[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]
[[Page 5917]]
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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.
[[Page 5919]]
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.
* * * * *
[[Page 5920]]
(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
