[Federal Register Volume 66, Number 188 (Thursday, September 27, 2001)]
[Rules and Regulations]
[Pages 49276-49278]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-24127]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration.

21 CFR Part 341

[Docket No. 76N-052G]
RIN 0910-AA01


Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products for Over-the-Counter Human Use; Partial Final Rule for 
Combination Drug Products Containing a Bronchodilator

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 
establishing that cough-cold combination drug products containing any 
oral bronchodilator active ingredient in combination with any 
analgesic(s) or analgesic-antipyretic(s), anticholinergic, 
antihistamine, oral antitussive, or stimulant active ingredient are not 
generally recognized as safe and effective and are misbranded for over-
the-counter (OTC) use. FDA is issuing this final rule after receiving 
no public comments on the agency's proposed nonmonograph status of 
these specific combination drug products, which was issued in the form 
of a tentative final monograph for OTC cough-cold combination drug 
products. This final rule is part of the ongoing review of OTC drug 
products conducted by FDA.

DATES: This regulation is effective October 29, 2001.

FOR FURTHER INFORMATION CONTACT: Cazemiro R. Martin, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 9, l976 (41 FR 38312), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC cold, 
cough, allergy, bronchodilator, and antiasthmatic (cough-cold) drug 
products, together with the recommendations of the Advisory Review 
Panel on OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic 
Drug Products (the Panel), which was the advisory review panel 
responsible for evaluating data on the active ingredients in this drug 
class. The Panel placed the combination of an oral bronchodilator with 
either an analgesic-antipyretic, anticholinergic, antihistamine, or 
antitussive (when the product is labeled only for cough associated with 
asthma) ingredient in Category II (not generally recognized as safe 
and/or effective) (41 FR 38312 at 38326).
    The agency concurred with the Panel in the tentative final 
monograph for cough-cold combination drug products (53 FR 30522 at 
30556, August 12, 1988). The agency also classified the combination of 
caffeine and ephedrine or pseudoephedrine in Category II (53 FR 30522 
at 30557). No comments on these specific combinations were submitted in 
response to the tentative final monograph.
    The current monograph oral bronchodilator active ingredients are 
ephedrine, ephedrine hydrochloride, ephedrine sulfate, and racephedrine 
hydrochloride (21 CFR 341.16(a), (b), (c), and (f)). The agency is not 
aware of any OTC drug products currently marketed containing an oral 
bronchodilator active ingredient in combination with any analgesic(s) 
or analgesic-antipyretic(s), anticholinergic, antihistamine, oral 
antitussive, or stimulant active ingredient.

II. The Agency's Conclusion

    The OTC drug review program establishes conditions under which OTC 
drugs are generally recognized as safe and effective and not 
misbranded.

[[Page 49277]]

 Two principal conditions examined during the review are allowable 
ingredients and allowable labeling. The Panel evaluated the submitted 
data on active ingredients in combination products from the standpoint 
of safety and effectiveness and, based on its evaluation, recommended 
specific combinations of ingredients from the same and different 
pharmacologic groups. The Panel classified a number of cough-cold 
combinations as Category II (41 FR 38312 at 38326) and considered 
medical rationale and drug interaction in making these recommendations.
    In the tentative final monograph for OTC cough-cold combination 
drug products (53 FR 30522 at 30556 to 30557), the agency agreed with 
the Panel's recommended Category II status of any oral bronchodilator 
active ingredient in combination with any analgesic(s) or analgesic-
antipyretic(s), anticholinergic, antihistamine, oral antitussive, or 
stimulant active ingredient. The agency invited interested persons to 
submit written comments and new data demonstrating the safety and 
effectiveness of those conditions not classified in Category I (53 FR 
30522 at 30560). The agency did not receive any comments in response to 
its request for such information concerning the proposed Category II 
status of any of the above-mentioned OTC cough-cold combination drug 
products containing an oral bronchodilator.
    Accordingly, in this final rule the agency is finalizing the 
nonmonograph status of any oral bronchodilator active ingredient in 
combination with any analgesic(s) or analgesic-antipyretic(s), 
anticholinergic, antihistamine, oral antitussive, or stimulant active 
ingredient. Thus, any drug product labeled, represented, or promoted 
for use as an OTC cough-cold combination drug that contains any oral 
bronchodilator active ingredients in combination with any of these 
specific active ingredients may be considered a new drug within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 321(p)) and misbranded under section 502 of the 
act (21 U.S.C. 352). These specific combination drug products can not 
be marketed for OTC cough-cold use unless they are the subject of an 
approved application under section 505 of the act (21 U.S.C. 355) and 
part 314 of the regulations (21 CFR part 314). Any OTC cough-cold 
combination drug product included in new Sec. 310.545(a)(6)(iv)(D) that 
is initially introduced or initially delivered for introduction into 
interstate commerce after the effective date stated in 
Sec. 310.545(d)(33) of this final rule that is not in compliance with 
the regulations is subject to regulatory action.

III. Analysis of Impacts

    The agency did not receive any comments in response to its request 
in the tentative final monograph (53 FR 30522 at 30560) for specific 
comment on the economic impact of this rulemaking. FDA has examined the 
impacts of this final 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 has a significant economic 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. Section 202(a) of the Unfunded Mandates Reform Act requires 
that agencies prepare a written statement and economic analysis 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 in any one year (adjusted annually for inflation).
    The agency believes that this final rule is consistent with the 
regulatory philosophy and principles identified in the Executive order. 
In addition, the final rule is not a significant regulatory action as 
defined by the Executive order and so is not subject to review under 
the Executive order.
    The purpose of this final rule is to declare any oral 
bronchodilator active ingredient in combination with any analgesic(s) 
or analgesic-antipyretic(s), anticholinergic, antihistamine, oral 
antitussive, or stimulant active ingredient as not generally recognized 
as safe and effective. The agency does not believe that any of these 
combination drug products are currently marketed OTC. Therefore, this 
final rule should have no economic impact on any manufacturer.
    Under the Unfunded Mandates Reform Act, FDA is not required to 
prepare a statement of costs and benefits for this final rule because 
this final rule is not expected to result in an expenditure that would 
exceed $100 million adjusted for inflation in any one year.
    The agency certifies that the final rule will not have a 
significant impact on a substantial number of small entities.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that is categorically excluded from the preparation of an 
environmental assessment because these actions, as a 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.

V. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the 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 has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the order and, consequently, a federalism 
summary impact statement is not required.

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, 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 adding paragraph (a)(6)(iv)(D), by 
revising paragraph (d) introductory text, by adding and reserving 
paragraph (d)(32), and by adding paragraph (d)(33) to read as follows:


Sec. 310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) *  *  *  
    (6) *  *  *  
    (iv) *  *  *  
    (D) Approved as of October 29, 2001. Any oral bronchodilator active 
ingredient (e.g., ephedrine, ephedrine

[[Page 49278]]

hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any 
other ephedrine salt) in combination with any analgesic(s) oranalgesic-
antipyretic(s), anticholinergic, antihistamine, oralantitussive, or 
stimulant active ingredient.
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initiallyintroduced or 
initially delivered for introduction intointerstate commerce after the 
dates specified in paragraphs(d)(1) through (d)(33) of this section.
* * * * *
    (32) [Reserved]
    (33) October 29, 2001, for products subject to paragraph 
(a)(6)(iv)(D) of this section.

    Dated: September 20, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-24127 Filed 9-26-01; 8:45 am]
BILLING CODE 4160-01-S