    [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