[Federal Register Volume 70, Number 245 (Thursday, December 22, 2005)]
[Proposed Rules]
[Pages 75988-75998]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E5-7646]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 341, and 357
[Docket Nos. 1976N-0052N (formerly 1976N-052N) and 1981N-0022 (formerly
81N-0022)]
RIN 0910-AF34, 0910-AF45
Phenylpropanolamine-Containing Drug Products for Over-the-Counter
Human Use; Tentative Final Monographs
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of
proposed rulemaking (notice) for over-the-counter (OTC) nasal
decongestant and weight control drug products containing
phenylpropanolamine preparations. This proposed rule reclassifies
phenylpropanolamine preparations from their previously proposed
monograph status (Category I) for these uses to nonmonograph (Category
II)
[[Page 75989]]
status based on safety concerns. FDA is issuing this proposed rule
after considering new data and information on the safety of
phenylpropanolamine as part of its ongoing review of OTC drug products.
DATES: Submit written and electronic comments and new data by March 22,
2006. Written and electronic comments on the agency's economic impact
determination by March 22, 2006. Please see section X of this document
for the effective date of any final rule that may be published based on
this proposal.
ADDRESSES: You may submit comments, identified by Docket Nos. 1976N-
0052N and 1981N-0022 and/RIN number 0910-AF34 and 0910-AF45, by any of
the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal information provided. For detailed
instructions on submitting comments and additional information on the
rulemaking process, see the ``Comments'' heading of the SUPPLEMENTARY
INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow or Robert L.
Sherman, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5426, Silver
Spring, MD 20993, 301-796-2090.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of September 9, 1976 (41 FR 38312), FDA
published an advance notice of proposed rulemaking (ANPR) under 21 CFR
330.10(a)(6) to establish a monograph for OTC cold, cough, allergy,
bronchodilator, and antiasthmatic drug products together with the
recommendations of the Advisory Review Panel on OTC Cold, Cough,
Allergy, Bronchodilator, and Antiasthmatic Drug Products (Cough-Cold
Panel). This Panel was the advisory review panel responsible for
evaluating data on the active ingredients in these drug classes. This
Panel recommended monograph (Category I) status for phenylpropanolamine
preparations (phenylpropanolamine bitartrate, phenylpropanolamine
hydrochloride, and phenylpropanolamine maleate) as an oral nasal
decongestant.
In the Federal Register of February 26, 1982 (47 FR 8466), FDA
published an ANPR to establish a monograph for OTC weight control drug
products, together with the recommendations of the Advisory Review
Panel on OTC Miscellaneous Internal Drug Products (Miscellaneous
Internal Panel). This Panel was the advisory review panel responsible
for evaluating data on the active ingredients in this drug class. This
Panel recommended monograph status for phenylpropanolamine
hydrochloride for weight control use. However, after the Panel
submitted its report, FDA became aware of and discussed studies
indicating that certain dosages of phenylpropanolamine cause blood
pressure elevation (47 FR 8466). Therefore, in the preamble to the
Panel's report, FDA specifically requested data and information on the
extent to which phenylpropanolamine induces or aggravates hypertension
(47 FR 8466 at 8468).
In the Federal Register of January 15, 1985 (50 FR 2220), FDA
published a proposed regulation for OTC nasal decongestant drug
products in the form of a tentative final monograph. Because the issues
concerning the safety of phenylpropanolamine for nasal decongestant and
weight control use were closely related, FDA stated in that document
that it was deferring phenylpropanolamine and would consider the issues
concurrently in a future Federal Register publication (50 FR 2220 at
2221).
Phenylpropanolamine was not included in the October 30, 1990 (55 FR
45788), proposed rule or the August 8, 1991 (56 FR 37792), final rule
for OTC weight control drug products, in which 111 weight control
active ingredients were determined to be nonmonograph. Benzocaine and
phenylpropanolamine hydrochloride, the two ingredients the
Miscellaneous Internal Panel classified as Category I, were deferred to
a future publication. The current document addresses
phenylpropanolamine. FDA will discuss benzocaine for weight control use
in a future issue of the Federal Register.
In a letter to the Nonprescription Drug Manufacturers Association
dated March 9, 1993 (Ref. 1), FDA stated that, based on a relatively
small number of spontaneous reports of intracranial bleeding associated
with weight control drug products containing phenylpropanolamine, FDA's
principal safety concern was the possibility that phenylpropanolamine
might increase the risk of stroke. FDA further stated that although the
available data could not support a conclusion that phenylpropanolamine
increased the rate of strokes, these data could not rule out the
possibility of an increased stroke risk associated with OTC
phenylpropanolamine use.
Phenylpropanolamine preparations also were not included in the
final rule for OTC nasal decongestant drug products that published in
the Federal Register of August 23, 1994 (59 FR 43386). FDA stated that
because of still unresolved safety issues concerning
phenylpropanolamine preparations, it was deferring action on this drug
(59 FR 43386).
In the Federal Register of February 14, 1996 (61 FR 5912), FDA
published a proposed regulation requiring new warning labeling for all
OTC phenylpropanolamine preparations. In that document, FDA stated that
dose-response studies submitted by drug manufacturers to investigate
phenylpropanolamine's effects on blood
[[Page 75990]]
pressure were inadequate to alleviate FDA's concern that
phenylpropanolamine used in OTC drug products might increase the risk
of hemorrhagic stroke.
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.
Thus, the status of phenylpropanolamine had been deferred pending
further study. In an effort to resolve these issues, representatives of
the manufacturers of products containing phenylpropanolamine and FDA
staff met in 1991 to plan a study that could further examine whether
there was an association between phenylpropanolamine use and 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 Yale investigators submitted protocols to FDA for review.
The results of the study are discussed in section II of this document.
In this proposed rule, FDA proposes to categorize all
phenylpropanolamine preparations as nonmonograph (Category II) for OTC
use in both nasal decongestant and weight control drug products. This
action is based on reports published in the medical literature, FDA's
initial review of adverse drug event reports associated with OTC
phenylpropanolamine drug products between 1969 and 1991, continuing
adverse drug event reports since 1991, and the results of the Yale
Hemorrhagic Stroke Project (Ref. 2). Because safety concerns are the
basis for this proposed nonmonograph status, FDA does not address the
effectiveness of phenylpropanolamine preparations in this document.
II. Data on the Safety of Phenylpropanolamine from the Yale Hemorrhagic
Stroke Project
A. Introduction and Rationale
The following discussion was developed from the study report (Ref.
2) submitted to FDA.
The Yale Hemorrhagic Stroke Project (Ref. 2) was a case-control
study. Because several case reports had involved strokes in young women
who took phenylpropanolamine as an appetite suppressant, often after a
first dose, the study examined three questions: (1) Whether all users
of phenylpropanolamine, compared to nonusers, had an increased risk of
hemorrhagic stroke, (2) the possible association between
phenylpropanolamine 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) (unrelated to ischemic infarction, trauma, cerebral
thrombosis, or thrombolytic therapy). The subjects were recruited from
44 hospitals in 4 geographic regions of the United States.
Both SAH and ICH were determined by clinical symptoms and specific
diagnostic information from computed tomography. Magnetic resonance
imaging was accepted for the diagnosis of SAH or ICH only if other
procedures were not diagnostic. Because misclassification of exposure
status by surrogate responders could increase or reduce the observed
odds ratio and the true level of risk (Ref. 2), subjects were
ineligible for enrollment if they died (n=389) or were not able to
communicate (n=194) within 30 days after their event. Subjects were
also ineligible if they had a previously diagnosed brain lesion
predisposing to hemorrhage risk (e.g., arteriovenous malformation,
vascular aneurysm, or tumor) (n=48), a prior stroke (n=120), or first
experienced stroke symptoms after being in the hospital for 72 hours
(e.g., for an unrelated matter) (n=33).
For each case subject, random digit dialing (matched to the first
three digits of the case subject's telephone number) 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 and within 5 years for
subjects 30 years or over), (4) educational level, and (5) telephone
exchange (as a surrogate for socioeconomic status). Case subjects 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 case 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. Reported phenylpropanolamine
exposures were verified by the study investigators, who documented the
actual product(s) used and their ingredients.
A focal time (the calendar day and the time of onset of symptoms
plausibly related to hemorrhagic stroke that caused a subject to seek
medical help) was identified for each case subject. The focal time used
for each control subject was matched to the day of the week and the
time of day that corresponded to the case subject's focal time. Control
subjects were interviewed within 7 days of their focal time to minimize
recall bias.
The exposure window referred to the interval before the focal time
(onset of symptoms) when the status of a subject's exposure to
phenylpropanolamine was defined. For analyses other than those
involving first use of phenylpropanolamine, the exposure window was
defined as 4 days preceding the focal time. For first use of
phenylpropanolamine, the exposure window was within 24 hours before the
focal time, provided that the subject had not used any other
phenylpropanolamine products during the preceding 2 weeks. To maintain
a consistent reference group, nonexposure for all analyses was defined
as no use of phenylpropanolamine within 2 weeks before the focal time.
Exposure windows for control subjects were matched to those for the
corresponding case subjects.
B. Statistical Analysis
Case and control subjects were compared on a variety of clinical
and demographic features, including those used in matching, to
determine the comparability of the two groups. 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
[[Page 75991]]
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 increased the
risk of stroke and this was the pre-specified analysis. 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 (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)
because these are the major risk factors for stroke. Other underlying
diseases and/or conditions (i.e. diabetes, polycystic kidney disease,
congestive heart failure, sickle cell anemia, and clotting disorders)
were also examined to determine if any of them, when added to this
basic adjusted model, altered the matched odds ratio by at least 10
percent.
C. 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 to 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 (0.05) 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 changed 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 demonstrated an association between
hemorrhagic stroke and use of phenylpropanolamine (in both nasal
decongestant and weight control drug products) in the 3 days prior to
the event. Such use of phenylpropanolamine, compared to 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 to 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 (AOR) 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 AOR 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 pre-specified 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 (AOR=1.61, LCL=0.93, p=0.078)
than for prior use (AOR=l.16, LCL=0.47, p=0.393). Within current use,
odds ratios were then calculated according to first use or non-first
use. First use was defined as current use with no other use within the
prior 2 weeks. Non-first use included other uses within the 2-week
interval. The odds ratio was higher for first use (AOR=3.14, LCL=l.16,
p=0.029) than for non-first 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 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 AOR was 16.58 (LCL=2.22, p=0.0l1). All hemorrhagic stroke events
that occurred within the 3-day exposure window were in women. In the
analyses of the 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 AOR 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=l.10, p=0.031) than for lower doses
(AOR=l.0l, 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 AORs did not change substantially.
D. Study Conclusions
According to the investigators, several features of the study
supported the validity of the study findings regarding a demonstrated
association between phenylpropanolamine use and risk of hemorrhagic
stroke in subjects between
[[Page 75992]]
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
demonstrate an association between both types of phenylpropanolamine
drug products (nasal decongestant and weight control) 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 (when using phenylpropanolamine) is different from
that of women.
E. 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 previously, 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. The interviews were highly
structured and scripted to protect against interviewer bias. 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 similar opportunities for
exposure. Controls were also matched to cases for day of the week and
time of day of the stroke. This matching strategy helped increase the
probability that exposure to any seasonal 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). Because controls were population-based, the
results were 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 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
were 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, FDA did not find any evidence of recall or misclassification
bias.
Several key elements of study design and conduct determine the
success of a case-control study. Studies must have adequate sample size
and/or power to detect a difference between treatment groups if a
difference really exists, and detection of rare events can require
substantial numbers of study subjects. FDA had concerns that the
protocol might result in an underpowered study because the sample size
calculation was based on an odds ratio of five for an association
between first-day use of phenylpropanolamine and hemorrhagic stroke.
This ratio was derived primarily from study conduct considerations,
such as time and cost, rather than on predictive epidemiologic data
that may have suggested that a greater number of subjects would be
needed to show a difference between groups. Because case-control
studies also demand adherence to strict matching criteria between case
and control subjects, the duration of this study was longer than
expected due to difficulties in recruiting well-matched controls.
The resultant study was the largest prospective case-control study
ever conducted on hemorrhagic stroke. FDA finds that, despite these
limitations, this study was well-conducted and the statistical analyses
demonstrate an association between phenylpropanolamine and hemorrhagic
stroke, as explained as follows.
FDA 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, FDA considers the
conditional logistic regression model appropriate to calculate both
unadjusted and AORs. 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. FDA 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, FDA 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 the Yale investigators to 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 several qualitative
and quantitative measures of smoking and alcohol consumption.
The investigators examined the association between current
[[Page 75993]]
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 AOR 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.
The odds ratio was higher (AOR=2.31, LCL=1.10, p=0.031) for current
doses above 75 mg than for doses below 75 mg (AOR=1.01, LCL=0.43,
p=0.490).
FDA concludes that the Yale study (Ref. 2) was well-designed and
demonstrated an association between use of phenylpropanolamine and an
increased risk of hemorrhagic stroke. The increased risk was most
striking in women and was associated with both use in appetite
suppressants and first-dose use in cough-cold products. The case-
control design was best suited for this study because the outcome under
investigation was rare. The investigators took reasonable steps to
minimize bias and confounding and built quality control measures into
the study design. Analysis was appropriate for the type of study and
was performed according to the protocol. The study had clear objectives
and sound epidemiology practices were used in its design and execution.
F. Additional Reports
FDA reviewed its adverse events reporting system 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. 3). 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 for use was provided, 10 reported use for respiratory
symptoms. FDA believes that the fact that there were no reports
associated with immediate release drug products marketed under the OTC
drug monograph system may be related to the lack of a requirement to
submit any such reports to the agency.
Therefore, the absence of such reports does not indicate these
products are not associated with adverse events.
G. Advisory Committee Recommendations
On October 19, 2000, at a public meeting, FDA presented to its
Nonprescription Drugs Advisory Committee (NDAC) the regulatory history
of OTC phenylpropanolamine (including FDA's concerns about case reports
of hemorrhagic stroke associated with phenylpropanolamine prior to
1991), the data from the Yale Hemorrhagic Stroke Project, and
additional case reports of stroke since 1991.
The Yale investigators 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. 4). NDAC evaluated whether the Yale study showed an
association between phenylpropanolamine use and an increased risk of
stroke in different populations aged 18 to 49 (female, male, both) and
for different uses (nasal decongestant, appetite suppressant, all)
(Ref. 5). More importantly, NDAC was asked if the data support the
conclusion that there is an association between phenylpropanolamine and
an increased risk of hemorragic stroke, taking into account all
currently available information, including: (1) Phenylpropanolamine's
effects on blood pressure, (2) spontaneous reports of hemorrhagic
stroke associated with phenylpropanolamine from 1969 to 1991, (3) case
reports in the medical literature, (4) continuing adverse drug reports
to FDA from 1991 to the present, and (5) the results of the Yale
Hemmorhagic Stroke Project. Thirteen of 14 NDAC members voted (with 1
voting ``uncertain'') that there is such an association (Ref. 5). When
asked whether phenylpropanolamine can be generally recognized as safe
for use as a nasal decongestant, 12 of the 14 NDAC members voted (with
2 abstaining) that phenylpropanolamine could not be considered to be
generally recognized as safe for OTC nasal decongestant use. In
addition, when asked whether phenylpropanolamine can be generally
recognized as safe for use as an appetite suppressant, 13 of the 14
NDAC members voted (with 1 abstaining) that phenylpropanolamine could
not be considered to be generally recognized as safe for OTC weight
control use.
III. FDA's Tentative Conclusions on the Safety of Phenylpropanolamine
FDA believes that the known scientific evidence supports the
conclusion that nasal decongestant and weight control drug products
containing phenylpropanolamine cannot be generally recognized as safe
and should no longer be available for OTC use. This evidence includes
the results of the Yale study suggesting an association between
phenylpropanolamine and hemorrhagic stroke, previous and continuing
adverse event reports, reports in the published medical literature, and
the biological plausibility related to phenylpropanolamine's ability to
cause increases in blood pressure. As stated in section II.E of this
document, FDA concludes that the Yale study (Ref. 2) was well-designed
and demonstrated an association between use of phenylpropanolamine and
an increased risk of hemorrhagic stroke. The increased risk was most
striking in women and was associated with both use in appetite
suppressants and first-dose use in cough-cold products. The case-
control design was best suited for this study because the outcome under
investigation was rare. The investigators took reasonable steps to
minimize bias and confounding and built quality control measures into
the study design. Analysis was appropriate for the type of study and
was performed according to the protocol. The study had clear objectives
and sound epidemiology practices were used in its design and execution.
Regardless of the analytic methods used, the findings were consistent.
Although the Yale study focused on men and women 18 to 49 years of
age, FDA has no data to show that the increased risk of hemorrhagic
stroke is limited to a specific age range. While the Yale study was
being conducted, FDA received spontaneous reports of hemorrhagic stroke
in people 28 to 54 years of age with cough-cold products that contain
OTC doses of phenylpropanolamine.
Because the factors that may cause some individuals to be
particularly sensitive to the effects of phenylpropanolamine are
unknown, individuals at risk cannot be adequately warned through
labeling. Although there is no other active ingredient that is
generally recognized as safe and effective for OTC weight control use,
OTC nasal decongestant drug products can be reformulated with other
ingredients, such as pseudoephedrine and phenylephrine. Because
hemorrhagic strokes often lead to catastrophic, irreversible outcomes,
[[Page 75994]]
FDA concludes that the benefits of the intended uses of
phenylpropanolamine do not outweigh the potential risk, and that
phenylpropanolamine is not considered to be generally recognized as
safe.
IV. Analysis of Impacts
FDA has examined the impacts of this proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, if a rule might have a significant economic impact on
a substantial number of small entities, an agency must consider
alternatives that would minimize any significant economic impact of the
rule on small entities. Section 202(a) of the Unfunded Mandates Reform
Act of 1995 requires that agencies prepare a written statement of
anticipated costs and benefits before proposing any rule that may
result in an expenditure by state, local, and tribal governments, in
the aggregate, or by the private sector, of $100 million (adjusted
annually for inflation) in any one year.
FDA tentatively concludes that this proposed rule is consistent
with the principles set out in Executive Order 12866 and in these two
statutes. As shown as follows, FDA does not believe the proposed rule
will be economically significant as defined by the Executive order.
Based on its preliminary Regulatory Flexibility Analysis, FDA
tentatively concludes that this proposed rule would not impose a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 does not require FDA to
prepare a statement of costs and benefits for the proposed rule,
because the proposed rule is not expected to result in an expenditure
that would exceed $100 million adjusted for inflation in any one year.
The current inflation-adjusted statutory threshold is about $110
million.
The purpose of the proposed rule is to establish that
phenylpropanolamine preparations are not generally recognized as safe
for OTC use both as a nasal decongestant and for weight control. This
proposed rule would assure the removal of OTC drug products containing
phenylpropanolamine, if any are still marketed, and prohibit future
marketing of such products.
FDA believes that the benefits of this rule justify the costs. Our
estimate of the benefits of complete elimination of phenylpropanolamine
preparations suggests that they could be as high as $250 million to
$625 million annually, if estimated using a willingness to pay
approach. The vast majority of these benefits are not directly
attributable to this rule, however, because industry previously took
voluntary action to discontinue production and marketing of
phenylpropanolamine preparations.
Similarly, most costs of product withdrawal or reformulation have
already been incurred because of the voluntary actions. However, a few
affected products may still be available and products that have been
withdrawn could still, in principle, be reintroduced in the absence of
the rule. Any remaining products containing phenylpropanolamine will
need to cease OTC marketing upon the effective date of any final rule,
but can be reformulated with another ingredient, where applicable.
Products that are reformulated will also need to be relabeled.
A. Background for Analysis of Impact
In November 2000, FDA issued a public health advisory on the safety
of phenylpropanolamine and announced that it would take steps to remove
phenylproanolamine from all drug products and had requested all drug
companies to voluntarily discontinue marketing products containing
phenylpropanolamine (Ref. 6). As a result of this announcement and the
publication of the Yale Hemorrhagic Stroke Project, national chain
drugstore and major and smaller manufacturers voluntarily removed
phenylpropanolamine-containing OTC drug products from the market.
Manufacturers of phenylpropanolamine-containing OTC drug products were
aware of the potential health problem and some manufacturers of OTC
nasal decongestant drug products containing phenylpropanolamine had
already reformulated or were in the process of reformulating their
products to remove phenylpropanolamine in advance of FDA's
announcement. Nevertheless, a number of factors markedly accelerated
this trend:
The recommendation of FDA's NDAC
The publication of the results of the Yale Hemorrhagic
Stroke Project
FDA's subsequent announcement of its intent to reclassify
phenylpropanolamine as a Category II ingredient, and FDA's request for
a voluntary recall.
These events led to the voluntary removal from the market of most
remaining phenylpropanolamine-containing OTC drug products. Both market
forces (i.e., avoidance of tort liability) and FDA's request for a
voluntary recall contributed to the decision by retail establishments
and manufacturers to discontinue sales. Because public awareness,
market forces, and FDA's announcement and request to voluntarily
withdraw occurred within a short span of time, it is not possible for
FDA to disentangle the impact these various factors had on
manufacturers' decisions to voluntarily recall phenylpropanolamine drug
products.
OMB guidelines on economic impact analyses direct agencies to
estimate costs and benefits from an appropriate baseline. ``This
baseline should be the best assessment of the way the world would look
absent the proposed regulation'' (Ref. 7). We do not believe that the
conditions prior to FDA's announcement of its intent to classify this
ingredient as nonmonograph are the appropriate baseline because the
publication of the Yale Hemorrhagic Stroke Project in a leading medical
journal alone would have generated a market response. We acknowledge
that the timing and wording of FDAs public announcement and request for
voluntary recalls contributed to the magnitude of the incurred costs.
However, because the costs attributable to the withdrawal of
phenylpropanolamine-containing OTC drug products have already occurred,
and may have occurred absent this proposed rule, albeit at a slower
pace, FDA believes present conditions are the appropriate baseline from
which to estimate the impact of this proposed rule.
Even if all of these costs were attributed to this proposed rule,
however, they would not rise to the $100 million per year threshold
sufficient to categorize this rule as economically significant under
section 3.f. of E.O. 12866. Nonetheless, we account for as much of the
cost as possible using 2000 as the baseline year for the number of
affected products
B. Costs of Regulation
a. Costs of removing products from the market. FDA finds that a
number of affected firms incurred substantial costs from these
voluntary product withdrawals. In addition, we are not aware of any
phenylpropanolamine-containing OTC drug products currently marketed, so
we believe the removal-
[[Page 75995]]
related costs have already been incurred.
The voluntary product withdrawals primarily affected two major OTC
drug markets--weight control and cough-cold medications. The weight
control drug products sector reported $48 million in annual sales for
phenylpropanolamine-containing drug products in 2000. The much larger
cough-cold products sector had total sales of about $1.2 billion (Ref.
8), but FDA does not have an estimate of the proportion of this figure
that included only phenylpropanolamine-containing products. As a
result, FDA cannot estimate the total sales of all OTC drug product
lines that contained phenylpropanolamine.
In 2000, FDAs drug listing system included approximately 400 drug
products containing phenylpropanolamine, with approximately 100
manufacturers and 250 distributors and repackers. Many of the 400
products were marketed by distributors and hence do not represent
unique formulations. FDA estimates that there may have been around 150
distinct products for both cough-cold and weight loss. Not all of these
products, however, were reformulated. Some manufacturers had already
added product lines containing a substitute active ingredient and had
no plans to reformulate the older product. The sales volume of some
products was too small to cover the cost of reformulation. Also, only
one substitute active ingredient was available for weight control drug
products. Hence, FDA estimates that only about 100 products were
reformulated.
The cost to reformulate a product varies greatly depending on the
nature of the change in formulation, the product, the process, and the
size of the firm. To reformulate, manufacturers also have to redo
validation (product, process, new supplier), conduct stability tests,
and change master production records. FDA estimates that the full cost
of reformulation ranged from $100,000 to $500,000 per product. Assuming
that 100 products were reformulated implies a total estimated one-time
reformulation cost of from $10 million to $50 million.
Manufacturers that reformulated would also have incurred costs to
relabel their products. They would have had to revise the active (and
for some the inactive) ingredient list and may have had to make other
labeling changes if they removed the phenylpropanolamine from a
combination product and did not replace it with another ingredient. FDA
believes that relabeling costs of the type required by this proposed
rule generally averaged about $3,000 to $4,000 per stockkeeping unit
(SKU) (individual products, packages, and sizes). Assuming 350 OTC SKUs
in the marketplace were relabeled, the total one-time costs of
relabeling would have ranged from $1.05 to $1.4 million.
Using 2000 as the baseline year for affected products, the total
estimated one-time costs for reformulation and labeling range from $11
million to $51 million. Annualized over 20 years yields annual costs of
$0.7 - $3.4 million (at 3 percent) and $1.0 - $4.8 million (at 7
percent).
b. Distributional issues and impact on industry. Other costs
incurred by the industry include costs associated with the recall and
destruction of inventory and the loss of product sales. FDA does not
have reliable information to estimate either the incremental impacts of
recalling and destroying product or to distinguish the market response
to the results of the Yale study from FDAs announcement and request for
voluntary withdrawal . Moreover, industry costs would be offset
substantially by countervailing events including avoided lawsuits
associated with continued marketing of products containing
phenylpropanolamine and possibly reduced insurance costs. The value of
lost profit due to lost product sales would generally be offset as
firms gain sales by distributing substitute products. These gains and
losses represent transfers within the industry and are not a social
cost.
Reports of withdrawal related expenses from trade press and some
10-K filings with the Securities and Exchange Commission include other
costs not attributable to costs of this regulation, such as set-asides
for potential litigation. Because of this, we cannot use these reports
as a basis for estimating regulatory costs. These reports, however,
provide anecdotal information about the magnitude of the impact of the
voluntary actions on specific firms. One of the hardest hit large
multinational firms explained that the Company immediately ceased
global production and shipments of any products containing
phenylpropanolamine and voluntarily withdrew any such products from
customer warehouses and retail store shelves. As a result, the Company
recorded a special charge of $80,000,000 to provide primarily for
product returns and the write-off of inventory'' (Ref. 9). Another
heavily impacted large firm claimed that withdrawal would cost between
$51 and $68 million (Ref. 10). Similarly, a large private-label
manufacturer reportedly took a $24 million charge against earnings
(Ref. 11). These last two figures likely included costs of product
reformulation as well as lost inventory value and sales revenues. These
accounts represent projections and are estimates for financial
reporting requirements but do not accurately reflect actual costs used
for regulatory impact analyses.
FDA believes that the lost sales estimates may be overstated, as
alternative cough-cold drug products were widely available. Most
manufactures quickly offered alternative products and received
offsetting increases in sales revenues. OMB guidelines for economic
analysis state that, ``[t]he preferred measure of cost is the
`opportunity cost of the resources used or the benefits forgone as a
result of the regulatory action'' (Ref. 7).
The costs of reformulation, recalls, and lost inventories are
clearly ``opportunity costs,'' but the company sales revenues lost from
recalled phenylpropanolamine-containing cough-cold drug products were
likely matched by increased sales of other phenylpropanolamine-free
products, frequently manufactured by the same or competing drug
companies. These distributional effects are important to individual
firms, but are not considered ``opportunity costs.''
c. Summary of costs. The regulatory costs of the proposed rule
would include: (1) The one-time costs to reformulate and relabel
affected products, (2) lost inventory, and (3) the cost of recalls. We
estimate one-time costs of $11 million to $51 million for reformulation
and labeling. Annualized over 20 years yields annual costs of $0.7 -
$3.4 million (at 3 percent) and $1.0 - $4.8 million (at 7 percent). We
lack sufficient information to estimate the value of lost inventories
or the costs of recall. The uncertainty associated with the costs
presented in financial reports and the inability to adjust for
transfers makes it impossible to use these data to estimate the
potential incremental regulatory impact of this proposed rule.
C. Benefits of Regulation
The benefit of removing phenylpropanolamine-containing products
from the market was the reduction in the number of hemorrhagic strokes
that would otherwise occur each year. Because phenylpropanolamine-
containing OTC drug products have already been removed from the market,
most of the expected health benefits are attributable to these past
voluntary product withdrawals, rather than to FDA's future regulatory
action. FDA has estimated that phenylpropanolamine causes 200 to 500
hemorrhagic strokes per year in people 18 to 49 years old (Ref. 5).
[[Page 75996]]
Assigning a monetary value to the prevention of strokes is
problematic and there is no consensus on how it should be calculated.
Taylor (Ref. 12) used a lifetime cost model to estimate the cost, by
type of stroke. The model accounts for direct medical costs and
indirect costs, such as earnings and premature mortality and morbidity.
Updating this estimate to 2003 dollars (Ref. 13) and weighting it for
the occurrence rate of subarachnoid and intracerebral hemorrhage (60
percent and 40 percent, respectively) (Ref. 14) results in an estimated
figure of about $304,719 for the lifetime cost of stroke per person.
With these values, the monetized benefit of preventing from 200 to 500
strokes per year by removing all phenylpropanolamine-containing OTC
drug products from the market ranges from $60.9 million to $152.4
million per year. When groups less than 18 and over 49 years old (the
ages of the subjects in the Yale Hemorrhagic Stroke Project) are
included, the total yearly benefits will be higher.
Another method of calculating benefits is to value the statistical-
lives saved due to the removal of drug products containing
phenylpropanolamine. Assuming a mortality rate from
phenylpropanolamine-caused strokes of about 25 percent, an estimated 50
to 125 lives saved per year in people 18 to 49 years old would be
attributed to the removal of products containing phenylpropanolamine.
The value of a statistical-life has been estimated to range from $1.6
million to $8.5 million 1986-dollars (Ref. 15). Using a rough midpoint
value of $5 million per statistical-life, the estimated benefit of
averting these stroke-induced fatalities ranges from $250 million to
$625 million per year. Again, FDA is not asserting that this proposed
rule will generate such benefits, because the benefit-producing
activities have already occurred. Nevertheless, to the extent that some
phenylpropanolamine-containing OTC drug products might remain available
or might return to the market, some fraction of these benefits would be
attributable to the issuance of this proposed rule.
D. Small Business Impacts
A drug manufacturer is defined as small by the Small Business
Administration if it employs fewer than 750 people. Approximately 70
percent of all OTC drug manufacturers meet the definition of a small
entity, and FDA believes that the same rate applies to manufacturers of
phenylpropanolamine-containing OTC drug products. Hence, 70 of the 100
manufacturers were classified as small. The cost to distributors and
repackers was not significant because the manufacturers of the products
bore the brunt of the recall costs, product destruction, and usually
were responsible for designing new labels. As explained in this
section, to the extent that there are still phenylpropanolamine-
containing OTC drug products being marketed, the impact on a
manufacturer can vary greatly depending on the number and type of
phenylpropanolamine-containing products it produces, the availability
of substitute ingredients, and the number of SKUs that will require
reformulation and/or relabeling. For example, a small branded product
manufacturer may have to reformulate three products and relabel nine
SKUs for a total one-time reformulation and relabeling cost ranging
from $327,000 (3 products x $100,000 reformulation + 9 SKUs x $3,000
label) to $1.536 million (3 products x $500,000 reformulation + 9 SKUs
x $4,000 label). Because there is only one substitute available for OTC
weight control drug products, the manufacturer would have to cease
production of its existing product and the impact to the firm would be
lost sales. The lost sales could be partially offset by sales of a
substitute product, if marketed. The cost of the voluntary product
recall would also vary by firm and again depend on the number and
quantity of products that needed to be recalled and destroyed.
Because these products must be manufactured in compliance with the
pharmaceutical current good manufacturing practices (21 CFR parts 210
and 211), all firms would have the necessary skills and personnel to
perform these tasks either in-house or by contractual arrangement. No
additional professional skills are needed. In addition, there are no
other Federal rules that duplicate, overlap, or conflict with the
proposed rule.
FDA considered but rejected alternatives such as leaving products
containing this ingredient on the OTC market, or not publicly
announcing our intent to reclassify phenylpropanolamine as a Category
II ingredient. These alternatives were unacceptable because the health
risk posed by products containing phenylpropanolmine was greater than
the benefits the products provided, especially given the number of
substitute OTC drug products available that did not pose such risks. To
have further delayed the removal of OTC phenylpropanolamine drug
products from the market would have left consumers exposed to an
unacceptable level of risk.
Because the cost of removal and reformulation of
phenylpropanolamine containing OTC drug products has already been
incurred when the products were voluntarily recalled, and FDA has
chosen to use the present as a baseline for its analysis, FDA
tentatively concludes that this proposed rule will not have a
significant impact on a substantial number of small entities.
V. Paperwork Reduction Act of 1995
FDA tentatively concludes that there are no paperwork requirements
in this document under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501 et seq.).
VI. Environmental Impact
The agency has determined under 21 CFR 25.31(a) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
the agency tentatively concludes that the proposed rule does not
contain policies that have federalism implications as defined in the
Executive order and, consequently, a federalism summary impact
statement has not been prepared.
VIII. Request for Comments
Three copies of all written comments are to be submitted.
Individuals submitting written comments or anyone submitting electronic
comments may submit one copy. Comments are to be identified with the
docket numbers found in brackets in the heading of this document and
may be accompanied by a supporting memorandum or brief. Received
comments may be seen in the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
IX. Time for Submission of New Data
The OTC drug review procedures (21 CFR 330.10(a)(7)(iii)) provide
for a 12-month period after publication of a TFM for any interested
person to file new data and information to support a condition excluded
from the monograph
[[Page 75997]]
in the TFM. As discussed in section I of this document, FDA has
published proposed and final rules for OTC nasal decongestant and
weight control drug products and deferred a decision on the status of
phenylpropanolamine so new data on this ingredient could be included in
the record before a TFM or notice of proposed rulemaking was published.
Manufacturers have been aware of this deferral for a number of years
and have waited for the results of the study described in section II of
this document to resolve the monograph status of phenylpropanolamine.
It has taken many years for the phenylpropanolamine study to be
completed, and the results indicate a major safety concern about this
ingredient. FDA does not believe that any additional significant new
safety data and information will be presented in the next 12 months.
Because of the need to address and finalize FDA action on the existing
safety concerns, and because there has already been public
consideration of the issues before an FDA advisory committee, the
comment period and the time for submission of new data is 90 days. FDA
considers it an important public health concern to complete its
classification of phenylpropanolamine preparations in OTC drug products
as quickly as possible.
X. Proposed Effective Date
FDA is proposing that any final rule that may issue based on this
proposal become effective 30 days after its date of publication in the
Federal Register.
XI. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the
Web site address, but we are not responsible for subsequent changes to
the Web site after this document publishes in the Federal Register.)
1. Comment No. LET86, Docket No. 1981N-0022 (formerly Docket No.
81N-0022).
2. Horwitz et al., ``Phenylpropanolamine & Risk of Hemorrhagic
Stroke: Final Report of The Hemorrhagic Stroke Project,'' May 10, 2000
in Comment No. C230, Docket No. 1976N-0052N (formerly Docket No. 76N-
052N) and Comment No. RPT14, Docket No. 1981N-0022 (formerly Docket No.
81N-0022).
3. Phenylpropanolamine case reports from 1991 to 2000 on file in
Docket Nos. 1976N-0052N (formerly 76N-052N) and 1981N-0022 (formerly
81N-0022).
4. Consumer Healthcare Products Association (CHPA), ``Comments on
the Hemmorhagic Stroke Project Report,'' May 24, 2000, in Comment No.
C231, Docket No. 1976N-0052N (formerly Docket No. 76N-052N) and Comment
No. C113, Docket No. 1981N-0022 (formerly Docket No. 81N-0022).
5. Food and Drug Administration, Transcript of Nonprescription
Drugs Advisory Committee meeting, October 19, 2000, in Docket Nos.
1976N-0052N, (formerly 76N-052N) and 1981N-0022 (formerly 81N-0022).
6. Food and Drug Administration, Public Health Advisory, ``Safety
of Phenylpropanolamine,'' November 6, 2000, Comment No. M1 in Docket
No. 1976N-0052N (formerly 76N-052N) and Comment No. M7 in Docket No.
1981N-0022 (formerly 81N-0022).
7. Office of Management and Budget, ``Guidelines to Standardized
Measures of Costs and Benefits and the Format of Accounting
Statements,'' M0008, March 22, 2000, downloaded from http://www.whitehouse.gov/omb/memoranda/index.html, accessed June, 13, 2001.
8. Jarvis, Lisa, ``PPA Ban Is a Serious Threat to OTC Diet Aids,''
Chemical Market Reporter, November 20, 2000.
9. U.S. Security and Exchange Commission, Form 10-K, Voluntary
Market Withdrawals, fiscal year ended December 31, 2000, American Home
Products Corp., in Docket Nos. 1976N-0052N (formerly Docket No. 1976N-
052N) and 1981N-0022.
10. F-D-C Reports-``The Tan Sheet,'' ``Dexatrim Natural Fattens
Chattem's First Quarter; Extensions Planned,'' vol. 9, no. 14, April 2,
2001.
11. F-D-C Reports-``The Tan Sheet,'' ``AHP Dimetapp, Robitussin PPA
Withdrawals Lead To $80 Mil. Charge In 2000,'' vol. 9, no. 5, January
29, 2001.
12. Taylor, Thomas N., ``The Medical Economics of Stroke,'' Drugs,
supp. 3:51-58, 1997.
13. U.S. Census Bureau, No. 768, Consumer Price Index by Major
Group., downloaded from http://www.census.gov/statab/freq/00s0768.txt,
accessed June 12, 2001. U.S. Bureau of Labor Statistics, accessed July
23, 2004. Updated 1999 data to 2003 (18.56 percent increase in medical
care CPI).
14. Kernan, Walter N. et al., ``Phenylpropanolamine and the Risk of
Hemorrhagic Stroke,'' The New England Journal of Medicine, 343: 1826-
1832, 2000.
15. Fisher, A., L., G. Chestnut, and D. M. Violette, ``The Value of
Reducing Tisks of Death: a Note on New Evidence,'' Journal of Policy
Analysis and Management, 8: 88-100, 1989.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 341
Labeling, Over-the-counter drugs.
21 CFR Part 357
Labeling, Over-the-counter drugs, Reporting and recordkeeping
requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 310, 341 (as proposed in the Federal
Register of September 9, 1976 (41 FR 38312)), and 357 (as proposed in
the Federal Register of February 26, 1982 (47 FR 8466)) be amended as
follows:
PART 310-NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
2. Section 310.545 is amended by redesignating the text of
paragraph (a)(20) as paragraph (a)(20)(i) and by adding paragraph
(a)(20)(i) heading, by adding paragraphs (a)(6)(ii)(D), (a)(20)(ii),
and (d)(35), and by revising paragraph (d)(2) to read as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(6) * * *
(ii) * * *
(D) Approved as of January 23, 2006. Any phenylpropanolamine
ingredient.
* * * * *
(a) * * *
(20) * * *
(i) Approved as of February 8, 1991. * * *
(ii) Approved as of January 23, 2006. Any phenylpropanolamine
ingredient.
* * * * *
(d) * * *
(2) February 10, 1992, for products subject to paragraph (a)(20)(i)
of this section.
* * * * *
(35) January 23, 2006, for products subject to paragraphs
(a)(6)(ii)(D) and (a)(20)(ii) of this section.
[[Page 75998]]
PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
3. The authority citation for 21 CFR part 341 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
Sec. 341.20 [Amended]
4. Section 341.20 of the proposed rule published at 41 FR 38312 is
amended by removing paragraph (e) and redesignating paragraphs (f),
(g), and (h) as paragraphs (e), (f), and (g), respectively.
PART 357--MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER
HUMAN USE
5. The authority citation for 21 CFR part 357 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
Sec. 357.510 [Amended]
6. Section 357.510 of the proposed rule published at 47 FR 8466 is
amended by removing and reserving paragraph (b).
Sec. 357.520 [Removed]
7. Section 357.520 of the proposed rule published at 47 FR 8466 is
removed.
Sec. 357.550 [Amended]
8. Section 357.550 of the proposed rule published at 47 FR 8466 is
amended by removing and reserving paragraphs (c)(2) and (d)(2).
Sec. 357.555 [Removed]
9. Section 357.555 of the proposed rule published at 47 FR 8466 is
removed.
Dated: December 5, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E5-7646 Filed 12-21-05; 8:45 am]
BILLING CODE 4160-01-S