[Federal Register Volume 65, Number 120 (Wednesday, June 21, 2000)]
[Rules and Regulations]
[Pages 38426-38429]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-15631]


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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