[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

[[Page 44998]]

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