98-22568. Status of Certain Additional Over-the-Counter Drug Category II and III Active Ingredients  

  • [Federal Register Volume 63, Number 163 (Monday, August 24, 1998)]
    [Rules and Regulations]
    [Pages 44996-44998]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 98-22568]
    
    
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    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    
    Food and Drug Administration
    
    21 CFR Part 310
    
    [Docket No. 98N-0636]
    RIN 0910-AA01
    
    
    Status of Certain Additional Over-the-Counter Drug Category II 
    and III Active Ingredients
    
    AGENCY: Food and Drug Administration, HHS.
    
    ACTION: Final rule.
    
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    SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
    stating that certain ingredients in over-the-counter (OTC) drug 
    products are not generally recognized as safe and effective or are 
    misbranded. FDA is issuing this final rule after considering the 
    reports and recommendations of various OTC drug advisory review panels 
    and public comments on proposed agency regulations, which were issued 
    in the form of a tentative final monograph (proposed rule). Based on 
    the absence of any submissions on these ingredients to the panels, as 
    well as the failure of interested parties to submit new data or 
    information to FDA under the proposed regulations, the agency has 
    determined that the presence of these ingredients in an OTC drug 
    product would result in that drug product not being generally 
    recognized as safe and effective for its intended use or would result 
    in misbranding. This final rule is part of the ongoing review of OTC 
    drug products conducted by FDA.
    EFFECTIVE DATE: February 22, 1999.
    
    FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug 
    Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
    Fishers Lane, Rockville, MD 20857, 301-827-2307.
    
    SUPPLEMENTARY INFORMATION:
    
    I. Background
    
        In the Federal Register of November 7, 1990 (55 FR 46914), FDA 
    published under Sec. 330.10(a)(7)(ii) (21 CFR 330.10(a)(7)(ii)) a final 
    rule on the status of certain OTC drug Category II and III active 
    ingredients. That final rule declared as not generally recognized as 
    safe and effective certain active ingredients that had been proposed as 
    nonmonograph (Category II or Category III) under the agency's OTC drug 
    review. The periods for submission of comments and new data following 
    the publication of a notice of proposed rulemaking (NPRM) had closed 
    and no significant comments or new data had been submitted to upgrade 
    the status of these ingredients. In each instance, a final rule for the 
    class of ingredients involved had not been published to date.
        In the Federal Register of May 10, 1993 (58 FR 27636), FDA 
    published a final rule establishing that certain additional active 
    ingredients in OTC drug products are not generally recognized as safe 
    and effective or are misbranded. That final rule included active 
    ingredients from a number of OTC drug rulemakings that were not covered 
    by the November 7, 1990, final rule (see Table I of the May 10, 1993, 
    final rule (58 FR 27636 at 27639 to 27641) for a list of OTC drug 
    rulemakings and active ingredients covered by that final rule). The 
    final rule included a number of active ingredients found in OTC 
    internal analgesic and orally administered menstrual drug products. 
    Those ingredients are listed in Sec. 310.545(a)(23) and (a)(24) (21 CFR 
    310.545(a)(23) and (a)(24)), respectively.
        The ingredients listed in these sections do not include ephedrine, 
    ephedrine salts (ephedrine hydrochloride, ephedrine sulfate, 
    racephedrine hydrochloride), atropine, or atropine salts (atropine 
    sulfate). The agency is aware of several combination drug products 
    marketed for OTC internal analgesic or menstrual use that include 
    ephedrine sulfate and atropine sulfate among their ingredients, in 
    addition to aspirin or acetaminophen (Ref. 1). No submissions of data 
    supporting the use of ephedrine or atropine singly or in combination 
    were made to the advisory review panels that reviewed these classes of 
    OTC drug products. No information was provided following publication of 
    the tentative final monographs for OTC orally administered menstrual 
    drug products or internal analgesic, antipyretic, and antirheumatic 
    drug products on November 16, 1988 (53 FR 46194 and 46204, 
    respectively). A final rule has not been published to date for either 
    of these classes of OTC drug products.
         FDA is not aware of any information that supports the use of 
    ephedrine or atropine as active ingredients in OTC orally administered 
    menstrual or internal analgesic, antipyretic, and antirheumatic drug 
    products. Accordingly, these active ingredients will not be included in 
    the relevant final monographs because they have not been shown to be 
    generally recognized as safe and effective for their intended use(s). 
    These ingredients should be eliminated from OTC drug products 180 days 
    after the date of publication in the Federal Register of this final 
    rule, regardless of whether further testing is undertaken to justify 
    future use.
        Publication of a final rule under this proceeding does not preclude 
    a manufacturer's testing an ingredient. New, relevant data can be 
    submitted to the agency at a later date as the subject of a new drug 
    application (NDA) that may provide for prescription or OTC marketing 
    status (see part 314 (21 CFR part 314)). As an alternative, where there 
    are adequate data establishing general recognition of safety and 
    effectiveness, such data may be submitted in an appropriate citizen 
    petition to amend a monograph (see Sec. 10.30 (21 CFR 10.30)).
    
    II. The Agency's Final Conclusions on Certain OTC Drug Category II 
    and III Ingredients
    
        The agency notes that no comments or data have been submitted to 
    the OTC drug review to support any ephedrine or atropine ingredient as 
    being generally recognized as safe and effective for any OTC uses in 
    orally administered menstrual or internal analgesic, antipyretic, and 
    antirheumatic drug products. The agency has determined that these 
    ingredients should be deemed not generally recognized as safe and 
    effective for OTC use before a final monograph for each respective drug 
    category is established. Accordingly, any drug product containing any 
    of these ingredients and labeled for OTC
    
    [[Page 44997]]
    
    oral menstrual or internal analgesic, antipyretic, and antirheumatic 
    use will be considered nonmonograph and misbranded under section 502 of 
    the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352) and 
    a new drug under section 201(p) of the act (21 U.S.C. 321(p)) for which 
    an approved application under section 505 of the act (21 U.S.C. 355) 
    and part 314 of the regulations is required for marketing. As an 
    alternative, where there are adequate data establishing general 
    recognition of safety and effectiveness, such data may be submitted in 
    a citizen petition to amend the appropriate monograph to include any of 
    these ingredients in OTC drug products (see Sec. 10.30). Any OTC drug 
    product containing any of these ingredients and labeled for the uses 
    discussed in this document that is initially introduced or initially 
    delivered for introduction into interstate commerce after the effective 
    date of this final rule and that is not the subject of an approved 
    application will be in violation of sections 502 and 505 of the act 
    and, therefore, subject to regulatory action. Further, any OTC drug 
    product subject to the final rule that is repackaged or relabeled after 
    the effective date of the rule would be required to be in compliance 
    with the rule regardless of the date the product was initially 
    introduced or initially delivered for introduction into interstate 
    commerce. Manufacturers are encouraged to comply voluntarily with the 
    rule at the earliest possible date.
    
    III. Reference
    
        (1) American Pharmaceutical Association, Handbook of 
    Nonprescription Drugs, 10th ed., pp. 646, 648, and 667, 1993.
    
    IV. Analysis of Impacts
    
        FDA has examined the impacts of the final rule under Executive 
    Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
    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 has a significant impact on a substantial 
    number of small entities, an agency must analyze regulatory options 
    that would minimize any significant impact of the rule on small 
    entities.
        Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et 
    seq.) requires that agencies prepare a written statement and economic 
    analysis before proposing any rule that may result in an expenditure in 
    any 1 year by State, local, and tribal governments, in the aggregate, 
    or by the private sector, of $100 million (adjusted annually for 
    inflation).
        The agency believes that this final rule is consistent with the 
    principles set out in the Executive Order and in these two statutes. 
    The purpose of this final rule is to act on the nonmonograph status of 
    certain ingredients in advance of finalization of other monograph 
    conditions in order to expedite completion of the OTC drug review. 
    There are a limited number of products currently marketed that will be 
    affected by this rule. The agency is aware of at least three products, 
    although there may be more. These products are marketed by three 
    different manufacturers, all of which are considered small entities, 
    using the U.S. Small Business Administration designation for this 
    industry (750 employees).
        Manufacturers of these products will no longer be able to market 
    products containing the ephedrine or atropine ingredients included in 
    this final rule after its effective date. However, the manufacturers 
    will be able to reformulate these products and continue to market them 
    with proposed monograph ingredients. The cost of reformulation and 
    relabeling to any one manufacturer should be minimal as only one 
    product per manufacturer appears to be affected. Total costs should be 
    minimal ($500,000 to $1 million) as only a limited number of products 
    appear to be affected. The lost sales from the products containing 
    nonmonograph ingredients may be offset by sales of the substitute 
    products containing monograph ingredients. In addition, manufacturers 
    have been aware of the status of these products since 1988 and have not 
    submitted any safety and effectiveness data to the agency.
        The agency considered but rejected not acting on these ingredients 
    in advance of the finalization of other monograph conditions. The final 
    monographs for OTC orally administered menstrual and internal 
    analgesic, antipyretic, and antirheumatic drug products are not 
    expected to be completed for a period of time. The agency also 
    considered publishing an additional notice alerting manufacturers that 
    the ingredients in this final rule would be removed earlier. However, 
    safety and effectiveness have not been established for these 
    ingredients and manufacturers have not submitted the necessary data. 
    Based on past experience, FDA has found that manufacturers do not 
    submit the necessary data after a proposed rule is published when no 
    data or petitions have been submitted in response to prior requests. In 
    addition, consumers will benefit from the early removal from the 
    marketplace of products containing ingredients for which safety and 
    effectiveness have not been established. Consumers can then purchase 
    products containing only ingredients proposed for monograph status. 
    Manufacturers who choose to reformulate or replace affected products 
    will be able to use alternative ingredients that are proposed as 
    monograph conditions without incurring any additional expense of 
    clinical testing for those ingredients.
        While this final rule may cause manufacturers to discontinue 
    marketing or to reformulate some products prior to issuance of the 
    applicable final monograph, these manufacturers have known for some 
    time that if adequate data were not submitted to support safety and 
    effectiveness, cessation of marketing of the current products would be 
    required, in any event, when the final monographs are published. 
    Because this rule imposes no additional reporting or recordkeeping 
    requirements, no additional professional skills are necessary to 
    comply.
        The analysis shows that this final rule is not economically 
    significant under Executive Order 12866 and that the agency has 
    considered the burden to small entities. Based on the above analysis, 
    the agency does not believe that the few affected manufacturers will 
    incur a significant economic impact, although there may be some 
    reformulation costs or inventory losses. Thus, this economic analysis, 
    together with other relevant sections of this document, serves as the 
    agency's regulatory flexibility analysis, as required under the 
    Regulatory Flexibility Act. Finally, this analysis shows that the 
    Unfunded Mandates Act does not apply to the final rule because it would 
    not result in an expenditure in any 1 year by State, local, and tribal 
    governments, in the aggregate, or by the private sector, of $100 
    million.
    
    V. Paperwork Reduction Act of 1995
    
        This final rule contains no collections of information. Therefore, 
    clearance by the Office of Management and Budget under the Paperwork 
    Reduction Act of 1995 is not required.
    
     VI. Environmental Impact
    
        The agency has determined under 21 CFR 25.30(h) that this action is 
    of a type that is categorically excluded from the preparation of an 
    environmental assessment because these actions, as a
    
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    class, will not result in the production or distribution of any 
    substance and therefore will not result in the production of any 
    substance into the environment.
    
     List of Subjects in 21 CFR Part 310
    
        Administrative practice and procedure, Drugs, Labeling, Medical 
    devices, Reporting and recordkeeping requirements.
        Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
    authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
    310 is 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, 357, 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 
    paragraphs (a)(23) and (a)(24) as paragraphs (a)(23)(i) and (a)(24)(i), 
    respectively; by adding paragraphs (a)(23)(i) and (a)(24)(i) headings, 
    by adding paragraphs (a)(23)(ii), (a)(24)(ii), and (d)(26); and by 
    revising paragraph (d)(11) to read as follows:
    
    Sec. 310.545  Drug products containing certain active ingredients 
    offered over-the-counter (OTC) for certain uses.
    
        (a) * * *
        (23) Internal analgesic drug products--(i) Approved as of November 
    10, 1993. * * *
        (ii) Approved as of February 22, 1999.
    Any atropine ingredient
    Any ephedrine ingredient
        (24) Orally administered menstrual drug products--(i) Approved as 
    of November 10, 1993. * * *
        (ii) Approved as of February 22, 1999.
    Any atropine ingredient
    Any ephedrine ingredient
    * * * * *
        (d) * * *
        (11) November 10, 1993, for products subject to paragraphs 
    (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except 
    products that contain ferric subsulfate) through (a)(18)(vi), 
    (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.
    * * * * *
        (26) February 22, 1999, for products subject to paragraphs 
    (a)(23)(ii) and (a)(24)(ii) of this section.
    
        Dated: August 11, 1998.
    William K. Hubbard,
    Associate Commissioner for Policy Coordination.
    [FR Doc. 98-22568 Filed 8-21-98; 8:45 am]
    BILLING CODE 4160-01-F
    
    
    

Document Information

Effective Date:
2/22/1999
Published:
08/24/1998
Department:
Food and Drug Administration
Entry Type:
Rule
Action:
Final rule.
Document Number:
98-22568
Dates:
February 22, 1999.
Pages:
44996-44998 (3 pages)
Docket Numbers:
Docket No. 98N-0636
RINs:
0910-AA01: Over-the-Counter (OTC) Drug Review
RIN Links:
https://www.federalregister.gov/regulations/0910-AA01/over-the-counter-otc-drug-review
PDF File:
98-22568.pdf
CFR: (1)
21 CFR 310.545