[Federal Register Volume 61, Number 31 (Wednesday, February 14, 1996)]
[Proposed Rules]
[Pages 5918-5920]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-3325]



      

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Part IX





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 333



Topical Antimicrobial Drug Products for Over-the-Counter Human Use; 
Proposed Rule

  Federal Register / Vol. 61, No. 31 / Wednesday, February 14, 1996 / 
Proposed Rules  
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food And Drug Administration

21 CFR Part 333

[Docket No. 95N-0062]
RIN 0910-AA01


Topical Antimicrobial Drug Products For Over-The-Counter Human 
Use; Proposed Amendment of Final Monograph for OTC First Aid Antibiotic 
Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking that would amend the final monograph for over-the-
counter (OTC) first aid antibiotic drug products (the regulation that 
establishes conditions under which these drug products are generally 
recognized as safe and effective and not misbranded). The amendment 
would add a warning statement concerning allergic reactions resulting 
from topical antibiotic drug products containing bacitracin, bacitracin 
zinc, neomycin, neomycin sulfate, polymyxin B, or polymyxin B sulfate. 
This proposal is part of the ongoing review of OTC drug products 
conducted by FDA.

DATES: Written comments on the proposed regulation by May 14, 1996; 
written comments on the agency's economic impact determination by May 
14, 1996. FDA is proposing that any final rule based on this proposal 
become effective 12 months after its date of publication in the Federal 
Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-105),-Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2304.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of December 11, 1987 (52 FR 47312), FDA 
issued a final monograph for OTC first aid antibiotic drug products in 
part 333 (21 CFR part 333) subpart B. The monograph provides for single 
ingredient products containing bacitracin, bacitracin zinc, neomycin, 
or neomycin sulfate and various combinations containing bacitracin, 
neomycin sulfate, and polymyxin B sulfate.
    FDA has been informed (Ref. 1) that manufacturers of OTC topical 
antibiotic drug products containing bacitracin zinc, neomycin sulfate, 
and polymyxin B sulfate voluntarily have added the following 
information about the possibility of allergic reactions associated with 
these antibiotics in the warnings for these products: ``Stop use and 
consult a physician if * * * a rash or other allergic reaction 
develops. Do not use this product if you are allergic to any of the 
listed ingredients.'' This allergy warning resulted from an industry 
task group's review of adverse event reports involving products 
containing bacitracin zinc, neomycin sulfate, and polymyxin B sulfate. 
The reports showed that these products have been reported to be 
associated with hypersensitivity reactions in susceptible individuals 
and, in rare instances, nonfatal systemic hypersensitivity reactions.
    The agency requested that the task group provide these reports for 
evaluation (Ref. 2), and the industry subsequently submitted them (Ref. 
3). The reports included: (1) Listings from FDA's Spontaneous Reporting 
System (SRS) of adverse experience reports for prescription and OTC 
drug products containing bacitracin, neomycin, and polymyxin B sulfate, 
and (2) sublistings of reports of allergic reactions to bacitracin, 
neomycin, and polymyxin B sulfate in OTC, prescription, unclassified, 
and all types of products, not just topical first aid antibiotics. The 
sublistings showed 923 cases of allergic hypersensitivity; 631 related 
to prescription products, 261 related to OTC products, and 31 that 
could not be classified from the available information. No deaths 
attributable to allergic hypersensitivity have been reported from use 
of any OTC drug products containing these ingredients. Beginning in 
1983, the total number of reports of allergic reactions associated with 
OTC antibiotic drug products containing bacitracin, neomycin, and/or 
polymyxin B sulfate increased. The industry believed this increase was 
associated with more OTC topical antibiotic drug products being 
marketed following publication of the tentative final monograph for 
these products in 1982. Industry reported that over the past 4 years, 
the number of units of these products sold per year has been constant 
at approximately 29 million units per year.
    The industry stated that incidence figures cannot be generated from 
the data because the denominator (total number of exposures) cannot be 
accurately determined and the numerator may be confounded by over- and/
or underreporting of adverse reactions. The industry concluded that 
reference to the possibility of allergic reactions in the products' 
label warnings would benefit consumers who use these products.

II. The Agency's Proposal

    The agency has reviewed the adverse experience reports and 
determined that the labeling suggested by the industry would be 
beneficial to consumers who use these OTC first aid antibiotic drug 
products. For the OTC drug products, the majority of reports appear to 
be nonserious skin reactions characterized as either rash or contact 
dermatitis. No fatalities were reported for OTC drug products; however, 
the outcome was listed as unknown in the majority of the reports. More 
than 50 percent of the allergic reactions reported in the SRS involved 
antibiotic combination products (e.g., containing at least two of the 
ingredients, bacitracin, polymyxin B sulfate, and/or neomycin). As with 
all combination products, an adverse effect may be due to one or 
several of the ingredients in the product. However, the SRS lists 
allergic (or rash) reports individually for bacitracin and neomycin. 
The SRS also contains a few such reports for polymyxin B sulfate 
products singly. In addition, the Physicians' Desk Reference (Ref. 4) 
lists such allergic reactions for a single-ingredient polymyxin B 
sulfate powder for parenteral and/or ophthalmic use.
    The final monograph for OTC first aid antibiotic drug products, 
issued on December 11, 1987, did not include an allergy warning for 
products containing bacitracin, neomycin, and polymyxin B sulfate. 
Based on the new information provided by industry, showing an increase 
in the total number of reports of allergic reactions since 1983, the 
agency is proposing to add a new warning for products containing 
bacitracin (zinc), neomycin (sulfate), and polymyxin B (sulfate). The 
warning adds the words ``or if a rash or other allergic reaction 
develops. Do not use if you are allergic to any of the ingredients.'' 
in the middle of the existing warning in Sec. 333.150(c)(2) that has 
been used for all OTC first aid antibiotic drug products for years. The 
new warning would read:
    Stop use and consult a doctor if the condition persists or gets 
worse, or if a rash or other allergic reaction develops. Do not use 
if you are allergic to any of the ingredients. Do not use longer 
than 1 week unless directed by a doctor.

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    The agency is including this new warning in proposed 
Sec. 333.150(c)(3) under the heading For any product containing 
bacitracin, bacitracin zinc, neomycin, neomycin sulfate, polymyxin B, 
and/or polymyxin B sulfate. The agency is retaining the current warning 
in Sec. 333.150(c)(2) for products containing chlortetracycline 
hydrochloride and tetracycline hydrochloride and is adding the heading 
For products containing chlortetracycline hydrochloride or tetracycline 
hydrochloride to Sec. 333.150(c)(2). Combinations containing 
oxytetracycline hydrochloride and polymyxin B sulfate in 
Sec. 333.120(a)(11) and (a)(12) would use the new warning in proposed 
Sec. 333.150(c)(3).
    Manufacturers of OTC topical first aid antibiotic drug products 
containing bacitracin, bacitracin zinc, neomycin, neomycin sulfate, 
and/or polymyxin or polymyxin B sulfate are encouraged to voluntarily 
implement this labeling addition as of the date of publication of this 
proposal, subject to the possibility that FDA may change the wording of 
the warning statement as a result of comments filed in response to this 
proposal. Manufacturers may include this labeling under the heading 
``FDA APPROVED INFORMATION'' in accord with Sec. 330.1(c)(2) (21 CFR 
330.1(c)(2)) if that heading is used in product labeling. Because FDA 
is encouraging that the proposed additional warning statement be used 
on a voluntary basis at this time, the agency advises that 
manufacturers doing so will be given ample time after publication of a 
final rule to use up any labeling implemented in conformance with this 
proposal.

III. References

    The following references have been placed 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) Letter dated June 20, 1992, from R. W. Soller, 
Nonprescription Drug Manufacturers Association, to W. E. Gilbertson, 
FDA, in OTC Vol. 190036, Docket No. 95N-0062, Dockets Management 
Branch.
    (2) Letter dated July 22, 1992, from W. E. Gilbertson, FDA, to 
R. W. Soller, Nonprescription Drug Manufacturers Association, in OTC 
Vol. 190036, Docket No. 95N-0062, Dockets Management Branch.
    (3) Letter dated October 7, 1992, from R. W. Soller, 
Nonprescription Drug Manufacturers Association, to W. E. Gilbertson, 
FDA, in OTC Vol. 190036, Docket No. 95N-0062, Dockets Management 
Branch.
    (4) Physicians' Desk Reference, 48th ed., Medical Economics Co., 
Montvale, NJ, p. 738, 1994.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
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). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The proposed rule is estimated to generate a one-
time label modification, the cost of which will not be significant. 
Similarly, the costs incurred by small businesses are estimated to be 
insufficient to warrant a regulatory flexibility analysis. FDA believes 
that small marketers use relatively simple and inexpensive packaging 
and labeling. Hence, labeling change costs (for one warning) to small 
firms are not expected to be substantial. Accordingly, the agency 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on 
manufacturers of OTC first aid antibiotic drug products that contain 
bacitracin (zinc), neomycin (sulfate), and/or polymyxin B (sulfate). 
Comments regarding the impact of this rulemaking on such manufacturers 
should be accompanied by appropriate documentation. The agency is 
providing a period of 90 days from the date of publication of this 
proposed rulemaking in the Federal Register for comments to be 
developed and submitted. The agency will evaluate any comments and 
supporting data that are received and will reassess the economic impact 
of this rulemaking in the preamble to the final rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirement proposed in 
this document is not subject to review by the Office of Management and 
Budget because it does not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the proposed warning statement is a ``public disclosure of 
information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) 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.
    Interested persons may, on or before May 14, 1996, submit written 
comments to the Dockets Management Branch (address above). Written 
comments on the agency's economic impact determination may be submitted 
on or before May 14, 1996. Three copies of all comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number 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 office above between 9 a.m. 
and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 333

    Labeling, Over-the-counter drugs.
    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 part 333 be amended as follows:

PART 333--TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

    1. The authority citation for 21 CFR part 333 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371), unless otherwise noted.

    2. Section 333.150 is amended by adding a heading to paragraph 
(c)(2) and by adding new paragraph (c)(3) to read as follows:

Sec. 333.150  Labeling of first aid antibiotic drug products.

* * * * *

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    (c) * * *
    (2) For products containing chlortetracycline hydrochloride or 
tetracycline hydrochloride. * * *
    (3) For any product containing bacitracin, bacitracin zinc, 
neomycin, neomycin sulfate, polymyxin B and/or polymyxin B sulfate. 
``Stop use and consult a doctor if the condition persists or gets 
worse, or if a rash or other allergic reaction develops. Do not use 
this product if you are allergic to any of the ingredients. Do not use 
longer than 1 week unless directed by a doctor.''
* * * * *

    Dated: February 6, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-3325 Filed 2-13-96; 8:45 am]
BILLING CODE 4160-01-F