98-4531. Ophthalmic Drug Products for Over-The-Counter Human Use; Proposed Amendment of Final Monograph  

  • [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
    
    
    

Document Information

Published:
02/23/1998
Department:
Food and Drug Administration
Entry Type:
Proposed Rule
Action:
Proposed rule.
Document Number:
98-4531
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.
Pages:
8888-8890 (3 pages)
Docket Numbers:
Docket No. 98N-0002
RINs:
0910-AA01: Over-the-Counter (OTC) Drug Review
RIN Links:
https://www.federalregister.gov/regulations/0910-AA01/over-the-counter-otc-drug-review
PDF File:
98-4531.pdf
Supporting Documents:
» Reference
» Background from Regulatory Counsel Division of OTC Drug Products
CFR: (4)
21 CFR 349.18)
21 CFR 349.75(c)(2)
21 CFR 349.75(c)(5)
21 CFR 349.75