to the exact exposure 
under study. Because phenylpropanolamine use might be seasonal, 
controls were identified and interviewed within 30 days of the date of 
their matched case subject's stroke, to ensure that cases and controls 
had an equal opportunity of exposure. Controls were also matched to 
cases for day of the week and time of day of the stroke. This matching 
strategy ensured the probability that exposure to any medication or 
other covariates (e.g., alcohol drinking or cigarette smoking) was 
similar between cases and controls.
    The investigators attempted to identify two controls per case by 
using random digit dialing (with a match for the first three digits of 
the telephone number). This was considered a good strategy for two 
reasons. First, controls were chosen completely at random. Second, 
controls were population-based, so that the results are generalizable 
to the source population from which the cases and controls were drawn. 
Matching on race and educational level was slightly unequal between 
cases and controls. The investigators further controlled for these 
inequalities by adjustment during analysis. The agency concludes that 
matching was largely successful.
    The investigators reduced the possibility of misclassification of 
phenylpropanolamine use by using a highly structured questionnaire. 
Each reported medication was verified by asking subjects to present the 
actual container or by picking out reported brand-name medications from 
a book containing photographs. Verification of medication use in the 3-
day window prior to the focal time was 96 percent and 94 percent for 
cases and controls, respectively. The investigators conducted two 
additional steps to further ensure that the possibility of exposure 
misclassification error was reduced to an absolute minimum: (1) Only 
``definite'' and ``possible'' exposure responses were considered in the 
analyses, and (2) the use of other OTC drugs between cases and controls 
was compared to ensure that the cases did not have greater recall of 
the use of any drugs as a reason for their stroke. Based on this 
analysis, the agency finds no evidence of recall or misclassification 
bias.
    A key element in designing a case-control study of a rare event is 
calculating the sample size and/or power to ensure the study is large 
enough to detect a difference if one really exists. FDA had concerns 
that the study might be underpowered to detect an association because 
the original sample size calculation was based on an odds ratio of five 
for an association between hemorrhagic stroke and first-day use of 
phenylpropanolamine. This ratio was not determined by any public health 
or clinical considerations, but on considerations related to time and 
cost constraints. The investigators difficulties in recruiting controls 
contributed to the study taking longer than expected. Despite these 
limitations, this was the largest prospective case-control study ever 
conducted on hemorrhagic stroke. In spite of initial reservations about 
the adequacy of sample size and power, the agency finds that this study 
identified an association between phenylpropanolamine use and 
hemorrhagic stroke, as explained below.
    The agency notes that the three most important risk factors (race, 
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 percent. High school 
education was the only covariate determined to change the odds ratio by 
at least 10 percent.
    Because the study had a matched design, the agency considers the 
conditional logistic regression model appropriate to calculate both 
unadjusted and adjusted odds ratios. In addition, the number of 
exposures was small, particularly for analysis of appetite suppressant 
and first use. Thus, the authors calculated the confidence interval of 
the unadjusted odds ratio based on an exact method.
    Hypertension is the single most important risk factor for a stroke. 
Misclassification of hypertension status could result in residual 
confounding. FDA examined the possible effects of this residual 
confounding on the results of the study. The agency found that the odds 
ratio for appetite suppressant use was 15.92, a substantial increase in 
risk. Its very magnitude makes it difficult to explain by confounding 
alone. Because product labeling advises hypertensive persons to avoid 
phenylpropanolamine use, the association of phenylpropanolamine use 
with hypertension should be negative. Such a negative association would 
result in biasing the result towards no association if the confounding 
factor is not controlled for. In addition to the steps taken by the 
investigators, the agency examined this further by additional analyses 
restricted to subjects without a past history of hypertension, and the 
results were not significantly different, thereby providing additional 
evidence that confounding by hypertension was not present in the study.
    FDA requested that the Yale investigators explore the possible 
impact of cigarette smoking and alcohol consumption in more detail. The 
investigators found that the odds ratios for phenylpropanolamine and 
stroke were essentially unchanged by inclusion of any quantitative 
measures of smoking and alcohol consumption.
    The investigators examined the association between current 
phenylpropanolamine dose and risk for hemorrhagic stroke. Among 21 
exposed control subjects, the median current dose of 
phenylpropanolamine (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 greater 
than 75 mg of phenylpropanolamine. As 75 mg is a single dose of many 
OTC extended-release phenylpropanolamine cough-cold drug products with 
recommended adult dosing every 12 hours (150 mg a day), the agency 
further evaluated the association between risk of hemorrhagic stroke 
and a range of current phenylpropanolamine doses. Exploratory analyses 
suggest that there may be an increased risk of hemorrhagic stroke with 
labeled doses at or above 75 mg a day. Although not statistically 
significant, a trend toward a dose-ordering of odds ratios was seen.

[[Page 42670]]

C. Additional Reports

    FDA reviewed its adverse events reporting system (AERS) for 
spontaneous reports of hemorrhagic stroke from 1991 to 2000 and 
identified 22 cases, 16 in the 18 to 49 age group with 13 cases in 
women (Ref. 2). In all cases, the suspect drug was an extended-release 
product containing 75 mg of phenylpropanolamine per unit dose. Of 11 
cases for which the indication of use was provided, 10 reported use for 
respiratory symptoms.

D. Advisory Committee Recommendations

    On October 19, 2000, at a public meeting, FDA's Nonprescription 
Drugs Advisory Committee (NDAC) discussed the Yale Hemorrhagic Stroke 
Project and additional case reports of hemorrhagic stroke since 1991. 
The investigators of the Yale study presented the study results and 
their conclusions. Industry representatives raised concerns about the 
design of the study that they believed made interpretation of the 
results difficult (Ref. 3). When NDAC was asked if, taking all 
currently available information into account, the data support the 
conclusion that there is an association between phenylpropanolamine and 
an increased risk of hemorrhagic stroke, 13 of 14 committee members 
voted (with 1 voting ``uncertain'') that there is such an association 
(Ref. 4). When asked whether phenylpropanolamine can be generally 
recognized as safe for use as a nasal decongestant, 12 of the 14 
committee members voted (with 2 abstaining) that phenylpropanolamine 
could not be considered to be generally recognized as safe for OTC 
nasal decongestant use. When asked whether phenylpropanolamine can be 
generally recognized as safe for use as an appetite suppressant, 13 of 
the 14 committee members voted (with 1 abstaining) that 
phenylpropanolamine could not be considered to be generally recognized 
as safe for OTC weight control use. Minutes of the NDAC meeting are 
available in the Dockets Management Branch (address above) under the 
docket number listed in brackets in the heading of this document.

IV. The Agency's Tentative Conclusions on the Safety of 
Phenylpropanolamine

    The agency concludes that the Yale study (Ref. 1) was well designed 
and demonstrated that the association between phenylpropanolamine use 
(as an appetite suppressant and first time use as a nasal decongestant) 
and an increased risk of hemorrhagic stroke was significant and was 
most striking in women. The case-control design was best suited for 
this study because the outcome under investigation was rare. All 
reasonable steps were taken to minimize bias and confounding. Quality 
control measures were built into the design. Analyses were appropriate 
for the type of study and were performed according to the protocol. 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, 
discussed earlier. Despite this limitation, the study was nevertheless 
able to find a consistent association between phenylpropanolamine use 
and hemorrhagic stroke, particularly in women.
    Although the Yale study focused on men and women 18 to 49 years of 
age, the agency has no reason to believe that the increased risk of 
hemorrhagic stroke is limited to this population. While the Yale study 
was being conducted, FDA continued to receive spontaneous reports of 
hemorrhagic stroke with cough-cold products that contain high doses of 
phenylpropanolamine. Some reports indicate that only one dose was 
administered.
    FDA believes that the data from the Yale study demonstrating an 
association between phenylpropanolamine and hemorrhagic stroke, taken 
together with spontaneous reports and reports in the published medical 
literature, provide evidence that nasal decongestant and weight control 
drug products containing phenylpropanolamine are no longer shown to be 
safe. Because hemorrhagic strokes often lead to catastrophic, 
irreversible outcomes and the factors that may predispose some 
individuals to develop this adverse event are not fully known, 
individuals at risk cannot be adequately warned. The agency tentatively 
concludes that the benefits of the intended uses of this ingredient do 
not outweigh the potential risk. All of the applications listed in 
section II of this document are for nasal decongestant use of 
phenylpropanolamine. None are for appetite control.
    Accordingly, the Director of the Center for Drug Evaluation and 
Research (CDER) concludes with respect to the NDA and ANDA products 
containing phenylpropanolamine listed in section II of this document 
that phenylpropanolamine is no longer shown to be safe for use under 
the conditions that formed the basis upon which the applications were 
initially approved. The Director is proposing to withdraw approval of 
those NDAs and ANDAs in accordance with section 505(e)(2) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(e)(2)). 
This notice of opportunity for a hearing applies to all persons who 
manufacture or distribute a drug product that contains 
phenylpropanolamine and that are considered new drugs (e.g., extended-
release products and any prescription product).
    In lieu of requesting a hearing, manufacturers of products 
containing phenylpropanolamine as a nasal decongestant are urged to 
reformulate their products to remove phenylpropanolamine. Reformulated 
products may result in products that require an approved NDA or ANDA 
prior to marketing. Inquiries regarding proposed reformulations should 
be sent to the Division of Pulmonary and Allergy Drug Products (address 
above) or the Office of Generic Drugs (address above), as appropriate.

V. Notice of Opportunity for a Hearing

    The Director has evaluated the information discussed above and, on 
the grounds stated, is proposing to withdraw approval of the previously 
listed NDAs and ANDAs. Therefore, notice is given to the holders of the 
NDAs and ANDAs listed in section II of this document that the Director 
proposes to issue an order, under section 505(e)(2) of the act, 
withdrawing approval of the NDAs and ANDAs and all amendments and 
supplements thereto. The Director finds that new evidence of clinical 
experience, not contained in the applications or not available to the 
Director until after the applications were approved, evaluated together 
with the evidence available to the Director when the applications were 
approved, shows that phenylpropanolamine is not shown to be safe for 
use under the conditions that formed the basis upon which the 
applications were approved.
    In accordance with section 505 of the act and part 314 (21 CFR part 
314), applicants and all other persons subject to this notice are 
hereby given an opportunity for a hearing to show why approval of the 
NDAs or ANDAs should not be withdrawn.
    An applicant who decides to seek a hearing shall file: (1) On or 
before September 13, 2001, a written notice of appearance and request 
for hearing, and (2) on or before October October 15, 2001, the data, 
information, and analyses relied on to demonstrate that there is a 
genuine issue of material fact to justify a hearing, as specified in 
Sec. 314.200. Any other interested person

[[Page 42671]]

may also submit comments on this notice. The procedures and 
requirements governing this notice of opportunity for a hearing, a 
notice of appearance and request for a hearing, information and 
analyses to justify a hearing, other comments, and a grant or denial of 
a hearing are contained in Sec. 314.200 and in 21 CFR part 12.
    The failure of an applicant to file a timely written notice of 
appearance and request for hearing, as required by Sec. 314.200, 
constitutes an election by that person not to use the opportunity for a 
hearing concerning the action proposed and a waiver of any contentions 
concerning the legal status of that person's drug products. Any new 
drug product marketed without an approved new drug application is 
subject to regulatory action at any time.
    A request for a hearing may not rest upon mere allegations or 
denials, but must present specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If it 
conclusively appears from the face of the data, information, and 
factual analyses in the request for a hearing that there is no genuine 
and substantial issue of fact that precludes the withdrawal of approval 
of the applications, or when a request for hearing is not made in the 
required format or with the required analyses, the Commissioner of Food 
and Drugs will enter summary judgment against the person who requests 
the hearing, making findings and conclusions, and denying a hearing.
    All submissions under this notice of opportunity for a hearing are 
to be filed in four copies. Except for data and information prohibited 
from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, the 
submissions may be seen in the Dockets Management Branch (address 
above) between 9 a.m. and 4 p.m., Monday through Friday.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (section 505 (21 U.S.C. 355)) and under authority delegated to the 
Director, CDER (21 CFR 5.82).

VI. References

    The following references are on display in the Dockets Management 
Branch (address above) and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday.
    1. Horwitz et al., ``Phenylpropanolamine & Risk of Hemorrhagic 
Stroke: Final Report of The Hemorrhagic Stroke Project,'' May 2000 
in Comment No. C230, Docket No. 76N-052N and Comment No. C114, 
Docket No. 81N-0022.
    2. Phenylpropanolamine Case Reports From 1991-2000 on File in 
Docket Nos. 76N-052N and 81N-0022.
    3. Consumer Healthcare Products Association (CHPA), ``Comments 
on the Hemorrhagic Stroke Project Report,'' May 24, 2000, in Comment 
No. C231, Docket No. 76N-052N and Comment No. C113, Docket No. 81N-
0022.
    4. Food and Drug Administration, Summary Minutes of 
Nonprescription Drugs Advisory Committee Meeting, October 19, 2000.

    Dated: June 1, 2001.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 01-20300 Filed 8-13-01; 8:45 am]
BILLING CODE 4160-01-S