7076 ae
`
`Federal Register / Vol. 53, No. 43 / Friday, March 4, 1988 / Rules and Regulations
`
`
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`Food and Drug Administration
`21 CFR Parts 349 and 369
`
`[Docket Ne. SON-0145]
`
`Ophthalmic Drug Products for Over-
`the-Counter Human Use; Final
`Monograph
`
`AGENCY:Food and Drug Administration.
`ACTION:Finalrule.
`
`SUMMARY: The Food and Drug
`Administration (FDA)is issuing a final
`rule in the form of a final monograph
`establishing conditions under which
`over-the-counter (OTC) ophthalmic drug
`products (drug products applied tothe
`eyelid orinstilled in the eye), other than
`antiinfective OTC ophthalmic drug"
`products, are generally recognized as
`safe and effective and not misbranded.
`FDAis issuing this final rule after
`considering public comments on the
`agency's proposed regulation, which
`wasissued in the form of a tentative
`iinal monograph, and new data and
`information on OTC ophthalmic drug
`products that have cometo the agency’s
`attention. This final monographis part
`of the ongoing review of OTC drag
`products conducted by FDA. Elsewhere -
`in this issue of the Federal Register, FDA
`is reopening the administrative record
`for OTC ophthalmic drug preducts to
`include only those data on antiinfective
`ingredients that were submitted after the
`closingof the administrative record. The
`administrative record will remain open
`until July 5, 1988, for submission of
`public comments on that data.
`EFFECTIVE DATE: March6, 1988.
`FOR FURTHER INFORMATION CONTACT:
`William E. Gilbertson, Center for Drug
`Evaluation and Research (HFN-210),
`Food and Drug Administration, 5600
`Fishers Lane, Rockville, MD 20857, 301-
`295-8000.
`SUPPLEMENTARY INFORMATION: In the
`Federal Register of May 6, 1980 (45 FR
`30002}, FDA published, under
`§ 330.10(a)(6) (21 CFR 330.10(a}(6}), an
`advance notice of proposed rulemaking
`to establish a monograph for OTC
`ophihalmic drug products, together with
`the recommendations of the Advisory
`Review Panel on OTC Ophthalmic Drug
`Products, which was the advisory
`review panel responsible for evaluating
`' data on the active ingredients in this
`drug class. Interested persons were
`invited to submit comments by August4,
`1980. Reply comments in response to
`commentsfiled in the initial comment
`
`period could be submitted by September
`3, 1980.
`In accordance with § 330.10(a){10), the
`data and information considered by the
`Panel were put on display in the
`Dockets Management Branch (HFA-
`' 305), Food and Drug Administration, Rm.
`4-62, 5600 Fishers Lane, Rockville, MN
`20857, after deletion of a small amount
`of trade secret information.
`The agency's proposed regulation, in
`the form of a tentative final monograph,
`fer OTC ophthalmic drug products was
`published in the Federal Register of June
`28, 1983 (48 FR 29788). Interested
`persons were invited to file by August
`29, 1983, written comments, objections,
`or requests for oral hearing before the
`Commissioner of Food and Drugs
`regarding the proposal.Interested
`persons wereinvitedto file comments
`on the agency's economic impact
`determination by October 27, 1983. New
`data could have been submitted until
`June 28, 1984 and comments on the new
`data until August 28, 1984.
`in considering the antiinfective
`portion of the ophthalmic monograph,
`the agency has determined that there
`are.complex scientific issues that need
`to be resolved before a final
`determination can be made with respect
`to ingredients in this class. These issues
`do not directly relate to the other
`segments of the ophthalmic monograph.
`Accordingly, in order to complete the.
`publication of other segments of the
`ophthalmic final monograph without
`undue delay, the agency is not including
`an antiinfective segment inthis
`~
`document. Elsewhere in this issue of the
`Federal Register, FDA is reopening the
`administrative record for OTC
`ophthalmic drug producis to include
`only those data on antiinfective
`ingredients that were submitted after the
`closing of the administrative record. The
`- administrative record will remain open
`until July 5, 1988, for submission of
`public comments on that data. The
`agency intends to publish its final
`decision on ophthalmic antiinfectives in
`a future issue of the Federal Register.
`Final agency action for the other
`segments of the ophthalmic drug preduct
`rulemaking occurs with the publication
`of this final monograph, whichis a final
`rule establishing a monograph for OTC
`ophthalmic drug products.
`The OTC drug procedural regulations
`(21 CFR 330.10) now provide that any
`testing necessary to resolve the safety or
`effectiveness issues that formerly
`resulted in a Category Il classification,
`and submission to FDA ofthe results of
`that testing or any other data, must be
`done during the OTC drug rulemaking
`process before the establishmentof a
`final monograph. Accordingly, FDA is
`
`no longer using theterms ‘Category I”
`{generally recognized as safe and
`effective and not misbranded),
`“Category Il” {not generally recognized
`as safe and effective or misbranded),
`and “Category III’ (available data are
`insufficient to classify as safe and
`effective, and further testing is required}
`at the final monographstage, but is
`using instead the terms “monograph
`conditions” (old Category I) and
`“nonmonograph conditions” (old
`Categories [I and HJ).
`As discussed in the proposed
`regulation for OTC ophthalmic drug
`preducts (48 FR 29788), the agency
`advises that the conditions under which
`the drug products that are subjectto this
`monograph will be generally recognized
`as safe and effective and not
`misbranded (monograph conditions) will
`be effective 12 months after the date of
`publication in the Federal Register.
`Therefore, on or after March 6, 1989, no
`OTC drug product that is subject to the
`monograph and that contains a
`nonmonograph condition,ie., a
`condition that would cause the drug te
`be not generally recognized as safe and
`effective or to be mishranded, may be
`initially introducedorinitially delivered
`for introduction into interstate
`commerce unlessit is the subject of an
`approved application. Further, any OTC
`drug product subject to this monograph
`that is repackaged or relabeled after the
`effective date of the monograph must be
`in compliance with the monograph
`regardless of the date the product was
`initially introducedor initially delivered
`for introduction into interstate
`commerce. Manufacturers are
`encouraged to comply voluntarily with.
`the monographat the earliest possible
`date.
`In response to the propesed rule on
`OTC ophthalmic drug products, one drug
`manufacturers’ association, eight drug
`manufacturers, two consumergroups,
`one professional medical organization,
`and one consumer submitted comments.
`A request for an oral hearing before the
`Commissioner was also received on one
`issue. Copies of the comments and the
`hearing request received are on public
`_ display in the Dockets Management
`Branch. Additional information that has
`cometo the agency’s attention since
`_ publication of the proposedruleis also
`on public display in the Dockets
`ManagementBranch.
`In proceeding withthis final
`monograph, the agency has considered
`the objections, a request for oral
`hearing, and changes in the procedural
`regulations.
`All “OTC Volumes” cited throughout
`this documentrefer to the submissions
`
`ALCON 2032
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
`
`

`

`i. The Agency’s Conclusions on the
`Commenis
`
`Federal Register / Vol.
`53, No. 43 / Friday, March 4, 1988 / Rules and Regulations
`
`
`made by interested persons pursuantto
`description of eyewashesin § 349,20 be
`astringent and an eyewash as stated in
`the call-for-data notice published in the
`amended to read: “These products may
`the notice of proposed rulemaking (48
`Federal Register of April 26, 1973 (38 FR
`only contain water, tonicity agents to
`FR 29791): For astringents—“helps to
`10306) or io additional information that
`establish isotonicity with tears, agents
`clear mucus from the outer surface of
`has come to the agency’s attention since
`for establishing pH and buffering to
`the eye.” and For eyewashes—‘bathes
`publication of the notice of proposed
`achieve the same pH astears, anda
`or mechanically flushes the eye.” The
`rulemaking. The volumes are on public
`suitable preservative agent.” The
`comment stated that “some cognizance
`display in the Dockets Management
`’ comment added that the definition of
`must be taken of the long history of
`Branch.
`ee
`eyewashes should be consistent with
`mishap-free use of mild boric acid
`§ 349.20.and proposed the following
`solution in eyewashes, etc.” The
`definition: “Eyewash, eye lotion,
`corument maintained that, although
`irrigating solution. A sterile aqueous
`boric acid is not bactericidal, it has
`solution for bathing or mechanically
`demonstrated some bacteriostatic
`flushing the eye containing tonicity
`properties, is a pharmaceutical necessity
`agents to establish isotonicity with tears
`asa pH buffer and a preservative, and
`and agents to. establish pH and buffering
`ite “efficacy in ophthalmic preparations
`to achieve the same pH as tears.” The
`is more of an astringency action thana .
`second comment asserted that a
`therapeutic action.” The comment
`definition without the phrase
`further noted that ophthalmologists
`“containing nopharmacologically active
`often prescribe mild boric acid solution
`ingredients” is more appropriate
`and that the product is.a standardfirst
`because classes of products should be
`aid item, which is noncorrosive,
`defined positively, in terms of what
`nonirritating, and nonmutagenic.
`those products are or-what they contain,
`The “definitions” cited by the
`rather than -what they are not or do not
`comment appeared at 48 FR 29791 as
`contain. The comment suggested
`“claims based on the Panel’s
`_ substituting the word “washing” for-the
`definitions” and are partial-excerpts
`term “flushing” for additionalclarity.
`from the definition of each of these
`The agency agrees with the comments
`ophthalmic drug classes proposed in
`that the statement that eyewashes
`§ 349.3 of the tentative final monograph
`“contain no pharmacologically active
`{48 FR 29797 and 29798). The compleie
`ingredients” is unnecessary. As one of
`definitions:read as follows: “Astringent.
`the commentsnoted, this staternent may
`A locally acting pharmacologic agent
`be unclear because many of the
`which, by precipitating protein, helps to
`ingredients present in low
`clear mucus from the outer surface of
`concentrations in eyewashes as buffers
`the eye”; and “Eyewash, eye lotion,
`or pH adjusters are pharmacologically
`irrigating solution. A-sterile aqueous
`active at higher concentrations. The
`solution containing no
`agency also agrees that, wherever
`pharmacologically active ingredients,
`possible, classes of products should be
`intended for bathing or mechanically
`defined positively by stating what those
`flushing the eye.”
`products contain, rather than what they
`. Boric acid was reviewed by the
`de not contain. Therefore, in this final
`Ophthalmic Panel as an antiinfective
`monograph, the agency is deleting the
`ingredient and-was foundto be safe
`words “contain no pharmacologically
`when used in the amounts contained in
`active ingredients” from the product
`OTC ophthalmic drug products:
`description for eyewashes in § 349.20
`however, the Panel found that there
`~
`and is revising the statement to read:
`were insufficient data to proveits
`“These products contain water, tonicity
`effectiveness as an ophthalmic
`agenis to establish isotonicity with
`antiinfective (45 FR 30029). Although the
`tears, agents for establishing pH and
`Ophthalmic.Panel did not evaluate boric
`buffering to achieve the same pH as
`acid as an ophthalmic astringent, the
`tears, and a suitable preservative
`Advisory Review Panel on OTC
`agent.”
`Miscellaneous External Drug Producis
`In addition, the agency is deleting the
`included boric acid in its review of
`words “containing no pharmacologically
`astringent drug products. That Panel did
`active ingredients” from the definition
`not find any data demonstrating the
`for eyewash, eyelotion, and irrigating
`safety and effectiveness of boric acid
`solution in § 349.3{i). The agencyalso
`when used as an OTC astringent active
`believes that the word “mechanically” is
`ingredient and, therefore, classified it as
`unnecessary in this definition and thus
`Category Il for that purpose. (See the
`is revising the definition to read: “A
`' Federal Register ofSeptember 7, 1982; 47
`sterile aqueous solution intended for
`FR 39426 and 39444.) The comment did
`washing, bathing,-or flushing the eye.”
`not submit any data or cite any
`B. Commenis on OTC Ophthalmic Drug
`references:to show that boric acid in an
`Ingredients
`ophthalmic formulation acts as an
`3. One comment contended that boric
`asiringent by precipitating protein.
`acid meets the definition of an
`Therefore, because the agency has-no
`
`A. General Commenis on OTC
`Ophthalmic Drug Products
`1. One comment coniended thatOTC
`drug monographs are interpretive, as
`opposed to substantive, regulations. The
`comment referred to statements on this
`issue submitted earlier to other OTC
`drug rulemaking proceedings.
`The agency addressed this issue in
`paragraphs 85 through 91 of the
`preamble to the procedures for
`classification of OTC drug products,
`published in the Federal Register of May
`11, 1972 (37 FR 9464) and in paragraph 3
`of the preamble to the tentative final
`monograph for antacid drug products,
`published in the Federal Register of
`November 12, 1973 (38 FR 31260). FDA
`reaffirms the conclusions stated there.
`Subsequentcourt decisions have
`confirmed the agency's authority to
`issue substantive regulations by
`rulemaking. See, e.g., National
`Nutritional Foods Association v.
`Weinberger, 512 F.2d 688, 696-98 (2d Cir.
`1975) and National Association of
`Pharmaceutical Manufacturers v. FDA,
`487 F, Supp. 412 (S.D.N.Y. 1980), aff'd 637
`“F.2d 887 (2d Cir. 1981).
`2, Two comments disagreed with the
`definition of eyewash products proposed
`in § 349.3(f) and the description of
`eyewashes proposed in § 349.20 of the
`tentative final monograph (48 FR 29798).
`Both commentsfelt that a-statement that
`these products contain no
`pharmacologically active ingredients is
`unnecessary and should be deleted from
`both the definition and the description
`of eyewashes. One commentlisted the
`ingredients suggested by the Panel as
`suitable for buffering or adjusting the pH
`of ophthalmic solutions (45 FR 30818)
`and stated that many of these
`ingredients are pharmacclogically active
`ai concentrations higher than the
`amounts usually present when these
`ingredients are used as buffers or pH
`adjusters in eyewash products. The
`comment contended that manufacturers
`should not have to be concerned if an
`ingredient happens:te reach a level that
`is pharmacologically active if ne claim
`for.any pharmacologic action is being
`made for these ingredients. The
`comment recommended that the
`
`

`

`Federal Register. / Vol.53, No. 43 / Friday, March4, 1988 / Rules and Regulations
`7078_
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`
`data to establish boric acid as a safe
`and effective astringent in ophthalmic
`drug products,it is not including this
`ingredient as an ophthalmic astringent
`in this final monograph.
`~
`The Ophthalmic Panel found boric
`acid solutions to be “at best
`bacteriostatic when in contact with
`. pathogenic bacteria for less than one
`hour” (45 FR 30029}. The Panel stated
`that studies were neededto éstablish
`the usefulness of boric acid in the
`treatmentof eye infections, e.g., the
`bacteriostatic effects of boric acid must
`be demonstrated to be sufficiently rapid
`to be useful in infections of the eye. The
`Panel acknowledged that boric acid and
`its sodium salt are used as a buffer.
`system in ophthalmic preparations and
`that this buffer system is effective and
`well tolerated in eye drops. The Panel
`listed boric acid among the buffering
`agents, but not among the preservative
`agents, suitable for theformulation of
`. eyewashesand other ophthalmic
`solutions (45 FR 30016). In the tentative
`final monograph for OTC ophthalmic
`drug products, the agency proposed in
`§ 349.20 that eyewash products contain
`no pharmacologically active ingredients,
`but contain water, tonicity agents to
`establish isotonicity with tears, agents
`for establishing pH and buffering to
`achieve the same pH astears, anda
`suitable preservative agent.
`Boric acid is not being includedas an
`active ingredientin this final
`monograph.It is considered an inactive
`ingredient when usedas part of a
`buffering system in ophthalmic drug
`products. Inactive ingredients, although
`not included in OTC drug monographs,
`must meet the requirements of § 330.1{e}
`(21 CFR 330.1(e}) that they be suitable
`ingredients that are safe in the amounts
`administered and do not interfere with
`the effectiveness of the product or with
`tests to be performed on the product.
`Boric acid may be included as a
`buffering agent in the formulation of
`OTC ophthalmic drug products provided
`that it meets the abovecriteria. (For
`further discussion of inactive
`ingredients, see comment4 below.)
`4. Acknowledging that preservative
`systems were not addressedin the
`tentative final monograph, one comment
`submitted, for the record, data to
`support a sorbic acid/edetate disodium
`{EDTA] preservative system for
`ophthaimic solutions. The data
`consisted of: (1) Summaries of clinical
`investigationsin support of sorbic acid/
`EDTAasa suitable preservative system
`for saline and cleaning solutions for
`contact lenses, (2) a bibliography of
`articles on sorbic acid from the scientific
`literature, (3) summaries of animal
`
`testing data, and (4) summaries of
`laboratory testing data. The comment
`stated that the Panel concluded inits
`report that sorbic acid in combination
`with suitable preservatives might be an
`effective preservative system (45 FR
`30020). The commentpointed out that
`the sorbic acid/EDTA combination
`preservativesystem has been approved
`as safe and effective in ophthalmic
`solutions by FDA's Office of Medicai
`Devices and described a variety of
`currently marketed ophthalmic solutions
`preserved with sorbic acid/EDTA, such
`as various wetting, cleaning, and storage
`solutions for soft (hydrophilic) contact
`lenses. The comment claimedthat a
`sorbic acid preservative system is less
`toxic than preservatives such as
`thimerosal, chlorhexidine, and
`quaternary ammonium compounds.
`Although the data submitied were
`compiled from ophthalmic solutions
`used with soft (hydrophilic) contact
`lenses, the commentbelieved that the
`sorbic acid/EDTApreservative system
`_ has been extensively studied for use in
`the eye area and that the data support
`this preservative system in general for
`OTC ophthalmic drug products.
`Sorbic acid and EDTA,used as
`preservatives, are inactive ingredients.
`The OTC drug review is an active, not
`an inactive, ingredient review. The OTC
`panels occasionally made
`recommendations with respect to
`inactive ingredients: however, these
`recommendations were madefor public
`awareness and were not intended to be
`included in the OTC drug monographs.
`Accordingly, the agencyis not reviewing
`the data submitted by the commentin
`this rulemaking proceeding.
`Inactive ingredients, although not
`included in OTC drug monographs, must
`meet the requirements of § 330.1(e) (21
`CFR 330.1{e)) that they be suitable
`ingredients that are safe and de not
`interfere with the effectiveness of the
`product or with tests to be performed on
`the product. In addition, § 330.1{a)
`requires that all products covered by an
`applicable OTC drug monograph be
`manufactured in compliance with
`current good manufacturing practices, as
`established in 21 CFR Parts 210 and 211.
`Section 200.50 {21 CFR 200.50) requires
`all ophthalmic drug products to be
`sterile. Paragraph (b)(1} states that
`liquid ophthalmic drug products
`packaged in multiple-dose containers
`should: “contain one or more suitable
`and harmless substances that will |
`inhibit the growth of microorganisms.”
`In conclusion, based on these
`regulations, the agency evaluates
`inactive ingrédients used as
`preservatives on an individual basis for
`
`each ophthalmic drug product and does
`not include such conditions in the
`applicable OTC drug monograph.
`C. Comments on Labeling of OTC
`Ophthalmic Drug Products
`.
`5. Several comments contended that
`FDAshould not prescribe exclusivelists
`of terms from which indications for use
`for OTC drugs must be drawn,thereby
`prohibiting alternative OTC drug
`labeling terminology to describe such
`indications whichis truthful, not
`misleading, andintelligible to the
`consumer. Two comments stated that
`their views on this subject were
`presented to FDAin oral and written
`testimony in connection with the
`September 29, 1982 agency hearing on
`the exclusivity policy.
`In the Federal Register of May 1, 1986
`(51 FR 16258), the agency published a
`final rule changingits labeling policy for
`stating the indications for use of OTC
`drug products. Underthe final rule, the
`label and labeling of OTC drug products
`are required to contain in a prominent
`and conspicuouslocation, either (1) the
`specific wording on indications for use
`established under an OTC drug
`monograph, which may appearwithin a
`boxed area designated “APPROVED
`USES”; (2) other wording describing
`such indications for use that meets the
`statutory prohibitions againstfalse or
`misleading labeling, which shall neither
`appear within a boxed area nor be
`designated “APPROVED USES”; or(3)
`the approved monograph language on
`indications, which may appear within a
`boxed area designated “APPROVED
`USES,” plus alternative language
`describing indications for use that is not
`false or misleading, which shall appear
`elsewhere in the labeling. All required
`OTC drug iabeling other than
`indications for use (e.g., statement of
`identity, warnings, and directions) must
`appearin the specific wording
`established under an OTC drug
`monograph where exact language has
`been established andidentified by
`quotation marks in an applicable
`monograph orcther regulation, e.g., 21
`CFR 201.63 or 330,1(g). The finalrule in
`this documentis subject to the final rule
`revising the labeling policy.
`8. One commentobjected to the
`agency's proposed substitution of the
`word ‘doctor’ for “physician” in OTC
`drug labeling. The commentindicated an
`essential difference between these
`terms. The term “physician” means
`“doctor of medicine,” whereas the term
`“doctor” can refer to any of a broad
`spectrum of academic disciplines. The
`comment recommended that the agency
`specify use of the term “physician,” as
`
`-
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`

`Federal Register / Vol. 53, No. 43 /- Friday, March 4, 1988 / Rules and Regulations
`7078
`
`opposed to the term “doctor,” on OTC
`drug labels to enhance consumers’
`awarenessof the proper individual they
`should consult if further medical careis
`needed. The comment also stated thatit
`seemed contradictory to label OTC
`drugs with their-scientific names(e.g.,
`ophthalmic hypertonicity agent) and, at
`the same time, be concerned that the
`common term “physician” would
`confuse consumers.
`In an effort to simplify OTC drag
`labeling, the agency proposed in a
`numberof tentative final monographs,
`including the one for OTC ophthalmic
`drug products, to substitute the word
`“doctor” for “physician” in OTC drug
`monographs on the basis that the word
`“doctor” is more commonly used and
`betier understood by consumers. Based
`on comments received to these
`proposals, the agency has determined
`that final monographs and any
`applicable OTC drug regulation will give
`manufacturers the option of using either
`the word “physician” or the word
`“doctor.” This final monograph provides
`that option. (See § 349.50(a).J ©
`7, Expressing concern about the
`labeling “verbiage” proposed in the
`tentative final monograph for OTC
`ophthalmic drug products, one comment
`maintained that the use of this verbiage
`on small bottles and cartons will deter
`consumers from reading the labeling,
`thus decreasing the chances that
`consumers will be made aware of
`important information and warnings..
`The comment recommended
`“streamlining” and combining the
`proposed warning for all ophthalmic .
`drug products in § 349.50(b)(1) with the
`proposed warnings for ophthalmic
`_ demulcent drug products in § 849:60(c}
`{1} and {2) to read: “Do not touch bottle
`tip to any surface since this may
`contaminate solution. Replace cap after
`using. Ifirritationpersists or increases,
`discontinue use and consult a
`physician.” The commentalso
`recommended that the proposed
`warning in § 349.50(b)(1) and the
`warnings proposed for ophthalmic
`vasoconstrictor drug products in
`§ 349.75(c) (1) through (4) -be combined
`and revised as follows: “Do not touch -
`bottle tip to any surface since this may
`coniaminate solution. Replace cap after
`using. If irritation persisis for more than
`72 hours, discontinue use and -consult a
`physician. If you have glaucoma, do not
`use except under the supervision of a
`physician. Overuse of this product may
`produce increased redness of the eye.”
`The comment contendedthat these
`revisions would convey the intended
`message in a concise manner.
`
`The agency recognizes the need for:
`concise wording in the labeling of
`ophthalmic drug preducts that are likely
`to be marketedin small packages.In the -
`tentative final monograph, the agency
`revised the Panel's recommended
`labeling statements to include only .
`essential information. (See comment 18
`at 48 FR 29795.) The agency emphasizes
`that its proposed warnings provide
`information that is essential for the safe
`and effective use of OTC ophthalmic
`drug products by the consumer. The
`comment's suggested combining and
`“streamlining” of the warnings for OTC
`ophthalmic demulcent and
`vasoconstrictor drug products deletes
`some of the warnings proposed by the
`agency. The comment neglected to
`include the statements about “eye pain,”
`“changes in vision,” and “continued
`redness”in its suggested warning
`statements. The Panelfelt that this type
`of information was necessary in the
`labelingfor these products [45 FR
`30024), and the agency concurs. In the
`proposed rulemaking for OTC
`ophthalmic drug preducts, the agency
`modified the wording of this information
`without changing the Panel's intent.in
`order to make the warning more
`understandable to consumers, (See
`comment 16 at 48 FR 29794.)
`The general term “irritation,”
`suggested by the comment, does not
`inform the consumerof specific
`symptoms which may indicate a serious
`condition requiring medical attention.
`The comment also suggested deleting
`the warning “If solution changes color.or
`becomes cloudy, do not use.” The
`agency feels that this statementis
`necessary because it alerts the .
`consumer against using a possibly
`‘defective preduct. The comment’s
`suggested revision of the warning for
`ophthalmic-demulcent drug products
`deletes the:phrase limiting the OTC use
`of the product:to 72 hours. The agency
`believes that such.a limitation is
`necessary. (See comment-9 below.) The
`comment's proposed alternatives do not
`' provide the consumerwith all of the
`essential warning information; therefore,
`the warnings for ophthalmic demulcents
`and vasoconstrictors proposed in
`§§ 349.60(c) and 349.75{c), respectively,
`are being included in this final
`monograph without the requested
`. changes.
`The agencybelieves that the warning
`proposed in § 349.50(b}(1) of the
`tentative final monograph may be
`shortened without changingits intent.
`Although the comment's suggested
`rewording shortened the warning,it also
`changed the emphasis of the warning by
`rearranging it and changedthe intent of
`
`the warning by stating that it applies
`only to solutions, whereasit equally
`-applies to ointments. The agency is -
`revising the warning. and including it in
`§ 349.50(c)(1) of the final monograph to
`read in part as follows: ‘To avoid
`contamination, do not touch tip of
`container to any surface *
`* *.” This
`wording is also included in a warning in
`§ 349.50{c}{2) to accommodate single-use
`packages. (See comment 8 below.)
`The agency concludesthat all of the
`warnings included in this final
`‘monographare essential to ensure the
`proper.and safe use of OTC ophthalmic
`drug products by the public. Therefore,
`all.the warnings needto appear on OTC
`ophthalmic drug products regardless of
`the size of the container. In those
`instances where an OTC ophthalmic
`drug product is packaged in a container
`that is too small to include all the
`required labeling, the product can be
`enciosed in a carton or be accompanied
`by a package insert that contains the
`information complying with the
`monograph. The labeling previsions in
`Part 201 (e.g., 88 201.10(i}, 201.15, 201.60,
`201.61, and 201.62) address various
`requirements for labeling drugs
`including drugs packaged in containers
`too small to accommodate a label with
`sufficient space to bear all the
`information required for compliance
`with various regulations. When an OTC
`ophthalmic drug preduct is packaged in
`a container that is too small or
`otherwise unable to accommodate a
`label with sufficient space to bearall of
`the information required by this final
`monograph, the required information
`shall appear elsewhere in the label in
`accord with the labeling requirements in
`Part 201. Manufacturers are also
`encouraged to print a statement on the
`product container label, carton, or
`- package insert suggesting that the
`consumerretain the carton or package
`insert for complete information about
`the:use of the product whenall the
`required labeling does not appear on the
`preduct containerlabel.
`8. One comment pointed out that the
`part of the warning proposed in
`§ 349.50(b}(1) that reads “replace cap
`after using” is inappropriate for
`ophthalmic drug products which are
`packaged in single-use containers. The
`comment suggested that-wording such
`as “Do not reuse—Once opened,
`discard” be permitted for single-use
`packages.
`The agency agrees that an alternative
`warning statement is appropriate for
`single-use ophthalmic drug products.
`Therefore, in this final monograph, the
`agency is specifying that the warningin
`§ 349.50(c)(1) applies to multi-use
`
`

`

`AFederal Register / Vol. 53, No. 43 / Friday, March 4, 1988 / Rules and Regulations
`therefore, may be indicated for daily
`use. The Panel strongly recommended
`limiting self-medication with OTC
`ophthalmic drug products to 72 hours
`because the symptoms treated may
`indicatea serious conditionrequiring
`treatment by a physician. The Panel
`specifically addressed the treatment of
`dry eye with OTC ophthalmic demuicent
`products and recommendedthatlong-
`term use be allowed only under the
`direction of a physician (45 FR 30008).
`The Panel stated that while “these
`products are intended to serveas tear
`substitutes and are used on an ongoing
`basis, safeguards against the
`unsupervised use of tear substitute
`preparationsfor long periods must be
`established through properlabeling to
`warn consumersthat professicnal
`consultation should be soughtif
`symptoms persist for more than 72
`hours.” The agency agrees with the
`Panel’s recommendation and is
`including a 72-hour time limit in the
`warnings for OTC ophthalmic demulcent
`drug products in this final monograph.
`10. Several comments objected to
`FDA’s requirement that data be
`submitted to support use of the term
`“tired eyes” in the labeling of OTC
`ophthalmic drug products. (See comment
`10 at 48 FR 29792.) Two of the comments
`contended that the agency’s use of
`informal rulemaking to declare that
`certain words are false or misleadingis
`unauthorized by statute and improper
`“irrespective of whether such data will
`be made. available” to show that
`. consumers equate “tired eyes” with
`symptomsof minorirritation and
`redness in the eyes. One of these
`comments maintained that the term
`“tired eyes” should be allowed to
`continue in use until evidenceis
`produced to show that consumers are
`being deceived or misled byit.
`Another comment contendedthat the
`term ‘tired eyes” should be allowed as
`an indication for eyewashesandfor
`ophthalmic vasoconstrictor drug
`- products, and an additional comment
`proposed thatthe term “tired eyes”
`should be allowed as an indication for
`ophthalmic demulcent drug products as
`well as for ophthalmic vasoconstrictor
`drug products. The comment submitted
`a report summarizing two marketing
`research surveys of users of eye drops to
`supportits request (Ref. 1). The first
`survey had two parts. In one part,
`consumerschosetheir own wordsto
`describe their reasons for using eye
`drops. In the second part, the same
`consumersrated the importance of 58
`product features or benefits enumerated
`by the market.research firm. In the
`second study, the. subjects were given
`cards, each stating a product feature or
`
`benefit, and were asked to rate the
`importance of each feature or benefit in
`choosing an eye drop product. The
`comment contended thatthe results of
`the studies make it apparent that users
`of eye drops “express” the feeling of eye
`discomfort with the term “tired eyes.” -
`The agency has previously addressed
`the legality of the OTC drug review
`procedures. (See comment 1 above.) The
`. classification of a labeling claim and the
`requirement for data