[Federal Register: June 21, 2000 (Volume 65, Number 120)]
[Rules and Regulations]
[Page 38426-38429]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21jn00-7]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 349

[Docket No. 98N-0002]
RIN 0910-AA01

Ophthalmic Drug Products for Over-the-Counter Human Use;
Amendment of Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the
monograph for over-the-counter (OTC) ophthalmic drug products (the
regulation that establishes conditions under which these drug products
are generally recognized as safe and effective and not misbranded). The
amendment adds a new warning and revises an existing warning for
ophthalmic vasoconstrictor drug products. These products contain the
ingredients ephedrine hydrochloride, naphazoline hydrochloride,
phenylephrine hydrochloride, or

[[Page 38427]]

tetrahydrozoline hydrochloride and are used to relieve redness of the
eye due to minor eye irritations. This final rule is part of the
ongoing review of OTC drug products conducted by FDA.

DATES: Effective Date: This rule is effective May 16, 2002.
    Compliance Date: The compliance date for products with annual sales
less than $25,000 is May 16, 2003. The compliance date for all other
OTC drug products is May 16, 2002.

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 March 4, 1988 (53 FR 7076), FDA
published a final monograph for OTC ophthalmic drug products in part
349 (21 CFR part 349). That monograph includes four ophthalmic
vasoconstrictor active ingredients in Sec. 349.18. Section 349.3(i)
defines an ophthalmic vasoconstrictor as ``A pharmacologic agent which,
when applied topically to the mucous membranes of the eye, causes
transient constriction of conjunctival blood vessels.'' Section
349.75(a) and (b) provide that these products are labeled with the
statement of identity ``redness reliever'' or ``vasoconstrictor
(redness reliever)'' ``eye'' or ``ophthalmic'' [dosage form, e.g.,
``drops''] and with the indication for use ``Relieves redness of the
eye due to minor eye irritations.'' Section 349.75(c)(2) requires these
products to bear the warning statement: ``If you have glaucoma, do not
use this product except under the advice and supervision of a doctor.''
    In the Federal Register of February 23, 1998 (63 FR 8888), the
agency published a proposed amendment of the monograph for OTC
ophthalmic drug products to revise this glaucoma warning by adding the
words ``narrow angle'' before the word ``glaucoma'' and to add a new
warning for ophthalmic vasoconstrictor drug products that states:
``Pupils may become dilated (enlarged).'' The agency also invited
comment on whether to add the words ``This is temporary and not
serious'' as a required or optional statement after the proposed new
warning. The agency explained that these proposed labeling revisions
were based primarily on the labeling approved in recent years for three
new drug applications (NDA's) for ophthalmic drug products containing
pheniramine maleate and naphazoline hydrochloride and adverse drug
experience (ADE) reports submitted to those NDA's.
    Interested persons were invited to submit comments on the proposal
and on the agency's economic impact determination by May 26, 1998. In
response to the proposed monograph amendment, one trade association of
OTC drug manufacturers submitted a comment, a copy of which is on
public display in the Dockets Management Branch (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    The agency has considered the comment in proceeding with this final
rule. A summary of the comment with FDA's response follows.

II. Summary of the Comment Received

    The comment supported the agency's rationale for the proposed
warning regarding narrow angle glaucoma, stating that the clarification
of the warning was clinically rational and in the best interest of the
public health. The agency is including this revision in this final
rule.
    The comment disagreed with the warning statement about pupils
becoming dilated, stating that the warning is not appropriate for
single ingredient ophthalmic vasoconstrictor drug products. The comment
noted that the agency's proposal is based on ADE reports from
combination antihistamine-vasoconstrictor ophthalmic products, while
pupil dilation reports for single ingredient vasoconstrictor ophthalmic
products are rare, given the high incidence of exposure to these
products. The comment provided comparative figures to show that the ADE
profile is different for the two types of products, concluding that the
numbers do not justify a new warning on single ingredient products. The
comment requested the agency to withdraw its proposal for this pupil
dilation warning for single ingredient, monographed ophthalmic
vasoconstrictor drug products.
    The agency does not accept the comment's suggestion. Both the
Advisory Review Panel on OTC Ophthalmic Drug Products (45 FR 30002 at
30033, May 6, 1980) and standard text books (Ref. 1) state that pupil
dilation is a known pharmacologic effect of sympathomimetic drugs such
as these ophthalmic vasoconstrictors. In both the combination
(antihistamine-vasoconstrictor) and the single ingredient
(vasoconstrictor) products, the vasoconstrictor ingredient is
considered the cause of the pupil dilation. The difference in ADE
reports between single ingredient and combination products may be
because the combination products are marketed under NDA's, which have
ADE reporting requirements. The agency stated in the proposal and
concludes here that it would be beneficial and informative to consumers
who use these products (single ingredient or combination) to know that
their pupils may become enlarged temporarily. Therefore, the agency is
including a warning in this final rule.
    The comment contended that the pupil dilation warning appears to
have little practical relationship to the goal of reducing ADE reports
to the agency. The comment added that the potential for pupil dilation
is not serious and, thus, questioned the need to mention the event in
product labeling. The comment did not offer any alternative language
for the warning.
    The agency believes that the comment misunderstood the agency's
objective, which was not to reduce the number of ADE reports to the
agency. Rather, the agency's objective in proposing to add the warning
was to inform consumers about this effect of the drug and to improve
their self-use of these products. The agency concludes that information
in the product's labeling about pupil dilation will enable many
consumers to continue using these products and not discontinue use
after one or two instillations because they do not know to expect
possible temporary pupil enlargement to occur. The agency has decided
to combine the second statement discussed in the proposal (``This is
temporary and not serious.'') with the first statement in a shortened
version in this final rule. The warning, in the new OTC drug labeling
format, now reads: ``When using this product [in bold type] pupils may
become enlarged temporarily.''

III. The Agency's Final Conclusions

    The agency concludes that adding the following new warning in
Sec. 349.75(c)(5) would benefit consumers who use an OTC ophthalmic
drug product containing a vasoconstrictor active ingredient: ``When
using this product [in bold type] pupils may become enlarged
temporarily.'' The agency is amending Sec. 349.75(c)(2) to add the
words ``narrow angle'' before ``glaucoma.'' The warning now reads, in
the new OTC drug labeling format: ``Ask a doctor before use if you have
[in bold type] narrow angle glaucoma.''

IV. Reference

    1. ``Drug Facts and Comparisons,'' Facts and Comparisons, St.
Louis, p. 483b, 1998 ed.

[[Page 38428]]

V. Analysis of Impacts

    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 (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.
    Title II 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 in any one year by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100 million (adjusted annually for inflation).
    The agency concludes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
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. This section constitutes the agency's final regulatory
flexibility analysis under the Regulatory Flexibility Act. Further,
because this final rule makes no mandates on government entities and
will result in expenditures less than $100 million in any one year, FDA
need not prepare additional analyses under the Unfunded Mandates Reform
Act.
    The purpose of this final rule is to add a new warning and to
revise an existing warning for OTC ophthalmic vasoconstrictor drug
products. These warning statements should improve consumers' self use
of these drug products and enable some consumers with glaucoma to self
medicate when necessary. The agency stated in the proposal that
manufacturers of these products will incur costs to relabel their
products to include the new labeling information (63 FR 8888 at 8889).
The agency indicated that relabeling costs of the type required by this
rule generally average about $2,000 to $3,000 per stock keeping unit
(SKU) (individual products, packages, and sizes). In determining this
cost, the agency did not believe that manufacturers would need to
increase the package size to add the few additional words in the new
warning. Almost all of these products are marketed in an outer carton
which should have adequate space for the additional information. The
agency noted that 50 manufacturers, most of which are small
manufacturers, together produce about 100 SKU's of OTC ophthalmic
vasoconstrictor drug products marketed under the monograph. There may
be a few additional small manufacturers or products in the marketplace
that are not identified in the sources FDA reviewed. Assuming that
there are about 100 affected OTC SKU's in the marketplace, FDA
estimated that the rule would impose total one-time compliance costs on
industry for relabeling of about $200,000 to $300,000. The agency did
not receive any comments on these estimates.
    The agency believes the actual cost could be lower for several
reasons. First, most of the label changes will be made by private label
small manufacturers that tend to use simpler and less expensive
labeling. However, the final rule will not require any new reporting
and recordkeeping activities. Therefore, no additional professional
skills are needed. Second, the agency has made the compliance dates for
this final rule the same as the dates for these monographed products to
be in compliance with the new standardized format and standardized
content requirements for the labeling of OTC drug products (21 CFR
201.66), which are now May 16, 2002 (and May 16, 2003, for products
with annual sales less than $25,000). Thus, all required labeling
changes can be made at the same time, thereby reducing the labeling
cost of this final rule.
    The agency considered but rejected several labeling alternatives:
(1) A shorter or longer implementation period, and (2) an exemption
from coverage for small entities. While the agency believes that
consumers would benefit from having this new labeling in place as soon
as possible, the agency also acknowledges that coordination of this
labeling change with implementation of the new OTC ``Drug Facts''
labeling may significantly reduce the costs of this final rule. Both a
shorter and a longer time period for this rule may cost more if firms
would have to undertake two successive labeling revisions. In addition,
a longer time period would unnecessarily delay the benefit of the new
labeling to consumers who self-medicate with these OTC ophthalmic
vasoconstrictor drug products. The agency rejected an exemption for
small entities because the new labeling information is also needed by
consumers who purchase products marketed by those entities. However,
the agency is providing a compliance date of May 16, 2003 for products
with annual sales less than $25,000.
    This analysis shows that the agency has undertaken important steps
to reduce the burden to small entities. Thus, this economic analysis,
together with other relevant sections of this document, serves as the
agency's final regulatory flexibility analysis, as required under the
Regulatory Flexibility Act.

VI. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this final rule are
not subject to review by the Office of Management and Budget because
they do not constitute a ``collection of information'' under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the
warning statements are 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)).

VII. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) 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.

List of Subjects in 21 CFR Part 349

    Labeling, Ophthalmic goods and services, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
349 is amended as follows:

PART 349--OPHTHALMIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    1. The authority citation for 21 CFR part 349 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    2. Section 349.75 is amended by revising paragraph (c)(2) and by
adding paragraph (c)(5) to read as follows:

Sec. 349.75  Labeling of ophthalmic vasoconstrictor drug products.

* * * * *
    (c) * * *
    (2) ``Ask a doctor before use if you have [in bold type] narrow
angle glaucoma.''
* * * * *

[[Page 38429]]

    (5) ``When using this product [in bold type] pupils may become
enlarged temporarily.''
* * * * *

    Dated: June 14, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-15631 Filed 6-20-00; 8:45 am]
BILLING CODE 4160-01-F