[Federal Register Volume 63, Number 35 (Monday, February 23, 1998)]
[Proposed Rules]
[Pages 8888-8890]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-4531]


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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; Proposed 
Amendment of Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the final monograph for over-the-counter (OTC) ophthalmic drug 
products. 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 tetrahydrozoline 
hydrochloride; and they are used to relieve redness of the eye due to 
minor eye irritations. This proposal is part of the ongoing review of 
OTC drug products conducted by FDA.

DATES: Submit written comments by May 26, 1998; written comments on the 
agency's economic impact determination by May 26, 1998. FDA is 
proposing that any final rule that may issue 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, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

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 included 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.'' Paragraphs (a) 
and (b) of Sec. 349.75 provide that these products are labeled with the 
statement of identity ``redness reliever'' or ``vasoconstrictor 
(redness reliever)'' ``eye'' or ``ophthalmic'' ``insert (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.''

II. Recent Developments

    In the last 3 years, FDA has approved three new drug applications 
(NDA's) (Ref. 1) for ophthalmic drug products containing pheniramine 
maleate and naphazoline hydrochloride. These products are used for eye 
allergy relief to relieve itching and redness of the eye due to pollen, 
ragweed, grass, animal hair, and dander. These products are not covered 
by the OTC ophthalmic drug products monograph because the ingredient 
pheniramine maleate is not included in that monograph.
    The agency has received more than 400 adverse drug experience (ADE) 
reports involving these three products (Ref. 1) in which consumers have 
reported pupil dilatation (enlarged pupils) after using the eye drops 
(Ref. 2). Because of the vasoconstrictor action of naphazoline 
hydrochloride (and the other active ingredients included in 
Sec. 349.18), pupil dilatation is a known pharmacologic effect of these 
drugs. The Advisory Review Panel on OTC Ophthalmic Drug Products (the 
Panel), in its report (May 6, 1980, 45 FR 30002 at 30033), stated that, 
even at the low concentrations used in OTC drug products, 
vasoconstrictors occasionally may cause some dilation of the pupil, 
especially in people who wear contact lens, whose cornea is abraded, or 
who have lightly colored irides. However, the Panel did not recommend 
any labeling warning based on this pharmacologic effect of these drugs. 
The agency also did not include a labeling warning in the past because 
the enlargement of the pupil(s) is not clinically significant (usually 
persists for 1 to 4 hours) and does not affect pupil reactivity. As a 
result, the agency did not mention this pharmacologic side effect in 
product labeling. Thus, OTC ophthalmic drug products marketed under the 
monograph or under NDA's do not contain this type of information in 
their labeling.
    The more than 400 ADE reports that have been received have caused 
the agency to rethink its position on including information about pupil 
enlargement in the labeling of these OTC vasoconstrictor drug products. 
The agency now believes that it would be beneficial and informative to 
consumers to inform them that their pupils may become dilated 
(enlarged). The agency believes this information in product labeling 
will reduce the number of ADE reports and will enable consumers to 
continue using these products and not discontinue use after one or two 
instillations because they do not expect this pupil enlargement to 
occur. Accordingly, the agency is proposing to add the following 
warning in new Sec. 349.75(c)(5) to state: ``Pupils may become dilated 
(enlarged).''
    The agency recognizes that space on OTC ophthalmic drug product 
labeling is limited, but it considers these additional five words 
worthwhile because of the number of consumers who have reported this 
pupil

[[Page 8889]]

enlargement as a problem. The agency questions whether it would be 
additionally beneficial to add several more words, i.e., ``This is 
temporary and not serious,'' after the first statement so that 
consumers will not be alarmed if this pupil enlargement occurs and will 
not discontinue use of the product for this reason. These additional 
words could be required or optional, if the manufacturer wishes to 
include them. The agency invites specific comment on the wording of 
both statements, and the desirability of including the second statement 
(even if optional).
    The Panel also noted that the dilation of the pupil caused by the 
ophthalmic vasoconstrictor drug may in turn trigger an attack of 
narrow-angle glaucoma in a susceptible individual (45 FR 30002 at 
30033). The Panel recommended the following glaucoma warning for 
ophthalmic vasoconstrictors: ``If you have glaucoma, do not use this 
product except under the advice and supervision of a physician.'' (See 
45 FR 30002 at 30033.) The agency included this warning in 
Sec. 349.75(c)(2) of the final monograph for OTC ophthalmic drug 
products (with the word ``physician'' changed to ``doctor'').
    In the three NDA's for the pheniramine maleate-naphazoline 
hydrochloride eye drop products approved in the last several years, the 
agency has changed the glaucoma warning to state: ``Do not use this 
product if you have * * * narrow angle glaucoma unless directed by a 
physician.'' This was done because the potential risk only applies to 
people with narrow angle glaucoma, a condition where it is not 
desirable to use a drug of this type that could cause mid-dilation of 
the pupil. The agency believes that a number of physicians inform their 
patients what type of glaucoma they have. Further, it is beneficial for 
consumers to know this information, and the agency encourages consumers 
to ask their physician in order to be fully informed and knowledgeable.

III. The Agency's Tentative Conclusions and Proposal

    The agency is proposing to add the following new warning in 
Sec. 349.75(c)(5) to state: ``Pupils may become dilated (enlarged).'' 
The agency invites comment whether to expand this warning to also 
state: ``This is temporary and not serious.'' This second statement 
could be a required or optional statement (because of the limited space 
available in ophthalmic drug product labeling), added if the 
manufacturer desires.
    The agency is proposing to amend Sec. 349.75(c)(2) to add the words 
``narrow angle'' before ``glaucoma.'' The warning would then read: ``If 
you have narrow angle glaucoma, do not use this product except under 
the advice and supervision of a doctor.''
    The agency is proposing that any final rule that may issue based on 
this proposal become effective 12 months after its date of publication 
in the Federal Register. The agency considers this new labeling an 
improvement to the current labeling of OTC ophthalmic vasoconstrictor 
drug products, but it recognizes that existing products have used the 
current monograph labeling for over 9 years. Therefore, to reduce 
relabeling costs for manufacturers of these specific products, the 
agency might consider an 18-month effective date for any final rule 
that may issue based on this proposal. This longer effective date would 
enable manufacturers to use up existing labeling and implement the new 
labeling in the normal course of reordering labeling for these 
products. The agency invites specific comment on this extended 
effective date.

IV. 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. Approved labeling from NDA's 20-065, 20-226, and 20-485.
    2. Center for Drug Evaluation and Research, FDA, ``Adverse Drug 
Experience Report for OTC Ophthalmic Drug Products Containing 
Pheniramine Maleate and Naphazoline Hydrochloride, May 29, 1997.

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
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 (2 U.S.C. 1501 et 
seq.) 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 believes that this proposed rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this proposed 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.
    Manufacturers of these products will incur costs to relabel their 
products to include the new labeling information. The agency has been 
informed that relabeling costs of the type required by this proposed 
rule generally average about $2,000 to $3,000 per stock keeping unit 
(SKU) (individual products, packages, and sizes). The agency is aware 
of 50 manufacturers that 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, total one-time costs of relabeling would be $200,000 to 
$300,000. The agency believes the actual cost could be lower for 
several reasons. Most of the label changes will be made by private 
label manufacturers that tend to use simpler and less expensive 
labeling. In addition, the agency is considering and inviting public 
comment on an 18-month effective date for the final rule, rather than 
the standard 12-month effective date. This extended effective date may 
allow the new labeling to be implemented concurrently with the general 
labeling changes that may be required by the new OTC drug labeling 
format. (See the Federal Register of February 27, 1997, 62 FR 9024.) 
The agency believes that these actions provide substantial flexibility 
and reductions in cost for small entities.
    The agency considered but rejected several labeling alternatives, 
such as: (1) A shorter implementation period, and (2) an exemption from 
coverage for small entities. While the agency would like to have this 
new labeling in place as soon as possible, it considers a period less 
than 1 year difficult for manufacturers to implement and not critical 
in this situation. The agency

[[Page 8890]]

does not consider an exemption for small entities appropriate because 
consumers who use these manufacturers' products would not have the most 
recent information for the safe and effective use of these OTC 
ophthalmic vasoconstrictor drug products.
    This analysis shows that this proposed rule is not economically 
significant under Executive Order 12866 and that the agency has 
undertaken important steps to reduce the burden to small entities. 
Nevertheless, some entities may incur some impacts, especially private 
label manufacturers that provide labeling for a number of the affected 
products. Thus, this economic analysis, together with other relevant 
sections of this document, serves as the agency's initial regulatory 
flexibility analysis, as required under the Regulatory Flexibility Act. 
Finally, this analysis shows that the Unfunded Mandates Act does not 
apply to the proposed rule because it would not 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.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements proposed 
in this document 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 proposed 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 25.30(h) 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.

VIII. Request for Comments

    Interested persons may, on or before May 26, 1998, submit written 
comments on the proposed regulation to the Dockets Management Branch 
(address above). Written comments on the agency's economic impact 
determination may be submitted on or before May 26, 1998. 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 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, it is 
proposed that 21 CFR part 349 be 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 
adding paragraph (c)(5) to read as follows:

Sec. 349.75  Labeling of ophthalmic vasoconstrictor drug products.

* * * * *
    (c) * * *
    (2) ``If you have narrow angle glaucoma, do not use this product 
except under the advice and supervision of a doctor.''
* * * * *
    (5) ``Pupils may become dilated (enlarged).''
* * * * *

    Dated: January 20, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-4531 Filed 2-20-98; 8:45 am]
BILLING CODE 4160-01-F