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

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