[Federal Register Volume 59, Number 27 (Wednesday, February 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2262]
[[Page Unknown]]
[Federal Register: February 9, 1994]
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Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Part 356
Oral Health Care Drug Products for Over-the-Counter Human Use;
Tentative Final Monograph for Oral Antiseptic Drug Products; Proposed
Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 356
[Docket No. 81N-033A]
RIN 0905-AA06
Oral Health Care Drug Products for Over-the-Counter Human Use;
Tentative Final Monograph for Oral Antiseptic Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of
proposed rulemaking in the form of a tentative final monograph that
would establish conditions under which over-the-counter (OTC) oral
antiseptic drug products (drug products used to help decrease the
chance of infection in wounds in the mouth) are generally recognized as
safe and effective and not misbranded. FDA is issuing this notice of
proposed rulemaking after considering the report and recommendations of
the Advisory Review Panel on OTC Oral Cavity Drug Products and public
comments on an advance notice of proposed rulemaking that was based on
those recommendations. This proposal is part of the ongoing review of
OTC drug products conducted by FDA.
DATES: Written comments, objections, or requests for oral hearing on
the proposed regulation before the Commissioner of Food and Drugs by
August 8, 1994. Because new testing procedures for OTC oral antiseptic
drug products are included in this tentative final monograph, the
agency is allowing a period of 180 days for comments and objections
instead of the normal 60 days. New data by February 9, 1995. Comments
on the new data by April 10, 1995. Written comments on the agency's
economic impact determination by August 8, 1994.
ADDRESSES: Written comments, objections, new data, or requests for oral
hearing to the Dockets Management Branch (HFA-305), Food and Drug
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-810), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-5000.
SUPPLEMENTARY INFORMATION: In the Federal Register of May 25, 1982 (47
FR 22760), FDA published, under Sec. 330.10(a)(6) (21 CFR
330.10(a)(6)), an advance notice of proposed rulemaking to establish a
monograph for OTC oral health care drug products, together with the
recommendations of the Advisory Review Panel on OTC Oral Cavity Drug
Products (Oral Cavity Panel), 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 August 23,
1982. Reply comments in response to comments filed in the initial
comment period could be submitted by September 22, 1982. In the Federal
Register of July 30, 1982 (47 FR 32953), in response to a request for
an extension of time, the comment period and reply comment period for
OTC oral health care drug products were extended to November 22, 1982
and December 22, 1982, respectively.
In the Federal Register of December 28, 1982 (47 FR 57739), the
reply comment period was extended to January 21, 1983.
In accordance with Sec. 330.10(a)(10), the data and information
considered by the Panel were put on public display in the Dockets
Management Branch (address above), after deletion of a small amount of
trade secret information.
In response to the advance notice of proposed rulemaking, 11 drug
manufacturers, 3 professional organizations, 4 health professionals,
and 1 individual consumer submitted comments. Copies of the comments
received are on public display in the Dockets Management Branch
(address above).
FDA is issuing the tentative final monograph for OTC oral health
care drug products in several segments. This document is the third
segment to be published, and it contains the agency's responses to
comments on OTC oral antiseptic drug products and to comments on the
drug or cosmetic status of certain oral antiseptic ingredients and
claims. The first segment of the tentative final monograph covering OTC
oral health care anesthetic/analgesic, astringent, debriding agent/oral
wound cleanser, and demulcent drug products was published in the
Federal Register of January 27, 1988 (53 FR 2436). The second segment,
an amendment to the tentative final monograph to include OTC relief of
oral discomfort drug products, was published in the Federal Register of
September 24, 1991 (56 FR 48302). Another part of the OTC oral health
care drug products rulemaking involves antiplaque and antiplaque-
related products. The agency published a call-for-data for OTC
antiplaque ingredients in the Federal Register of September 19, 1990
(55 FR 38560). The data received in response to that call-for-data are
currently being evaluated by the Dental Products Panel. The Panel's
recommendations to the agency regarding the safety and effectiveness of
antiplaque and antiplaque-related drug products will be published in an
advance notice of proposed rulemaking in a future issue of the Federal
Register.
The advance notice of proposed rulemaking, which was published in
the Federal Register on May 25, 1982 (47 FR 22760), was designated as a
``proposed monograph'' in order to conform to terminology used in the
OTC drug review regulations (21 CFR 330.10). Similarly, the present
document is designated as a ``tentative final monograph.'' In this
tentative final monograph (proposed rule) to amend part 356 (21 CFR
part 356) (proposed in the Federal Register of January 27, 1988, 53 FR
2436), FDA states for the first time its position on the establishment
of a monograph for OTC oral antiseptic drug products. Final agency
action on this matter will occur with the publication at a future date
of a final monograph, which will be a final rule establishing a
monograph for OTC oral health care drug products and will include oral
antiseptic drug products.
This proposal constitutes FDA's tentative adoption of the Oral
Cavity Panel's conclusions and recommendations on OTC oral antiseptic
drug products, as modified on the basis of the comments received and
the agency's independent evaluation of that report. Modifications have
been made for clarity and regulatory accuracy and to reflect new
information. Such new information has been placed on file in the
Dockets Management Branch (address above). These modifications are
reflected in the following summary of the comments and FDA's responses
to them.
The OTC drug procedural regulations (21 CFR 330.10) provide that
any testing necessary to resolve the safety or effectiveness issues
that formerly resulted in a Category III classification, and submission
to FDA of the results of that testing or any other data, must be done
during the OTC drug rulemaking process before the establishment of a
final monograph. Accordingly, FDA does not use the terms ``Category I''
(generally recognized as safe and effective and not misbranded),
``Category II'' (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 monograph stage. In place of Category I, the term ``monograph
conditions'' is used; in place of Categories II or III, the term
``nonmonograph conditions'' is used. This document retains the concepts
of Categories I, II, and III at the tentative final monograph stage.
The agency advises that the conditions under which the drug
products that are subject to this monograph would be generally
recognized as safe and effective and not misbranded (monograph
conditions) will be effective 12 months after the date of publication
of the final monograph in the Federal Register. On or after that date,
no OTC drug product that is subject to the monograph and that contains
a nonmonograph condition, i.e., a condition that would cause the drug
to be not generally recognized as safe and effective or to be
misbranded, may be initially introduced or initially delivered for
introduction into interstate commerce unless it 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 introduced or initially delivered
for introduction into interstate commerce. Manufacturers are encouraged
to comply voluntarily with the monograph at the earliest possible date.
In the advance notice of proposed rulemaking for OTC oral health
care drug products (47 FR 22760), the agency suggested that the
conditions included in the monograph (Category I) be effective 6 months
after the date of publication of the final monograph in the Federal
Register and that the conditions excluded from the monograph (Category
II) be eliminated from OTC drug products effective 6 months after the
date of publication of the final monograph, regardless of whether
further testing was undertaken to justify their future use. Experience
has shown that relabeling of products covered by the monograph is
necessary in order for manufacturers to comply with the monograph. New
labels containing the monograph labeling have to be written, ordered,
received, and incorporated into the manufacturing process. The agency
has determined that it is impractical to expect new labeling to be in
effect 6 months after the date of publication of the final monograph.
Experience has shown also that if the deadline for relabeling is too
short, the agency is burdened with extension requests and related
paperwork.
In addition, some products will have to be reformulated to comply
with the monograph. Reformulation often involves the need to do
stability testing on the new product. An accelerated aging process may
be used to test a new formulation; however, if the stability testing is
not successful, and if further reformulation is required, there could
be a further delay in having a new product available for manufacture.
The agency wishes to establish a reasonable period of time for
relabeling and reformulation in order to avoid an unnecessary
disruption of the marketplace that could not only result in economic
loss, but also interfere with consumers' access to these products.
Therefore, the agency is proposing that the final monograph be
effective 12 months after the date of its publication in the Federal
Register. The agency believes that within 12 months after the date of
publication most manufacturers can order new labeling and reformulate
their products and have them in compliance in the marketplace.
If the agency determines that any labeling for a condition included
in the final monograph should be implemented sooner than the 12-month
effective date, a shorter deadline may be established. Similarly, if a
safety problem is identified for a particular nonmonograph condition, a
shorter deadline may be set for removal of that condition from OTC drug
products.
In the event that new data submitted to the agency during the
allotted 12-month comment and new data period are not sufficient to
establish ``monograph conditions'' for OTC oral antiseptic drug
products, the final rule will declare these products to be new drugs
under section 201(p) of the Federal Food, Drug, and Cosmetic Act (the
act) (21 U.S.C. 321(p)), for which new drug applications approved under
section 505 of the act (21 U.S.C. 355) and 21 CFR part 314 are required
for marketing. That rule would also declare that in the absence of an
approved new drug application, these products would be misbranded under
section 502 of the act (21 U.S.C. 352). The rule will then be
incorporated into 21 CFR part 310, subpart E--Requirements for Specific
New Drugs or Devices, instead of into an OTC drug monograph in part
356.
All ``OTC Volumes'' cited throughout this document refer to the
submissions made by interested persons pursuant to the call-for-data
notices published in the Federal Registers of January 30, 1973 (38 FR
2781) (dental drug products) and July 20, 1973 (38 FR 19444) (oral
health care drug products) or to additional information that has come
to the agency's attention since publication of the advance notice of
proposed rulemaking. The volumes are on public display in the Dockets
Management Branch (address above).
I. The Agency's Tentative Conclusions on the Comments
A. General Comments on Oral Antiseptic Ingredients
1. Several comments objected to the recommendation of the majority
of the Oral Cavity Panel that only one Category III indication is
appropriate for oral antiseptics, i.e., for the treatment of sore mouth
and sore throat. One comment contended that antiseptic mouthwashes are
not intended to be used primarily in the treatment of sore mouth and
sore throat. Two comments maintained that the Oral Cavity Panel's
recommendations that antiseptic mouthwashes be used solely for this
indication is inconsistent with the commonly accepted purpose of these
products. Another comment stated that the use of oral antiseptics
solely for the treatment of sore mouth or sore throat, as the Panel
recommended, would result in a disservice to consumers by depriving
them of safe, familiar products upon which they depend. A number of
comments discussed the use of oral antiseptic ingredients to reduce
dental plaque, gingivitis, or both.
The agency notes that the Oral Cavity Panel used the term
``antimicrobial agent'' to describe an ingredient that kills
microorganisms or prevents or inhibits their growth and reproduction.
In this tentative final monograph, in order to be consistent with
terminology proposed in the tentative final monograph for OTC first aid
antiseptic drug products in the Federal Register of July 22, 1991 (56
FR 33644), the agency is proposing to replace the Panel's term
``antimicrobial'' with the term ``antiseptic.''
The Oral Cavity Panel only reviewed antiseptic ingredients for sore
mouth and sore throat claims and did not specifically evaluate the
effectiveness of oral antiseptics to inhibit plaque formation. Although
data on plaque reduction as a measure of the effectiveness of OTC oral
antiseptics were presented to that Panel, it did not accept such data
because it believed that ``the rationality of plaque reduction as a
criterion of effectiveness of antimicrobial agents for use in the mouth
and throat is highly debatable, and evidence of the validity of the
method is scant'' (47 FR 22760 at 22840 to 22842). The Panel was not
charged with reviewing drug products used to treat dental or
periodontal diseases, and it did not address ingredients with
antiplaque claims.
Because no advisory review panel reviewed the safety and
effectiveness data on particular ingredients, including oral
antiseptics, for antiplaque or gingivitis indications, the agency
announced a call-for-data for ingredients contained in products bearing
antiplaque and antiplaque-related claims in the Federal Register of
September 19, 1990 (55 FR 38560). A substantial amount of information
has been submitted to the agency pursuant to that call-for-data. The
safety and effectiveness data submitted to the agency for various
antiplaque and antiplaque-related ingredients are currently being
evaluated by the Dental Products Panel. That Panel will advise the
Commissioner of Food and Drugs on the promulgation of a monograph
establishing conditions under which oral antiseptic drugs for
antiplaque and antiplaque-related use are generally recognized as safe
and effective and not misbranded.
In the call-for-data, the agency stated that, in order to be
eligible for review under the OTC drug review procedures, an ingredient
must have been marketed in a product with the relevant indication to a
material extent and for a material time (21 U.S.C. 321(p)(2)). The
agency specifically requested information demonstrating such marketing.
The marketing data submitted to the agency by various manufacturers
includes data on ingredients marketed in the United States, as well as
data on ingredients that have only been marketed in other countries.
Agency policy currently requires ingredients to have been marketed in
the United States as of a certain date (December 4, 1975) to be
eligible for consideration in the OTC drug review. Because of the
passage of time, some antiplaque ingredients have entered the
marketplace since 1975 and have been marketed for a number of years.
The agency is reevaluating its policy for eligibility in the OTC drug
review in relation to the statutory language ``used to a material
extent and for a material time'' within the meaning of 21 U.S.C.
321(p)(2). The agency is also reevaluating its longstanding policy that
foreign marketing alone is not an adequate basis for an ingredient to
be considered in the OTC drug review. The agency's conclusions on these
matters will affect many other therapeutic categories of drugs in
addition to antiplaque products. For example, the agency is currently
reviewing petitions to include sunscreens and phytomedicines marketed
only in Europe in the OTC drug review. The ultimate review status of
some of the antiplaque ingredient(s) is dependent on the resolution of
this broader policy, which will be discussed in a future issue of the
Federal Register.
The agency agrees with the comments that more than one indication
may be appropriate for oral antiseptics. Although the Oral Cavity
Panel's recommended indication for temporary relief of sore throat and
sore mouth remains in Category III in this tentative final monograph,
the agency is proposing a Category I indication for oral antiseptics
used to help in the prevention of infection in minor sore mouth
conditions. The agency is also requesting additional data to support
the Panel's recommended Category III indication. (For a further
discussion regarding the indications for OTC oral antiseptic drug
products, see section I.K., comment 22.)
2. Two comments maintained that the safety of oral antiseptics is
well established. One of the comments noted that the Oral Cavity Panel
had initially placed oral antiseptic active ingredients in Category I
for safety, but after questions were raised about the carcinogenic,
teratogenic, and mutagenic potential of these ingredients, the Panel
placed them in Category III. Maintaining that the chemical nature and
the extensive scientific history of oral antiseptics do not lead to the
conclusion that these materials are carcinogenic, teratogenic, or
mutagenic, the comment noted that the review of quaternary ammonia
compounds written for the Panel by one of its members concludes that
quaternary ammonia compounds are safe for use in the oral cavity. The
comment also quoted the following from the tentative final monograph
for OTC topical antimicrobial drug products published in the Federal
Register of January 6, 1978 (43 FR 1210 at 1238 and 1239):
The Commissioner disagrees with the Panel that carcinogenicity,
mutagenicity, or teratogenicity studies must be completed. The
Commissioner concludes that, in the absence of any data suggesting
that * * * has any carcinogenic, mutagenic, or teratogenic
potential, testing for these properties should not be required.
The comment contended that ``the parallel with oral antiseptics is
striking and conclusive.''
Both comments disagreed with the Panel that long-term use of oral
antiseptics could cause harmful shifts of the oral flora, arguing that
no such effects have been reported for this class of products and the
available evidence suggests that their occurrence is unlikely. As an
example, one comment stated that fungal overgrowth leading to thrush
(candidiasis or moniliasis) that is commonly associated with the
administration of broad spectrum antibiotics is one type of floral
shift that could be troublesome. However, the comment asserted that
there is no basis for supposing that frequent or even abusive use of
OTC antiseptic mouthwashes could lead to thrush because part of the
testing procedure for active antiseptic ingredients has been an in
vitro test showing effectiveness against the fungus Candida albicans,
which is the organism principally responsible for thrush.
Regarding the Oral Cavity Panel's suggestion that antiseptic
mouthwashes could selectively eliminate ``beneficial'' organisms from
the mouth, opening the way to the adverse effects of pathogenic flora,
the comment asserted that in ``all the literature of the microbial
etiology of oral disease there are no reports stating or implying such
an adverse shift of oral flora.'' In support of this statement, the
comment cited reviews by Socransky (Ref. 1) and Loesche (Ref. 2). The
comment also cited a report by Volpe et al. (Ref. 3) that no harmful
floral shift resulted when mouthwashes containing cetylpyridinium
chloride, benzethonium chloride, or hexachlorophene were used.
The comment stated that members of the Nonprescription Drug
Manufacturers Association (NDMA) Task Group (formerly known as The
Proprietary Association Task Group) estimate that, over a period of 10
years, its companies have conducted studies of antiseptic mouthwashes
involving over 5,000 subjects for intervals ranging from 1 week to 1
year. Professional supervision and examination have demonstrated no
instances of adverse effects resulting from floral shifts. The comment
asserted that this is conclusive evidence of the safety of oral
antiseptics.
The comment noted that another example of an occasional and
undesirable effect of the prolonged use of antibiotics is lingua nigra
or black hairy tongue. Maintaining that this condition is associated
with Candida and with members of the related genera, Actinomyces,
Nocardia, and Streptomyces, the comment asserted that because in vitro
testing of oral antiseptics by the NDMA Task Group included proof of
effectiveness against Actinomyces as well as Candida, there is no
reason to believe that black hairy tongue would result from any use of
oral antiseptics.
The Oral Cavity Panel evaluated the adverse effects of antiseptic
ingredients contained in oral health care drug products from the
following two standpoints: (1) Short-term use to treat sore mouth and
sore throat and (2) long-term use for cleansing, elimination of mouth
odors, and other purposes where no symptoms of a disease exist (47 FR
22760 at 22848). The Panel did not consider OTC oral health care drug
products appropriate for prophylactic use to prevent the development of
symptoms or disease states of the mouth and throat (47 FR 22778). It
concluded that antiseptic ingredients should be used for oral health
care only when specific symptoms (e.g., sore throat or sore mouth) are
present to justify the need for a specific product whose effectiveness
has been established (47 FR 22834).
Although the Oral Cavity Panel placed no oral antiseptics in
Category I, it placed 25 antiseptic ingredients in Category III for
effectiveness. Additionally, the Panel determined that 16 of those 25
ingredients are safe for short-term use in the oral cavity. It did not
determine that any antiseptic ingredients are safe (i.e., Category I)
for long-term use in the oral cavity. Ingredients considered by the
Panel to be safe for short-term use as OTC antiseptics in the oral
cavity (i.e., Category III for effectiveness and Category I for safety)
include phenol, carbamide peroxide in anhydrous glycerin, ethyl
alcohol, and hydrogen peroxide. Ingredients placed in Category III for
safety and effectiveness by the Panel include cetylpyridinium chloride,
domiphen bromide, and povidone-iodine. The Panel also recommended
labeling for oral antiseptics in OTC oral health care drug products
that includes a warning restricting use to not more than 2 days (47 FR
22850).
The Panel did not clearly distinguish between the use of oral
antiseptic ingredients in mouthwashes (long-term) and oral first aid
products (short-term). The agency believes that many of these
ingredients were placed in Category III for safety by the Panel because
the ingredients are used in mouthwashes that are recommended by
manufacturers for long-term use on a daily basis. (For a discussion of
the time limits for use of oral antiseptics, see section I.K., comment
25.) The agency believes that the Panel's concerns are not necessarily
relevant to the short-term use of these ingredients (i.e., up to 7
days). For example, the Panel stated that ''extensive clinical
observations also indicate that PVP-I [povidone-iodine] is generally
nonirritating and nonsensitizing when applied to the skin and mucous
membranes`` (47 FR 22760 at 22884) and that dequalinium chloride has a
low degree of toxicity similar to other quaternary ammonia compounds
(quats) (47 FR 22760 at 22867). Nevertheless, the Panel placed
povidone-iodine and dequalinium chloride in Category III for safety.
The Panel recognized the safety of the commercially available
concentrations of domiphen bromide, but stated that because controlled
studies had not been done on the effects of domiphen bromide when used
on a long-term basis, its safety could not be assumed (47 FR 22868 and
22869).
Accordingly, the agency concludes that the assessment of short-term
safety of oral antiseptics should be determined on an individual basis
based upon customary use (see section I.E., comment 8; section I.G.,
comment 12; and section I.I., comment 15). The agency invites comment
on the safety of specific ingredients for use on a short-term basis.
When OTC oral antiseptics are indicated for short-term use and
there is an absence of data suggesting that the ingredients evaluated
by the Oral Cavity Panel have any carcinogenic, mutagenic, or
teratogenic activities, the agency agrees with the Panel that the
sponsor of a product should not be expected to conduct studies to
obtain data on their tumorigenicity, mutagenicity, or teratogenicity.
Such studies are often conducted by the National Cancer Institute and
other agencies when necessary. The agency notes that benzethonium
chloride is currently being evaluated for carcinogenic potential in the
National Toxicology Program (NTP). (See section I.C., comment 5.)
The safety of long-term daily usage of OTC oral antiseptic
ingredients in the oral cavity will be evaluated by the Dental Products
Panel as part of its safety and effectiveness review of OTC antiplaque
ingredients and will be discussed in a subsequent segment of the
rulemaking for OTC oral health care drug products, to be published in a
future issue of the Federal Register. (See section I.A., comment 1.)
References
(1) Socransky, S. S., ``Microbiology of Periodontal Disease--
Present Status and Future Considerations,'' Journal of
Periodontology, 48:497-504, 1977.
(2) Loesche, W. J., ``Chemotherapy of Dental Plaque
Infections,'' Oral Sciences Review, 9:65-107, 1976.
(3) Volpe, A. R. et al., ``Antimicrobial Control of Bacterial
Plaque and Calculus and the Effects of the Agents on Oral Flora,''
Journal of Dental Research, 48:832-841, 1969.
3. Several comments and two reply comments disagreed with the Oral
Cavity Panel's recommendation that OTC oral health care drug products
containing pharmacologically active concentrations of antimicrobial
ingredients should not be used to achieve a cosmetic effect, such as a
reduction of mouth odor (47 FR 22760 at 22844). The comments contended
that the use of ingredients in cosmetic mouthwash products is outside
the scope of the OTC drug review procedure, which is limited to drug
actions and drug claims. Arguing that the Panel's recommendation
advocates the position that the regulatory classification of a product
is dependent solely on the ingredient it contains, the comments
maintained that it is a well-established regulatory policy that the
intended use of a product determines whether it is regulated as a drug
or as a cosmetic and that the intended use is determined by the
manufacturer's representations and labeling claims. The comments stated
that claims for the reduction or suppression of mouth odor and for oral
cavity cleansing or refreshing are cosmetic claims. To support their
contentions, many of the comments cited the definitions of ``drug'' and
``cosmetic'' in sections 201(g) and 201(i) of the act (21 U.S.C. 321(g)
and 321(i)), the legislative history of the act, and prior case law.
Some comments also quoted the following statement delivered to the Oral
Cavity Panel in 1974 by the then FDA chief counsel:
Generally, a product label will be the determining factor as to
how a product will be classified, i.e., a drug or cosmetic. The
overall safety of a product will also be a major factor in such
classification. For example: The claim ``kills germs that cause
odor,'' would be considered a cosmetic claim; the claim ``kills
germs that cause disease'' would be considered a drug claim * * *.
(Ref. 1)
Several comments stated that the agency has a long-standing policy
that cosmetics containing antimicrobial ingredients or other
pharmacologic agents are not drugs unless drug claims are made for
them. Some of the comments pointed out that FDA's policy concerning
drug versus cosmetic status has been stated in many documents,
including the procedural regulations governing the OTC drug review (37
FR 9464 to 9475) and official trade correspondence, and that the policy
was restated in the tentative final monograph for OTC antiperspirant
drug products, published in the Federal Register of August 20, 1982 (47
FR 36492), and in the report of the Advisory Review Panel on OTC
Contraceptives and Other Vaginal Drug Products (Vaginal Panel),
published in the Federal Register of October 13, 1983 (48 FR 46694).
Many comments pointed out that in both the OTC antiperspirant drug
products rulemaking and the OTC topical antimicrobial drug products
rulemaking, the FDA agreed that a product that contains antimicrobial
ingredients to reduce microbial flora solely for the purpose of
cleansing or reducing odor is a cosmetic and not a drug and that such
cosmetic uses are outside the scope of OTC drug monographs. Concluding
that the Oral Cavity Panel's recommendations are without legal
foundation and are contrary to the provisions of the act and the legal
precedents established for more than 40 years, the comments requested
that FDA reject the Panel's recommendations and adhere to the
traditional drug/cosmetic distinctions.
One comment stated that the Oral Cavity Panel appeared to base its
proposal to delete all cosmetic indications for antimicrobial mouthwash
products on the finding that topical antimicrobials as a class are
unsafe and ineffective. Asserting that action to be contrary to the
substantial scientific evidence presented to that Panel and to the
Advisory Review Panels on OTC Topical Antimicrobial Drug Products (the
Antimicrobial I and II Panels), the comment stated that antimicrobial
ingredients, used appropriately, are no less safe than other
ingredients commonly used as cosmetics. A reply comment added that
there are extensive scientific data demonstrating the effectiveness of
an antimicrobial mouthwash in suppressing mouth odor.
Another reply comment agreed with the Panel that cosmetic claims
are not acceptable as ``indications'' for the OTC oral health care drug
products rulemaking insofar as cosmetic claims are not drug
indications. However, the reply comment stated that this should not
preclude truthful and nonmisleading information about the cosmetic
usefulness in the product's labeling and mentioned antidandruff
shampoos and anticaries toothpastes as two examples of OTC products
with both drug and cosmetic claims. The reply comment argued that dual
claims should be permitted for an OTC oral health care drug product,
e.g., that it refreshes or deodorizes the mouth (a cosmetic claim) and
aids in the temporary relief of discomfort due to occasional sore
throat or sore mouth (a drug claim), just as such dual claims are
permitted for antidandruff shampoos, which are represented to clean
hair (a cosmetic claim) and to prevent dandruff (a drug claim), and for
anticaries toothpastes, which are represented to clean teeth and to
prevent tooth decay.
The comments requested that the agency recognize the following
phrases as cosmetic claims for OTC oral health care products and,
therefore, consider them as outside the scope of the OTC drug review:
``Kills germs that cause bad breath,'' ``mouth refreshment,'' ``clean
feeling,'' ``control of mouth odor,'' ``control of bad breath,'' ``an
aid to the daily care of the mouth,'' and ``causing the mouth to feel
clean.'' Two comments argued that terms such as ``antimicrobial,''
``antiseptic,'' ``kills germs,'' ``kills germs by millions on
contact,'' ``antibacterial,'' and other synonymous phrases can be
properly used to describe cosmetic functions, i.e., cleansing or
refreshing and deodorizing, without creating drug connotations. The
comments stated that when used in connection with oral hygiene and
deodorizing representations, such claims are cosmetic claims because
the context in which they appear connotes cosmetic purposes only. These
comments concluded that mouthwashes, rinses, and gargles labeled solely
with traditional cosmetic claims for cleansing, refreshing, or
deodorizing the mouth or breath are subject to regulation only as
cosmetics and not as drugs.
The Oral Cavity Panel stated that claims for the suppression of
mouth odor in the labeling of OTC antiseptic health care products are
drug claims because they are linked to a drug action, i.e.,
antimicrobial activity (47 FR 22760 at 22844). Concluding that such
claims ``* * * indicate that a product is used for cosmetic purposes
but imply that the product exerts a therapeutic effect'' (47 FR 22857),
the Panel classified claims for the suppression of mouth odor as well
as claims for the cleansing or freshening of the mouth in Category II.
The act provides the statutory definitions that differentiate a
drug from a cosmetic. A ``drug'' is defined as an article ``intended
for use in the diagnosis, cure, mitigation, treatment, or prevention of
disease'' or ``intended to affect the structure or any function of the
body * * *,'' (21 U.S.C. 321(g)(1)(B) and 321(g)(1)(C)). A
``cosmetic,'' on the other hand, is defined as an article intended to
be ``* * * applied to the human body or any part thereof for cleansing,
beautifying, promoting attractiveness, or altering the appearance * *
*'' (21 U.S.C. 321(i)(1)). The agency agrees with the comments that the
intended use of a product is the primary determining factor as to
whether it is a drug, a cosmetic, or both. This intended use may be
inferred from the product's labeling, promotional material,
advertising, and any other relevant factor. (See, e.g., National
Nutritional Foods Ass'n v. Mathews, 557 F.2d 325, 334 (2d Cir. 1977).)
In determining whether a product is a drug or a cosmetic, the
intended use may be established from the type and amount of
ingredient(s) present, as well as the product's labeling. For example,
in some instances, the mere presence of certain therapeutically active
ingredients could make a product a drug even in the absence of drug
claims. In these cases, the intended use would be implied because of
the known or recognized drug effects of the ingredient (e.g., fluoride
in a dentifrice). However, in other instances, the presence of an
ingredient (e.g., an antimicrobial), in and of itself, does not make a
product a drug when no drug claim is made.
The agency does not agree with the Panel that claims for the
suppression of mouth odor in the labeling of an oral product containing
an antiseptic ingredient necessarily makes that product a drug. Oral
products that contain antiseptic ingredients are considered
``cosmetics,'' and not ``drugs,'' if only deodorant (or other cosmetic)
claims are made for the products. The agency stated in the tentative
final monograph for OTC first aid antiseptic drug products (56 FR 33644
at 33648) that the mere presence of an antimicrobial ingredient in a
product labeled for deodorant use, with the ingredient identified only
in the ingredient list and no reference to its antimicrobial properties
stated elsewhere in the labeling, would not cause the product to be
considered a drug. Claims such as ``mouth refreshment,'' ``clean
feeling,'' ``control of mouth odor,'' ``control of bad breath,'' and
``for causing the mouth to feel clean'' are considered cosmetic claims
in accordance with section 201(i) of the act and are not included in
this tentative final monograph.
However, any broader claims that represent or suggest a therapeutic
use for the product would subject it to regulation as a drug. For
example, the agency considers the phrase ``an aid to daily care of the
mouth'' to be a drug claim because it implies that the product exerts a
therapeutic benefit. The agency also considers terms such as
``antibacterial,'' ``antimicrobial,'' ``antiseptic,'' or ``kills
germs'' in the labeling of oral products to imply that the product will
have a therapeutic effect. The agency concludes that such statements
would constitute a drug claim for the product because consumers would
perceive the intended effect to be achieved by a drug action. Likewise,
any of the cosmetic statements mentioned above could become part of a
drug claim if additional statements are included. For example, cosmetic
claims such as ``control of mouth odor'' and ``for causing the mouth to
feel clean'' become drug claims when therapeutic terms are added as
follows: (1) ``antimicrobial for control of mouth odor,'' or (2)
``kills germs to help the mouth feel clean.'' Furthermore, use of the
term ``active ingredient(s)'' in the labeling of these products would
imply that the product possesses a drug-like property and, thus, would
cause the product to be considered a drug.
Products marketed only as cosmetics are not subject to this
rulemaking, but are subject to the provisions of sections 601 and 602
of the act (21 U.S.C. 361 and 362) relating to adulteration and
misbranding of cosmetics. The final OTC drug monograph for these
products will cover only the drug use of the active ingredients listed
therein. The concentration range, limitations, warnings, and directions
established for the ingredients in the monograph may not apply to the
use of the same ingredients in products intended solely as cosmetics.
However, some of these factors may be considered by the agency in
determining the safety of an ingredient for cosmetic uses. Those
products intended for both drug and cosmetic use will be required to
conform to the requirements of the final monograph. However, such
products, in addition to bearing the indications allowed for OTC oral
health care drug products, may also be labeled for cosmetic uses, such
as deodorancy or cleansing, in conformity with section 602 of the act
and the provisions of 21 CFR parts 701 and 740.
In accordance with the revised labeling requirements for OTC drug
products, it is the agency's view that cosmetic claims may not appear
within the boxed area designated ``APPROVED USES.'' As discussed in the
final rule on the agency's ``exclusivity policy'' (51 FR 16258 at 16264
(paragraph 14)), cosmetic terminology is not reviewed and approved by
FDA in the OTC drug monographs and therefore could not be placed in the
box. Cosmetic claims may appear elsewhere in the labeling, should
manufacturers choose the labeling alternative provided in
Sec. 330.1(c)(2)(i) or (c)(2)(iii) for labeling drug/cosmetic products.
Although the agency does not specifically prohibit commingled drug and
cosmetic labeling in other than the indications section, such claims
should be appropriately described so that consumers will more readily
be able to differentiate the drug aspects from the cosmetic aspects of
such labeling. If commingled drug and cosmetic labeling claims are
confusing or misleading, the product's labeling could be misleading
within the meaning of the act and misbranded under sections 502(a) and
602(a) of the act (21 U.S.C. 352(a) and 362(a)).
Reference
(1) Summary Minutes of the Advisory Review Panel on OTC Oral
Health Care Drug Products, June 13 and 14, 1974, OTC Vol. 130PA2,
Dockets Management Branch.
B. Comment on Alcohol
4. One comment expressed confusion regarding the Oral Cavity
Panel's discussion and conclusions on ethyl alcohol (47 FR 22760 at
22871 to 22873). As an example, the comment mentioned that the Panel
considered ethyl alcohol to be safe for use in the oral cavity while
also stating that ``Ethyl alcohol above 20 percent is considered to be
an irritant * * *.'' Pointing out that the Panel also mentioned 70
percent alcohol (47 FR 22873), the comment questioned if it was
permissible to use 70 percent alcohol as a solvent. The comment also
wondered how the Panel determined that ``The quantity [of alcohol]
absorbed from the mouth and throat is not significant,'' (47 FR 22872).
The comment concluded that, because it appears that the Panel's report
lacks sufficient proof of safety and effectiveness of alcohol in
concentrations over 20 percent and because of the high vulnerability of
elderly people and children to alcohol, oral health care products
containing more than 20 percent alcohol should not be permitted to stay
on the market.
The agency reviewed the Oral Cavity Panel's discussion regarding
ethyl alcohol (alcohol) as an active ingredient in OTC oral health care
drug products and did not find any statement concerning alcohol above
20 percent being considered an irritant. However, in a report on OTC
agents for the relief of oral discomfort published concurrently with
the Oral Cavity Panel's report in the Federal Register of May 25, 1982
(47 FR 22712), the Dental Panel stated that alcohol above 20 percent is
an irritant to the dental pulp and, therefore, concentrations above 20
percent should not be used in agents for the relief of toothache in an
open tooth cavity (47 FR 22712 at 22726).
The Oral Cavity Panel concluded that alcohol is safe for use as an
OTC oral antimicrobial ingredient (47 FR 22760 at 22872). However, the
Panel did not clearly define a safe concentration of alcohol. The Panel
also stated that commercially available mouthwashes contain alcohol as
a solvent in concentrations up to 35 percent, but that concentrations
above 35 percent cause burning of the mucous membranes (47 FR 22872).
The Panel specifically stated that concentrations of alcohol that kill
bacteria, e.g., 70 percent alcohol, cause burning and intense
discomfort and are too irritating when applied to inflammations of the
mucous membranes of the oral cavity (47 FR 22873). For the above
reasons and because alcohol has a marked potential for abuse, the Panel
recommended that the quantity of alcohol used as a solvent in
pharmaceutical preparations should be limited to 35 percent.
In its report on OTC agents for the relief of oral discomfort (47
FR 22712 at 22737), the Dental Panel accepted the safety of 1.5 percent
phenol in 70 percent alcohol for direct application to the gums for up
to 7 days. That Panel concluded that up to 70 percent alcohol was an
appropriate vehicle for 5 to 20 percent benzocaine with a maximum
dosage of 1 milliliter (mL) and that compound benzoin tincture (74 to
80 percent alcohol) and benzoin tincture (75 to 83 percent alcohol)
were safe for occasional application to small areas of the oral mucosa
regardless of the high alcohol content (47 FR 22746).
The Oral Cavity Panel considered alcohol ineffective as an
antimicrobial ingredient at concentrations below 70 percent (47 FR
22872 to 22873). However, that Panel also postulated that the lower
concentrations of alcohol used as a solvent for an antimicrobial
ingredient could act synergistically with the antimicrobial ingredient
to produce an enhanced antimicrobial effect. The Panel concluded that
there were insufficient data from controlled studies to establish the
effectiveness of alcohol alone as an antiseptic ingredient for the
treatment of symptoms such as sore mouth and sore throat, and the Panel
placed it in Category III.
In the advance notice of proposed rulemaking for OTC alcohol drug
products for topical antimicrobial use (47 FR 22324), the Advisory
Review Panel on OTC Miscellaneous External Drug Products (Miscellaneous
External Panel) stated that the ``irritant action of alcohols is
particularly marked on mucosa. The more concentrated the alcohol, the
more pronounced are its irritant effects.'' That Panel recommended
caution in the topical use of 60 to 95 percent alcohol and 50 to 91.3
percent isopropyl alcohol on the mucous membranes (47 FR 22324 at
22327) and placed the indication ``For application to mucous
membranes'' in Category II (47 FR 22332). In the tentative final
monograph for OTC first aid antiseptic drug products, the agency
discussed this indication and stated that the use of alcohol on the
mucous membranes of the mouth and throat would be addressed in the
rulemaking for OTC oral health care drug products (56 FR 33644 at
33656).
The agency is aware of a recent study (Ref. 1) indicating that men
and women using mouthwashes with 25 percent or higher alcohol content
on a regular long-term basis have a slightly increased risk of oral and
pharyngeal cancers. Moreover, the risk rose with longer and more
frequent mouthwash use. After adjusting for tobacco and alcohol
consumption, men had a 40-percent higher risk and women had a 60-
percent higher risk of these cancers, compared to those who did not use
a mouthwash product. Although these findings do not firmly establish
the risk relationship between use of an alcohol-containing mouthwash
product and these cancers, they show a need to look further at this
relationship. The agency is also aware of three earlier studies
demonstrating an apparent association between long-term mouthwash use
and an increased risk of oral and pharyngeal cancers (Refs. 2, 3, and
4). Although these studies may have no bearing on the safety of the
short-term use of drug products containing alcohol, the agency believes
that serious consideration must be given to the results of these
studies to determine whether there is a need to limit the amount of
alcohol permitted in oral health care drug products.
In 1992, the agency sent letters to two manufacturers' associations
requesting data and information on the relationship between alcohol-
containing drug products and oral and pharyngeal cancers and the extent
of alcohol in OTC oral health care drug products (Refs. 5 and 6). In
response, the associations jointly submitted a list of OTC mouthwashes,
their alcohol content, and their 1990 sales data (Ref. 7), a reanalysis
(Ref. 8) of the study on the association between the use of alcohol-
containing mouthwashes and oral/pharyngeal cancer (Ref. 1) discussed
previously, and a review (Ref. 8) of related medical and scientific
literature pertaining to the etiology of oral cancer. The agency is
currently evaluating the data and information submitted.
The agency notes that alcohol is used as a solvent in many OTC oral
health care drug products currently on the market. When alcohol is
included in oral antiseptic products, the agency believes that the
amount of alcohol absorbed from topical application of the product to
the mouth and throat to be insignificant. Such products are usually
formulated as mouthwashes (oral rinses) or gargles and are retained in
the mouth for a short period of time (usually 1 minute or less) and
then spit out, or are applied as very small amounts of the product to
discreet areas of the oral mucosa. However, the agency believes that
alcohol should be included in OTC oral health care drug products only
if the alcohol is necessary to dissolve the active ingredient(s).
The agency is currently evaluating the use of alcohol in all OTC
drug products. On December 17, 1992 (Ref. 9), the OTC Drugs Advisory
Committee discussed the use of alcohol in OTC drug products for oral
ingestion and recommended to the agency that such products should not
contain more than the minimum amount of alcohol needed as a solvent for
the active ingredient, for preservative purposes, or for taste
enhancement. The Committee specifically recommended the following:
1. For persons 12 years of age and above, a maximum alcohol
concentration up to and including 10 percent volume-to-volume;
2. For children age 6 to under 12, a maximum alcohol concentration
up to and including 5 percent volume-to-volume; and
3. For children under 6 years of age, a maximum alcohol
concentration up to and including 0.5 percent volume-to-volume.
Based on the Committee's recommendations, the agency published a
proposed rule on OTC drug products intended for oral ingestion that
contain alcohol in the Federal Register of October 21, 1993 (58 FR
54466). That proposal would establish a maximum concentration limit for
alcohol as an inactive ingredient in OTC drug products intended for
oral ingestion.
In conclusion, the agency is evaluating the use of alcohol in all
OTC drug products, is investigating a possible link between the regular
use of alcohol-containing mouthwashes and oral and pharyngeal cancers,
and is considering limiting the amount of alcohol permitted in such
products. Although the agency is not proposing in this tentative final
monograph to limit the amount of alcohol used as a solvent in OTC oral
health care drug products, it urges all manufacturers to limit the
alcohol content of all OTC drug products to the smallest amount
compatible with the dissolution of the active ingredient(s).
References
(1) Blot, W. J. et al., ``Mouthwash Use and Oral Conditions in
the Risk of Oral and Pharyngeal Cancer,'' Cancer Research, 51:3044-
3047, 1991.
(2) Wynder, E. L. et al., ``Oral Cancer and Mouthwash Use,''
Journal of the National Cancer Institute, 70:255-260, 1983.
(3) Blot, W. J., D. M. Winn, and J. F. Fraumeni, ``Oral Cancer
and Mouthwash,'' Journal of the National Cancer Institute, 70:251-
253, 1983.
(4) Weaver, A., S. M. Fleming, and D. B. Smith, ``Mouthwash and
Oral Cancer: Carcinogen or Coincidence?'' Journal of Oral Surgery,
37:250-253, 1979.
(5) Letter from W. E. Gilbertson, FDA, to E. E. Kavanaugh,
Cosmetic, Toiletry and Fragrance Association, coded LET 17, Docket
No. 81N-0033, Dockets Management Branch.
(6) Letter from W. E. Gilbertson, FDA, to J. D. Cope,
Nonprescription Drug Manufacturers Association (NDMA) coded LET 16,
Docket No. 81N-0033, Dockets Management Branch.
(7)Comment No. LET25, Docket No. 81N-0033, Dockets Management
Branch.
(8) Comment No. 53, Docket No. 81N-0033, Dockets Management
Branch.
(9) Summary Minutes of the Nonprescription Drugs Advisory
Committee Meeting, December 16 and 17, 1992, OTC Vol. 13CTFM.
C. Comment on Benzethonium Chloride
5. One comment disagreed with the Oral Cavity Panel's
classification of benzethonium chloride in Category III for safety. The
comment criticized the Panel's statement that ``Adequate data on
absorption and attainment of toxic blood levels and the metabolic fate
of quats [quaternary ammonium compounds] are not available'' (47 FR
22760 at 22860). The comment contended that information on the
absorption of benzethonium chloride is available and that submissions
to the Panel (Refs. 1 and 2) contained extensive data on the absorption
and distribution of benzethonium chloride in chickens and in pregnant
rats and their fetuses.
The comment also objected to the Oral Cavity Panel's statement that
``No data are available on the mutagenic, tumorigenic, or teratogenic
effects of benzethonium chloride when used in mouthrinses or gargles
for long-term use on a daily basis for oral health care'' (47 FR
22860). The comment contended that five studies submitted to the Panel
(Refs. 3 through 7) show that tumorigenicity and teratogenicity of
benzethonium chloride are not a problem. The comment mentioned several
other studies that were available to the Panel and supposedly further
substantiate that benzethonium chloride is not a teratogen and does not
impede fertility or adversely affect postnatal survival of pups (Refs.
8 through 12).
The comment pointed out that the Oral Cavity Panel made several
comments in its discussion of benzalkonium chloride (47 FR 22760 at
22858 to 22860) indicating concerns similar to those raised regarding
benzethonium chloride, but the Panel still placed benzalkonium chloride
in Category I for safety. The comment stated that it could not
understand how the Panel could conclude that benzalkonium chloride is
safe while concluding that benzethonium chloride is not safe, when the
supporting data for benzalkonium chloride were not as extensive. Adding
that 88 million units of a mouthrinse containing benzethonium chloride
have been used without any serious toxicity reported, the comment noted
that out of this large population of users, some must have been
pregnant. The comment contended that this use experience further
supports the rat and rabbit fertility and teratogenicity studies. The
comment requested that benzethonium chloride be reclassified in
Category I for safety.
Although acknowledging that quats are, in general, nonirritating
and nontoxic in their effective dosage ranges, the Oral Cavity Panel
was concerned about the effect of long-term, daily use of these
compounds. The Panel stated that adequate data are not available on:
(1) The absorption and attainment of toxic blood levels and the
metabolic fate of the quats and (2) the cumulative effects from
continued use on a day-to-day basis over the span of years or a
lifetime as would be the case when these ingredients are incorporated
in mouthwashes (47 FR 22760 at 22860). The Panel was also concerned
about the absence of data on the mutagenic, tumorigenic, or teratogenic
effects of quats when used on a long-term daily basis in the oral
cavity. The Oral Cavity Panel placed most of the quats it evaluated in
Category III for safety. Nevertheless, in spite of these concerns, the
Panel recommended that benzalkonium chloride and cetalkonium chloride
be considered safe for OTC use in the oral cavity.
Regarding the comment's contention that the Oral Cavity Panel was
inconsistent in its evaluation of benzethonium chloride and
benzalkonium chloride, the agency cannot determine from the Panel's
discussion of the two ingredients (47 FR 22760 at 22858 to 22861) what
caused the Panel to recommend that one ingredient was safe and the
other not safe. However, the Panel made its safety decisions based upon
an assumption that oral antiseptics were used on a long-term daily
basis. As discussed above, the agency is proposing in this tentative
final monograph that data relating to the long-term safety of oral
antiseptics is not relevant to the determination of safety for short-
term use in the oral cavity (see section I.A., comment 2). Therefore,
the agency agrees with the Panel's safety evaluation of benzalkonium
chloride and is proposing that benzalkonium chloride is safe for short-
term use as an oral antiseptic.
The agency has reevaluated the data submitted to the Oral Cavity
Panel as well as new information regarding the safety of benzethonium
chloride and concludes that benzethonium chloride should remain in
Category III. The agency agrees with the Panel that the studies
originally submitted to the Panel (Refs. 1 through 7) do not support
the safety of benzethonium chloride.
Regarding the data on absorption and attainment of adequate blood
levels and the metabolic fate of quats, the data referred to by the
comment (Refs. 1 and 2) do not answer the Panel's concerns. The most
meaningful data presented on absorption were contained in the rat
maternal and fetal absorption study (Ref. 2). Low levels of C14
were detected in maternal blood and urine following oral dosing of
pregnant rats with C14 labeled benzethonium chloride. After 15
days of dosing with 1.125 milligrams/kilogram (mg/kg) per day labeled
benzethonium chloride, 1.5 nanogram/gram of the labeled compound was
detected in maternal blood. The urinary level of labeled benzethonium
chloride found in this group was 28 nanograms per milliliter (mL).
These data suggest poor absorption, but there is no correlation with
toxic blood levels. Furthermore, the metabolic fate of benzethonium is
unknown and is not addressed in any of the studies mentioned by the
comment.
Two studies demonstrate that subcutaneous injection of benzethonium
chloride produces fibrosarcomas at the injection site in rats (Ref. 6),
but not in mice (Ref. 4). Another study demonstrates that this
ingredient is cytotoxic (Ref. 7). These data indicate that benzethonium
chloride is a weak carcinogen according to the classification scheme
proposed by Grasso and Golberg (Ref. 13).
In one study, rats were injected with the maximally tolerated dose
of 3 mg/kg and three lower doses twice weekly for 1 year (Ref. 6). Two
hundred animals were treated; 80 were in the high dose group. The study
also included 120 each in negative and vehicle control groups.
Observation continued for 6 months after termination of treatment.
Cumulative data from all dose groups show a 16-percent incidence of
tumors at the injection site in males and a 10-percent incidence in
females. No injection site tumors were noted in the vehicle control
animals; one injection site tumor was observed in the negative control
group. At other tested sites, tumor incidence numbers of the treated
animals were not different from the control groups. However, there was
a clear dose-related effect at the injection site. As stated above,
these data indicate that benzethonium chloride is a weak carcinogen.
The teratology studies (Refs. 9, 10, and 12) indicate that
benzethonium chloride has very slight teratogenic potential. Effects on
the fetus are largely related to the retardation of growth, which is
also evident in the dams. Maternal effects also influence fetal
viability, especially evident in rabbits (Ref. 12). Increased
ossification variations were significant only in the high dose groups
(i.e., 35.6 mg/kg/day) in rats (Ref. 10). Effects at lower doses that
were apparent in one study (Ref. 9) might be attributed to variability
as evidenced by the difference in the two control groups of one of the
other studies (Ref. 10). The reproductive capacity of rats does not
appear to be affected, although weight gains are affected in both
parents (Ref. 8).
The agency does not believe that sufficient data and information
are available at this time to categorize benzethonium chloride as safe
for use in the oral cavity and invites further comments and data on
this matter. The agency is aware that the NTP has undertaken studies to
characterize and evaluate the toxicological potential, including
carcinogenicity, of benzethonium chloride in laboratory animals. The
results of these studies may aid the agency in its determinations
regarding the safety of benzethonium chloride. At this time,
benzethonium chloride remains in Category III for safety in this
tentative final monograph.
References
(1) Research Report No. 23-19, ``A Study to Determine
Radioactive Residue Levels in Eggs, Tissues, and Excreta from Laying
Hens Which Were Fed C14-Hyamine 1622 Sanitized Water,'' Comment
No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(2) ``Rat Maternal and Fetal Absorption of C14-Benzethonium
Chloride (C1414-BTC),'' Comment No. C00009, Docket No. 81N-
0033, Dockets Management Branch.
(3) Finnegan, J. K. et al., ``Pharmacologic Observations on Two
Quaternary Ammonium Germicides,'' Comment No. C00009, Docket No.
81N-0033, Dockets Management Branch.
(4) Kirschstein, R. L., ``Toxicology and Carcinogenicity of
Preservatives Used in the Preparation of Biological Products,''
Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(5) ``Six Month Toxicity Study with BTC and ZnCl 2 on
Rats,'' Comment No. C00009, Docket No. 81N-0033, Dockets Management
Branch.
(6) ``Toxicology and Carcinogenesis of Various Chemicals Used in
the Preparation of Vaccines,'' Comment No. C00009, Docket No. 81N-
0033, Dockets Management Branch.
(7) ``Final Report, Contract PH-43-67-677, Project C-173,''
Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(8) ``Project 75-1343, Segment I Rat Fertility Study,'' Comment
No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(9) ``Project 75-1344, Segment II Rat Teratology Study,''
Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(10) ``Project 76-1495A, Segment II Rat Teratology Study,''
Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(11) ``Project 75-1345, Segment III Rat Peri and Post Natal
Study,'' Comment No. C00009, Docket No. 81N-0033, Dockets Management
Branch.
(12) ``Project 75-1346, Segment II Rabbit Teratology Study,''
Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.
(13) Grasso, P., and L. Golberg, ``Subcutaneous Sarcoma as an
Index of Carcinogenic Potency,'' Food and Cosmetic Toxicology,
4:297-320, 1966.
D. Comments on Boric Acid
6. One comment stated that the Oral Cavity Panel's discussion on
the safety and effectiveness of boric acid as an antimicrobial
ingredient (47 FR 22760 at 22850) should be considered arbitrary
because it is based on a limited search of the literature and a minimum
effort to evaluate this literature. The comment contended that the
Panel's statements that ``absorption of boric acid occurs readily from
the mucous membranes of the mouth, throat * * * '' and that ``it is
also absorbed from the surface of the vagina, the lining of the
conjunctival sac * * *'' (47 FR 22850) are not mentioned in the
discussion of this ingredient in the paper by George (Ref. 1) which the
Panel cited as the source of this information. The comment added that
the only statement this author makes regarding mucous membrane
absorption of boric acid is an inference taken from another reference
(Ref. 2), which in turn provided no chemical or laboratory evidence to
support the previous statements.
The comment also objected to the Oral Cavity Panel's statement
``Death has occurred from ingestion of less than 5 grams (g) [of boric
acid] in infants and from 5 to 20 g in adults,'' (47 FR 22760 at
22850), stating that these reported lethal doses are found in review
articles and appear repeatedly as a result of frequent cross-
referencing from publications used in the medical field. The comment
contended that the only absolute statement on a toxic dose of boric
acid appeared in a 1906 New York Medical Bulletin which discussed an
autopsy report on a 62-year-old man who had ingested 15 g of boric acid
on prescription for a bladder infection; however, no conclusion was
made that boric acid was the cause of death. The comment added that the
published reports on poisonings by boric acid resulted from special
circumstances, i.e., in the course of therapeutic treatments, erroneous
use of boric acid in place of other substances in hospitals, or similar
misuse, and usually only estimated dosages were reported. Although the
comment stated that boric acid should not be used indiscriminately, it
contended that the Panel made an inadequate study of the literature
concerning the safety of boric acid. The comment added that the only
carefully controlled clinical study on the ingestion of borax and boric
acid by humans was a study by Wiley, published in 1904 (Ref. 3). The
comment expressed surprise that this reference was not cited by the
Panel and has not been cited by other authors who have conducted a
literature review on boric acid. The comment reported that this study,
conducted by the ``poison squad'' who eventually made up the staff of
FDA, involved ingestion of borax or boric acid at varying dosages up to
5 g per day (as a single dose) for periods up to 50 days. The comment
claimed that no fatalities or chronic irreversible pathological
conditions were observed in any of the participants.
The comment also expressed concern about the Oral Cavity Panel's
classification of boric acid in Category II for effectiveness (47 FR
22760 at 22850) on what it considered a minimum effort to investigate
and evaluate the literature. For example, the comment mentioned that
the Panel cited a paper by Novak and Taylor (Ref. 4). In this study,
the investigators found that concentrations higher than 2 percent boric
acid may inhibit phagocytosis. The comment contended that although the
Panel acknowledged this finding, it ignored the absence of this action
at lower concentrations. The comment also referred to another paper by
these same authors (Ref. 5), which discusses the antibacterial action
of boric acid. The comment stated that this article appeared in the
same journal immediately following the article by Novak and Taylor but
was not cited by the Panel in its list of references on boric acid. The
comment concluded that the references cited as evidence to support the
Panel's conclusions on effectiveness are limited to one reference,
which is general in nature with no primary references or data
presented.
The agency has reviewed the article by George (Ref. 1) cited in the
Oral Cavity Panel's report and the reference cited therein (Ref. 2) and
agrees with the comment that these references do not present adequate
evidence to support the Panel's conclusion that boric acid is absorbed
from mucous membranes. Although the literature contains many incidences
of boric acid toxicity resulting from the absorption of the drug after
application to abraded skin or from ingestion, there is a lack of data
and information on the degree of absorption of boric acid from mucous
membranes (Refs. 6 through 9).
The agency agrees with the comment that the human lethal doses used
in the Oral Cavity Panel's report appear in review articles and other
biomedical publications as a result of cross-referencing from older
literature. However, because most reports of poisoning with boric acid
are due to accidental ingestion of the drug, exact doses cannot be
determined; thus, varying human lethal doses, such as 15 to 30 g in
adults and 3 to 6 g in children, are reported in the literature (Refs.
8, 9, and 10).
The agency notes that the study by Wiley (Ref. 3) was conducted to
determine the effects of borax and boric acid upon digestion and
overall human health. At the end of this study, Wiley reported that the
continuous administration of borax and boric acid created disturbances
of appetite, digestion, and health.
As more reports of the toxic effects of boric acid appeared and
more effective antiseptics were developed, the Vaginal Panel noted that
this ingredient fell into disfavor except for a few minor uses (48 FR
46694 at 46712). This may have been due in part to the findings of
Novak and Taylor (Ref. 4) who suggested that normal phagocytosis is
inhibited by boric acid in concentrations greater than 2 percent, thus
counteracting the drug's antibacterial action.
The agency reviewed the second study by Novak and Taylor (Ref. 5)
and notes that this in vitro study was designed to determine the
bacteriostatic action of boric acid, in the presence of tears, against
three species of bacteria commonly found in minor eye infections. The
authors reported that boric acid in concentrations from 0.5 to 2
percent was bacteriostatic against the three species of bacteria
tested. However, the agency does not consider this in vitro study to be
a valid substitute for a well-controlled clinical study in the intended
target population. The agency believes that the Panel did not include
this study in the list of references cited for boric acid because it
did not consider the study relevant to the efficacy of this ingredient
in OTC oral health care drug products. The agency concludes that this
study does not support the effectiveness of boric acid for antiseptic
use in OTC oral health care drug products.
The agency points out that the Oral Cavity Panel's discussion
concerning the safety and effectiveness of boric acid was not intended
to include all available information on the subject, but was intended
to be representative of the available data. The Panel members selected
the studies to be cited according to their best scientific judgment at
that time. In addition, because the comment did not submit new data or
information that offer evidence contrary to the Panel's conclusion and
other information that exists in the literature (as discussed above),
the agency is proposing in this tentative final monograph that boric
acid remain in Category II (not safe and not effective) as an
antiseptic agent in OTC oral health care drug products.
References
(1) George, A. J., ``Toxicity of Boric Acid through Skin and
Mucous Membranes,'' Food and Cosmetic Toxicology, 3:99-101, 1965.
(2) Gleason, M. N. et al., ``Borate Section III, Therapeutics
Index'' in ``Clinical Toxicology of Commercial Products: Acute
Poisoning (Home & Farm),'' The Williams and Wilkins Co., Baltimore,
p. 122, 1957.
(3) Wiley, H. W., ``1. Boric Acid and Borax,'' in ``Influence of
Food Preservatives and Artificial Colors on Digestion and Health,''
U. S. Department of Agriculture, Bureau of Chemistry-Bulletin No.
84, pp. 254-255, 1904.
(4) Novak, M., and W. I. Taylor, ``Phagocyticidal and
Antibacterial Action of Boric Acid,'' Journal of the American
Pharmaceutical Association (Scientific Edition), 40:428-430, 1951.
(5) Novak, M., and W. I. Taylor, ``Antibacterial Action of Boric
Acid in Lacrima (Tears),'' Journal of the American Pharmaceutical
Association (Scientific Edition), 40:430-432, 1951.
(6) Pfeiffer, C. C. et al., ``Boric Acid Ointment: A Study of
Possible Intoxication in the Treatment of Burns,'' Journal of the
American Medical Association, 128:266-274, 1945.
(7) Goldbloom, R. B., and A. Goldbloom, ``Boric Acid Poisoning--
Report of Four Cases and a Review of 109 Cases from the World
Literature,'' The Journal of Pediatrics, 43:631-643, 1953.
(8) Kingma, H., ``The Pharmacology and Toxicology of Boron
Compounds,'' Canadian Medical Association Journal, 78:620-622, 1958.
(9) McNally, W. D., and C. A. Rust, ``The Distribution of Boric
Acid in Human Organs in Six Deaths Due to Boric Acid Poisoning,''
Journal of the American Medical Association, 90:382-383, 1928.
(10) Valdes-Dapena, M. A., and J. B. Arey, ``Boric Acid
Poisoning: Three Fatal Cases with Pancreatic Inclusions and a Review
of the Literature,'' Journal of Pediatrics, 61:531-546, 1962.
7. Referring to the Oral Cavity Panel's statement that ``Boric acid
is used as a pharmaceutical necessity for buffering as well as for an
active ingredient (Ref. 1)'' (47 FR 22760 at 22850), one comment stated
that the cited reference discusses only the use of boric acid as a
pharmaceutical necessity, but not as a buffer or as an active
ingredient. The comment contended that the Panel's statement as written
gives the connotation that the buffering action of boric acid and its
use as an active ingredient are both cited in the reference. The
comment recommended that the statement be amended to read ``Boric acid
is used as a pharmaceutical necessity (Ref. 1) for buffering * * *.''
The comment is correct in stating that the cited pages of the
National Formulary (Ref. 1) discuss the use of boric acid as a
pharmaceutical necessity, but the cited pages do not discuss its use as
a buffer or as an active ingredient. The agency notes, however, that
boric acid is discussed as a buffering agent on pages 935 to 936 of the
same reference (Ref. 2), and that these pages should have been included
as part of the citation. The agency also agrees with the comment that
the National Formulary does not discuss the use of boric acid as an
active ingredient.
References
(1) ``National Formulary,'' 14th ed., American Pharmaceutical
Association, Washington, pp. 776-777, 1975.
(2) ``National Formulary,'' 14th ed., American Pharmaceutical
Association, Washington, pp. 935-936, 1975.
E. Comments on Cetylpyridinium Chloride
8. Two comments contended that cetylpyridinium chloride at
concentrations of up to 0.1 percent is safe for use as an OTC
antiseptic agent and should be placed in Category I. The first comment
described the results of various safety testing (e.g., acute toxicity,
oral mucosal and eye irritation, subchronic, and teratology studies) on
cetylpyridinium chloride alone and on cetylpyridinium chloride in
combination with domiphen bromide. The comment also submitted a safety
report (Ref. 1) prepared from data available through August, 1982. The
comment stated that, in all these studies, there have been no
remarkable pathologic findings and thus 0.045 percent cetylpyridinium
chloride is safe for OTC oral use as a single ingredient and in
combination with 0.005 percent domiphen bromide.
The other comment stated that cetylpyridinium chloride is the
active ingredient in a commercially available mouthwash that has been
used by millions of consumers for over 40 years and that the product
continues to be the subject of an approved application based on the
established safety of the product. The comment summarized the safety
data that had been submitted to the Oral Cavity Panel, including long-
term usage studies involving acute and subacute toxicity exposure to
cetylpyridinium chloride and related compounds in humans and animals
(Ref. 2). The comment contended that these studies failed to reveal
evidence of any teratogenic effects and added that in studies involving
life time exposure of mice and rats to benzalkonium chloride, a
representative quat, no evidence of carcinogenic or mutagenic potential
was found. The comment concluded that these experimental data, in
conjunction with the extremely low order of toxicity seen in the more
than four decades of human use, reinforce and justify the National
Cancer Institute's (NCI) apparent lack of concern regarding the
carcinogenicity and mutagenicity of cetylpyridinium chloride and other
quats.
The comment added that the safety of cetylpyridinium chloride is
further substantiated by the infrequent number of adverse drug
experience reports, particularly when considered in relation to the
extensive usage of products containing this ingredient. For example,
marketing studies in 1979 indicated that one mouthwash product was used
by approximately 13 million consumers and that 500,000 people had used
the product more or less continuously for a 10-year period. The comment
stated that, in the 20-year period between 1963 and 1982, there were
only 110 drug experience reports, an average of 5.5 reports per year.
The comment contended that these reports show that cetylpyridinium
chloride is safe because it has not been associated with any
deleterious effects of a significant nature when routinely used as an
oral hygiene product. The comment also submitted the results of several
clinical evaluations of irritation and/or allergic reactions of mucous
membrane and skin surface exposure to cetylpyridinium chloride-
containing solutions (Ref. 3). The comment concluded that the drug
experience reports and clinical evaluations support a Category I
classification of cetylpyridinium chloride for safety.
As part of FDA's Drug Efficacy Study Implementation (DESI) program,
mouthwash products containing povidone-iodine, cetylpyridinium
chloride, and other ingredients were reviewed by the National Academy
of Sciences-National Research Council, Drug Efficacy Study Group (NAS-
NRC/DESG) and found ineffective for claims relating to antimicrobial,
antiseptic, germicidal, and analgesic uses (35 FR 12423). In a
subsequent notice published in the Federal Register of December 2, 1971
(36 FR 23000), the agency stated that because of the implementation of
the OTC drug review, mouthwash and gargle products reviewed under the
DESI program would now be under the purview of the OTC drug review;
thus, final agency action on these products would be deferred pending
evaluation of the data and information concerning such products under
the OTC drug review.
The agency believes that many of the oral antiseptic ingredients
reviewed by the Oral Cavity Panel, including cetylpyridinium chloride,
were placed in Category III for safety because they were used
commercially in mouthwashes that were recommended for long-term use on
a daily basis. The agency believes that the Panel's concerns regarding
the safety of the long-term OTC use of oral antiseptic ingredients are
not necessarily relevant to the short-term OTC use of these ingredients
(see section I.A., comment 2).
The Oral Cavity Panel discussed the results of several
cetylpyridinium chloride toxicity studies in its report (47 FR 22760 at
22865). According to the Panel, the LD50 of cetylpyridinium
chloride is 250 kg/mg subcutaneously, 6 mg/kg intraperitoneally, 30 mg/
kg intravenously, and 200 mg/kg orally. When 50 mg/kg cetylpyridinium
chloride in water was administered daily for 60 days to rats, no toxic
effects or alterations in the rate of growth were noted. Doses of 5 to
10 mg/kg administered through the esophagus showed no toxic effects
over a 6-day period.
The Panel noted that a 1:3,000 (0.033 percent) solution of
cetylpyridinium chloride is irritating to the mucous membranes of the
conjunctiva, but not to the skin (47 FR 22865). It also stated that a
1:200 (0.5 percent) alcoholic or aqueous solution of cetylpyridinium
chloride does not cause skin irritation. The Panel added that
percutaneous absorption of cetylpyridinium chloride is not believed to
be significant. However, the agency notes that the presence of the
cetyl group on the basic quat molecule increases the lipid solubility
of the molecule and, thus, cetylpyridinium chloride has a potential for
increased absorption and irritation (47 FR 22865).
The agency has reviewed its adverse reaction files covering 1969 to
August 1993 (Ref. 4). During those years, 249 cases of adverse
reactions were associated with the use of products containing
cetylpyridinium chloride. None of the adverse reaction reports could be
attributed solely to cetylpyridinium chloride. Of these cases, 10 had a
serious outcome (e.g., death, coma, or hospitalization). Two reports
involved children under 4 years of age who died after ingesting unknown
amounts of a mouthwash containing cetylpyridinium chloride and 14
percent alcohol. In both cases, alcohol was the most likely cause of
death.
Four adverse reaction reports described coma as an outcome. Two
involved young children (3 and 4 years old) who lapsed into comas after
ingesting unknown amounts of a mouthwash product containing
cetylpyridinium chloride and 14 percent alcohol. As is the case with
the deaths described above, these comas are more likely due to alcohol
ingestion than cetylpyridinium chloride ingestion. One adverse reaction
report in which coma is listed as the outcome involved an individual
who ingested 44 cetylpyridinium chloride-containing lozenges, became
gradually and imperceptively unconscious, and caused a head-on
automobile collision. Another report described a middle-aged male with
a history of alcoholism who was hospitalized in a coma after possibly
ingesting a mouthwash containing cetylpyridinium chloride.
Two anaphylactic-type reactions were reported. One was determined
to be an allergic reaction to bisulfites. The other was not clear-cut
because the subject had experienced several similar anaphylactic-like
attacks, only one of which followed use of a cetylpyridinium chloride-
containing product.
Two cases reported the hospitalization of people who had severe
allergic-type reactions. One report described a 21-year-old female with
swelling in her throat, a sensation of feeling hot and flushed,
followed by dyspnea, dysphagia, angioedema of the face (especially the
eyelids), hands, and feet, and near faintness following the ingestion
of one cetylpyridinium chloride lozenge. Another case report described
a young male (8 years old) with a burning sensation, redness, and
swelling on areas of the skin (chin and neck) where a cetylpyridinium
chloride-containing mouthwash was spilled during gargling.
The most frequently reported less serious events are as follows: 26
cases of stomatitis, 13 reports of pain, 12 reports of taste
perversion, 10 cases of nausea, 9 cases of contact dermatitis, 9 cases
of pharyngitis, 8 cases of malaise, and 7 cases of allergic responses.
Other less frequently reported reactions included rash, tooth caries,
dry mouth, and rhinitis.
The agency believes that the information contained in its adverse
reaction files regarding cetylpyridinium chloride demonstrates that the
ingredient can be safely used in an OTC drug product. None of the
adverse reaction reports could be attributed solely to cetylpyridinium
chloride. All reports involved products containing many ingredients in
addition to cetylpyridinium chloride. In addition, other drugs (e.g.,
alcohol) were implicated in the most serious cases.
The agency believes that the information contained in its adverse
reaction files, 30 years of safe marketing of an OTC mouthwash
containing cetylpyridinium chloride (NDA 14-598), and the safety data
evaluated by the Oral Cavity Panel are sufficient to conclude that
0.025 to 0.1 percent cetylpyridinium chloride is safe as an OTC oral
antiseptic when labeled for short-term use (not to exceed 7 days).
However, the agency is concerned that using cetylpyridinium chloride
where excessive gum irritation or bleeding exists could increase the
absorption and systemic load of the ingredient and possibly lead to
some of the toxicological effects discussed by the Oral Cavity Panel
(e.g., neuromuscular blocking of nicotinic and muscarinic receptors)
(47 FR 22760 at 22865). Therefore, the agency is proposing labeling
that would caution consumers not to use a product containing
cetylpyridinium chloride if excessive gum irritation or bleeding exists
unless directed to do so by a doctor or dentist as follows: ``Do not
use this product if gums are irritated or bleeding unless directed to
do so by a doctor or dentist.'' This labeling will be included in the
final monograph for OTC oral antiseptics if cetylpyridinium chloride
becomes Category I in that rulemaking. The agency requests comment
regarding this proposed labeling.
Data on the combination of cetylpyridinium chloride and domiphen
bromide are discussed in section I.L., comments 30 and 31.
References
(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management
Branch.
(2) OTC Vol. 130167.
(3) Attachment C, Comment No. C00015, Docket No. 81N-0033,
Dockets Management Branch.
(4) Food and Drug Administration, Center for Drug Evaluation and
Research, Adverse Reaction Summary Listing for Cetylpyridinium
Chloride for the years 1969 to August 1993, OTC Vol. 13CTFM, Docket
No. 81N-0033, Dockets Management Branch.
9. Two comments contended that 0.025 to 0.1 percent cetylpyridinium
chloride is an effective antiseptic agent and should be placed in
Category I. One comment stated that complete proof of the ability of
cetylpyridinium chloride to kill bacteria in vitro had been submitted
to the Oral Cavity Panel (Ref. 1) and that this proof had been accepted
at the time by the Panel. The comment also discussed several tests
(Ref. 2) purporting to demonstrate the effectiveness of 0.045 percent
cetylpyridinium chloride in combination with 0.005 percent domiphen
bromide and stated that these tests supported the antiseptic
effectiveness of cetylpyridinium chloride. The other comment discussed
data from seven in vitro studies designed to demonstrate the antiseptic
activity of cetylpyridinium chloride (Ref. 3). The comment stated that
two of these studies fulfilled the in vitro guidelines established by
the Oral Cavity Panel (47 FR 22760 at 22890 to 22893) and that the
other five studies demonstrated complementary activity against other
test organisms (Ref. 3). The comment also summarized a number of in
vivo studies designed to demonstrate the antimicrobial activity of
cetylpyridinium chloride. The comment mentioned that all of these in
vitro and in vivo studies had been submitted to the Oral Cavity Panel.
That Panel discussed in vitro and in vivo testing protocol
guidelines for upgrading oral antiseptic ingredients to Category I (47
FR 22760 at 22890 to 22893). The in vitro studies submitted by the
second comment (Ref. 3) do not fulfill the guidelines recommended by
the Panel. For example, in one study (Ref. 4), the protocol closely
resembled that recommended by the Panel. However, the incubation
conditions used to prepare the test cultures were unlike those
recommended by the Panel, and some culture conditions were not
specified (i.e., whether the cultures were grown aerobically or
anaerobically). The test method used in this study was also different
from the method recommended by the Panel in that culture tubes that
showed no growth after 48 hours incubation were not transferred to 90
mL of sterile inactivating media and further incubated for 1 week. In
another study where the protocol was similar to that recommended by the
Panel (Ref. 5), a product containing cetylpyridinium chloride was used
as the test material, but cetylpyridinium chloride alone was not
tested. Therefore, there is no way of knowing whether or not other
ingredients in the test product affected its antimicrobial activity.
Several other in vitro studies (Refs. 6 through 9) tested the
antiseptic effectiveness of cetylpyridinium chloride and
cetylpyridinium chloride-containing products against organisms other
than those recommended by the Panel. One study (Ref. 10) tested the
effectiveness of several mouthwash formulations against pooled human
saliva. Critical killing times against the organisms in the saliva were
determined, but specific organisms were not identified.
Fifteen of the in vivo studies submitted were based upon plaque
reduction. The Panel had considered using plaque reduction as a
criterion for antiseptic activity in the oral cavity, but discarded it
(47 FR 22760 at 22840). The Panel did not accept plaque reduction as a
criterion for determining the effectiveness of oral antiseptics, and
the agency agrees. A subsequent segment of the rulemaking for OTC oral
health care drug products will cover plaque-related claims and
ingredients used for the reduction of plaque. (See section I.A.,
comment 1 and section I.M., comment 32.)
The agency believes that the other in vivo studies submitted (Ref.
3) are not adequate to demonstrate the effectiveness of cetylpyridinium
chloride in reducing the bacterial population of the oral cavity. These
studies were not designed to demonstrate the antibacterial activity of
the ingredient cetylpyridinium chloride alone. They were designed to
demonstrate the antibacterial activity of products such as commercial
mouthwashes or lozenges containing cetylpyridinium chloride and other
ingredients that could affect the antibacterial activity of the
product. The complete formulations of these products were not
identified, and the antiseptic activity of the ingredient
cetylpyridinium chloride was not compared to the activity of a placebo
containing all of the ingredients in the commercial product except for
the cetylpyridinium chloride. Therefore, any antiseptic activity
demonstrated in those studies cannot be solely attributed to the
presence of cetylpyridinium chloride. In order to demonstrate
antiseptic activity of cetylpyridinium chloride, studies must be
designed with one arm consisting of the ingredient cetylpyridinium
chloride alone to demonstrate that cetylpyridinium chloride decreases
the number of microorganisms in the oral cavity. In addition, the
agency is not aware of any data from clinical studies demonstrating a
therapeutic benefit from the OTC use of cetylpyridinium chloride as an
antiseptic in the oral cavity. Data on the combination of
cetylpyridinium chloride and domiphen bromide are discussed in section
I.L., comments 30 and 31.
The agency concludes that additional data are needed to establish
the effectiveness of cetylpyridinium chloride as an oral antiseptic to
help prevent infection in the oral cavity. The agency believes that the
Panel's proposed in vitro and in vivo testing guidelines and its
discussion of clinical studies represent a good starting point for the
design of studies to upgrade a Category II or Category III oral
antiseptic ingredient to Category I. (See section I.M., comment 33 for
a further discussion of testing guidelines.) However, the agency notes
that specific testing guidelines for upgrading ingredients to monograph
status are not included in the tentative final monograph. (See part II.
paragraph A.2.--Testing of Category II and Category III conditions.)
All such testing should be designed using the most current technology
available. The agency will meet with industry representatives or other
interested parties at their request to discuss testing protocols. Any
party interested in conducting studies should request a meeting at its
earliest convenience.
References
(1) OTC Vols. 130007 through 130011, 130089, 130090, and 130167
through 130171.
(2) Comment No. C00013, Docket No. 81N-0033, Dockets Management
Branch.
(3) Comment No. C00015, Docket No. 81N-0033, Dockets Management
Branch.
(4) Project Report No. M-75-03, OTC Vol. 130167.
(5) Project Report No. M-77-03, OTC Vol. 130167.
(6) Project Report No. M-76-05, OTC Vol. 130167.
(7) Myers, G. E., J. K. Logan, and V. J. Mitchell,
``Microbiological Problems in Oral Hygiene,'' OTC Vol. 130167.
(8) ``An In-Vitro Evaluation of Cepacol,'' OTC Vol. 130167.
(9) Hicks, G. F., L. L. Nisonger, and I. Ruchman, ``Germicidal
Effects of Various Combinations of Cetyl Pyridinium Chloride Against
Antibiotic-Resistant Staphylococci,'' OTC Vol. 130167.
(10) ``Comparison of the Antibacterial Activity of Colgate
100, Listerine, Lavoris,
Micrin, and Cepacol,'' OTC Vol. 130167.
F. Comments on Chlorophyllin Copper Complex
10. One comment complained that the Oral Cavity Panel's discussion
of chlorophyllin under the heading ``Antimicrobial Agents'' (47 FR
22760 at 22866 to 22867) contains inaccurate and misleading statements
about other properties of the ingredient. The comment specifically
objected to the statement that chlorophyllin ``has fallen into disuse
over recent years since it has not been demonstrated that it is an
effective deodorant'' and added that support for this statement was one
unidentified reference to a study in which ingested chlorophyll
decreased halitosis in dogs but had no effect on the odor in the dogs'
coats (hair).
The comment maintained that 15 laboratory and human clinical
studies demonstrating the deodorancy effectiveness of chlorophyll were
submitted to the Panel (Ref. 1). Emphasizing that chlorophyllin has not
fallen into disuse as a deodorant, the comment asserted that
chlorophyllin is widely used in hospitals and nursing homes as a
deodorant for ostomy patients and incontinent patients. The comment
cited an article by Young and Beregi (Ref. 2) to support the wide use
of chlorophyllin as an aid in controlling odors of incontinent
patients. The comment suggested that ``a less frequent but pertinent''
indication for chlorophyllin is to reduce odor from cancer of the oral
cavity.
The agency notes that chlorophyllin copper complex is the name
adopted for chlorophyllin by the United States Adopted Names Council
(Ref. 3). Therefore, chlorophyllin copper complex is the name used for
this ingredient in this tentative final monograph.
The agency agrees with the comment that chlorophyllin copper
complex is appropriate for use in hospitals and nursing homes as an
internal deodorant for ostomy patients and incontinent patients. In the
final monograph for OTC deodorant drug products for internal use
published in the Federal Register of May 11, 1990 (55 FR 19862), the
agency concluded that chlorophyllin copper complex (100 to 200 mg
daily) is generally recognized as safe and effective for OTC (internal)
use in controlling ostomy odors and in controlling the odors of fecal
and urinary incontinence. The agency considers the local deodorancy
effect of chlorophyllin copper complex when used topically in the oral
cavity to be a cosmetic rather than a drug effect and, as such, would
not be subject to the rulemaking for OTC oral health care drug
products. (For a discussion of the cosmetic uses of OTC oral health
care drug products, see section I.A., comment 3.) However, if a product
containing this ingredient makes a claim that the product ``reduces
odor from cancer of the oral cavity,'' this claim would need to be
supported by data from appropriate studies in patients with cancer of
the oral cavity.
References
(1) OTC Vol. 130015.
(2) Young, R. W., and J. S. Beregi, Jr., ``Use of Chlorophyllin
in the Care of Geriatric Patients,'' Journal of the American
Geriatrics Society, 28:46, 1980.
(3) ``USAN and the USP Dictionary of Drug Names,'' United States
Pharmacopeial Convention, Inc., Rockville, MD, p. 136, 1993.
11. Noting that the Oral Cavity Panel had classified chlorophyllin
solely as an ``antimicrobial agent,'' one comment stated that its
antibacterial properties are less significant than its healing effects.
The comment asserted that the data submitted to the Panel emphasized
that chlorophyllin is primarily a healing agent that acts to relieve
discomfort due to minor irritations, inflammation, and other lesions by
encouraging tissue repair and reducing inflammation. The comment
contended that there should be a classification for ingredients, such
as chlorophyllin, that encourage repair of minor irritations or
inflammation. Acknowledging that there might be some problems with
using the term ``healing agents'' for OTC drug products, the comment
suggested using the term ``tissue-repair agents'' for products
containing this ingredient. The comment referred to the statement in
the Panel's report that no data were submitted or are available from
controlled studies to substantiate a wound healing claim (47 FR 22760
at 22867) and argued that its own submission to the Panel contained
many controlled studies on the wound healing effects of chlorophyllin.
The agency has reviewed the submissions on chlorophyllin copper
complex made to the Oral Cavity Panel (Refs. 1 and 2) as well as
submissions made to the Advisory Review Panel on OTC Dentifrice and
Dental Care Drug Products (Dental Panel) (Refs. 3 and 4). Although no
antiseptic claims appear in the labeling of chlorophyllin copper
complex-containing products submitted to these panels, the submissions
contain data purporting to show the bacteriostatic effectiveness of
water-soluble chlorophyllins as well as data to support the wound
healing claims (Refs. 1 and 3). The Oral Cavity Panel evaluated the
data submitted in support of the antiseptic effectiveness of
chlorophyllin copper complex, and the Dental Panel evaluated the data
submitted to support the wound healing claims.
The Oral Cavity Panel concluded that chlorophyllin copper complex
is safe, but that there are insufficient data available to permit final
classification of its effectiveness as an OTC antiseptic active
ingredient for topical use on the mucous membranes of the mouth and
throat (47 FR 22760 at 22866). Because no additional data were
submitted to the agency in support of the antiseptic effectiveness of
chlorophyllin copper complex, the agency concludes that the Panel's
Category III classification is appropriate. Therefore, in this
tentative final monograph, the agency is proposing a Category III
classification for chlorophyllin copper complex as an OTC oral health
care antiseptic ingredient.
In its report on OTC oral mucosal injury drug products published in
the Federal Register of November 2, 1979 (44 FR 63270), the Dental
Panel concluded that water-soluble chlorophyllins are safe, but that
there were insufficient effectiveness data available to permit final
classification of water-soluble chlorophyllins as oral wound healing
agents (44 FR 63270 at 63286). Therefore, the Dental Panel classified
water-soluble chlorophyllins in Category III. In response to the
publication of the Panel's report, the agency received no comments
regarding chlorophyllin copper complex as an OTC oral wound healing
agent. Therefore, in the tentative final monograph for OTC oral mucosal
injury drug products published in the Federal Register of July 26, 1983
(48 FR 33984), the agency accepted the Panel's evaluation and proposed
a Category III classification for chlorophyllin copper complex as an
oral wound healing agent. Again, the agency received no comments
regarding chlorophyllin copper complex in response to the publication
of the tentative final monograph for OTC oral mucosal injury drug
products. Accordingly, in the final rule for OTC oral wound healing
agents published in the Federal Register of July 18, 1986 (51 FR
26112), the agency concluded that there was insufficient evidence to
support the effectiveness of chlorophyllin copper complex as an oral
wound healing agent. Therefore, chlorophyllin copper complex is
considered a nonmonograph oral wound healing ingredient.
References
(1) OTC Vol. 130015.
(2) OTC Vol. 130088.
(3) OTC Vol. 080043.
(4) OTC Vol. 080168.
G. Comments on Domiphen Bromide
12. One comment requested that the agency approve domiphen bromide
at concentrations of up to 0.1 percent for safety. The comment
described the results of various safety testing (e.g., acute toxicity,
oral mucosal and eye irritation, subchronic, and teratology studies) on
domiphen bromide alone and on domiphen bromide in combination with
cetylpyridinium chloride. The comment also included a safety report
(Ref. 1) prepared from data available through August 1982. The comment
stated that, in all these studies, there have been no remarkable
pathologic findings and thus up to 0.1 percent domiphen bromide is safe
for OTC oral use as a single ingredient.
As stated in section I.A., comment 2, the agency believes that many
of the oral antiseptic ingredients reviewed by the Oral Cavity Panel,
including domiphen bromide, were placed in Category III for safety
because they were used commercially in mouthwashes that were
recommended for long-term use on a daily basis. The agency believes
that the Panel's concerns regarding the safety of the long-term OTC use
of oral antiseptic ingredients are not necessarily relevant to the
short-term OTC use of these ingredients.
The agency has reevaluated the data submitted to the Oral Cavity
Panel regarding the safety of domiphen bromide in light of labeling
that would limit use of oral antiseptic drug products to 7 days or
less. The Panel noted in its discussion of domiphen bromide (47 FR
22760 at 22868 to 22869) that ``the concentrations of domiphen bromide
used in commercial lozenges and mouthwashes appear to be nontoxic.'' It
cited several studies in which no toxicity could be demonstrated.
According to the Panel, the intravenous LD50 was determined to be
18 mg/kg for rats, 31 mg/kg for mice, and 11 to 12 mg/kg for rabbits.
An oral LD50 (species unspecified) could not be determined because
marked diarrhea resulted, but it was suspected to be above 800 mg/kg/
day. The intraperitoneal LD50 was 40 to 45 mg/kg for rats and 10
to 20 mg/kg for guinea pigs. One study (Ref. 2) discussed in the
Panel's report concluded that clinical use of a mouthwash containing
0.01 percent domiphen bromide two to six times daily for up to 52 weeks
resulted in no apparent toxicity.
The Panel noted that only six adverse reactions were reported
between 1958 and 1970 for a lozenge product containing domiphen bromide
(47 FR 22869). These included one complaint of lack of effectiveness,
two cases of burns on the tongue, one case of soreness of the mouth,
one case of fungal growth after use of the product, and one case of
chalk-like taste. The agency has reviewed its adverse reaction files
covering 1969 to May 1993. During those years, no adverse event reports
associated with domiphen bromide were received.
The agency tentatively concludes that the safety data evaluated by
the Oral Cavity Panel, 30 years of safe marketing of an OTC mouthwash
product containing domiphen bromide (NDA 14-598), and the lack of
adverse event reports in its files are sufficient to conclude that up
to 0.1 percent domiphen bromide is safe as an OTC oral antiseptic when
labeled for short-term use (not to exceed 7 days). However, when this
ingredient is used in conjunction with cetylpyridinium chloride as an
oral antiseptic (see section I.E., comment 8), the agency is concerned
that using domiphen bromide where excessive gum irritation or bleeding
exists could increase the absorption and systemic load of the
ingredient and possibly lead to some of the toxicological effects
discussed by the Oral Cavity Panel (e.g., convulsions, central nervous
system depression followed by death due to the curare-like action of
quats) (47 FR 22760 at 22869). Therefore, the agency is proposing
labeling that would caution consumers not to use a product containing
domiphen bromide if excessive gum irritation or bleeding exists unless
directed to do so by a doctor or dentist as follows: ``Do not use this
product if gums are irritated or bleeding unless directed to do so by a
doctor or dentist.'' This labeling will be included in the final
monograph for OTC oral antiseptics if domiphen bromide becomes Category
I in that rulemaking. The agency requests comment regarding this
proposed labeling.
Data on the combination of cetylpyridinium chloride and domiphen
bromide are discussed in section I.L., comments 30 and 31.
References
(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management
Branch.
(2) Kutscher, A. H., and J. Budowsky, ``Observations on the
Clinical Use of Bradosol,'' Oral Surgery, Oral Medicine, and Oral
Pathology, 7:873-875, 1954.
13. One comment requested that the agency approve 0.05 percent
domiphen bromide for effectiveness. The comment stated that
effectiveness was proven in tests against three organisms, and that the
results of these tests were included in the comment (Ref. 1) and had
been reported to the Oral Cavity Panel (Ref. 2). The comment added that
the protocol for these studies was reviewed and approved by the Panel.
The comment mentioned that, in several votes taken over a period of
more than 3 years, the Panel placed domiphen bromide in Category I. The
comment added that, at its next-to-last meeting, the Panel rescinded
its action and placed domiphen bromide, along with all other antiseptic
ingredients, in Category III for effectiveness. The comment argued that
the Panel's decision was ill-advised and urged the agency to give
monograph status to domiphen bromide.
The agency believes that there are not enough data to conclude that
domiphen bromide is an effective oral antiseptic. The effectiveness
studies (Refs. 1 and 2) were conducted according to the July 12, 1977,
version of tentative guidelines developed and submitted to the Panel by
the NDMA (formerly known as The Proprietary Association) (Ref. 3).
Those guidelines were under consideration by the Oral Cavity Panel, but
were subsequently revised as described in the Panel's 1982 report (47
FR 22760 at 22890 to 22893). A notable revision made by the Panel was
to increase the inoculum of test culture; the 1977 NDMA guidelines
provided for a 1 mL aliquot of a 1 to 4 dilution of inoculum added to
10 mL of the mouthwash product or active ingredient, while the Panel's
final guidelines specified 1 mL of undiluted culture in 9 mL of product
or active ingredient. The Panel also proposed additional in vitro
testing that included a determination of the minimum inhibitory
concentration (MIC) of the antiseptic agent, and testing of freshly
obtained clinical isolates from mouth and throat infections to provide
updated, relevant data on the susceptibility of these isolates to the
antiseptic agent (47 FR 22760 at 22890 to 22891). Since publication of
the Panel's report, no such data for domiphen bromide have been
provided to the agency. In addition, the agency is not aware of any
data from clinical studies demonstrating a therapeutic benefit from the
OTC use of domiphen bromide in the oral cavity. The agency concludes
that additional data are necessary to establish the effectiveness of
domiphen bromide as an oral antiseptic to help prevent infection in the
oral cavity.
The agency believes that the Panel's 1982 proposed testing
guidelines and its discussion of clinical studies represent a good
starting point for the design of studies to upgrade a Category II or
Category III oral antiseptic ingredient to Category I. (See section
I.M., comment 33 for a further discussion of testing guidelines.) Since
testing requirements are subject to change over time because of
technological advancements, the agency notes that specific testing
guidelines for upgrading ingredients to monograph status are not
included in the tentative final monograph. (See part II. paragraph
A.2.--Testing of Category II and Category III conditions.) All such
testing should be designed using the most current technology available.
The agency will meet with industry representatives or other interested
parties at their request to discuss testing protocols. Any party
interested in conducting studies should request a meeting at its
earliest convenience.
References
(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management
Branch.
(2) OTC Vol. 130134.
(3) OTC Vol. 130131.
H. Comment on Phenol
14. One comment requested that the agency classify 1.4 to 1.5
percent phenol in Category I as an antiseptic mouthwash. The comment
stated that until its next-to-last meeting, the Oral Cavity Panel
believed that the antiseptic capability of a mouthwash could be
demonstrated through the use of in vitro and in vivo studies, but that
the Panel arbitrarily decided to reverse its long-standing position
without additional evidence. The comment further stated it had
presented documentation to the Panel prior to its reversal that phenol
met the requirements of both the in vitro and in vivo protocols. The
comment resubmitted the same studies it had submitted to the Panel and
requested that the agency accept these data (Ref. 1).
The agency has evaluated the studies submitted to the Panel and
concludes that they are not adequate to establish the effectiveness of
phenol as an OTC oral antiseptic. The comment's data include one in
vitro study and two in vivo efficacy studies. No data from clinical
studies were submitted to the agency to demonstrate a therapeutic
benefit from the OTC use of phenol in the oral cavity.
The in vitro study was conducted according to the July 12, 1977,
NDMA tentative guidelines that had been submitted to the Panel (Ref.
2). Those guidelines were under consideration by the Oral Cavity Panel
at the time the comment's studies were conducted, but were subsequently
revised as described in the Panel's report (47 FR 22760 at 22890). A
notable revision made by the Panel was to increase the inoculum of test
culture; the 1977 NDMA guidelines provided for a 1 mL aliquot of a 1 to
4 dilution of inoculum added to 10 mL of the product or active
ingredient, while the Panel's final guidelines specified 1 mL of
undiluted culture in 9 mL of product or active ingredient. The Panel
also proposed additional in vitro testing that included a determination
of the MIC of the antiseptic agent, and testing of freshly obtained
clinical isolates from mouth and throat infections to provide updated,
relevant data on the susceptibility of these isolates to the antiseptic
agent (47 FR 22760 at 22890 to 22891). No such data were provided for
phenol following the Panel's final recommendations.
The two in vivo studies were also designed following tentative
guidelines (Ref. 3) under consideration by the Panel. According to
those guidelines, an oral antiseptic ingredient that reduced the
accumulation of dental plaque was considered to reduce microorganisms,
and thus was deemed an oral antiseptic. The Panel had originally
considered this in vivo method, based on plaque reduction on the teeth
and periodontal tissues, as a criterion for antiseptic activity in the
oral cavity, but subsequently discarded it, stating that the method was
inexact and had no rational basis because dental plaque is not a
disease per se (47 FR 22760 at 22840). There was considerable
discussion of this issue by the Panel, and in making its final
determination, the Panel relied upon the opinions of consultants and
statisticians who are experts in the field, as well as on the expertise
of the Panel members (47 FR 22840 to 22842). In its final report, the
Panel did not accept plaque reduction as a criterion for determining
effectiveness of antiseptic agents, and the agency agrees. A subsequent
segment of the rulemaking for OTC oral health care drug products will
cover plaque-related claims and ingredients. (See section I.M., comment
32.)
The agency disagrees with the comment that the Oral Cavity Panel
arbitrarily reversed its position regarding in vitro and in vivo
studies. Rather, after careful deliberations, the Panel modified its
tentative in vitro guidelines, and replaced its tentative in vivo
guidelines with others it believed were more appropriate. The agency
believes that the Panel's proposed testing guidelines and its
discussion of clinical studies represent a good starting point for the
design of studies to upgrade a Category II or Category III oral
antiseptic ingredient to Category I. (See section I.M., comment 33 for
a further discussion of testing guidelines.) However, the agency notes
that specific testing guidelines for upgrading ingredients to monograph
status are not included in the tentative final monograph. (See part II.
paragraph A.2.--Testing of Category II and Category III conditions.)
All such testing should be designed using the most current technology
available. The agency will meet with industry representatives or other
interested parties at their request to discuss testing protocols. Any
party interested in conducting studies should request a meeting at its
earliest convenience.
References
(1) Comment No. C00014 and OTC Vol. 130131, Docket No. 81N-0033,
Dockets Management Branch.
(2) Letter from J. D. Cope, NDMA (formerly The Proprietary
Association), dated July 15, 1977, OTC Vol. 130PA3.
(3) Letter from J. D. Cope, NDMA (formerly The Proprietary
Association), dated February 23, 1977, OTC Vol. 130110-B.
I. Comments on Povidone-Iodine
15. Three comments objected to the Oral Cavity Panel's conclusion
that there are insufficient data available to permit classification of
povidone-iodine as safe for OTC topical antimicrobial use on the mucous
membranes of the mouth and throat. One comment (Ref. 1) stated that
most of the safety concerns raised by the Oral Cavity Panel had been
fully addressed by data submitted earlier to several other OTC drug
rulemakings: (1) Topical antimicrobial drug products, (2) contraceptive
and other vaginal drug products, (3) topical acne drug products, and
(4) antifungal drug products. The comment contended that had the data
and testimony to these other panels been considered by the Oral Cavity
Panel, many safety concerns would have been resolved and duplicative
efforts precluded. Another comment maintained that the Panel's
conclusion that there are insufficient data available to permit
classification of povidone-iodine as safe for antiseptic use on the
mucous membranes of the mouth and throat is in error. A third comment
mentioned that a commercially available mouthwash containing povidone-
iodine has been marketed under an approved new drug application (NDA)
(NDA 10-290) for a quarter century without reports of any significant
adverse effects related to this product.
One comment contended that clinical and experimental studies have
shown that povidone-iodine can reduce infection in wounds or surgical
procedures without impairing wound healing or causing adverse
reactions. The comment submitted several studies to support its
statement (Refs. 2 through 9). Another comment also submitted data to
establish that povidone-iodine preparations do not inhibit normal wound
healing (Refs. 10, 11, and 12). The comment stated that the concern as
to whether povidone-iodine accelerates or delays wound healing was
addressed in detail in the Antimicrobial II Panel's report on the
antifungal use of povidone-iodine, published in the Federal Register of
March 23, 1982 (47 FR 12480 at 12545).
One comment submitted three studies (Refs. 13, 14, and 15), one of
which (Ref. 13) was also submitted by another comment, designed to
demonstrate that no carcinogenic or mutagenic effects are associated
with the use of povidone-iodine. Another comment submitted data
regarding the capability of povidone-iodine to alter DNA in living
cells. These data were also presented to the Vaginal Panel in 1978
(Refs. 15 and 16). A third comment maintained that all data relevant to
the mutagenic potential of povidone-iodine had been considered by the
Vaginal Panel, which concluded that povidone-iodine is not
carcinogenic, teratogenic, or mutagenic. The comment submitted a review
of the available data (Ref. 17).
One comment discussed the Oral Cavity Panel's statement that
``chronic, indiscriminate use of PVP-I [povidone-iodine] has been
associated with iodism, an increase in protein-bound iodine, and
altered thyroid function,'' (47 FR 22760 at 22883). The comment agreed
that indiscriminate use of any substance may cause harm and stated that
one of the functions of proper OTC drug labeling is to instruct the
consumer with appropriate directions so that indiscriminate use of
pharmaceutical products can be avoided. The comment submitted FDA
approved labeling (from NDA 10-290) (Ref. 18) for a commercially-
available product and noted that the labeling should eliminate concerns
about chronic, indiscriminate use of the product. The comment added
that application of povidone-iodine to mucosal tissue does not affect
normal thyroid function and stated that data had been submitted to FDA
in support of this contention (Ref. 19).
One comment indicated that the Oral Cavity Panel's basis for the
following statement was misdirected: ``The toxic effects of PVP-I
[povidone-iodine] are due to the release of free iodine and since the
release occurs slowly, its toxicity and irritancy is low,'' (47 FR
22883). The comment agreed with the Panel that the toxicity and
irritancy of povidone-iodine is low; however, the comment maintained
that the low toxicity and irritancy exhibited by povidone-iodine is due
to the kinetics of the available iodine dynamic equilibrium as well as
the physical and chemical properties of the iodine moiety in povidone-
iodine rather than the slow release of free iodine as suggested by the
Panel.
One comment stated that povidone-iodine has been the subject of
extensive scientific study for decades and that the medical literature
contains approximately 4,000 references, including extensive long-term
feeding studies in animals and humans. The comment pointed out the Oral
Cavity Panel reported that povidone-iodine is nontoxic and that the
free iodine released from povidone-iodine has low toxicity and
irritancy (47 FR 22760 at 22883). The comment mentioned that the Panel
also stated that ``Povidone is practically nontoxic,'' ``povidone is
not metabolized,'' and ``the greatest portion [of povidone] is excreted
unchanged by the kidney.'' The comment submitted a toxicology review of
data to show no biologically significant toxicity or other adverse
effects of povidone-iodine following oral administration (Refs. 20
through 23). The comment contended that povidone-iodine is completely
safe for use on either a short- or long-term basis.
One comment stated that the rate of absorption of povidone and
iodine from the povidone-iodine complex through intact skin, vaginal
mucosa, and the peritoneal cavity has been shown to be insignificant or
virtually nonexistent. The comment submitted data to support its
statement (Refs. 20, 24, 25, and 26). Citing ``dental academicians,''
the comment contended that a valid comparison can be made between the
histology and function of the vaginal mucosa and the oral mucosa. One
comment asserted that the safety concerns raised by the Oral Cavity
Panel regarding the use of povidone-iodine in the oral cavity are based
upon uses of povidone-iodine solution that are not relevant to the use
of low concentrations of povidone-iodine in the oral cavity. For
example, the comment noted that the Panel's concern about the behavior
of povidone-iodine after parenteral administration is not pertinent to
the safety of oral health care drug products used topically on the
mouth and throat (47 FR 22760 at 22883 to 22884). Another comment
stated that because the oral mucosa and the peritoneum are very
different histologically and functionally, studies on the peritoneum
cited by the Oral Cavity Panel cannot be applied to the use of
povidone-iodine in the oral cavity.
The agency has considered the data submitted in support of the
safety of povidone-iodine, the Oral Cavity Panel's discussion of the
safety of povidone-iodine (47 FR 22760 at 22883 to 22884), and the
other advisory panels' evaluations of the safety of povidone-iodine.
Based on this information, FDA concludes that povidone-iodine should be
classified in Category I for safety as an OTC antiseptic ingredient for
short-term (i.e., no more than 7 days) topical use on the mucous
membrane of the mouth and throat.
As stated elsewhere in this document (see section I.A., comment 2),
the agency believes that many of the oral antiseptic ingredients
reviewed by the Panel, including povidone-iodine, were placed in
Category III for safety because they were used commercially in
mouthwashes that were recommended for long-term use on a daily basis.
The agency believes that the Oral Cavity Panel's concerns regarding the
safety of the long-term OTC use of oral antiseptic ingredients are not
necessarily relevant to the short-term OTC use of these ingredients. In
its discussion of povidone-iodine (47 FR 22760 at 22884), the Panel
stated that extensive clinical observations indicated that povidone-
iodine is generally nonirritating and nonsensitizing when applied to
skin and mucous membranes. The Panel concluded that although povidone-
iodine may be safe for occasional application to the mucous membranes,
there were insufficient data to establish its safety for long-term
daily use.
The Oral Cavity Panel's concern about povidone-iodine's effect on
wound healing was based upon a statement in the Antimicrobial I Panel
report on antimicrobial drug products published in the Federal Register
of September 13, 1974 (39 FR 33102) that ``conflicting data [had been
presented] concerning the role of PVP-iodine use on the rate of wound
healing.'' Some data presented to the Antimicrobial I Panel suggested
that povidone-iodine had no effect on the rate of wound healing, while
other data suggested a delay in wound healing after povidone-iodine use
in animal model studies (39 FR 33102 at 33131). In its evaluation of
povidone-iodine as a topical antifungal ingredient, the Antimicrobial
II Panel relied on new data as well as the recommendations of the
Antimicrobial I Panel. In its report, the Antimicrobial II Panel
specifically addressed the effects of povidone-iodine on wound healing
(47 FR 12480 at 12545), concluded that povidone-iodine has no adverse
effects on wound healing, and determined that 10 percent povidone-
iodine is safe for OTC use as an antifungal agent. In the tentative
final monograph for OTC first aid antiseptic drug products, the agency
evaluated additional new data regarding the effect of povidone-iodine
on wound healing and concluded that this ingredient does not delay
wound healing (56 FR 33644 at 33662). The agency has no reason to
believe that the mechanism for wound healing in the oral cavity is
significantly different from the mechanism for skin wound healing.
Therefore, the agency believes that the data discussed above are
applicable to wound healing in the oral cavity. The agency tentatively
concludes that povidone-iodine does not inhibit normal wound healing in
the oral cavity.
In the tentative final monograph for OTC first aid antiseptic drug
products (56 FR 33644 at 33661 to 33662), the agency discussed data
from published and unpublished studies to show that povidone-iodine
does not alter thyroid function. The agency reviewed the data and
agreed that thyroid disfunction does not occur from topical use of
povidone-iodine. In addition, studies following the application of
povidone-iodine to the mucous membranes (vagina) and intact and damaged
skin in humans and animals reported protein-bound iodine elevations,
but no alterations in thyroid function. The agency concluded that 0.5
to 5 percent povidone-iodine is safe for OTC use as a topical first aid
antiseptic.
The agency also agrees with one comment that the currently
available information indicates that povidone-iodine is not mutagenic
or carcinogenic. In its evaluation of povidone-iodine as a topical
antifungal ingredient, the Antimicrobial II Panel relied on new safety
data as well as the recommendations of the Antimicrobial I Panel (39 FR
33102 at 33129). In its report, the Antimicrobial II Panel specifically
discussed data on the mutagenicity potential of povidone-iodine (47 FR
12480 at 12545) and concluded that povidone-iodine has no significant
mutagenic or carcinogenic capabilities. That Panel determined that 10
percent povidone-iodine is safe for OTC use as an antifungal agent. The
Vaginal Panel reviewed a povidone-iodine migration and absorption study
in three experimental animal species using radioactively tagged
povidone-iodine (48 FR 46694 at 46705). Although there was evidence of
absorption of iodine from the vagina into the systemic circulation, the
experiments showed little or no flow of radioactively tagged povidone
into the uterus from the vagina. Stating that ``the weight of evidence
is sufficient to conclude that povidone-iodine does not have a
significant mutagenic or carcinogenic effect'' (48 FR 46694 at 46705),
that Panel classified povidone-iodine as Category I for the relief of
minor vaginal irritations. In addition, the agency has searched the
scientific literature covering 1982 through May 1993, and has not found
any information indicating that povidone-iodine might be mutagenic or
carcinogenic.
The agency has reviewed its adverse reaction files covering 1970 to
August 1993 (Ref. 26). During those years there were no cases of
adverse reactions associated with the use of povidone-iodine as an oral
antiseptic. There were numerous cases of adverse reactions associated
with the use of topical products containing povidone-iodine, e.g.,
first aid antiseptics or surgical scrubs. Of these cases, 20 were
classified as serious. Five deaths occurred. However, each death
occurred after the professional use of povidone-iodine as a health care
antiseptic in a hospital setting (i.e., (1) use as surgical scrub on a
patient who had previously been exposed to multiple radiographic
examinations, (2) use to sterilize the peritoneal cavity after surgery,
(3) administration concurrent with an electrolyte solution by enema and
subsequently through a nasogastric tube, and (4) continuous irrigation
of a hip wound). The other serious case reports involved chest pain,
contact dermatitis, or chemical burns resulting from the preoperative
use of povidone-iodine solutions as health-care antiseptics. These
cases resulted in prolonged hospitalizations and/or disability (e.g.,
loss of vision or burns of varying degrees). The most frequently
reported events included: reports of rash, reports of contact
dermatitis, reports of application site reactions, reports of
vaginitis, and reports of pain. Other less frequently reported
reactions (i.e., 1 or 2 reports per reaction) included conjunctivitis,
anaphylactic shock, iodism, rhinitis, and dry skin. The agency notes
that the majority of these cases were the result of povidone-iodine
products being used by health care professionals on people who were in
the hospital for surgery or who were otherwise compromised. In
addition, the povidone-iodine concentration in the products used in
these cases was 5 to 10 percent, which is much higher than its
concentration in oral antiseptic products (0.5 percent). The agency
does not believe that these reports are relevant to the use of
povidone-iodine as an oral antiseptic product used in small amounts in
the oral cavity for a limited period of time (i.e., up to 7 days).
The agency believes that the information contained in its adverse
reaction files and the safety data evaluated by the Oral Cavity Panel
are sufficient to conclude that 0.5 percent povidone-iodine (i.e., the
concentration evaluated by the Oral Cavity Panel) is safe as an OTC
oral antiseptic for short-term use (not to exceed 7 days).
References
(1) Comment No. C00020, Docket No. 81N-0033, Dockets Management
Branch.
(2) Bradley, S. G., ``A Review on Some Microbiological Aspects
of Povidone-Iodine (PVP-I),'' Addendum 20, Comment No. C00020,
Docket No. 81N-0033, Dockets Management Branch.
(3) Prince, H. N. et al., ``Drug Resistance Studies with Topical
Antiseptics,'' Journal of Pharmaceutical Sciences, 67:1629-1630,
1973.
(4) Eitzen, H. E., ``Efficacy of Povidone-Iodine (PVP-I),''
Addendum 22, Comment No. C00020, Docket No. 81N-0033, Dockets
Management Branch.
(5) Gilmore, O. J. A., and P. J. Sanderson, ``Prophylactic
Interparietal Povidone-Iodine in Abdominal Surgery,'' British
Journal of Surgery, 62:792-799, 1975.
(6) Eitzen, H. E. et al. ``A Microbiological In-Use Comparison
of Surgical Hand-Washing Agents,'' The Journal of Bone and Joint
Surgery, Incorporated, 61-A:403-406, 1979.
(7) Steere, A. C., and G. F. Mallison, ``Handwashing Practices
for the Prevention of Nosocomial Infections,'' Annals of Internal
Medicine, 83:683-690, 1975.
(8) Morgan, W. J., ``Povidone-Iodine Spray for Wounds Sutured
the Accident Department,'' Addendum 26, Comment No. C00020, Docket
No. 81N-0033, Dockets Management Branch.
(9) Carchman, R. A., ``The Effects of Povidone-Iodine on Wound
Healing,'' Addendum 27, Comment No. C00020, Docket No. 81N-0033,
Dockets Management Branch.
(10) Fischer, E., and Z. Paster, ``A Study of the Effect of
Polydine on Wound Healing,'' Appendix 10, Comment No. C00019, Docket
No. 81N-0033, Dockets Management Branch.
(11) Gilmore, O. J. A., ``A Reappraisal of the Use of
Antiseptics in Surgical Practice,'' Annals of the Royal College of
Surgeons of England, 59:93-103, 1977.
(12) Gilmore, O. J. A., and C. Reid, ``A Study of the Effect of
Povidone-iodine on Wound Healing,'' Postgraduate Medical Journal,
53:122-125, 1977.
(13) Schwartz, S. L., ``Evaluation of the Safety of Povidone and
Crospovidone,'' Addendum 16, Comment No. C00020, Docket No. 81N-
0033, Dockets Management Branch.
(14) ``Studies on Testing of Povidone-Iodine U.S.P. XIX for
Mutagenic Effects in Mice and Chinese Hamsters,'' Comment No.
C00019, Docket No. 81N-0033, Dockets Management Branch.
(15) Merkle, J., and H. Zeller, ``Absence of Povidone-Iodine-
Induced Mutagenicity in Mice and Hamsters,'' Journal of
Pharmaceutical Sciences, 68:100-102, 1979.
(16) Kessler, F. K. et al., ``Assessment of Somatogenotoxicity
of Povidone-Iodine Using Two In Vitro Assays,'' Addendum 15, Comment
No. C00020, Docket No. 81N-0033, Dockets Management Branch.
(17) Brusick, D. J., ``A Review of the Genotoxic Effects of
Povidone-Iodine,'' Attachment B, Comment No. C00010, Docket No. 81N-
0033, Dockets Management Branch.
(18) Attachment A, Comment No. C00010, Docket No. 81N-0033,
Dockets Management Branch.
(19) ``Serum Fodides and Thyroid Function; Betadine Mouthwash/
Gargle (Povidone-Iodine),'' Attachment C, Comment No. C00010, Docket
No. 81N-0033, Dockets Management Branch.
(20) Borzelleca, J. F., ``A Review of the Basic Toxicology of
Povidone-Iodine,'' Addendum 4, Comment No. C00020, Docket No. 81N-
0033, Dockets Management Branch.
(21) ``Toxicology Summary of PVP,'' Addendum 17, Comment No.
C00020, Docket No. 81N-0033, Dockets Management Branch.
(22) Blecher, L. et al., ``Polyvinylpyrrolidone,'' Addendum 18,
Comment No. C00020, Docket No. 81N-0033, Dockets Management Branch.
(23) Digenis, G. A., ``Behavior of Povidone-Iodine in the
Vaginal Vault of the Rat, Dog, and Sheep,'' Addendum 11, Comment No.
C00020, Docket No. 81N-0033, Dockets Management Branch.
(24) Istin, M., ``Study of the Urinary, Biliary, and Fecal
Excretion of C14 by Rats Treated with Labeled
Polyvinylpolypyrrolidone (PVPP-C14) by Gastric Intubation,''
Addendum 12, Comment No. C00020, Docket No. 81N-0033, Dockets
Management Branch.
(25) Ingbar, S. H., ``Studies of the Effects of Surgical
Scrubbing with PVP-I,'' Addendum 13, Comment No. C00020, Docket No.
81N-0033, Dockets Management Branch.
(26) Food and Drug Administration, Center for Drug Evaluation
and Research, Adverse Reaction Summary Listing for Povidone-iodine
for the years 1970 to August 1993, OTC Vol. 13CTFM, Docket No. 81N-
0033, Dockets Management Branch.
16. Two comments objected to the Oral Cavity Panel's conclusion
that there is insufficient evidence available to classify povidone-
iodine in Category I as an effective oral antiseptic. One comment
stated that a commercial mouthwash has been marketed under an approved
NDA for a quarter century and that reports of clinical studies
involving thousands of patients had been submitted to the Panel.
The comments objected to the Panel's statement that the ``* * *
slow release [of povidone-iodine] also raises doubts about its
effectiveness, since the active ingredient is elemental iodine,'' (47
FR 22760 at 22883). One comment stated that the Panel's speculation on
the release of iodine and its impact on the effectiveness of povidone-
iodine is unfounded. The comment added that the effectiveness of
povidone-iodine solution as a topical microbicide is proven in the
hundreds of studies submitted or referenced to the Panel. The comment
contended that the Panel did not develop an independent viewpoint
regarding the effectiveness of povidone-iodine but relied upon the
Antimicrobial I Panel's evaluation. The comment argued that the issues
raised by the Antimicrobial I Panel were fully answered by the data
submitted in response to that Panel's report.
Another comment stated that the efficacy of the povidone-iodine
complex is independent of the initial content of free iodine and that
biocidal effect is determined by iodine liberated from the complex
during the reaction with amino acids of the proteins of bacteria,
fungi, etc. The comment mentioned that substantial data submissions to
the Antimicrobial I Panel and other panels showed that iodine is freely
released from the complex and that the rate of iodine release is
controlled by tissue demand. The comment submitted data regarding the
rate of release and germicidal activity of povidone-iodine (Refs. 1, 2,
and 3). The comment stated that the studies established that: (1) The
biocidal activity of the complex is independent of the initial free
iodine content; (2) the clinical effectiveness of the complex is caused
by the amount of available iodine; (3) the iodine becomes effective by
oxidation or iodizing reaction of amino acids of the proteins of
bacteria, fungi, etc.; (4) the iodine is liberated from the povidone-
iodine complex at a rate in the milliseconds time range; and (5) within
the acidity levels studied (i.e., those levels relevant to the field of
medicine, between pH 3 and 5), no significant change with regard to the
rapidity of iodine release from the povidone-iodine complex could be
observed. The comment concluded that there are sufficient data
available to establish the effectiveness of povidone-iodine for use as
an OTC oral antiseptic.
As part of FDA's DESI program, mouthwash products containing
povidone-iodine, cetylpyridinium chloride, and other ingredients were
reviewed by the NAS-NRC/DESG and found ineffective for claims relating
to antimicrobial, antiseptic, germicidal, and analgesic uses (35 FR
12423). In a subsequent notice published in the Federal Register of
December 2, 1971 (36 FR 23000), the agency stated that because of the
implementation of the OTC drug review, mouthwash and gargle products
reviewed under the DESI program would now be under the purview of the
OTC drug review; thus, final agency action on these products would be
deferred pending evaluation of the data and information concerning such
products under the OTC drug review.
The agency has reviewed the data submitted regarding the
availability of iodine from the povidone-iodine complex and considered
the data discussed in the tentative final monograph for OTC topical
acne drug products, published in the Federal Register of January 15,
1985 (50 FR 2172 at 2173 to 2174) and in the tentative final monograph
for OTC first aid antiseptic drug products (56 FR 33644 at 33661). The
agency agrees with the comment that the issues regarding the
availability of iodine from povidone-iodine complex and the stability
of the complex have been resolved for this ingredient. However, the
agency has determined that further studies are needed to demonstrate
the effectiveness of povidone-iodine for OTC topical use in the oral
cavity to help prevent infection.
As discussed in section I.K., comment 27, the agency believes that
0.5 percent povidone-iodine is an effective oral antiseptic for
professional use when used for the preparation of the oral mucosa prior
to injection, dental surgery, or tooth extraction by a health care
professional. However, the data discussed in that comment do not
support OTC use of povidone-iodine as an OTC oral antiseptic. The data
demonstrate that applying povidone-iodine according to the specialized
professional labeling directions proposed in Sec. 356.80(c)(3) of this
tentative final monograph results in a decrease of bacteremia after
oral surgery or tooth extraction. They did not demonstrate a
therapeutic benefit from using povidone-iodine as an OTC oral rinse.
Although the gingival mucosa surrounding the operation sites were
sampled prior to and immediately after surgery or tooth extraction, the
studies did not demonstrate a decrease in the number of oral bacteria
over an extended period of time, and the organisms affected by the
povidone-iodine treatment were not completely identified. These studies
do not demonstrate the effectiveness of povidone-iodine when used as an
OTC oral rinse. In addition, the agency is not aware of any data from
clinical studies demonstrating a therapeutic benefit from the OTC use
of povidone-iodine in the oral cavity.
The agency believes that the Panel's proposed in vitro and in vivo
testing guidelines and its discussion of clinical studies represent a
good starting point for the design of studies to upgrade a Category II
or Category III oral antiseptic ingredient to Category I. (See section
I.M., comment 33 for a further discussion of testing guidelines.)
However, the agency notes that specific testing guidelines for
upgrading ingredients to monograph status are not included in this
monograph. (See part II. paragraph A.2.--Testing of Category II and
Category III conditions.) All such testing should be designed using the
most current technology available. The agency will meet with industry
representatives or other interested parties at their request to discuss
testing protocols.
References
(1) Appendix 2, Comment No. C00019, Docket No. 81N-0033, Dockets
Management Branch.
(2) Appendix 3, Comment No. C00019, Docket No. 81N-0033, Dockets
Management Branch.
(3) Appendix 4, Comment No. C00019, Docket No. 81N-0033, Dockets
Management Branch.
17. One comment objected to the Oral Cavity Panel's statement (47
FR 22760 at 22882) that ``There is some disagreement concerning the
chemical nature of povidone-iodine. Some believe that it is a specific
chemical entity; others claim that it is merely a complex. The
prevalent consensus is that povidone-iodine is a complex of povidone
and elemental iodine.'' Maintaining that there is no disagreement among
qualified scientists concerning the chemical nature of povidone-iodine,
the comment stated that povidone-iodine is a specific chemical entity
that is defined in the Official Compendia and the scientific
literature. Referring to the ``United States Pharmacopeia (U.S.P.) XX''
description of povidone-iodine as ``* * * a complex of iodine with
povidone'' (Ref. 1), the comment contended that the fact that povidone-
iodine is described as a complex does not contradict its existence as a
chemical entity. The comment stated that a ``complex'' is formed by the
``bonding of two or more compounds, resulting in a new chemical entity
having properties distinguishable from those of the component parts.''
According to the comment, data in the public record demonstrate that
povidone-iodine is a well-defined chemical entity that retains the full
antimicrobial spectrum of iodine without the noxious chemical and
physical properties of elemental iodine, thereby providing a stable,
essentially nonirritating and nontoxic compound.
Another comment agreed with the Oral Cavity Panel's recognition of
the ``prevailing consensus'' that povidone-iodine is a complex composed
of povidone and iodine. However, this comment felt that the Panel may
have been unaware of the nature of povidone-iodine, and contended that
this lack of awareness may have affected other considerations
concerning the source of the complex's effectiveness, the rate of
iodine release, and the complex's effect on the rate of healing. The
comment included a detailed chemical description of povidone-iodine and
of povidone-iodine's activity (Ref. 2).
One comment asserted that the Panel's misunderstanding of the
nature of povidone-iodine is indicated by its statement that ``Povidone
is available as a series of aggregates having mean molecular weights
ranging from 10,000 to 700,000 daltons,'' (47 FR 22760 at 22883).
Stating that the U.S.P. XX described povidone as a series of products
rather than a series of aggregates (Ref. 1), the comment maintained
that the povidone product used in the synthesis of povidone-iodine does
not spread over the broad range of molecular weights described by the
Panel but has a molecular weight average of less than 40,000. The
comment added that this specificity in molecular weight must be
recognized when considering the properties of the povidone used to
synthesize povidone-iodine.
The agency has reviewed the literature and believes that povidone-
iodine is a well-defined chemical. Povidone-iodine is described in
``U.S.P. XXII'' (Ref. 3) and in ``Martindale, The Extra Pharmacopeia''
(Ref. 4) as a complex of iodine with povidone (2-pyrrolidinone, 1-
ethenyl-, homopolymer or 1-vinyl-2-pyrrolidinone polymer) that contains
not less than 9 percent and not more than 12 percent of available
iodine calculated on a dried basis. ``U.S.P. XXII'' (Ref. 3) provides
standards for the purity and acceptability of iodine, povidone, and
povidone-iodine. Other references describe povidone-iodine as iodine
compounded or complexed with povidone (Refs. 5 and 6).
Regarding the Panel's statement that ``Povidone is * * * a series
of aggregates * * *'' (47 FR 22760 at 22883), the agency notes that
``U.S.P. XXII'' describes povidones as a ``synthetic polymer consisting
essentially of linear 1-vinyl-2-pyrrolidinone groups, the degree of
polymerization of which results in polymers of various molecular
weights,'' (Ref. 3). Povidone is produced commercially as a series of
products having mean molecular weights ranging from about 10,000 to
about 700,000 (Ref. 6), and the Panel correctly described the range of
molecular weights of povidone available. However, it neglected to point
out that povidone having an average molecular weight of 40,000 is used
in the preparation of povidone-iodine (Ref. 6). For the above reasons,
the agency concludes that there is little or no disagreement regarding
the chemical nature of povidone-iodine.
References
(1) ``The United States Pharmacopeia XX,'' United States
Pharmacopeial Convention, Inc., Rockville, MD, p. 647, 1980.
(2) Comment No. C00020, Docket No. 81N-0033, Dockets Management
Branch.
(3) ``The United States Pharmacopeia XXII--The National
Formulary XVII,'' United States Pharmacopeial Convention, Inc.,
Rockville, MD, pp. 1118-1119, 1989.
(4) Reynolds, J. E., editor, ``Martindale, The Extra
Pharmacopoeia,'' 29th ed., The Pharmaceutical Press, London, p.
1187, 1989.
(5) Gardner, W., E. I. Cooke, and R. W. I. Cooke, ``Handbook of
Chemical Synonyms and Trade Names,'' CRC Press, Inc., Cleveland, p.
576, 1978.
(6) Gennaro, A. R., editor, ``Remington's Pharmaceutical
Sciences,'' 18th ed., Mack Publishing Co., Easton, PA, pp. 1169 and
1307, 1990.
18. Two comments maintained that several of the Oral Cavity Panel's
statements in its discussion of povidone-iodine (47 FR 22760 at 22882
to 22885) showed a basic misunderstanding of the behavior of povidone-
iodine in solution. One comment requested that the Panel's introductory
discussion of povidone-iodine be rewritten to properly reflect the
chemical and physical properties of povidone-iodine and that the
information provided should accurately describe the product used in the
formulation of OTC oral health care antimicrobial preparations.
The comment asserted that the Panel's statement which reads ``The
iodine that can be released in its free form from povidone-iodine is
approximately 10 percent of the labeled iodine content of the complex''
(47 FR 22883) is misleading. The comment noted that povidone-iodine
powder contains about 10 percent available iodine and a 10-percent
aqueous solution of povidone-iodine provides 1 percent titratable
iodine, all of which is available for germicidal use.
The comment indicated that the following statement made by the
Panel is in error: ``Freshly prepared solutions of povidone-iodine do
not give a blue color with starch as do tinctures and other solutions
of elemental iodine. Solutions that have been standing for some time do
give a blue color'' (47 FR 22883). The comment referred to the two
identification tests required by the U.S.P. for povidone-iodine
solution (Ref. 1) and stated that identification test A requires a blue
color upon mixture of a povidone-iodine solution with starch TS (test
solution), and test B requires that no blue color be produced. Stating
that test B detects the presence of uncomplexed free iodine, the
comment asserted that properly manufactured povidone-iodine solutions
conform to these U.S.P. standards and do not deteriorate and release
free iodine vapor under normal storage conditions, as the Panel's
quoted statement implies.
The comment objected to the following statement in the Panel's
discussion of povidone-iodine: ``The addition of sodium bicarbonate
makes aqueous solutions less acidic, but also less stable,'' (47 FR
22760 at 22883), and noted that ``a current In-Process Revision of the
U.S.P.'' provides for a pH range of 2.0 to 6.5. Citing the
``Pharmacopeial Forum'' (Ref. 2), the comment stated that this pH range
reflects the range of values found in commercial formulations and is
consistent with adequate stability, germicidal activity, and dermal
safety. Noting that product stability is fully regulated under Current
Good Manufacturing Practice (CGMP) regulations found in 21 CFR parts
210 and 211, the comment maintained that its povidone-iodine mouthwash
gargle product is stable, has a documented shelf-life stability, and is
labeled with an expiration date.
Citing the Panel's statement ``When an aqueous solution is applied
topically, a slow release of free iodine occurs which exerts
antimicrobial action'' (47 FR 22760 at 22883), the comment asserted
that the activity of povidone-iodine solution is not the result of a
slow, ``trickle type'' of release of free iodine, but occurs because
iodine is available in the course of a continuous, dynamic equilibrium
reaction. The comment added that the dynamic equilibrium results in the
immediate availability of all the iodine present in the solution at
virtually the same rate as for tincture of iodine. The comment
maintained that data submitted to the Oral Cavity Panel, the
Antimicrobial I Panel, and the rulemaking for OTC topical acne drug
products demonstrate that all of the iodine present in an aqueous
solution of povidone-iodine is instantly (i.e., within milliseconds)
available upon application to the tissue site; therefore, the Panel's
reference to a ``slow release of free iodine'' is incorrect.
The second comment maintained that a key factor in the availability
of elemental iodine from the povidone-iodine complex is the ability of
the complex to keep the antimicrobial iodine in reserve and supply it
only on demand. The comment stated that when there is no iodine demand,
the level of free iodine is kept quite low, contrary to the Panel's
statement regarding the continuous ``slow-release'' of iodine. The
comment contended that at equilibrium the concentration of iodine is
low, but as the iodine is depleted from the solution, it is replaced
instantaneously from the available pool. Thus, the comment concluded
that the rate of release of iodine is not variable, but is always the
same and that the germicidal activity of povidone-iodine is not
affected until the entire pool is depleted. The comment submitted data
describing the structure and the kinetics of iodine release from the
povidone-iodine complex (Refs. 3 and 4) and purporting to confirm the
in vitro microbiological consequences of the release mechanism (Ref.
5).
The agency considers the following statement made by the Panel in
its discussion of povidone-iodine to be unclear and undocumented:
``Freshly prepared solutions * * * do not give a blue color * * *'' (47
FR 22760 at 22883). The agency agrees with the comments that properly
manufactured povidone-iodine solution must comply with the appropriate
U.S.P. standards that include two identification tests: one in which
the formation of a blue color confirms the presence of available iodine
in the povidone-iodine solution, and the other in which the lack of a
blue color confirms that free iodine is not being released into the
atmosphere (Ref. 6). The absence of free iodine in the atmosphere is
indicative that the vapor pressure of povidone-iodine solution is
virtually zero in contrast to the high vapor pressure demonstrated by
iodine tincture.
Regarding the Panel's statement that ``The addition of sodium
bicarbonate makes aqueous solutions [pH 2.0] less acidic, but also less
stable'' (47 FR 22760 at 22883), the agency notes that the U.S.P.
specifies a pH range between 1.5 and 6.5 for povidone-iodine topical
solutions (Ref. 6). Therefore, a povidone-iodine topical solution
should be stable for its shelf life at any pH between 1.5 and 6.5. The
agency also agrees with the comment that issues regarding stability
would be governed by the CGMP regulations (21 CFR parts 210 and 211).
These regulations require a written testing program to assess the
stability of finished products and to determine appropriate storage
conditions and an expiration date. Section 211.137(a) (21 CFR
211.137(a)) requires that products bear an expiration date supported by
appropriate stability testing. However, Sec. 211.137(g) provides that
expiration dating requirements are not enforced for human OTC drug
products if their labeling does not bear dosage limitations and they
have been shown to be stable for at least 3 years by appropriate
stability data.
The agency has reviewed the data submitted on the kinetics of
iodine released from the povidone-iodine complex in solution (Refs. 3
and 4) and discussed the data in the tentative final monograph for OTC
topical acne drug products (50 FR 2172 at 2173 and 2174) and in the
tentative final monograph for OTC topical antifungal drug products
published in the Federal Register of December 12, 1989 (54 FR 51136 at
51143 and 51144). The agency agrees with the comment that all of the
iodine in a povidone-iodine solution is immediately available and that
the rate of iodine release from the povidone-iodine complex is neither
slow nor variable.
Regarding the comment's statement that povidone-iodine powder
contains 10 percent available iodine and that a 10-percent solution of
povidone-iodine contains 1 percent available iodine, the agency notes
that ``U.S.P. XXII'' states that povidone-iodine powder contains not
less than 9 percent and not more than 12 percent available iodine (Ref.
6). Earlier compendia (e.g., ``U.S.P. XIX'' (Ref. 7)) characterized a
10-percent povidone-iodine solution as equivalent to 1 percent
available iodine.
Regarding the data submitted to confirm the in vitro
microbiological consequences of the povidone-iodine complex's release
mechanism (Ref. 5), the agency discusses the oral antimicrobial
effectiveness of povidone-iodine in section I.I., comment 16.
One comment requested that the introductory portion on povidone-
iodine in the Panel's report should be rewritten to reflect these
corrections. Although the agency acknowledges some ambiguities in the
Panel's introductory discussion of povidone-iodine (47 FR 22760 at
22882 to 22885), it does not see a need to rewrite that discussion. The
agency believes that the above response should add to and clarify the
Panel's discussion of the chemical and physical nature of povidone-
iodine in solution.
References
(1) Comment No. C00010, Docket No. 81N-0033, Dockets Management
Branch.
(2) ``Pharmacopeial Forum,'' The United States Pharmacopeial
Convention, Inc., Rockville, MD, p. 2343, September and October,
1982.
(3) Schenck, H. U. et al., ``Structure of Povidone-Iodine,'' in
``Current Chemotherapy and Infectious Disease,'' Vol. I, American
Society of Microbiology, Washington, pp. 477-478, 1980.
(4) Ditter, W., D. Horn, and E. Luedekke, ``Thermodynamic and
Kinetic Examinations Concerning the Complex Binding State and the
Rate of Liberation of Iodine from Aqueous Iodine-PVP-Solutions,'' in
Comment No. C00020, Docket No. 81N-0033, Dockets Management Branch.
(5) Marcus Research Laboratory Inc., Chemists, ``Povidone-Iodine
U.S.P., Chemistry, Microbiology, and Toxicology,'' in Comment No.
C00020, Docket No. 81N-0033, Dockets Management Branch.
(6) ``United States Pharmacopeia XXII-The National Formulary
XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD,
p. 1119, 1989.
(7) ``United States Pharmacopeia XIX,'' United States
Pharmacopeial Convention, Inc., Rockville, MD, p. 396, 1975.
J. Comments on Dosages for Oral Antiseptic Ingredients
19. One comment stated that the dosage level of 0.025 percent
eucalyptol, as recommended in the Oral Cavity Panel's majority report
on antimicrobial agents (47 FR 22760 at 22873), is incomplete. The
comment contended that the dosage should read 0.025 to 0.1 percent
concentration, the range reviewed by the Panel and correctly listed in
the Panel's evaluation of eucalyptol as an anesthetic/analgesic (47 FR
22827).
The agency has reviewed the administrative record regarding the
Panel's evaluation of eucalyptol as an antimicrobial agent and notes
that one product submitted to the Panel contained eucalyptol at a
concentration of 0.025 percent (Ref. 1), while another submitted
product contained 0.091 percent eucalyptol (Ref. 2). The Panel also
reviewed data on products containing eucalyptol used as an anesthetic/
analgesic ingredient in the same dosage range (i.e., 0.025 to 0.091
percent) and apparently rounded off the 0.091 percent dose in the data
to 0.1 percent in its report. Therefore, the agency agrees with the
comment that the proposed dosage range for eucalyptol as an antiseptic
agent should also have read 0.025 to 0.1 percent. However, because
eucalyptol is classified as Category III as both an oral health care
antiseptic and anesthetic/analgesic ingredient in the OTC oral health
care drug products rulemaking, the proposed dosage range serves only as
a guide to anyone interested in testing eucalyptol for upgrading to
Category I. However, data on any concentration of eucalyptol may be
submitted.
References
(1) OTC Vol. 130053.
(2) OTC Vol. 130042.
K. Comments on Labeling for Oral Antiseptic Ingredients
20. Three comments objected to the Oral Cavity Panel's
recommendation that the term ``antiseptic'' and any reference to the
pharmacologic effects of antimicrobial agents not be included in its
recommended monograph. One comment stated that the Panel's position is
contrary to the act, which requires a statement of pharmacologic effect
or class of drug in OTC labeling. Another comment contended that the
term ``antiseptic'' should be preserved in the statement of identity
because, by traditional definition, an antiseptic is a substance that
kills or inhibits the growth of microorganisms. Stating that antiseptic
activity is synonymous with antimicrobial activity, the comment
requested the approval of the following terms as statements of identity
for OTC oral antimicrobials: (1) Oral antimicrobial, (2) oral
antiseptic, and (3) oral antibacterial. The other comment added that
the terms ``antiseptic'' and ``kills germs'' should be placed in
Category I in the tentative final monograph.
In discussing the use of the terms ``antiseptic,''
``disinfectant,'' and ``antimicrobial agent,'' the Oral Cavity Panel
stated that the term ``antimicrobial agent'' describes an ingredient in
OTC oral health care drug products that kills or interferes with the
proliferation and activity of microorganisms, both pathogenic or
nonpathogenic, and that a therapeutic benefit may or may not be derived
from its use (47 FR 22760 at 22833). The Panel defined the term
``antiseptic'' as an antimicrobial agent that, when used on living
tissue, produces some therapeutic benefit and acts to counteract an
infection. A ``disinfectant'' was defined as an antimicrobial agent
used on inanimate objects. Thus, the Panel considered the term
``antimicrobial agent'' to be a general term that encompasses both
antiseptics and disinfectants, disregarding how the ingredient is used.
The Panel included the following statement of identity in
Sec. 356.51(a) of its recommended monograph (47 FR 22760 at 22928):
``oral health care antimicrobial.''
The agency disagrees with the Panel's recommendation that the term
``antiseptic'' not be used as part of the statement of identity for
antimicrobial agents contained in OTC oral health care drug products
(47 FR 22760 at 22833). The agency believes that the Panel was opposed
to the term ``antiseptic'' because, according to the Panel's
definition, this term implies therapeutic benefit and the Panel was not
convinced of the effectiveness of OTC antiseptics in providing a
therapeutic benefit, i.e., relief of sore mouth and sore throat
symptoms. However, the agency believes that the term ``oral
antiseptic'' is appropriate for use in the statement of identity for
the active ingredients included in this segment of the oral health care
drug products rulemaking. Those found effective could provide a
therapeutic benefit. An antiseptic is a substance that can kill or
inhibit the growth of microorganisms when applied to living tissues
without significant harm to the tissues (Ref. 1). This definition is in
keeping with the definition of an antiseptic in section 201(o) of the
act (21 U.S.C. 321(o)). If safety and effectiveness data support the
inclusion in Category I of any antiseptic active ingredient(s) for OTC
use in oral health care drug products, the agency believes that the
term ``antiseptic'' is well recognized by consumers and can
appropriately be used in the labeling for such products.
The agency believes that the term ``health care,'' while
appropriate for classification purposes and used to identify this
rulemaking, is cumbersome and unnecessary in consumer labeling as a
statement of identity for an OTC oral antiseptic. Therefore, in this
tentative final monograph, the agency is proposing to revise the
statement of identity in Sec. 356.51(a) of the Panel's recommended
monograph (47 FR 22928) to include the term ``antiseptic'' instead of
the term ``health care antimicrobial.'' The agency is also revising the
statement of identity to include dosage forms (see section I.K.,
comment 21), and is renumbering the statement of identity section as
Sec. 356.64(a).
Because the term ``antiseptic'' is well recognized by consumers and
because the agency wishes to minimize consumer confusion about the
labeling of similar marketed products, the terms ``oral antimicrobial''
and ``oral antibacterial'' are not being included as alternate
statements of identity for this class of drug products. However, the
agency has no objection to such terms appearing in the labeling as
other information provided it does not appear in any portion of the
labeling required by the monograph and does not detract from such
required information.
The agency is not including in this tentative final monograph the
Panel's definition for an antimicrobial agent in Sec. 356.3(c) of its
recommended monograph (47 FR 22760 at 22927). Instead, the agency is
proposing definitions for the terms ``antiseptic drug'' and ``oral
antiseptic'' in Sec. 356.3 as follows:
Antiseptic drug. In accordance with section 201(o) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(o)), ``The
representation of a drug, in its labeling, as an antiseptic shall be
considered to be a representation that it is a germicide, except in
the case of a drug purporting to be, or represented as, an
antiseptic for inhibitory use as a wet dressing, ointment, dusting
powder, or such other use as involves prolonged contact with the
body.''
Oral antiseptic. An antiseptic-containing drug product applied
topically to the oral cavity to help prevent infection in wounds
caused by minor oral irritations, cuts, scrapes, or injury following
minor dental procedures.
The agency believes that claims such as ``kills germs'' could be
potentially misleading to the average consumer if directly associated
with the term ``infection'' that is included in the indication. The
term ``kill germs'' may be interpreted to imply elimination of all
bacteria in the mouth when, in fact, oral antiseptics used in the mouth
only decrease the number of certain bacteria. However, the agency
believes this term is familiar to the average consumer and may be
useful in describing a product's action or intended effect. Although
this term is not included in the monograph, it may be included in
labeling of oral antiseptic drug products provided it is not
intermingled with labeling established by the monograph and is not used
in a false or misleading manner.
Reference
(1) Berkow, R., editor, ``The Merck Manual of Diagnosis and
Therapy,'' 14th ed., Merck and Co., Inc., Rahway, NJ, p. 2300, 1982.
21. One comment requested that the agency approve the following
statements of identity, and any reasonably synonymous statements, for
the combination of 0.045 percent cetylpyridinium chloride and 0.005
percent domiphen bromide: ``(1) oral antiseptic, (2) oral
antimicrobial, (3) mouthwash, (4) gargle, and (5) mouthwash and
gargle.''
The statement of identity for oral health care antiseptics is
discussed in section I.K., comments 20 and 22. As explained there, the
agency believes that the term ``oral antiseptic'' is appropriate as the
statement of identity for these products. Because the term
``antiseptic'' is well recognized by consumers, and in order to avoid
confusion in the marketplace, the term ``oral antimicrobial'' is not
being included in the monograph as an alternate statement of identity.
However, the agency has no objection to the term ``oral antimicrobial''
appearing in the labeling as other information provided it is not
intermingled with labeling established by the monograph, and it is not
used in a false or misleading manner.
In accord with 21 CFR 201.61, wherever possible, the agency prefers
to use the general pharmacological category as the statement of
identity for OTC drug products; where this is not appropriate, the
principal intended action is used. The terms ``mouthwash,'' ``gargle,''
or ``mouthwash and gargle'' by themselves do not inform consumers of
the pharmacological category or the principal intended action of a drug
product. The agency recognizes that oral products have been marketed
for years as ``mouthwashes,'' ``gargles,'' and ``mouthwashes and
gargles.'' However, many of these products have been marketed for daily
long-term use as cosmetics, and the agency believes that consumers
associate the term mouthwash with such unlimited cosmetic use. In this
document, the agency is proposing to limit the use of oral antiseptic
drug products to 7 days or less. The agency believes that use of the
term ``mouthwash'' on such products could be confusing to consumers,
who might be led to assume that the product could be used for an
unlimited period of time. However, the agency believes that use of the
term ``rinse'' in the statement of identity would be acceptable because
the term ``rinse'' implies a therapeutic use (e.g., fluoride rinse).
Also, the agency does not oppose the inclusion of the term ``gargle''
in the statement of identity, when included in addition to the required
pharmacological category. Therefore, in this tentative final monograph,
the agency is proposing an alternate statement of identity for oral
antiseptics to include a choice of terms describing the appropriate
dosage form of the product, i.e., ``rinse,'' ``gargle,'' or ``rinse and
gargle,'' as follows: The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
``oral antiseptic,'' or an ``antiseptic'' (select one of the following:
``rinse,'' ``gargle,'' or ``rinse and gargle''). (See section I.K.,
comment 20.)
In this tentative final monograph, the agency is classifying
cetylpyridinium chloride, domiphen bromide, and a combination of
cetylpyridinium chloride and domiphen bromide in Category III for
effectiveness as oral health care antiseptics. (See section I.E.,
comment 9; section I.G., comment 13; and section I.L., comments 30 and
31.) If cetylpyridinium chloride, domiphen bromide, or a combination of
these ingredients are upgraded to Category I for OTC oral antiseptic
use, the product may be labeled with either statement of identity
proposed in Sec. 356.64(a) of this tentative final monograph.
22. Four comments objected to the Oral Cavity Panel's position that
antimicrobial agents should not be used for therapeutic purposes in OTC
oral health care products. Three of the comments disagreed with the
Panel's statement that antiseptics are used in an attempt to sterilize
intact cutaneous and mucous surfaces, contaminated or infected wounds,
mucosal ulcerations, or other lesions caused by pathogenic microbial
activity (47 FR 22760 at 22831). The comments pointed out that topical
antimicrobials are used to decrease the number of bacteria present and
to help prevent the chance of infection after minor injury to the mouth
or gums; they are not used as sterilizing agents. The comments
presented excerpts from the advance notice of proposed rulemaking on
alcohol drug products for topical antimicrobial OTC human use published
in the Federal Register of May 21, 1982 (47 FR 22324) and the tentative
final monograph on OTC topical antibiotic drug products published in
the Federal Register of July 9, 1982 (47 FR 29986) which, they stated,
show that the Miscellaneous External Panel and the agency,
respectively, favor the use of antimicrobial agents to reduce the
number of bacteria on the skin and thus help prevent infection. One of
the comments also pointed out that the Oral Cavity Panel's position is
directly contrary to that of the Dental Panel which found that the use
of an oral antimicrobial is rational therapy (47 FR 22712 at 22720).
One comment noted that the Oral Cavity Panel identified and
evaluated two categories of products containing antimicrobial active
ingredients: (1) Those used on a short-term basis to relieve symptoms
of sore mouth or sore throat, or both, due to microbial infections, and
(2) those used on a long-term, often day-to-day, basis. The comment
contended that the category of products used on a short-term basis
should be further divided into two groups: (1) Products used on a
short-term basis that are applied locally (i.e., to the affected site
of infection to reduce the number of bacteria), and (2) products used
on a short-term basis that are applied to the total oral cavity.
Stating that presentations had been made to the Oral Cavity Panel
concerning the existence of a target population for locally applied
topical antiseptics, the comment felt that the data supplied on the
historical use of topical antiseptics to assist in preventing infection
were adequate to establish an oral first aid antiseptic category (Ref.
1). The comment stated that the only indication provided by the Panel
for any OTC oral antimicrobial ingredient does not address the issue of
reducing organisms at the lesion or site of infection to help prevent
oral infection, i.e., the ``first aid'' category. The comment requested
that the following indication and other allowable indications be
included as Category I labeling:
Indication: First aid and/or antiseptic to help prevent
infection in wounds caused by minor oral irritation; cuts, scrapes
or injury such as following minor dental procedures or from dentures
and orthodontic appliances.
Other Allowable Indications: (i) ``Decreases'' or ``Helps''
reduce the number of bacteria on the treated area.
(ii) Helps ``prevent,'' ``guard against,'' or ``protect
against'' oral infections.
(iii) Helps reduce the ``risk'' or ``chance'' of oral infection.
(iv) Helps prevent bacterial contamination in minor injuries or
lesions of the mouth.
The comment also requested that, based upon available data,
carbamide peroxide in anhydrous glycerin, sodium phenolate and phenol,
and povidone-iodine be classified in Category I as topical antiseptics
for local application.
Regarding the Oral Cavity Panel's statement that antiseptics are
used in an attempt to sterilize surfaces, wounds, and lesions caused by
pathogenic microbial activity (47 FR 22760 at 22831), the agency agrees
with the comments that most of the antiseptic agents used in OTC health
care drug products are not effective as sterilizing agents. For an
antiseptic agent to be an effective sterilizing agent, the ingredient
must be sporicidal, i.e., must kill bacterial spores. The majority of
the antiseptics used in OTC oral health care products will not destroy
bacterial spores. However, as the Panel stated, ``Topical antimicrobial
ingredients are applied to the mucous membranes of the mouth and throat
to kill, inhibit the proliferation of, or alter the metabolic activity
of all types of microorganisms, both pathogenic and nonpathogenic,''
(47 FR 22760 at 22831). The antiseptics are used in an ``attempt to
sterilize'' intact surfaces with complete sterilization of the wound
site viewed as the ultimate achievement by the drug. In an ideal sense,
a drug that could sterilize a wound site would be very beneficial in
the treatment of cuts and scratches. The agency believes that is the
point the Panel was trying to relate in its description of the effects
of these drugs.
The agency notes that the Panel listed nine reasons why it believed
that antiseptic ingredients should not be used in OTC oral health care
drug products (47 FR 22760 at 22834). Most of the reasons were based on
the Panel's belief that: (1) Antiseptics are nonspecific ingredients
that would not be effective in treating wounds in the oral cavity and
could possibly be harmful, (2) these ingredients do not penetrate
deeply into tissue, and (3) the ingredients would be significantly
diluted and removed from the wound site by the action of saliva.
Therefore, the Panel did not recommend any Category I indications for
antiseptics, but instead included a Category III indication, ``For the
temporary relief of minor sore mouth and sore throat by decreasing the
germs in the mouth.'' However, the agency disagrees with the Panel's
position that antiseptic ingredients should not be used for other
therapeutic purposes in OTC oral health care drug products. The agency
believes that antiseptics may be useful in helping to reduce the chance
of infection in minor sore mouth conditions by decreasing the number of
bacteria on the mucous membranes of the mouth.
Two of the studies submitted by one comment provide support that
there is a target population that would benefit from the availability
of an OTC antiseptic drug product to help prevent or reduce the
incidence of certain oral conditions (Ref. 1). Addy et al. (Ref. 2)
reported that an antibacterial mouthwash (0.2 percent chlorhexidine
gluconate) reduced the incidence, duration, and severity of aphthous
ulcers (canker sores) as compared to a control and an astringent
mouthwash when evaluated subjectively. The mouthwash was used for 1
minute three times daily for a period of 5 weeks. The authors
speculated that, in such conditions, oral hygiene is frequently
neglected due to oral discomfort that further increases the possibility
of infection from bacterial plaque deposits. Thus, attempts to reduce
secondary infection of the aphthous ulcers may be of value for the
patient. Olsen (Ref. 3) evaluated patients with denture stomatitis. The
treatment consisted of each patient sucking placebo, amphotericin B, or
chlorhexidine chloride lozenges combined with denture soaking in a 0.2-
percent aqueous solution of chlorhexidine digluconate. Olsen concluded
that denture disinfection was an essential part in the management of
denture stomatitis, finding that denture immersion in 0.2 percent
chlorhexidine solution significantly reduced the number of organisms
both on the mucous membranes and on the denture. The combination of
amphotericin B lozenges and chlorhexidine denture disinfection was the
most effective regimen. Although chlorhexidine, a drug available by
prescription for oral use, was used in the studies, the agency believes
that these studies do support the existence of a target population that
would benefit from the use of antiseptic ingredients in helping to
alleviate some oral conditions. However, additional data are needed to
support the above indications for OTC oral antiseptics.
The Panel identified two categories of products containing
antiseptics for oral use: (1) Those used on a short-term basis to
relieve symptoms of sore mouth and sore throat, or both, due to
microbial infections, and (2) those used on a long-term, often day-to-
day, basis for cleansing the mouth, suppressing mouth odors, and other
related purposes in which no symptoms of an infectious process are
evident but for which antiseptic claims are made (47 FR 22760 at
22890).
The agency does not see a need at this time to follow one comment's
request to subdivide the category of OTC oral antiseptic products used
on a short-term basis into two groups: (1) Those applied locally, and
(2) those applied to the total oral cavity. The agency believes that on
a short-term basis antiseptic ingredients can be used for local
application or for application to the total oral cavity to help prevent
infection in minor sore mouth conditions. Other monographs, e.g., the
tentative final monograph for OTC first aid antiseptic drug products
(56 FR 33644 at 33677) and the amendment to the tentative final
monograph for OTC oral health care drug products (56 FR 48302 at 48343
to 48346), identify situations where short-term use of a product for
minor sore mouth conditions is appropriate for consumer selfmedication
(e.g., use in minor oral wounds, accidental injury or irritation of the
mouth or gums, or minor wounds resulting from orthodontic appliances or
dentures). Accordingly, the agency is proposing the following
indication for these products in this tentative final monograph:
``First aid to help'' (select one of the following: ``prevent,''
(``decrease'' (``the risk of'' or ``the chance of'')), (``reduce''
(``the risk of'' or ``the chance of'')), ``guard against,'' or
``protect against'') (select one of the following: ``infection'' or
``bacterial contamination'') ``in'' (select any of the following:
``minor cuts,'' ``minor scrapes,'' or ``minor oral irritation'') (which
may be followed by) ``caused by'' (select any of the following:
``dental procedures,'' ``dentures,'' ``orthodontic appliances,'' or
``accidental injury'').
The Panel's Category III indication for oral antiseptics also
included use of these ingredients for sore throat by decreasing the
number of germs in the mouth. The agency has determined that this part
of the indication should remain in Category III because inadequate data
have been submitted to support a ``relief of sore throat'' indication.
The agency notes that the Panel discussed long-term uses of oral
antiseptics to cleanse the mouth and suppress mouth odors. The agency
considers such uses to be cosmetic in nature. Cosmetic claims are not
subject to this rulemaking. (See section I.A., comment 3.) However,
antiseptic mouthwashes used on a long-term basis for plaque reduction
are considered drugs. The agency will address the long-term use of
antiseptic mouthwash products for plaque reduction in a subsequent
segment of the OTC oral health care drug product rulemaking. (See
section I.A., comment 1 and section I.M., comment 32.)
In conclusion, the agency agrees with the comment that a first aid
claim is appropriate for OTC oral antiseptics and is proposing such a
claim in this tentative final monograph. Claims related to ``sore
throat,'' ``canker sores,'' and ``denture stomatitis'' are Category III
because additional data are needed to support these claims for OTC oral
antiseptics. The agency's evaluations of the ingredients phenol and
povidone-iodine, requested by the comment for Category I
classification, are discussed in section I.H., comment 14 and section
I.I., comment 16. No additional data were submitted to support the
efficacy of carbamide peroxide; thus, this ingredient remains in
Category III in this tentative final monograph. The agency invites the
submission of data to support reclassification of any oral antiseptic
ingredient(s) from Category III to Category I.
References
(1) Comment No. LET004 and OTC Vols. 130132 and 130163, Docket
No. 81N-0033, Dockets Management Branch.
(2) Addy, M. et al., ``Trial of Astringent and Antibacterial
Mouthwashes in the Management of Recurrent Aphthous Ulceration,''
British Dental Journal, 136:452-455, 1974.
(3) Olsen, I., ``Denture Stomatitis--Effects of Chlorhexidine
and Amphotericin B on the Mycotic Flora,'' Acta Odontologica
Scandinavica, 33:41-46, 1974.
23. One comment requested that the agency amend the Oral Cavity
Panel's Category III indication for oral health care antimicrobials
that states ``For the temporary relief of minor sore mouth and sore
throat by decreasing the germs in the mouth'' (47 FR 22760 at 22889).
The comment claimed that a portion of the statement, ``by decreasing
the germs in the mouth,'' is not an indication for use, but is a
statement of mechanism of action and should be deleted from the
proposed indication. The comment stated that including a mechanism of
action in the indication is not consistent with the labeling of other
OTC oral health care products such as anesthetic/analgesic agents,
astringents, debriding agents, or demulcents. Another comment requested
that the agency place the following labeling claim in Category I for
the combination of 0.045 percent cetylpyridinium chloride and 0.005
percent domiphen bromide: ``Temporarily reduces bacteria in the mouth
and throat.''
The agency acknowledges that the Oral Cavity Panel's recommended
Category III indication for oral antiseptics contains a phrase denoting
a mechanism of action as does the agency's proposed Category I
indication (see section I.K., comment 22). However, this type of
labeling is not inconsistent with some of the labeling indications
proposed by the agency for other oral health care drug products. For
example, the agency's proposed indication for debriding agents, which
states ``aids in the removal of phlegm, mucus * * * associated with
occasional sore mouth'' (56 FR 48302 at 48345), and the proposed
indication for demulcent drugs, which states ``* * * protection of
irritated areas in sore mouth and sore throat'' (56 FR 48346), contain
wording denoting a mechanism of action. Thus, although monograph
indications do not always include a mechanism of action, at times such
labeling is included in a monograph.
The agency does not believe that the labeling claim requested by
one comment, ``Temporarily reduces bacteria in the mouth and throat,''
is an appropriate indication for OTC oral health care drug products.
The indication does not inform consumers of what benefit might be
expected to result from reducing the bacteria in the mouth and throat.
Furthermore, the agency is not aware of any data demonstrating that
reducing the bacteria in the throat has a therapeutic benefit. However,
the agency has no objection to labeling referring to reduction of
bacteria in the mouth (e.g., temporarily reduces the number of bacteria
in the mouth) appearing in the labeling of OTC oral antiseptic drug
products as other information, provided it is not intermixed with
labeling established by the monograph and it is not used in a false or
misleading manner.
24. One comment objected to the Oral Cavity Panel's Category II
classification of the indication that states ``Helps provide soothing
temporary relief of dryness and minor irritations of the mouth,'' (47
FR 22760 at 22858) for mouthwash products containing povidone-iodine.
The comment mentioned that the Panel concluded that this statement
indicates that the product is used for cosmetic purposes but implies
that the product exerts a therapeutic effect (47 FR 22857 to 22858).
The comment felt that dryness and irritation of the mouth and throat
are recognized by the consumer as an abnormal condition and are thought
to be synonymous with such statements as ``minor irritation, pain, sore
mouth, and sore throat,'' ``discomfort,'' and ``irritated areas in sore
mouth and sore throat.'' The comment claimed that these statements
should be permitted as an alternate or adjunct to Category I labeling
for antimicrobial products, where the effects are documented with
substantial evidence.
The comment added that substantial evidence was submitted to show
that a povidone-iodine mouthwash provides relief of dryness and minor
irritations of the mouth and throat. The comment referred to evidence
supporting this indication, approved under NDA 10-290, but the comment
did not include any additional data concerning this claim. The comment
requested that the following indications be allowed under Sec. 356.51
for antimicrobial drug products containing povidone-iodine: (1) ``To
help (or Helps) provide soothing temporary relief of dryness and minor
irritations of the mouth and throat,'' and (2) ``Aids in the temporary
relief of occasional minor irritation, pain, sore mouth, and sore
throat.'' The comment noted that this second indication was recommended
by the Oral Cavity Panel for astringent drug products.
A second comment stated that the indications ``An aid to daily oral
care,'' and ``Provides soothing temporary relief of dryness and minor
irritations of the mouth and throat,'' and any reasonably synonymous
statements, should be approved for the combination of cetylpyridinium
chloride 0.045 percent and domiphen bromide 0.005 percent. A third
comment requested that the following claim be approved for use on
products containing cetylpyridinium chloride: ``For daily use as an
adjunct to good oral hygiene.''
In the Federal Register of December 2, 1971 (36 FR 23000), as part
of the agency's DESI program, the agency stated that mouthwash and
gargle products reviewed under the DESI program would now be under the
purview of the OTC drug review; thus, final agency action on these
products was deferred pending evaluation of the data and information
concerning such products under the OTC drug review. However, in the
meantime, the agency found the following labeling claims acceptable for
mouthwash products, on an interim basis: ``To help provide soothing
temporary relief of dryness and minor irritations of the mouth and
throat,'' ``an aromatic mouth freshener,'' ``an aid to daily care of
the mouth,'' and ``for causing the mouth to feel clean.'' Thus, the
comments' requested indication, ``To help provide soothing temporary
relief of dryness and minor irritations of the mouth and throat,'' was
allowed as a result of that DESI notice. In this tentative final
monograph, the agency is further addressing the claims permitted by
that DESI notice and requested by the comments.
The agency believes that the Panel was correct in placing the
statement ``Helps provide soothing temporary relief of dryness and
minor irritations of the mouth'' and similar statements in Category II
as an indication for the use of drug products containing antiseptic
ingredients. However, the agency believes that the Panel erred when it
included this statement under the heading of ``Statements or phrases
that indicate a product is used for cosmetic purposes but imply that
the product exerts a therapeutic effect'' (47 FR 22760 at 22857 and
22858). Statements containing phrases such as ``relief of dryness'' and
``irritation of the mouth and throat'' are more appropriate as
indications for drug products containing astringents (47 FR 22904) and
demulcents (47 FR 22919). Astringents alleviate irritation of the mouth
and throat and demulcents exert therapeutic actions that will alleviate
the conditions of ``dryness'' and ``irritation.'' On the other hand,
the agency does not have adequate evidence showing that antiseptic
ingredients are effective in alleviating dryness or irritation of the
mouth. These ingredients act by destroying microorganisms that may be
present, and there is no proof that the destruction of microorganisms
alleviates dryness or irritation.
Regarding the substantial evidence supporting the claim of ``relief
of dryness and minor irritations of the mouth and throat'' mentioned by
the first comment, the agency notes that no data were submitted to show
that consumers associate the therapeutic activity of an antiseptic
agent with the relief of dryness and minor irritations, nor were
adequately controlled studies substantiating the claim included in NDA
10-290. Therefore, the agency is not proposing such claims for any
antiseptic products.
The agency has already proposed a ``relief of dryness'' claim for
demulcent ingredients as part of this rulemaking in Sec. 356.58 of the
amendment to the tentative final monograph for OTC oral health care
drug products (56 FR 48302 at 48346). That claim states: ``For
temporary relief of minor discomfort and protection of irritated areas
in sore mouth and sore throat.'' As mentioned by one comment, the
proposed indications for oral health care astringent ingredients
presently include a claim for ``relief of minor irritation.'' (See
proposed Sec. 356.54 in the amendment to the tentative final monograph
for OTC oral health care drug products (56 FR 48345).)
With regard to the other labeling claims permitted in the December
2, 1971 DESI notice and the labeling claims suggested by the second and
third comments, i.e., ``An aid to daily oral care'' and ``For daily use
as an adjunct to good oral hygiene,'' the agency now considers these
types of claims to be cosmetic claims that are not subject to this
rulemaking. (See section I.A., comment 3.)
25. One comment stated that the 2-day duration of treatment
recommended by the Oral Cavity Panel for antimicrobial drug products
(47 FR 22760 at 22928) is insufficient ``to address normal healing
time.'' Stating that the Topical Antimicrobial Drug Products Panel
provided a 7-day use limit, the comment recommended that a 7-day
duration of use be adopted for this monograph.
The Oral Cavity Panel recommended the 2-day use limit for all OTC
oral health care drug products because of the risk of serious illness
if appropriate treatment of a sore throat is delayed. However, although
a sore mouth may denote the presence of a condition that requires
diagnosis and treatment by a physician, in most cases it is caused by
minor ulcerations and other benign conditions that are self-limited,
last only short periods of time, and generally heal spontaneously in 7
to 10 days (47 FR 22760 at 22774 to 22776). As stated in the first
segment of the oral health care drug products tentative final monograph
(53 FR 2436 at 2448), the agency believes that because symptoms
associated with a sore mouth are unlikely to be indicative of a serious
health threat, a 7-day use limitation of an OTC oral health care drug
product is appropriate for the relief of symptoms of a sore mouth,
e.g., pain and minor irritation. Because a sore throat can be the
symptom of a serious disease and may require more immediate attention,
the agency believes that it is necessary to place a 2-day limit on the
use of an OTC oral health care drug product that is used to relieve
symptoms of a sore throat.
For these reasons, in an amendment to the first segment of the OTC
oral health care drug products tentative final rulemaking (56 FR 48302
at 48343 and 48346), the agency subsequently proposed the following
warning for OTC oral health care drug products that are indicated for
the relief of sore mouth and sore throat symptoms: ``If sore throat is
severe, persists for more than 2 days, is accompanied or followed by
fever, headache, rash, swelling, nausea, or vomiting, consult a doctor
promptly. If sore mouth symptoms do not improve in 7 days, or if
irritation, pain, or redness persists or worsens, see your dentist or
doctor promptly.'' For products labeled for the relief of sore mouth
only, the proposed warning reads: ``Do not use this product for more
than 7 days unless directed by a dentist or doctor. If sore mouth
symptoms do not improve in 7 days, if irritation, pain, or redness
persists or worsens, or if swelling, rash, or fever develops, see your
dentist or doctor promptly.'' (See 56 FR 48302 at 48343, 48345, and
48346.)
Likewise, the agency believes that part of this proposed warning
may be applicable to OTC oral health care antiseptic drug products. At
this time, sore throat claims are Category III for oral antiseptic
ingredients. Therefore, in this document, the agency is not proposing
the first portion of the above warning for oral health care drug
products that are indicated for the relief of sore throat. If sore
throat claims for oral antiseptic ingredients are upgraded to Category
I, the agency will include the first portion of the above warning in
the final monograph for oral antiseptic drug products. The agency is
proposing in this amendment to the OTC oral health care tentative final
monograph that the second portion of the above warning replace the
warnings recommended by the Panel in Sec. 356.51(c)(1)(i) and
(c)(1)(ii). The agency believes that this warning fully conveys the
intent of the Panel's recommended warnings. This warning is included in
Sec. 356.64(c) of this tentative final monograph in case any oral
antiseptic ingredients are classified in Category I to help in reducing
the chance of infection in minor oral irritations.
26. One comment requested that the agency approve the following
wording, as well as reasonable variations thereof, for directions for
use for OTC oral antimicrobials/antiseptics: ``Rinse or gargle for 20
seconds with one ounce first thing in the morning, after meals, and
before social engagements.''
In this tentative final monograph, the agency is addressing only
the drug use of antiseptic ingredients in oral rinses and gargles. The
agency believes that the comment's suggested directions for use apply
to the cosmetic use of oral antiseptic products for the suppression of
oral malodor (e.g., ``first thing in the morning,'' and ``before social
engagements'') and for oral cleansing (e.g., ``after meals''). Such
directions are not appropriate for the drug use of these products and
therefore are not being included in this tentative final monograph.
However, antiseptic products intended for use only as cosmetics are not
subject to this rulemaking and may bear appropriate directions and
other labeling for cosmetic uses. (See section I.A., comment 3.)
27. One comment requested that the following professional labeling
for povidone-iodine be included in the oral health care drug products
monograph: ``Professional labeling--for local degerming prior to dental
prophylaxis and gingivectomy.'' Noting that the Antimicrobial I Panel
recommended labeling limited to professional use, the comment stated
that professional labeling should likewise be allowed for oral health
care drug products. The comment explained that the value of local
degerming using povidone-iodine mouthwash in dental prophylaxis and
gingivectomy procedures was shown in studies presented to the Panel
(Ref. 1). The comment added that the studies demonstrated substantial
evidence of the effectiveness of povidone-iodine mouthwash/gargle in
significantly reducing gingival surface bacteria prior to dental
prophylaxis and procedures, thereby reducing the risk of systemic
infection.
In the tentative final monograph for OTC health care antiseptic
drug products that will be published in a future issue of the Federal
Register, the agency intends to propose povidone-iodine in Category I
for use as a patient preoperative skin preparation, a surgical hand
scrub, and a health care personnel handwash. The agency has reevaluated
the data submitted to the Oral Cavity Panel (Ref. 1) and believes that
some of the submitted data (Refs. 2 and 3) support the requested
professional labeling for povidone-iodine in aqueous solution.
The Oral Cavity Panel stated that povidone-iodine's ``application
on the injection site of the oral mucosa prior to administering local
anesthesia virtually eliminates all readily cultivable organisms'' (47
FR 22760 at 22884). The Panel cited three studies (Refs. 2, 4, and 5)
that indicate that irrigation of the gingival sulcus and rinsing the
mouth with povidone-iodine immediately before tooth extraction or
gingivectomy markedly reduces the incidence of associated bacteremia
(i.e., the presence of bacteria in the blood). However, because two of
the cited studies (Refs. 4 and 5) were published only in abstract form,
the Panel considered the data insufficient in detail to be properly
evaluated (47 FR 22884).
One study cited by the Panel (Ref. 2) is supportive of professional
labeling for povidone-iodine solution for use in local degerming prior
to dental prophylaxis and gingivectomy. In this study, 52 patients
scheduled for gingivectomy were randomly divided into two equal groups.
Test patients were administered a 0.5-percent povidone-iodine solution,
whereas control patients were administered a placebo solution that was
identical in appearance to the povidone-iodine solution but contained
no povidone-iodine. Immediately prior to gingivectomy, each patient
rinsed for 30 seconds with about 20 mL of the assigned preparations.
The solution was then expectorated and, after a 2-minute interval, the
rinsing was repeated. The sulci of the teeth in the quadrant scheduled
for gingivectomy and the surrounding mucosa were then irrigated for
about 1 minute using 20 mL of the assigned liquid delivered by a
standard syringe with a blunt, angulated needle. Gingival surface
samples were obtained by swabbing the gingiva just prior to rinsing and
immediately after irrigation with the assigned preparation. These
gingival swabs provided the inoculum for blood agar plates that were
incubated aerobically and anaerobically at 36 deg.C for 48 hours.
After incubation, the colonies on the plates were counted. The grading
system for estimating the number of bacterial colonies per plate ranged
from 1+ (i.e., few) to 4+ (i.e., too-numerous-to-count), and the major
genera and/or species were enumerated. About 15 mL of blood were drawn
from each patient before rinsing with the assigned preparation and
within 3 minutes after the gingivectomy. The samples were cultured
aerobically and anaerobically, and subsequent isolates were identified
by standard bacteriological procedures.
The use of the povidone-iodine solution significantly reduced the
incidence of post-gingivectomy bacteremia (p < 0.5). Fifteen control
patients developed positive blood cultures, but only six patients in
the test group developed positive blood cultures. Virtually all
prerinse bacterial cultures resulted in colony count scores of 4+. Use
of the test preparation produced an average decrease of 33 to 42
percent in colony count scores (for example, a decrease from a average
score of 4+ to a average score of 2.7). Comparable degerming occurred
for both aerobic and anaerobic bacteria.
In a double-blind clinical study (Ref. 3), Scopp and Orvieto
randomly assigned 64 patients requiring dental extraction into two
groups. One group of 32 patients was prepared preoperatively by
gingival sulcal irrigation and rinsing with a 0.5-percent povidone-
iodine oral rinse; the other 32 patients were prepared preoperatively
in the same manner except that a placebo solution (colored, flavored,
and packaged to match the active drug) was used for irrigation and
rinsing. All patients were instructed to rinse for 30 seconds with 10
to 20 mL of the assigned oral rinse, then wait 2 minutes and repeat the
rinse. The gingival sulcus of each tooth to be extracted and the
surrounding gingival mucosa were then irrigated for approximately 1
minute with 10 to 20 mL of the assigned solution using a standard
syringe and blunt, angulated needle. Prior to rinsing and immediately
after irrigation, cultures of the gingival sulcus were obtained. Dental
extraction was performed without further antisepsis. Blood samples were
obtained for culture before rinsing and within 3 minutes after the
dental extraction.
Bacteremia (i.e., positive blood cultures) occurred in 28 percent
of the patients using the povidone-iodine oral rinse and in 56 percent
of the patients using the placebo solution. The difference between the
two groups is statistically significant in favor of povidone-iodine (p
< 0.05). The gingival sulcus cultures taken immediately after rinsing
and irrigation with the povidone-iodine oral rinse showed reduction or
elimination of bacteria in 14 patients, no change in 17 patients, and
increased growth in 1 patient. For the placebo group, the gingival
sulcus cultures showed no growth and reduced growth in 1 patient each,
no change in 28 patients, and increased growth in 2 patients. The
difference in bacterial reduction of the gingival sac in the two groups
is also statistically significant (p < 0.01).
The agency believes that these studies demonstrate the
effectiveness of a 0.5-percent povidone-iodine aqueous solution for the
preparation of the oral mucosa prior to injection, dental surgery, or
tooth extraction when used by a health care professional according to
the directions proposed in Sec. 356.80(c)(3) of this tentative final
monograph. However, these studies do not demonstrate the effectiveness
of povidone-iodine when used by consumers as an oral antiseptic. In
order for an ingredient to be classified in Category I as an oral
antiseptic, the agency believes that, among other things, the
ingredient should demonstrate the ability to decrease the number of
bacteria in the oral cavity over an extended period of time (e.g., up
to 4 hours). In addition, the ingredient should provide clinically
significant benefits under OTC conditions of use (e.g., helping to
prevent infection in minor wounds in the mouth, or relieving the
symptoms of sore throat). (See section I.M., comment 33 for further
discussion of testing procedures.) These data demonstrate that applying
povidone-iodine according to the directions proposed in
Sec. 356.80(c)(3) of this tentative final monograph results in an
immediate decrease of bacteria around the operation or extraction site
and a decrease of bacteremia after oral surgery or tooth extraction.
Although the studies sampled the gingival mucosa surrounding the
operation sites prior to and immediately after surgery or tooth
extraction, they did not demonstrate a decrease in the number of oral
bacteria over an extended period of time. In addition, the organisms
affected by the povidone-iodine treatment were not completely
identified. Furthermore, these data do not demonstrate a therapeutic
benefit from the OTC use of povidone-iodine. Therefore, the agency is
classifying povidone-iodine in Category III for effectiveness as an OTC
oral antiseptic in this tentative final monograph. (See section I.I.,
comment 16.) The agency is placing povidone-iodine in Category I for
use as a dental preoperative by health care professionals and is
proposing labeling for such products in Sec. 356.80.
References
(1) OTC Vol. 130176.
(2) Brenman, H. S., and E. Randall, ``Local Degerming with
Povidone-Iodine II. Prior to Gingivectomy,'' Journal of
Periodontology, 45:870-872, 1974.
(3) Scopp, I. W., and L. D. Orvieto, ``Gingival Degerming by
Povidone-Iodine Irrigation: Bacteremia Reduction in Extraction
Procedures,'' Journal of the American Dental Association, 83:1294-
1296, 1971.
(4) Brenman, H. S., and E. Randall,``Reduction of Gingival
Bacteria and Gingivectomy-Related Bacteremia by Povidone-Iodine,''
International Association of Dental Research, (Abstract #211), 1972.
(5) Randall, E., and H. S. Brenman, ``Antimicrobial Action of
Povidone-Iodine Mouthwash Before and During Dental Prophylaxis,''
Journal of Dental Research, 51:101, 1972.
L. Comments on Combination Oral Antiseptic Drug Products
28. One comment noted that the Dental Panel recognized that the
combination of an oral antiseptic (i.e., antimicrobial agent) and an
oral wound cleanser (i.e., debriding agent) was rational and should
provide additional protection for an oral wound (44 FR 63270 at 63276).
The Oral Cavity Panel, however, placed the same combination in Category
II because it believed that the antimicrobial agent would be diluted
and washed away from the diseased surface (47 FR 22760 at 22792). The
comment stated that manufacturer's directions state that these products
should remain in contact with the wound site for at least 1 minute. The
comment added that there are active ingredients that function as
antimicrobial agents as well as debriding agents and that ingredients
with both properties are effective when applied locally. The comment
explained that because the purpose of an antiseptic is to decrease the
number of bacteria and reduce the chance of infection after minor
injuries to oral cavity tissues, the combination of a debriding agent
and an antiseptic provides logical therapy to reduce chances of
infection, while cleansing the wound site.
In the first segment of the tentative final monograph for OTC oral
health care drug products (53 FR 2436), the agency incorporated
portions of the OTC oral mucosal injury rulemaking, which includes oral
wound cleansers and oral wound healing agents, into the oral health
care rulemaking and proposed that debriding agents and oral wound
cleansers be treated as a single therapeutic class of ingredients. The
agency addressed OTC oral wound healing agents separately in a final
rule (51 FR 26112) and deferred consideration of the combination of an
oral wound cleanser and an oral antiseptic (as recommended in
Sec. 353.20(b) by the Dental Panel) to this antiseptic segment of the
rulemaking for OTC oral health care drug products.
Although the Dental Panel recommended that the combination of an
oral wound cleanser and an oral antiseptic be classified as Category I,
it stated in a parenthetical note that ``the advisability of adding an
antiseptic for the stated purpose is under review by the OTC Advisory
Review Panel on Oral Cavity Drug Products'' (44 FR 63270 at 63276).
After reviewing both Panels' recommendations, the agency agrees with
the Oral Cavity Panel's Category II classification of one or more
antiseptic ingredients combined with any debriding agent. The agency is
concerned that combining an antiseptic ingredient with a debriding
agent/oral wound cleanser would decrease the effectiveness of the
antiseptic ingredient. Because debriding agent/oral wound cleansers
loosen and remove tissue, debris, mucus, etc., from mucosal surfaces by
their chemical and mechanical action (e.g., foaming, lowering surface
tension, and reducing viscosity of mucus), the antiseptic ingredient
might not be in direct contact with the oral mucosa for a long enough
period of time to exert a significant antiseptic effect, even though
the manufacturer's directions state that these products should remain
in contact with the wound site for at least 1 minute before spitting
out. The agency believes that a reasonable time to apply a Category I
antiseptic to an oral mucosal wound site or to the site of an oral
inflammation is after that site has been cleansed with a debriding
agent/oral wound cleanser. Additionally, the agency has surveyed the
marketplace and is not aware of any currently available OTC drug
product containing a combination of an oral health care antiseptic
ingredient and an oral wound cleanser or debriding agent, nor were data
on any such products submitted to either the Dental Panel or the Oral
Cavity Panel.
The comment mentioned that some debriding agents also function
effectively as antiseptic agents. However, there are no Category I
debriding agent/oral wound cleansers that are also Category I
antiseptic agents in this tentative final monograph.
In conclusion, for the reasons stated above, the agency is
classifying the combination of an antiseptic agent and a debriding
agent/oral wound cleanser in Category II in this tentative final
monograph. Data are needed to show that the two ingredients are
effective when used in combination.
29. Several comments pointed out that the Dental Panel had placed
the following combinations in Category I in Sec. 354.20(b), (c), and
(d), respectively, of its recommended monograph: (1) An oral mucosal
protectant and an oral antiseptic, (2) an oral mucosal analgesic and an
oral antiseptic, and (3) an oral mucosal protectant, an oral mucosal
analgesic, and an oral antiseptic. The comments noted that the Dental
Panel had deferred review of the antiseptic ingredients to the Oral
Cavity Panel, but that Panel failed to address locally applied
antiseptics in the combinations placed in Category I by the Dental
Panel. The comments maintained that these combinations are rational
because the antiseptic ingredient will help to prevent or reduce
possible infection while the oral mucosal analgesic will relieve the
pain due to minor irritations or injury to the oral mucosa, and the
addition of an oral mucosal protectant provides a coating over the
wound for protection and holds the analgesic and antiseptic ingredients
in place where they can act most effectively. The comments urged FDA to
accept the recommendations of the Dental Panel and permit these
combinations in the tentative final monograph for OTC oral health care
drug products.
One of the comments added that the labeling in the tentative final
monograph for OTC topical antimicrobial drug products (47 FR 22986 at
29989) is consistent with the rationale expressed by the Dental Panel
for its recommendation to place the combination of an oral mucosal
analgesic and an oral antiseptic in Category I. The comment contended
that the following claims could be used for topically applied oral
antiseptics in such combination products:
(1) (Select one of the following: ``Decreases'' or ``Helps
reduce'') ``the number of bacteria on the treated area.''
(2) ``Helps'' (select one of the following: ``prevent,'' ``guard
against,'' or ``protect against'') ``* * * infection.''
(3) ``Helps reduce the'' (select one of the following ``risk''
or ``chance'') ''of * * * infection.''
(4) ``Helps prevent bacterial contamination in minor cuts,
scrapes, and burns.''
The agency has reviewed the Dental Panel's discussion regarding
combinations (47 FR 22712 at 22720) and, in general, agrees with that
Panel that the following combinations are rational: (1) Oral antiseptic
and oral anesthetic/analgesic; (2) oral antiseptic and oral mucosal
protectant; (3) and oral antiseptic, oral anesthetic/analgesic, and
oral mucosal protectant. In addition, the agency has reviewed the Oral
Cavity Panel's evaluation of combinations containing oral antiseptic
active ingredients (47 FR 22760 at 22790 to 22793) and agrees that the
following combinations are reasonable: (1) Oral antiseptic and oral
astringent; (2) oral antiseptic and oral demulcent; (3) oral
antiseptic, oral anesthetic/analgesic, and oral astringent; and (4)
oral antiseptic, oral anesthetic/analgesic, and oral demulcent.
Accordingly, the agency is proposing these seven combinations in
Sec. 356.26 of this tentative final monograph.
However, this tentative final monograph does not include any
Category I oral antiseptic ingredients. Therefore, these combinations
will not be included in the final monograph unless at least one oral
antiseptic active ingredient achieves monograph status. Further, the
agency notes that the seven proposed Category I combinations may not be
appropriate for all Category III oral antiseptic ingredients. For
example, if hydrogen peroxide were upgraded to Category I as an oral
antiseptic, it might not be appropriate to combine hydrogen peroxide
with an oral mucosal protectant or an oral demulcent. As each oral
antiseptic ingredient achieves monograph status, the agency will
evaluate that ingredient specifically as to which combinations are
suitable.
In this tentative final monograph, the indication being proposed
for oral health care antiseptic drug products is similar in content to
those recommended by one of the comments. (See section I.K., comment
22.) Indications for oral anesthetic/analgesic, oral astringent, oral
demulcent, and oral mucosal protectant drug products were proposed in
Secs. 356.52(b), 356.54(b), 356.58(b), and 356.60(b) of the amendment
to the tentative final monograph for OTC oral health care drug products
(56 FR 48302 at 48343 to 48346).
The agency considers that the indication proposed for oral
anesthetic/analgesic ingredients in Sec. 356.52(b)(1) (``For the
temporary relief of occasional minor irritation, pain, sore mouth, and
sore throat,'') as not appropriate for a combination product containing
an oral antiseptic because ``temporary relief of sore throat'' is a
Category III indication for OTC oral antiseptics. (See section I.K.,
comment 22.) In addition, the agency considers the indication proposed
for oral anesthetic/analgesic ingredients in Sec. 356.52(b)(2) (``For
the temporary relief of pain associated with canker sores'') as not
suitable for a combination product containing an OTC oral antiseptic
ingredient because claims related to canker sores are Category III for
OTC oral antiseptics. Likewise, the agency does not consider the
indication proposed for oral anesthetic/analgesic ingredients in
Sec. 356.52(b)(7) for denture adhesive products containing an oral
anesthetic/analgesic (``For the temporary relief of pain or discomfort
of the mouth and gums due to dentures'') as appropriate for products
containing an oral antiseptic ingredient because there is no Category I
combination that includes an oral antiseptic and a denture adhesive.
Therefore, when an oral antiseptic is present in certain combination
products (i.e., with: (1) An oral anesthetic/analgesic, (2) an oral
anesthetic/analgesic and an oral mucosal protectant, (3) an oral
anesthetic/analgesic and an oral astringent, or (4) an oral anesthetic/
analgesic and an oral demulcent), the labeling of the product may not
contain the indications proposed for oral anesthetic/analgesic
ingredients in Sec. 356.52(b)(1), (b)(2), and (b)(7).
Additionally, the Oral Cavity Panel recommended that oral
antiseptics should not be used in children under 3 years of age (47 FR
22760 at 22928). In Sec. 356.50(d), Sec. 356.54(d), Sec. 356.56(d), and
Sec. 356.58(d) of the tentative final monograph for OTC oral health
care drug products, the agency proposed that the lower age limit for
OTC oral health care ingredients be 2 years, except for sodium
perborate monohydrate (6-year lower age limit), phenol preparations
that are intended for ingestion or that could be inadvertently ingested
(6-year lower age limit), tooth desensitizers (12-year lower age
limit), butacaine sulfate (12-year lower age limit), and teething
preparations (4-month lower age limit) (56 FR 48302 at 48343 to 48346).
The agency does not believe that oral antiseptics should be used in
children under 2 years of age unless done so under a doctor's
supervision. Therefore, the agency is not proposing the indication for
oral anesthetic/analgesic ingredients in Sec. 356.52(b)(6) for
benzocaine or phenol used in products for teething pain (``For the
temporary relief of sore gums due to teething in infants and children 4
months of age and older'') for a combination product containing an oral
antiseptic and an oral anesthetic/analgesic or an oral antiseptic, an
oral anesthetic/analgesic, and an oral mucosal protectant.
The agency does not consider the indication proposed for oral
astringents in Sec. 356.54 (``For the temporary relief of occasional
minor irritation, pain, sore mouth, and sore throat'') as appropriate
for a combination product containing an oral antiseptic and an oral
astringent because oral antiseptics are not indicated for use in
relieving the discomfort of sore throat. Therefore, when an oral
antiseptic is combined with an oral astringent or an oral anesthetic/
analgesic and an astringent, the indication proposed for oral
astringent drug products in Sec. 356.54 is not appropriate. Instead,
the agency is proposing the following indication for a combination
product containing an oral antiseptic and an oral astringent: ``For
temporary relief of occasional minor irritation, pain, and sore
mouth.'' The agency is also proposing that a combination product
containing an oral antiseptic, an oral astringent, and an oral
anesthetic/analgesic be labeled with any of the applicable indications
proposed in Sec. 356.52(b)(3), (b)(4), or (b)(5) or with the indication
proposed above for a combination drug product containing an oral
antiseptic and an oral astringent.
The agency does not consider the indication proposed for oral
demulcents in Sec. 356.58 (``For temporary relief of minor discomfort
and protection of irritated areas in sore mouth and sore throat'') as
appropriate for a combination product containing an oral antiseptic and
an oral demulcent because oral antiseptics are not indicated for use in
relieving the discomfort of sore throat. Therefore, when an oral
antiseptic is combined with an oral demulcent or an oral anesthetic/
analgesic and an oral demulcent, the indication proposed for oral
demulcent drug products in Sec. 356.58 is not appropriate. Instead, the
agency is proposing the following indication for a combination product
containing an oral antiseptic and an oral demulcent: ``For temporary
relief of minor discomfort and protection of irritated areas in sore
mouth.'' The agency is also proposing that a combination product
containing an oral antiseptic, an oral demulcent, and an oral
anesthetic/analgesic be labeled with any of the applicable indications
proposed in Sec. 356.52(b)(3), (b)(4), or (b)(5) or with the indication
proposed above for a combination product containing an oral antiseptic
and an oral demulcent.
The agency has determined that the indication proposed for oral
mucosal protectant active ingredients in Sec. 356.60(b)(4) (``For
protecting recurring canker sores'') should not be used for a
combination product containing an oral antiseptic and an oral mucosal
protectant because claims related to canker sores are Category III for
oral antiseptics. (See section I.K., comment 22.) Therefore, when an
oral antiseptic is combined with an oral mucosal protectant, the
indication proposed for oral mucosal protectants in Sec. 356.60(b)(4)
is not appropriate.
The agency also notes that certain warnings proposed for oral
anesthetic/analgesic ingredients in Sec. 356.52(c)(1), (c)(5), and
(c)(6), for oral astringents in Sec. 356.54(c), and for oral demulcents
in Sec. 356.58(c)(1) would not be applicable to certain combination
products containing an oral antiseptic. The warnings in
Sec. 356.52(c)(1), Sec. 356.54(c), and Sec. 356.58(c)(1) are partially
sore throat warnings that limit use of a product to 2 days if the sore
throat is severe or is accompanied by or followed by fever, headache,
rash, swelling, nausea, or vomiting. These warnings are not applicable
to a combination product containing an antiseptic because an oral
antiseptic is not indicated for use to relieve the symptoms of sore
throat. In addition, because oral antiseptics may not be used in
teething products or denture adhesives, the warnings related to such
products in Sec. 356.52(c)(5) and (c)(6) are not applicable to
combination drug products containing an oral antiseptic and an oral
anesthetic/analgesic or an oral antiseptic, an oral anesthetic/
analgesic, and any other oral health care ingredient.
Because this tentative final monograph does not include any
Category I antiseptic ingredients, the agency is not proposing any
directions for oral antiseptic ingredients. The agency is reserving
Sec. 356.64(d) for directions should any oral antiseptic ingredients be
included in the final monograph. Likewise, for the same reason, the
agency is not proposing any directions for oral health care combination
drug products containing antiseptic ingredients.
Based on the above discussion, the agency is proposing to include
specific indications and warnings in Sec. 356.66(b) and (c) for the
labeling of combination drug products that include an oral antiseptic.
This labeling will appear in the final monograph only if at least one
oral antiseptic active ingredient achieves monograph status.
30. One comment requested that the agency approve the combination
of 0.045 percent cetylpyridinium chloride and 0.005 percent domiphen
bromide as a Category I oral antiseptic. The comment contended that the
addition of small amounts of domiphen bromide to a formulation
containing cetylpyridinium chloride enhances the in vitro activity of
the formulation against gram-positive and gram-negative standard
bacterial cultures. The comment contended that this performance
improvement satisfies even the Oral Cavity Panel's criteria for the
combination of two active ingredients from the same therapeutic
category having the same pharmacological mechanism of action (47 FR
22760 at 22792). The comment added that in calling for ``improvement of
safety or enhanced effectiveness or both,'' the Panel went well beyond
the existing regulatory guidelines for OTC combinations in
Sec. 330.10(a)(4)(iv), which requires only that each ingredient in the
combination make a contribution to the claimed effect.
The comment submitted the results of two in vitro studies designed
to justify the combination of 0.045 percent cetylpyridinium chloride
and 0.005 percent domiphen bromide (Ref. 1). It also submitted a
published article suggesting that this combination was more effective
in a clinical study than a formulation containing cetylpyridinium as
the sole oral antiseptic ingredient (Ref. 2).
The agency discussed the Oral Cavity Panel's recommendations
regarding combination products in the first segment of the tentative
final monograph for OTC oral health care drug products (53 FR 2436 at
2450). The Panel recommended that any Category I oral health care
ingredient could be combined with one or more ingredients from the same
therapeutic category if each ingredient is present in its full
therapeutic dose, or subtherapeutic dose where appropriate, only when
there is a clear demonstration that there is an improvement of safety
or enhanced effectiveness or both (47 FR 22760 at 22927). However, the
agency currently uses the combination policy in Sec. 330.10(a)(4)(iv)
and its guidelines for OTC drug combination products (Ref. 3) as the
criteria for evaluating all OTC combination drug products.
The combination policy in Sec. 330.10(a)(4)(iv) states that an OTC
drug may combine two or more safe and effective (Category I)
ingredients when each ingredient makes a contribution to the claimed
effect(s); when combining the ingredients does not decrease the safety
or effectiveness of any of the individual ingredients; and when the
combination, used under adequate directions for use and warnings
against unsafe use, provides rational therapy for a significant
proportion of the target populations. Paragraph 3 of the agency's
guidelines (Ref. 3) requires that, for combinations of ingredients from
the same therapeutic category with the same mechanism of action, such
combinations should not ordinarily be combined unless there is some
advantage over the single ingredients in terms of enhanced
effectiveness, safety, patient acceptance, or quality of formulation.
The ingredients may be combined in selected circumstances to treat the
same symptoms or conditions if the combination meets the OTC
combination policy in all respects, the combination offers some
advantage over the active ingredients used alone, and the combination
is, on a benefit-risk basis, equal to or better than each of the active
ingredients used alone at its therapeutic dose.
Although the agency believes that the ingredients cetylpyridium
chloride and domiphen bromide in the concentrations mentioned by the
comment are safe for OTC use as oral antiseptics, neither ingredient
has been demonstrated to be an effective oral antiseptic. (See section
I.E., comment 9 and section I.G., comment 13.) The data submitted by
the comment are not adequate to demonstrate the effectiveness of either
ingredient or a combination of the two ingredients. The two in vitro
studies tested the ingredients against only two organisms,
Staphylococcus aureus and Salmonella typhosa (Ref. 1). The agency does
not believe that demonstrating antiseptic effectiveness against these
two microorganisms is relevant to the use of an antiseptic in the oral
cavity. The published article reported the results from a study of the
effects of two mouthwashes on bacterial plaque (Ref. 2). As stated in
section I.M., comment 32, the agency agrees with the Panel that
reduction of plaque accumulation is not an appropriate criterion for
establishing oral antiseptic effectiveness. (See section I.M., comment
33 for a discussion of appropriate testing procedures.)
References
(1) Attachment D, C00013, Docket No. 81N-0033, Dockets
Management Branch.
(2) Barnes, G. P. et al., ``Effects of Two Cetylpyridinium
Chloride-Containing Mouthwashes on Bacterial Plaque,'' C00013,
Docket No. 81N-0033, Dockets Management Branch.
(3) FDA, ``General Guidelines for OTC Drug Combination
Products,'' September 1978, Docket No. 78D-0322, Dockets Management
Branch.
31. One comment stated that cetylpyridinium chloride and domiphen
bromide are effective OTC oral antiseptics and that an application (NDA
14-598) for a product containing these ingredients had been approved
for 18 years, i.e., up to November 17, 1982, the date of the comment.
The comment stated that NDA 14-598 established the safety and
effectiveness of the active ingredients, cetylpyridinium chloride 0.045
percent and domiphen bromide 0.005 percent, and their combination; and
that the same combination is used today. The comment maintained that
supplementation of the application and periodic reporting have
supported and even strengthened the proof of safety and effectiveness.
In addition, the comment stated that extensive tests demonstrating the
ability of a product containing cetylpyridinium chloride and domiphen
bromide to kill bacteria and viruses in vitro were reported to the
Panel (Ref. 1) and are included in NDA 14-598. The comment also stated
that NDA 14-598 contains the results of numerous tests showing
reduction of bacterial counts after rinsing with the product and that
the application contains data showing effectiveness of the product in
temporarily relieving minor sore throat. The comment stated that
although the bulk of the material in NDA 14-598 is not publicly
available, it is in the agency's files and may be used by the agency to
support these comments. Moreover, the comment contended that it regards
the continuing validity of the application as conclusive evidence of
the product's safety and effectiveness for use as an OTC oral
antiseptic (Ref. 2).
The agency notes that data contained in an application are
confidential information covered by 21 CFR 20.61 and are not publicly
available. The sponsor of the application would have to affirmatively
submit these data as part of the public administrative record for the
agency to consider them in this rulemaking proceeding. As the agency
has indicated elsewhere under similar conditions concerning an
antitussive drug product containing diphenhydramine hydrochloride (48
FR 48576 at 48582), determination by FDA that a new drug is safe and
effective and the approval of an application for the drug are not
synonymous with a determination that a drug is generally recognized as
safe and effective in the OTC drug review. See Weinberger v. Bentex
Pharmaceuticals, Inc., 412 U.S. 645, 651 (1973). In addition, the
agency is aware that the commentor requested that approval of NDA 14-
598 be withdrawn because the product was no longer being marketed as a
drug (Ref. 4).
General recognition of the effectiveness of a drug in the OTC drug
review must be based on adequate published or publicly available
medical and scientific data. (United States v. 41 Cases * * * Naremco,
420 F.2d 1126 (C.A. 5, 1970); United States v. An Article of Drug * * *
Mykocert, 345 F. Supp. 571 (D.C. 1972); United States v. An Article of
Drug * * * Asper Sleep, CCH F.D. and Cosm. L. Rep. 40,821 Civil No. 70-
C-196 (N.D. Ill. 1971); United States v. An Article of Drug * * *
(Furestorol Vaginal Suppositories 294 F. Supp 1307 (N.D. Ga. 1968).)
There is not adequate information publicly available at this time to
demonstrate that cetylpyridinium chloride, domiphen bromide, or the
combination of the two ingredients are generally recognized as
effective for the Category I indication proposed in this document.
Therefore, the agency is unable to conclude at this time that these
ingredients or a combination of these ingredients are generally
recognized as effective oral antiseptic agents, and is proposing that
they be Category III for effectiveness. (See section I.E., comment 9;
section I.G., comment 13; and section I.L., comment 30.)
References
(1) OTC Vols. 130078, 130118, 130134, 130160, and 130187.
(2) Attachment F, Comment No. C00013, Docket No. 81N-0033,
Dockets Management Branch.
(3) Attachment G, Comment No. C00013, Docket No. 81N-0033,
Dockets Management Branch.
(4) Letter from W. E. Cooley, The Procter & Gamble Co., to the
Division of Radiopharmaceutical, Surgical, and Dental Drug Products,
FDA, NDA 14-598, dated January 5, 1990, OTC Vol. 130CTFM.
M. Comments on Testing
32. Addressing the Oral Cavity Panel's consideration of protocols
for testing antiseptic mouthwashes, two comments stated that the
measurement of plaque reduction is a valid technique to assess the
antimicrobial activity of oral antiseptics. Noting that dental plaque
is largely composed of living bacteria within a polysaccharide matrix,
one comment contended that experts recognize that ``antiseptic activity
may be measured in the mouth by taking counts of unattached organisms
before and after treatment, or by measuring plaque differences among
subjects receiving either the test substance or a control.'' The
comment mentioned that the Panel's minority report outlines a scheme of
reasonable in vitro and in vivo tests that are well accepted and have
been shown to be satisfactory in demonstrating the antiseptic activity
of mouthwashes (47 FR 22760 at 22893 to 22901). The comment added that,
in 1978, the Oral Cavity Panel voted approval of the clinical protocols
needed to support Category I status for oral antimicrobials for use in
mouthwashes, and that a professional association of manufacturers
concurred with that recommendation. The comment urged that these
protocols be reinstated as the proof required to obtain Category I
status for antimicrobial mouthwashes.
Also citing the Panel's minority report, the second comment stated
that the majority of the Panel, at its next-to-last meeting, voted to
reject the testing guidelines for demonstrating antiseptic activity
that the Panel had recommended to industry over the course of several
years and that the firm submitting the comment had relied upon to
confirm its product's antiseptic properties. Although pointing out that
the majority of the Panel evidently desired an objective test to
justify plaque reduction as a criterion for establishing antimicrobial
activity (47 FR 22760 at 22841), the comment contended that such an
objective test was originally prescribed by the Panel and successfully
conducted for the firm's mouthwash product containing a combination of
volatile oils. The comment stated that reductions in dental plaque
biomass have been shown to correlate with reductions in dental plaque
bacteria by objective weight measurement (47 FR 22894 to 22895) and
that other equally valid plaque reduction measurements, such as area
measurement, were also successfully conducted for the firm's product.
The comment concluded that these ``state of the art'' plaque reduction
measurements should be accepted as indices of antiseptic action.
The agency is aware that the majority of the Panel stated that
``the rationality of plaque reduction as a criterion of effectiveness
of antimicrobial agents for use in the mouth and throat is highly
debatable, and evidence of the validity of the method is scant. Plaque
reduction, therefore, is not accepted by this Panel as a criterion for
determining effectiveness of antimicrobial agents for oral health care
products intended to treat sore mouth or sore throat,'' (47 FR 22840).
The agency agrees with the Panel and believes that plaque reduction has
not been established as a valid technique for determining the
antiseptic effectiveness of ingredients used for the types of
indications being considered in this segment of the tentative final
monograph: (1) First aid to help prevent infection in the mouth, or (2)
for the temporary relief of minor sore throat symptoms.
The agency believes that the types of tests suggested in the
Panel's testing guidelines at 47 FR 22760 at 22890 to 22893 are better
suited to demonstrate the effectiveness of antiseptic ingredients in
reducing the risk of infection in the oral cavity or in relieving sore
mouth and sore throat symptoms. These testing guidelines are further
discussed in section I.M., comment 33. However, as discussed in the
previous segments of this tentative final monograph (see 53 FR 2436 and
56 FR 48302), in developing this monograph the agency is not addressing
specific testing guidelines for upgrading ingredients to Category I. In
revising the OTC drug review procedures relating to Category III,
published in the Federal Register of September 29, 1981 (46 FR 47730),
the agency advised that tentative final and final monographs will not
include recommended testing guidelines for conditions that industry
wishes to upgrade to monograph status. Instead, the agency will meet
with industry representatives at their request to discuss testing
protocols. The revised procedures also state the time in which test
data must be submitted for consideration in developing the final
monograph. (See also part II. paragraph A.2.--Testing of Category II
and Category III conditions.)
The agency wishes to point out that, as discussed in the call-for-
data for antiplaque ingredients and claims (55 FR 38560), the Dental
Products Panel will evaluate data regarding the safety and
effectiveness of active ingredients contained in products displaying
antiplaque and antiplaque-related claims. A subsequent segment of the
rulemaking for OTC oral health care drug products will cover that
Panel's recommendations to the agency regarding drug ingredients used
for the reduction of plaque and plaque-related claims. Methods
discussed by the comments and by the minority of the Oral Cavity Panel
may be appropriate to demonstrate antiseptic activity of ingredients
intended to reduce or prevent plaque.
33. Two comments stated that presentations had been made to the
Oral Cavity Panel concerning guidelines for in vitro and in vivo
testing of topical antiseptics (Refs. 1, 2, and 3) and that these data
were not considered or included in that Panel's discussion. The
comments contended that the guidelines were adequate to test
ingredients for effectiveness and to establish a first aid antiseptic
category for oral health care drug products that meet these guidelines.
The comments stated that the guidelines provide for a statistically
significant reduction in vivo combined with a 95-percent reduction in
vitro of the organisms tested and, thus, provide proof of clinically
useful antiseptic activity.
One comment paraphrased an agency statement that was published in
the tentative final monograph for OTC topical antimicrobial drug
products (i.e., first aid antibiotic drug products) (47 FR 29986 at
29991 to 29992) as follows:
The agency agrees with the comments that minor skin injuries,
such as cuts and scrapes, are self-healing and that the body's
healing mechanisms can handle some infections that might develop in
these injuries. However, as the reply comment pointed out, some
minor skin injuries do not heal without treatment and it is
impossible to make that distinction at the time of injury. It is
well documented that applying topical antibiotics to skin wound
lesions reduces the number of bacteria at the site of application
and serves as an adjunct to cleansing wounds.
The comment argued that, in view of the agency's medical assessments of
topical antibiotics as stated above, clinical testing of each
ingredient or product is unnecessary. The comment felt that in vitro
data demonstrating that a product's active ingredient is effective
against the organism(s) likely to be found at the site should be
sufficient to allow classification in Category I. The comment added
that such a decision would be consistent with the agency's acceptance
of all Category I topical antibiotics for the first aid indication to
help prevent infection in minor cuts, scrapes, and burns (47 FR 29986
at 29999).
The Oral Cavity Panel considered the presentations concerning
guidelines for in vitro and in vivo testing (Refs. 1, 2, and 3) and
made suggestions concerning requirements for conducting such studies
designed to obtain data for reclassifying Category III ingredients to
Category I for safety and effectiveness or both (47 FR 22760 at 22890
to 22893). The Panel suggested that preliminary, well-designed in vitro
studies be required to demonstrate antiseptic effectiveness and that
the data obtained from in vitro studies be verified and supported by in
vivo animal and human studies. The Panel stated that human model
studies should be followed by appropriate clinical trials. The Panel
included recommendations for in vitro and in vivo testing procedures to
indicate the types of data necessary to upgrade ingredients from
Category III to Category I and provided suggestions for obtaining such
data.
Clinical Testing of OTC Oral Antiseptics
The agency believes that data from in vitro testing alone are
insufficient to establish that an oral antiseptic is generally
recognized as effective in: (1) Decreasing the number of microorganisms
in the oral cavity and thus helping to prevent or reduce the chance of
infection or bacterial contamination in minor oral wounds, or (2)
temporarily relieving the symptoms of minor sore throat or mouth. The
agency's assessment of the effectiveness of topical antibiotics in
helping to prevent infection in minor skin cuts, scrapes, and burns (47
FR 29986 at 29991 to 29992) is not relevant in evaluating the
effectiveness of oral antiseptic ingredients in helping to prevent
infection in minor wounds in the mouth. Although demonstrated in vitro
antiseptic bactericidal or bacteriostatic action is of predictive value
in projecting clinical efficacy for antiseptics used on the skin (39 FR
33103 at 33110 and 56 FR 33644 at 33671), the agency believes that such
activity alone is not sufficient to allow classification of an
ingredient in Category I.
The environment of the oral cavity is very different from that of
the skin. The oral cavity supports one of the most concentrated and
varied microbial population of the body. The total microscopic count of
saliva has been given as anything from 43 million to 5.5 billion per mL
with an average of about 750 million. The microbial concentration of
the gingival sulcus and in plaque is at least 100 fold greater, or
approximately 200 billion cells per gram of sample (Ref. 4).
Conversely, the skin, for the most part, is an inhospitable place for
most microorganisms because the secretions of the skin are acidic and
most of the skin contains little moisture (Ref. 5). The agency believes
that, on the fairly dry surface of the skin, a reduction in
microorganisms caused by the application of a topical antiseptic will
persist for some time and, thus, may help to prevent minor skin
infections. However, even if one could demonstrate a reduction of
microorganisms on a site in the oral cavity, it is unlikely that this
reduction would result in a therapeutic benefit because the action of
saliva would reinoculate the site almost immediately. As the Oral
Cavity Panel stated, approximately 0.25 to 1 mL of saliva is excreted
per minute in the oral cavity (47 FR 22766). Therefore, oral surfaces
are constantly bathed with saliva, and organisms are readily
transported from one area of the mouth to another. This may be
particularly true of minor oral irritations, cuts, and scraps where
there is an almost irresistible urge to probe the site with the tongue.
This continuous reinoculation of the site with large numbers of
microorganisms is likely to counteract any therapeutic benefit that
might result from topical antiseptic action in the oral cavity.
Therefore, the agency tentatively concludes that clinical testing is
necessary to demonstrate that an antiseptic ingredient truly has a
therapeutic effect in the oral cavity.
Clinical trials to demonstrate the effectiveness of an OTC oral
antiseptic ingredient should be well-designed and well-controlled. Such
trials should be structured to closely approximate the clinical
situations for which a product is intended to be used and to
substantiate proposed claims. These studies should demonstrate that the
topically-applied antiseptic ingredient helps to prevent infection in
minor wounds in the mouth better than the vehicle alone.
In Vivo Testing Procedures
Three in vivo studies submitted to the Panel (Ref. 2), and
mentioned by the comments, were designed to answer specific questions
raised by the Panel during its evaluation of in vivo testing guidelines
for oral antiseptics (Ref. 1). The basic method used in the three
studies (Ref. 2) involved the use of 10 normal subjects with no medical
problems. The subjects were treated with cetylpyridinium chloride (0.1
or 1 percent) and a placebo (distilled or deionized water). In some of
the studies, a template was used to define the cheek treatment area,
and in other studies, no template was used. Each subject served as his
or her own control. The technique consisted of using a swab to sample
the cheek before treatment, treating the cheek with the designated
agent (i.e., active ingredient or placebo), and sampling again 1 minute
later. Samples were mixed, serially diluted, plated, incubated, and
visible bacterial colonies counted. A variety of mixing, plating
methods, and environmental conditions were used (e.g., drop plate
counting method, standard plating procedures, sonication, and
incubation under carbon dioxide, aerobic, and anaerobic conditions.)
The results of all three studies indicated that cetylpyridinium
chloride decreased the number of bacteria within 1 minute after
application on the cheek. Individual studies included the following
results: (1) Subjects differ from each other by 10 to 100 fold in their
normal bacterial counts, but vary little from 1 day to another in their
own bacterial counts; (2) a swab sampling procedure and a drop-plate
counting method are sensitive, adequate methods to detect small
decreases in bacterial counts in a 10-subject panel, and decreases
smaller than 2 logs or 100 fold are significant; (3) a template is not
necessary to limit the treatment area; (4) successive samples taken
before treatment invariably decrease, as do samples taken after
treatment with water while samples taken after treatment with
cetylpyridinium chloride level off or increase in successive samples,
indicating that the antiseptic killed bacteria in the top layer of the
oral mucosa but not in the lower layers; (5) sonication of swab samples
increases the sensitivity of the method, but does not affect the
estimate of antiseptic effectiveness; thus, this method may be used
optionally; (6) conventional plating methods and other well-tested
plating methods are highly reproducible; and (7) although results for
all three incubation environments were essentially the same, the effect
of some oral antiseptics could have differing effects against types of
bacteria requiring specific gaseous environments; thus, three
environments should be used in future studies.
The agency concludes that the techniques of the in vivo testing
guidelines presented to the Panel for demonstrating the effectiveness
of a locally applied antiseptic ingredient (Refs. 1 and 2) represent a
partial guide for helping to assess an ingredient's effectiveness as an
OTC oral health care antiseptic, but are not totally adequate for that
purpose. The agency believes that in vivo testing methods used to help
demonstrate the effectiveness of oral health care antiseptic
ingredients should stipulate the specific organisms to be tested, the
acceptable decrease in bacterial numbers, and the period of time for
which the antiseptic activity should persist. The Panel's discussion of
in vivo testing did not include such information (47 FR 22760 at
22891). Such testing methods should also take into account the
following: (1) The normal flora of the site to be used in the study,
(2) the complexity of the oral flora, (3) the site-to-site variation of
the oral flora within the mouth, (4) when tissue is abraded, burned, or
punctured, sites may be exposed that allow the binding of oral
microorganisms that would not otherwise reside in that particular
ecological niche, and (5) what shifts in the balance of the flora and/
or colonization by other species are to be expected if the site is
abraded or otherwise damaged. A spectrum of activity against a
representative battery of organisms should be developed (i.e., Candida
albicans, representative actinomyces and streptococcal species, and
other flora frequently isolated from the site). A thorough review of
the literature should identify the appropriate microorganisms.
In addition, the in vivo testing guidelines presented to the Panel
(Ref. 1) did not include adequate sampling intervals after treatment
with the oral antiseptic. Using the guidelines, a statistically
significant difference was obtained between treatment of the cheek with
the placebo and treatment with cetylpyridinium chloride; however, the
length of time that the antiseptic effect persists past the 1-minute
time interval used in the studies was not explored. The transient
decrease in the number of bacteria at the 1-minute interval after
cetylpyridinium chloride application, as noted in the comment's studies
(Ref. 2), is not unexpected. The ability to maintain such a decrease
over a reasonable interval of time is more significant and important,
especially when one considers the effect of the oral environment. The
agency believes that, for demonstrating antiseptic activity in the oral
cavity, more appropriate time intervals might be 1 minute, 10 minutes,
30 minutes, 1 hour, 2 hours, and 4 hours.
The agency also believes that it might be useful to use more than
one incubation environment because some microniches in the oral cavity
(e.g., the gingival crevice) support anaerobic growth, and organisms
commonly isolated from the oral cavity include facultative anaerobes as
well as strict anaerobes. One approach would be to use a nonselective
medium under anaerobic and carbon dioxide conditions and several
selective media under appropriate conditions depending upon the
microorganism of interest.
In Vitro Testing Procedures
The agency believes that the Panel's proposed in vitro testing
guidelines represent a good starting point for the design of in vitro
studies to help upgrade a Category II or Category III oral antiseptic
ingredient to Category I (47 FR 22760 at 22890 to 22891. However, all
such testing should be designed using the most current technology
available.
Although the agency offers the above comments on clinical, in vivo,
and in vitro testing as guidance, specific testing guidelines for
upgrading ingredients to Category I are not included in this monograph.
(See part II. paragraph A.2.--Testing of Category II and Category III
conditions.) Instead, the agency will meet with industry
representatives or other interested parties at their request to discuss
testing protocols. Any party interested in conducting studies should
request a meeting at its earliest convenience. (See also section I.M.,
comments 32 and 35.)
The above discussion applies only to the testing required to
upgrade OTC oral antiseptic ingredients from Categories II or III to
Category I. In addition, the agency has tentatively concluded that
final formulation testing of OTC oral antiseptic drug products is
necessary. For a further discussion of such testing, see part II.
paragraph B.10--Summary of the Agency's Changes.
References
(1) OTC Vol. 130117, Docket No. 81N-0033, Dockets Management
Branch.
(2) OTC Vol. 130132, Docket No. 81N-0033, Dockets Management
Branch.
(3) OTC Vol. 130163, Docket No. 81N-0033, Dockets Management
Branch.
(4) Burnett, G. W., H. W. Scherp, and G. S. Schuster, ``Oral
Microbiology and Infectious Disease,'' The Williams and Wilkins Co.,
Baltimore, 1976, p. 219.
(5) Tortora, G. J., B. R. Funke, and C. L. Case, ``Microbiology,
An Introduction,'' The Benjamin Cummings Publishing Co., Inc.,
Redwood City, CA, 1989, p. 502.
34. Three comments disagreed with the Oral Cavity Panel's
discussion concerning chlorhexidene as a standard for testing the
effectiveness of oral antimicrobials. One comment stated that the use
of chlorhexidene is inappropriate and unnecessary for this class of
products and that the proposed guidelines for topically applied
antiseptics for use on the skin do not include chlorhexidene as a
standard. The second comment stated that the use of chlorhexidene as a
standard is unreasonable because its usefulness is currently at issue,
and the drug is not yet accepted as a safe and effective oral
antiseptic. The third comment stated that chlorhexidine is unproven as
a standard reference for pathogens responsible for the production of
sore throat and sore mouth.
The agency acknowledges that neither the tentative final monograph
for OTC antimicrobial drug products (43 FR 1210) nor the amended
tentative final monograph (now called OTC first aid antiseptic drug
products) (56 FR 33644) includes chlorhexidene as a standard for
topical antiseptics. However, since the comment was submitted, a
chlorhexidene antiseptic mouthwash has been approved for oral use in
the U.S. (Ref. 1).
The Oral Cavity Panel's minority report recommended an in vitro
test utilizing chlorhexidene as a standard and recommended that all
antimicrobial oral products be compared to the standard (47 FR 22760 at
22897). However, as discussed in section I.M., comment 32, the testing
procedures recommended by the minority of the Panel are not being
accepted by the agency for testing the active ingredients that are
included in this segment of the oral health care drug products
rulemaking.
In its in vitro testing procedure for determining the effectiveness
of oral antimicrobials, the majority of the Panel recommended the use
of a positive standard control to validate the test procedure by
assuring the consistent susceptibility of the test organisms. The
Panel's majority report stated that ``chlorhexidene digluconate, 0.2
percent in sterile water, is acceptable for this purpose,'' (47 FR
22891). The agency does not agree with the Panel that chlorhexidine is
an appropriate positive control for this purpose. Determining whether
or not an organism is susceptible to chlorhexidine does not correlate
to whether or not the organism is susceptible to the test ingredient.
Furthermore, as discussed in prt II. paragraph B.10--Summary of the
Agency's Changes, the agency is suggesting that the active ingredient,
in a suitable inactive medium, be used as a positive control.
Reference
(1) ``Physician's Desk Reference,'' 47th ed., Medical Economics
Data, Montvale, NJ, 1993, pp. 1867-1868.
35. Two comments stated that the Oral Cavity Panel's guidelines for
testing topically applied antimicrobials (47 FR 22760 at 22890 to
22893) should permit variations in the methods used. One comment
mentioned that variations should be allowed depending on the ingredient
being tested. As an example of an appropriate variation, the other
comment suggested that a method that had been submitted to the Panel
would provide adequate status of in vivo antimicrobial activity (Ref.
1). The comment described that method as ``swabbing of the active
ingredient three times using a template and comparing this to a
control.''
The agency is not including specific guidelines for upgrading
active ingredients to Category I in this document. Instead, the agency
will meet with industry representatives at their request to discuss
testing protocols and, therefore, revisions may be made from time-to-
time. (See section I.E., comment 8; section I.G., comment 12; and
section I.M., comment 33 for a discussion of appropriate testing
procedures.)
The agency notes that the procedure referred to by one comment
calls for volunteer subjects with no symptoms of an oral disease state.
The agency does not believe this procedure by itself will provide
adequate proof of the in vivo effectiveness of an oral antiseptic.
Reference
(1) OTC Vol. 130153.
36. Referring to the Oral Cavity Panel's discussion of in vivo
testing, two comments disagreed with the suggested protocol for the
determination of an antimicrobial ingredient's adverse effect on wound
healing (47 FR 22760 at 22892). The comment felt that the procedure
described by the Panel would be impossible to control if there were
only one wound in the mouth. Expressing the opinion that, in order to
compare the rate of healing, a controlled study would require multiple
wounds, of comparable size and depth, in comparable locations in the
mouth, and at a comparable stage in the healing process, both comments
considered it virtually impossible to find such a situation occurring
naturally in human subjects. The comments agreed with the Panel that
such a study could be done in animals, but felt that animal studies
would be of little value because animals have different microbial
populations than humans. One of the comments added that if a product
does not have an excessively high degree of substantivity, the risks of
retarding wound healing are limited and such tests are unwarranted.
The agency agrees with the comments that it would be almost
impossible to find a representative population of human subjects with
multiple mouth wounds so that one wound could serve as a test site and
another as a control site in the same subject. However, the agency
believes that the Panel was referring to a ``controlled study'' as one
in which a population of subjects with comparable wounds is divided
into a group that is treated with the test ingredient and a group that
receives a control, such as the vehicle lacking the test ingredient. In
the Panel's discussion of general considerations applying to the
testing for recategorization of Category III oral health care
ingredients (47 FR 22760 at 22782 to 22783), the design for a
controlled study is described as one in which subjects who have similar
conditions are divided into a treated group and a placebo group. In the
discussion cited by the comments (47 FR 22891), the Panel stated that
control groups should receive treatment with inert vehicles that are
identical in appearance, color, and consistency to the test materials.
The agency believes that the general principles stated above can be
coordinated so that well-controlled studies to investigate the adverse
effects of oral health care antimicrobial ingredients on wound healing
could be designed according to the Panel's recommendations.
The agency disagrees with the comments' belief that animal studies
are of little value and concurs with the Panel's position on animal
studies. Although believing that the final appraisal of an oral
antiseptic must be done by clinical trials, the Panel recommended that
in vivo testing, including animal and human models, should be performed
prior to clinical studies (47 FR 22891). The agency agrees that an
initial assessment of safety and effectiveness of a drug should be made
using animal models before the test formulation is given to humans in a
controlled clinical study.
However, the agency does not believe that further wound healing
studies are necessary for OTC oral antiseptic ingredients. As part of
the rulemaking for OTC topical antiseptic drug products, the agency has
reviewed many studies designed to show the effect of antiseptic
ingredients on wound healing. The agency's conclusions on these data
are stated in the tentative final monograph for OTC first aid
antiseptic drug products (56 FR 33644 at 33658, 33660, and 33662).
Several of the first aid antiseptic ingredients for which wound healing
studies were submitted are also classified as Category III oral
antiseptic ingredients, i.e., benzalkonium chloride, iodine, and
povidone-iodine. The submitted studies show that these antiseptic
ingredients do not delay wound healing when used for a short period of
time, i.e., 7 days, on limited areas of the body. The agency believes
that these wound healing data are also relevant to oral antiseptic
ingredients that are limited to a maximum of 7 days of use on the
affected area of the mouth and throat. The Panel was concerned about
the lack of data on possible adverse effects on the oral mucosa
resulting from the use of oral antiseptic drug products on a daily
basis for months at a time (47 FR 22760 at 22834). However, the agency
is proposing labeling limiting self-medication with these products to a
7-day period for relief of the symptoms of sore mouth. (See section
I.K., comment 25.) In addition, the oral antiseptic ingredients are
used in lower concentrations than the first aid antiseptic ingredients
and are in contact with the affected area for a shorter time period
following application. This occurs because the oral antiseptic
ingredients are mixed with the saliva of the mouth and then
expectorated. Therefore, oral antiseptic ingredients would not be
expected to delay wound healing. For the above reasons, the agency
concludes that additional studies to demonstrate that oral antiseptic
ingredients do not delay wound healing are unnecessary. Further,
according to 21 CFR 310.534(b), any OTC drug product that is labeled,
represented, or promoted for use as an oral wound healing agent (e.g.,
``promotes wound healing'') is regarded as a new drug, and an approved
application is required before marketing.
37. One comment stated that the Oral Cavity Panel's recommended
studies to prove that antiseptic mouthwashes aid in the treatment of
sore mouth and sore throat are not feasible for the following reasons:
(1) It is not feasible to attempt to collect enough data in any
reasonable period of time from volunteers who have symptoms of a sore
throat or sore mouth due to the unique infection with a single pathogen
in order to prove specific activity of an antibacterial agent (47 FR
22760 at 22779); (2) Koch's Postulates would be virtually impossible to
fulfill because proof of the presence of the offending etiologic agent
specifically responsible for the sore mouth/sore throat, in addition to
correlation of relief of symptoms of sore mouth/sore throat with a
decrease or elimination of the etiologic agent, could of itself be
impossible to achieve; (3) complementary animal studies simulating
these symptoms would be difficult to perform without the introduction
of a systemic pathogen and, under these circumstances, the natural
conditions specified as a prerequisite for proof of efficacy could not
be approximated (47 FR 22890); (4) the test organisms originally
approved by the Panel to demonstrate antimicrobial activity (the Bahn
test), Streptococcus mutans, Actinomyces viscosus, C. albicans and
optionally, Pseudomonas aeruginosa, have no precedent for use as test
organisms for antibacterial activity relating to production of symptoms
of sore mouth or sore throat; and (5) such studies must by necessity
avoid the use of any systemic antimicrobial agent and would obviously
create a situation which is not only medically unsound but also
unethical.
In its discussion of the data required for the evaluation of oral
antiseptic ingredients (47 FR 22760 at 22890 to 22893), the Oral Cavity
Panel recommended general principles applicable to the design of
experimental protocols for demonstrating the safety and efficacy of
these ingredients. The Panel did not consider its recommendations for
testing the effectiveness of these ingredients to be mandatory
requirements, but presented its recommendations merely to indicate the
types of data it considered necessary and to provide suggestions for
obtaining such data. The agency is adopting this approach and treating
the Panel's recommendations as guidelines for obtaining data to upgrade
Category II or Category III ingredients to Category I. However, in this
tentative final monograph, the agency is proposing testing procedures
for final formulations containing Category I oral antiseptics. (See
section I.M., comments 32 and 35.)
The Panel recognized that it would be impossible to propose a
single general protocol because of the diverse etiology of oral
inflammation. The Panel recommended that the data obtained in support
of Category I status for oral antiseptic ingredients show that
preparations applied to the mucous membranes of the mouth and throat
act topically and relieve symptoms caused by an infection by reducing
pathogenic microbial populations (47 FR 22760 at 22890), but it also
recognized that appropriate individual tests must be devised to
demonstrate this for a particular ingredient and that the
responsibility of selecting or devising reliable methods for procuring
acceptable evidence of the effectiveness of an ingredient rests with
the manufacturer sponsoring the product.
The agency is, however, proposing testing procedures for OTC oral
antiseptic final formulations in Sec. 356.90 of this tentative final
monograph. In those testing procedures, the agency is accepting the
Panel's recommendations regarding the use of S. mutans, A. viscosus,
and C. albicans as test organisms. (See Part II. paragraph B.10--
Summary of the Agency's Changes.) These organisms are representative of
organisms commonly found in the oral cavity. The agency believes that a
decrease in the number of these organisms in the proposed in vitro
testing procedures indicates that the final formulation of a product
has not decreased the effectiveness of a Category I oral antiseptic.
II. The Agency's Tentative Conclusions and Adoption of the Panel's
Report
A. Summary of Ingredient Categories and Testing of Category II and
Category III Conditions
1. Summary of Ingredient Categories.
The agency has reviewed all claimed active ingredients submitted to
the Oral Cavity Panel, as well as other data and information available
at this time, and has made one change in the categorization of oral
antiseptic ingredients recommended by the Panel. As a convenience to
the reader, the following list is included as a summary of the
categorization of oral antiseptic ingredients recommended by the Panel
and the proposed categorization by the agency.
------------------------------------------------------------------------
Antiseptic Active
Ingredients Panel Agency
------------------------------------------------------------------------
Alcohol III.................... III
Benzalkonium chloride III.................... III
Benzethonium chloride III.................... III
Benzoic acid III.................... III
Boric acid II..................... II
Boroglycerin II..................... II
Camphor II..................... II
Carbamide peroxide in III.................... III
anhydrous glycerin
Cetalkonium chloride III.................... III
Cetylpyridinium III.................... III
chloride
Chlorophyllin copper III.................... III
complex
Cresol II..................... II
Dequalinium chloride III.................... III
Domiphen bromide III.................... III
Eucalyptol III.................... III
Ferric chloride II..................... II
Gentian violet III.................... II
Hydrogen peroxide III.................... III
Iodine III.................... III
Menthol III.................... III
Meralein sodium II..................... II
Methyl salicylate III.................... III
Nitromerso lII.................... II
Oxyquinoline III.................... III
Phenol preparations III.................... III
(phenol and/or
phenolate sodium)
Potassium chlorate II..................... II
Povidone-iodine III.................... III
Secondary III.................... III
amyltricresols
Sodium caprylate III.................... III
Sodium dichromate II..................... II
Thymol preparations III.................... III
(thymol and thymol
iodide)
Tincture of myrrh II..................... II
Tolu balsam III.................... III
------------------------------------------------------------------------
2. Testing of Category II and Category III Conditions.
The Oral Cavity Panel recommended testing guidelines for OTC oral
health care antimicrobial drug products (47 FR 22760 at 22890 to
22893). The agency's position regarding these testing guidelines is
discussed in Part I, paragraph E of this document. Interested persons
may communicate with the agency about the submission of data and
information to demonstrate the safety or effectiveness of any OTC oral
antiseptic active ingredient or condition included in the review by
following the procedures outlined in the agency's policy statement
published in the Federal Register of September 29, 1981 (46 FR 47740)
and clarified April 1, 1983 (48 FR 14050). That policy statement
includes procedures for the submission and review of proposed
protocols, agency meetings with industry or other interested persons,
and agency communications on submitted test data and other information.
B. Summary of the Agency's Changes
FDA has considered the comments and other relevant information and
concludes that it will tentatively adopt the antiseptic section of the
Oral Cavity Panel's report and recommended monograph with the changes
described in FDA's responses to the comments above and with other
changes described in the summary below. A summary of the changes made
by the agency follows.
1. In order to be consistent with terminology used in the
rulemaking for OTC topical antiseptic drug products, the agency is
proposing to replace the Panel's term ``antimicrobial'' with the term
``antiseptic'' in this tentative final monograph. (See section I.A.,
comment 1.)
2. The agency is not including in this tentative final monograph
the Panel's definition for an antimicrobial agent in Sec. 356.3(c) of
its recommended monograph (47 FR 22760 at 22927). Instead, the agency
is proposing to add definitions for the terms ``antiseptic drug'' and
``oral antiseptic'' to Sec. 356.3 of this tentative final monograph.
(See section I.K., comment 20.)
3. The Oral Cavity Panel concluded that gentian violet was safe for
use in the oral cavity, but that there were insufficient data available
to permit final classification of its effectiveness as an oral
antiseptic (47 FR 22760 at 22873 to 22875). The Panel based its safety
determination on several factors: (1) the oral LD50 of gentian
violet in mice and rats is 1.2 to 10 g/kg; (2) it is nontoxic when
applied to the mucous membrane and skin; and (3) gentian violet has
been used orally in both children and adults as an anthelmintic.
However, the Panel noted that when gentian violet is ingested, it may
cause nausea, vomiting, diarrhea, and lassitude, and that intravenous
injection of impure preparations may produce a severe shock-like
reaction.
Regarding the use of gentian violet as an anthelmintic, in its
report on OTC anthelmintic drug products published in the Federal
Register of September 9, 1980 (45 FR 59540), the Miscellaneous Internal
Panel reviewed the information available to it regarding the safety of
gentian violet and acknowledged both a scarcity of acute toxicity data
and ``a high incidence of undesirable side effects associated with its
clinical use in children.'' That Panel also reviewed reports regarding
the potential carcinogenicity of gentian violet and recommended ``that
further testing be performed to resolve the carcinogenic concerns.''
According to the Miscellaneous Internal Panel, these concerns were not
convincing when weighed against the lack of adverse effects reported
during the long marketing history of gentian violet. Thus, that Panel
concluded that gentian violet was safe when used as directed. FDA,
however, reviewed the available data relevant to the genetic toxicity
of gentian violet and stated in its preamble to the Panel's report on
OTC anthelmintic drug products that a definitive conclusion regarding
the carcinogenic activity of gentian violet could not be reached at
that time. On the basis of the available evidence, the agency nominated
gentian violet for study in the NTP. The agency concluded that the
potential risk of using gentian violet as an oral anthelmintic
outweighed the benefits and announced its intent to classify gentian
violet in Category II in the tentative final monograph for OTC
anthelmintic drug products (45 FR 49540).
In that tentative final monograph published in the Federal Register
of August 24, 1982 (47 FR 37062 at 37063), the agency further discussed
the genetic toxicity of gentian violet, and reaffirmed its earlier
conclusions regarding the safety of gentian violet. In that proposal,
gentian violet was classified in Category II as an oral anthelmintic.
In the final rule published in the Federal Register of August 1, 1986
(51 FR 27756 at 27758), the agency determined that gentian violet is a
nonmonograph drug for OTC anthelmintic use.
In a proposed rule published in the Federal Register of February
13, 1990 (55 FR 5194) regarding the safety of gentian violet in animal
feed, FDA discussed the National Center for Toxicology Research's
(NCTR) series of studies that provide additional new information on the
toxicity and carcinogenicity of gentian violet. One lifetime study
(chronic study) showed gentian violet to be a carcinogen in mice.
Another lifetime study in rats also resulted in a carcinogenic
response. A residue study showed that residues of gentian violet
occurred in the edible tissues of chickens after they were administered
gentian violet. Reproductive-teratology studies were negative or
inconclusive. A multigeneration study in rats showed a lower body
weight, a dose-related necrosis in the thymus, and a dose-related
effect on the kidneys in females. However, a pairwise statistical
evaluation of these parameters was not performed. Metabolism studies in
rats and mice showed that orally administered gentian violet is
absorbed, with the highest residue levels of the compound and its
metabolites occurring in fat and liver. The proposal also discussed the
results of an extensive search of the published literature relevant to
the safety of gentian violet (55 FR 5194 at 5200).
The agency concluded that even if the chronic studies that had been
performed by NCTR did not establish that gentian violet is an animal
carcinogen, they did not establish that gentian violet is safe. There
is a paucity in the scientific literature of the kind of studies that
are needed to support an expert opinion that gentian violet is
generally recognized as safe. In fact, FDA's literature survey
generally found that gentian violet tends to have mutagenic, genotoxic,
and other toxic properties. FDA believes where such incriminating
studies exist, experts generally agree that chronic studies must
affirmatively show that the substance does not cause cancer before it
can be recognized as safe (55 FR 5194 at 5201). The agency concluded
that gentian violet is not generally recognized as safe for use in
animal feed or as a food additive. The agency also concluded that
gentian violet for veterinary drug use in food animals is not generally
recognized as safe and effective and is a new animal drug (55 FR 5201).
In the Federal Register of August 15, 1991 (56 FR 40502), the
agency issued a final rule amending its regulations (21 CFR 500.29) to
declare that gentian violet is neither generally recognized as safe nor
prior sanctioned and is a food additive when added to animal feed for
any nondrug use. The agency also amended its regulations (21 CFR
500.30) to reflect its determination that gentian violet is not
generally recognized as safe, not generally recognized as effective, or
not ``grandfathered'' under the Drug Amendments of 1962 (Pub. L. 87-
781). Therefore, gentian violet is a new animal drug when used for any
veterinary drug purpose in food animals.
Based on the above, the agency concludes that gentian violet is not
safe for use as an oral antiseptic. Therefore, in this tentative final
monograph, the agency is reclassifying gentian violet from Category III
to Category II.
4. The agency believes that the safety data evaluated by the Panel
are sufficient to conclude that cetylpyridinium chloride, domiphen
bromide, and povidone-iodine are safe for use as OTC oral antiseptics
when labeled for short-term use (not to exceed 7 days). However, there
are insufficient data to demonstrate the effectiveness of these
ingredients, and they are classified in Category III. (See section
I.E., comments 8 and 9; section I.G., comments 12 and 13; and section
I.I., comments 15 and 16.)
5. The agency is proposing the following combinations in
Sec. 356.26 (and labeling for these combinations in Sec. 356.66): (1)
oral antiseptic and oral anesthetic/analgesic; (2) oral antiseptic and
oral astringent; (3) oral antiseptic and oral demulcent; (4) oral
antiseptic and oral mucosal protectant; (5) oral antiseptic, oral
anesthetic/analgesic, and oral astringent; (6) oral antiseptic, oral
anesthetic/analgesic, and oral demulcent; and (7) oral antiseptic, oral
anesthetic/analgesic, and oral mucosal protectant. (See section I.L.,
comment 29.)
6. The agency is proposing to revise the statement of identity in
Sec. 356.51(a) of the Panel's recommended monograph (and including the
revised statement in Sec. 356.64(a) of this tentative final monograph)
as follows: ``The labeling of the product contains the established name
of the drug, if any, and identifies the product as an `oral
antiseptic,' or an `antiseptic' (select one of the following: `rinse,'
`gargle,' or `rinse and gargle').'' (See section I.K., comments 20 and
21.)
7. The agency is proposing the following indication in
Sec. 356.64(b) of this tentative final monograph: ``First aid to help''
(select one of the following: ``prevent,'' (``decrease'' (``the risk
of'' or ``the chance of'')), (``reduce'' (``the risk of'' or ``the
chance of'')), ``guard against,'' or ``protect against'') (select one
of the following: ``infection'' or ``bacterial contamination'') ``in''
(select any of the following: ``minor cuts,'' ``minor scrapes,'' or
``minor oral irritation'') (which may be followed by) ``caused by''
(select any of the following: ``dental procedures,'' ``dentures,''
``orthodontic appliances,'' or ``accidental injury''). (See section
I.K., comment 22.)
8. The agency is proposing to replace the Panel's recommended
warnings in Sec. 356.51(c)(1)(i) and (c)(1)(ii) with the following
warning found in Sec. 356.64(c) of this document: ``Do not use this
product for more than 7 days unless directed by a dentist or doctor. If
sore mouth symptoms do not improve in 7 days, if irritation, pain, or
redness persists or worsens, or if swelling, rash, or fever develops,
see your dentist or doctor promptly.'' (See section I.K., comment 25.)
9. The agency is proposing professional labeling in Sec. 356.80 for
the use of povidone-iodine as a dental preoperative preparation by
health care professionals. (See section I.K., comment 27.)
10. The agency has determined that, because the final formulation
of an oral antiseptic drug product can affect the effectiveness of the
active ingredient, final formulation testing of oral health care
antiseptic drug products is necessary. Therefore, the agency is
proposing final formulation testing procedures be included in this
tentative final monograph. These testing procedures are being put forth
for comment in this document.
The Panel recommended that evidence be submitted to verify that
each antiseptic ingredient is released from its vehicle when applied to
mucous membranes, but it did not include final formulation testing
procedures for OTC oral antiseptics in its recommended monograph (47 FR
22760 at 22890). The agency, however, is aware that the final
formulation of an oral health care drug product can affect the activity
of an antiseptic ingredient included in that product. Therefore, in
keeping with the final formulation testing procedures proposed for
first aid antiseptic drug products (i.e., those applied to the skin)
(56 FR 33644 at 33673) and those that will be proposed for health care
antiseptic drug products (e.g., surgical scrubs) in a future issue of
the Federal Register, the agency is proposing procedures for testing
the final formulations of oral health care antiseptic drug products in
this tentative final monograph. These testing procedures are based upon
the in vitro effectiveness testing procedures recommended by the Oral
Cavity Panel (47 FR 22760 at 22890 to 22893) and the first aid
antiseptic testing procedures proposed by the agency in Sec. 333.70 of
the tentative final monograph for OTC first aid antiseptic drug
products (56 FR 33644 at 33673). In general, the proposed testing
procedures for first aid antiseptic drug products have been modified to
account for the different test organisms required for testing the
effectiveness of oral antiseptics. The agency has also taken into
account all comments pertaining to the Oral Cavity Panel's recommended
in vitro testing guidelines. (See section I.M., comments 34 and 35.)
In the testing procedures included in the tentative final monograph
for OTC first aid antiseptic drug products, the agency proposed in
Sec. 333.70(b)(2)(i) and (b)(2)(ii) a ``neutralizer inactivation of
antiseptic test'' and a ``neutralizer effect on bacterial viability
test'' (56 FR 33644 at 33678 and 33679). Differences in microbial plate
counts greater than 20 percent between test and control cultures
require that the overall test results be discarded. Based upon new
information, the agency is concerned that a 20-percent difference in
microbial plate counts might be too restrictive. There is a relatively
large inherent variation in microbial plate counts. In addition,
because the criterion for fulfilling the requirements of the overall
testing procedures is a 3-log10 reduction in viable organisms
(i.e., 99.9 percent), the agency now questions whether a 1-log10
(i.e., 90 percent) difference might not be a more reasonable criterion
for the differences in microbial plate counts for the neutralizer
tests. Although the agency is proposing the 20-percent criterion in
this tentative final monograph for consistency with the OTC first aid
antiseptic tentative final monograph, the agency requests comment on
this matter.
In addition, in Sec. 333.70(c)(5) of the OTC first aid antiseptic
tentative final monograph, the agency proposed a ``test organism
antiseptic resistance test'' in which the test organisms' resistance to
phenol is determined in order to ensure that the resistance of each
organism to antiseptics has not changed (56 FR 33679). The Oral Cavity
Panel recommended that a 0.2-percent chlorhexidine gluconate solution
be used as a positive control to assure the consistent susceptibility
of the test organisms (47 FR 22760 at 22891). However, the agency
believes that determining an organism's resistance or lack of
resistance to phenol or chlorhexidine gluconate has no bearing upon
whether or not that organism's susceptibility to a particular test
ingredient has changed. The mechanism of action of the test antiseptic
may be quite different than that of phenol or chlorhexidine gluconate.
Because the ``test organism antiseptic resistance test'' is designed to
demonstrate that the active ingredient is still active in the specific
formulation under test, and the active ingredient has presumably
already been shown to have in vitro and in vivo antiseptic activity by
itself, the proper control is the active ingredient alone. Therefore,
the agency is suggesting that the active ingredient, in a suitable
inactive medium, be used as a positive control.
The complete testing procedures are included in Sec. 356.90 of this
tentative final monograph. The agency invites specific comment at this
time on the final formulation testing procedures proposed in this
document. After reviewing any submitted comments or data, the agency
may revise the testing procedures prior to establishing a final
monograph. The agency also recognizes that the testing procedures may
need to be revised periodically as newer techniques are developed and
proven adequate.
11. For an active ingredient to be included in an OTC drug final
monograph, in addition to information demonstrating safety and
effectiveness, it is necessary to have publicly available sufficient
chemical information that can be used by all manufacturers to determine
that the ingredient is appropriate for use in their products. Only some
of the oral antiseptic active ingredients that the Panel evaluated are
standardized and characterized for quality and purity and are included
in official compendia. Alcohol, benzalkonium chloride, benzethonium
chloride, benzoic acid, boric acid, camphor, carbamide peroxide,
cetylpyridinium chloride, cresol, gentian violet, hydrogen peroxide,
iodine, menthol, methyl salicylate, nitromersol, oxyquinoline sulfate,
phenol, povidone-iodine, tolu balsam, and thymol are currently included
as articles in the U.S.P. (Ref. 1). The remaining oral antiseptic
active ingredients are not adequately characterized and would need to
be if data are submitted to upgrade them to monograph status.
The agency believes that it would be appropriate for parties
interested in upgrading nonmonograph ingredients to monograph status to
develop with the United States Pharmacopoeial Convention appropriate
standards for the quality and purity of any of these ingredients that
are not already included in official compendia. Should appropriate
standards fail to be established, ingredients otherwise eligible for
monograph status will not be included in the final monograph.
Reference
(1) ``United States Pharmacopeia XXII--National Formulary
XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD,
pp. 34, 146, 149, 219-220, 223, 268, 605, 663, 703-703, 821-822,
954, 1061, 1119, 1390, 1904-1905, 1906, 1921-1922, 1947-1948, 1955,
1991, 1989.
The agency has examined the economic consequences of this proposed
rulemaking and has determined that it does not require either a
regulatory impact analysis, as specified in Executive Order 12866, or a
regulatory flexibility analysis, as defined in the Regulatory
Flexibility Act (Pub. L. 96-354). This rulemaking for OTC oral
antiseptic drug products is not expected to have an impact on small
businesses.
This proposed rule does not include any Category I ingredients.
Some ingredients are in Category II (not generally recognized as safe
and effective), but most are in Category III (more data needed to
establish safety and effectiveness). If data are not submitted to
upgrade these ingredients to monograph status, OTC products containing
oral antiseptics will not bepermitted to display antiseptic drug claims
in labeling. However, most of these products could remain in the
marketplace. After relabeling, many products could be marketed as
cosmetics; others could be marketed as OTC oral wound cleansing drug
products. After reformulation and relabeling, a few products could be
sold as OTC oral anesthetic/analgesics. Many OTC products containing
oral antiseptics are labeled for use to reduce or prevent the
accumulation of dental plague. Unless a safety concern arises, such
products may remain on the market until the agency's evaluation of
antiplaque and antiplaque-related products is completed.
The impact of the proposed rule, if implemented, appears to be
minimal. Therefore, the agency concludes that the proposed rule is not
a major rule as defined in Executive Order 12866. Further, the agency
certifies that this proposed rule, if implemented, will not have a
significant economic impact on a substantial number of small entities
as defined in the Regulatory Flexibility Act.
The agency invited public comment in the advance notice of proposed
rulemaking regarding any impact that this rulemaking would have on OTC
oral antiseptic drug products. No comments on economic impacts were
received.
The agency invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC oral
antiseptic drug products. Comments regarding the impact of this
rulemaking should be accompanied by appropriate documentation. The
agency will evaluate any comments and supporting data that are received
and will reassess the economic impact of this rulemaking in the
preamble to the final rule.
The agency has determined under 21 CFR 25.24(c)(6) 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.
Interested persons may, on or before August 8, 1994, submit to the
Dockets Management Branch (address above) written comments, objections,
or requests for oral hearing before the Commissioner on the proposed
regulation. A request for an oral hearing must specify points to be
covered and time requested. Written comments on the agency's economic
impact determination may be submitted on or before August 8, 1994.
Three copies of all comments, objections, and requests are to be
submitted, except that individuals may submit one copy. Comments,
objections, and requests 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. Comments, objections,
and requests may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. Any scheduled oral hearing will be announced in
the Federal Register.
Interested persons, on or before February 9, 1995, may also submit
in writing new data demonstrating the safety and effectiveness of those
conditions not classified in Category I. Written comments on the new
data may be submitted on or before April 10, 1995. These dates are
consistent with the time periods specified in the agency's final rule
revising the procedural regulations for reviewing and classifying OTC
drugs, published in the Federal Register of September 29, 1981 (46 FR
47730). Three copies of all data and comments on the data are to be
submitted, except that individuals may submit one copy, and all data
and comments are to be identified with the docket number found in
brackets in the heading of this document. Data and comments should be
addressed to the Dockets Management Branch. Received data and comments
may also be seen in the office above between 9 a.m. and 4 p.m., Monday
through Friday.
In establishing a final monograph, the agency will ordinarily
consider only data submitted prior to the closing of the administrative
record on (insert date 14 months after date of publication in the
Federal Register). Data submitted after the closing of the
administrative record will be reviewed by the agency only after a final
monograph is published in the Federal Register, unless the Commissioner
finds good cause has been shown that warrants earlier consideration.
List of Subjects in 21 CFR Part 356
Labeling, 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 356 (as proposed in the Federal Register of
May 25, 1982 (47 FR 22760), the Federal Register of January 27, 1988
(53 FR 2436), and the Federal Register of September 24, 1991 (56 FR
48302)) be amended as follows:
PART 356--ORAL HEALTH CARE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN
USE
1. The authority citation for 21 CFR part 356 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).
2. Section 356.3 is amended by adding new paragraphs (m) and (n) to
read as follows:
Sec. 356.3 Definitions.
* * * * *
(m) Antiseptic drug. In accordance with section 201(o) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(o)), ``The
representation of a drug, in its labeling, as an antiseptic shall be
considered to be a representation that it is a germicide, except in the
case of a drug purporting to be, or represented as, an antiseptic for
inhibitory use as a wet dressing, ointment, dusting powder, or such
other use as involves prolonged contact with the body.''
(n) Oral antiseptic. An antiseptic-containing drug product applied
topically to the oral cavity to help prevent infection in wounds caused
by minor oral irritations, cuts, scrapes, or injury following minor
dental procedures.
3. New Sec. 356.11 is added to subpart B to read as follows:
Sec. 356.11 Antiseptics.
Povidone-iodine provided to health professionals (but not to the
general public).
4. Section 356.26 is amended by adding new paragraphs (i), (j),
(k), (l), (m), (n), and (o) to read as follows:
Sec. 356.26 Permitted combinations of active ingredients.
* * * * *
(i) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral anesthetic/analgesic
active ingredient identified in Sec. 356.12.
(j) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral astringent active
ingredient identified in Sec. 356.14.
(k) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral demulcent active
ingredient identified in Sec. 356.18.
(l) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral mucosal protectant
active ingredient identified in Sec. 356.20.
(m) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral anesthetic/analgesic
active ingredient identified in Sec. 356.12 and any single oral
astringent active ingredient identified in Sec. 356.14.
(n) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral anesthetic/analgesic
active ingredient identified in Sec. 356.12 and any single oral
demulcent active ingredient identified in Sec. 356.18.
(o) Any single oral antiseptic active ingredient identified in
Sec. 356.11 may be combined with any single oral anesthetic/analgesic
active ingredient identified in Sec. 356.12 and any single oral mucosal
protectant active ingredient identified in Sec. 356.20.
5. New Sec. 356.64 is added to subpart C to read as follows:
Sec. 356.64 Labeling of oral antiseptic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
``oral antiseptic,'' or an ``antiseptic'' (select one of the following:
``rinse,'' ``gargle,'' or ``rinse and gargle'').
(b) Indications. The labeling of the product states, under the
heading ``Indications,'' the following: ``First aid to help'' (select
one of the following: ``prevent,'' (``decrease'' (``the risk of'' or
``the chance of'')), (``reduce'' (``the risk of'' or ``the chance
of'')), ``guard against,'' or ``protect against'') (select one of the
following: ``infection'' or ``bacterial contamination'') ``in'' (select
any of the following: ``minor cuts,'' ``minor scrapes,'' or ``minor
oral irritation'') (which may be followed by) ``caused by'' (select any
of the following: ``dental procedures,'' ``dentures,'' ``orthodontic
appliances,'' or ``accidental injury'').
(c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings'': ``Do not use this product for
more than 7 days unless directed by a dentist or doctor. If sore mouth
symptoms do not improve in 7 days, if irritation, pain, or redness
persists or worsens, or if swelling, rash, or fever develops, see your
dentist or doctor promptly.''
(d) Directions. [Reserved]
6. Section 356.66 is amended by adding new paragraphs (b)(3),
(b)(4), (b)(5), (b)(6), (b)(7), (b)(8), (b)(9), (c)(1), (c)(2), (c)(3),
and (c)(4) to read as follows:
Sec. 356.66 Labeling of combination drug products.
* * * * *
(b) * * *
(3) For permitted combinations identified in Sec. 356.26(i). In
addition to any or all of the indications in Sec. 356.64(b), any or all
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be
used.
(4) For permitted combinations identified in Sec. 356.26(j). In
addition to any or all of the indications in Sec. 356.64(b), the
following indication for oral astringent active ingredients should be
used: ``For temporary relief of occasional minor irritation, pain, and
sore mouth.''
(5) For permitted combinations identified in Sec. 356.26(k). In
addition to any or all of the indications in Sec. 356.64(b), the
following indication for oral demulcent active ingredients should be
used: ``For temporary relief of minor discomfort and protection of
irritated areas in sore mouth.''
(6) For permitted combinations identified in Sec. 356.26(l). In
addition to any or all of the indications in Sec. 356.64(b), any or all
of the indications in Sec. 356.60(b)(1), (b)(2), and (b)(3) should be
used.
(7) For permitted combinations identified in Sec. 356.26(m). In
addition to any or all of the indications in Sec. 356.64(b), any or all
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be
used. The following indication for oral astringent active ingredients
should be used: ``For temporary relief of occasional minor irritation,
pain, and sore mouth.''
(8) For permitted combinations identified in Sec. 356.26(n). In
addition to any or all of the indications in Sec. 356.64(b), any or all
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be
used. The following indication for oral demulcent active ingredients
should be used: ``For temporary relief of minor discomfort and
protection of irritated areas in sore mouth.''
(9) For permitted combinations identified in Sec. 356.26(o). In
addition to any or all of the indications in Sec. 356.64(b), any or all
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) and in
Sec. 356.60(b)(1), (b)(2), and (b)(3) should be used.
(c) * * *
(1) For permitted combinations identified in Sec. 356.26(i). In
addition to the warnings in Sec. 356.64(c), the warnings in
Sec. 356.52(c)(2), (c)(3), and (c)(4), if applicable, should be used.
(2) For permitted combinations identified in Sec. 356.26(j). The
warnings in Sec. 356.64(c) should be used.
(3) For permitted combinations identified in Sec. 356.26(k). The
warnings in Sec. 356.64(c) should be used.
(4) For permitted combinations identified in Sec. 356.26(k). In
addition to the warnings in Sec. 356.64(c), the warnings in
Sec. 356.52(c)(2), (c)(3), and (c)(4), if applicable, should be used.
7. Section 356.80 is amended by adding new paragraph (d) to read as
follows:
Sec. 356.80 Professional labeling.
* * * * *
(d) The labeling of aqueous products containing povidone-iodine
identified in Sec. 356.11 provided to health professionals (but not to
the general public) may contain the following:
(1) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
``oral antiseptic,'' or an ``antiseptic'' (select one of the following:
``rinse,'' ``gargle,'' or ``rinse and gargle'').
(2) Indications. The labeling of the product states under the
heading ``Indications,'' the following: ``For preparation of the oral
mucosa prior to injection, dental surgery, or tooth extraction.''
(3) Directions. The labeling of the product contains the following
information under the heading ``Directions:'' For products containing
povidone-iodine identified in Sec. 356.11, the final product to be
applied is a 0.5 percent aqueous solution. Manufacturers may also
market a more concentrated solution provided that it contains adequate
directions to dilute the product to a 0.5 percent aqueous solution.
``Apply 10 to 20 milliliters of solution to the operative site.
Instruct the patient to rinse for 30 seconds and then spit out. Wait 2
minutes, and apply another 10 to 20 milliliters of solution to the
operative site. Instruct the patient to rinse again for 30 seconds and
then spit out. With a standard syringe and a blunt, angulated needle,
irrigate the operative site and the surrounding gingival mucosa for 1
minute with 10 to 20 milliliters of the solution. Instruct the patient
to spit out the solution after the irrigation procedure.''
8. New subpart D consisting of Sec. 356.90 is added to read as
follows:
Subpart D--Final Formulation Testing Procedures
Sec. 356.90 Testing of oral antiseptic drug products.
An oral antiseptic drug product in a form suitable for topical
application will be recognized as effective if it contains an active
ingredient included in Sec. 356.11 and if, at its lowest recommended
use concentration, it decreases the number of bacteria per milliliter
in Streptococcus mutans (ATCC No. 25175), Actinomyces viscosus (ATCC
No. 19246), and Candida albicans (ATCC No. 18804) cultures (available
from American Type Culture Collection (ATCC), 12301 Parklawn Dr.,
Rockville, MD 20852) by 3 log10 within 10 minutes at 37 deg.C in
the presence of 10 percent serum in vitro. Oral antiseptic drug
products must meet the specified requirements when tested in accordance
with the following procedures unless a modification is approved as
specified in paragraph (e) of this section.
(a) Laboratory facilities, equipment, and serum reagent--(1)
Laboratory facilities. To prevent the contamination of test
microorganism cultures with extraneous microorganisms, perform the test
using aseptic techniques in an area as free from contamination as
possible. Because test cultures of microorganisms may be adversely
affected by exposure to ultraviolet light or chemicals in aerosols, do
not test under direct exposure to ultraviolet light or in areas under
aerosol treatment. Do environmental tests to assess the suitability of
the testing environment frequently enough to assure the validity of
test results.
(2) Equipment. Use laboratory equipment that is adequate for its
intended use. Thoroughly cleanse the equipment after each use to remove
any antiseptic residues. Keep the equipment covered when not in use.
Sterilize clean glassware intended for holding and transferring the
test organisms in a hot air oven at 200 to 220 deg.C for 2 hours. Use
volumetric flasks, pipets, or accurately calibrated diluting devices
when diluting standard and sample solutions. Use plastic or glass Petri
dishes having dimensions of 20 X 100 millimeters. Use covers of
suitable material.
(3) Serum Reagent--Use inactivated fetal bovine serum without added
preservatives and/or antiinfective products.
(b) Culture media and diluting fluids--(1) Culture media. Use Brain
Heart Infusion Medium for culture media and diluting fluids. Prepare
the medium as follows:
------------------------------------------------------------------------
Brain Heart Infusion Medium
------------------------------------------------------------------------
Calf Brain, Infusion from 200 grams
Beef Heart, Infusion from 250 grams
Peptone 10 grams
Sodium chloride 5 grams
Disodium phosphate 2.5 grams
Dextrose 2 grams
Water, distilled q.s. to 1,000 milliliters
------------------------------------------------------------------------
Mix thoroughly. Heat with frequent agitation and boil for 1 minute.
Sterilize by autoclaving at 121 deg.C for 15 minutes. In lieu of
preparing the media from the individual ingredients, the media may be
made from dehydrated mixtures which, when reconstituted with distilled
water, have the same or equivalent composition as media prepared from
individual ingredients. Media prepared from dehydrated mixtures is to
have growth-promoting, buffering, and oxygen tension-controlling
properties equal to or better than media prepared from individual
ingredients. Adjust the pH of each medium with 1 Normal hydrochloric
acid or sodium hydroxide before sterilization, if necessary, so that
the medium will have a final pH of 7.4 after sterilization.
(i) Medium A (without neutralizers). Use Brain Heart Infusion
medium corresponding to that described in paragraph (b)(1) of this
section.
(ii) Medium B. Brain Heart Infusion agar medium. Same as Medium A,
except for the addition of 15 grams of agar per liter.
(iii) Medium C. Same as diluting fluid 1, except for the addition
of 15 grams of agar per liter.
(iv) Medium D. Same as diluting fluid 2, except for the addition of
15 grams of agar per liter.
(2) Diluting fluids--(i) Diluting fluid 1. Diluting medium for
neutralizing quaternary ammonium and phenolic antiseptic ingredients.
Same as Medium A, except for the addition of 5 grams of lecithin and 40
milliliters of polysorbate 20 per liter.
(ii) Diluting fluid 2. Diluting medium for neutralizing iodophor
antiseptic ingredients. Same as Medium A, except for the addition of 5
grams of sodium thiosulfate per liter.
(3) Neutralizers. When neutralizers are added to culture media and
diluting fluid, perform the following tests.
(i) Neutralizer inactivation of antiseptic test. Assay the
neutralizer efficacy for the test antiseptic as follows: Prewarm the
test antiseptic, culture medium, test culture, and serum to 37 deg.C
by incubating appropriate volumes of all solutions in a water bath at
37 deg.C for 5 minutes. Mix 0.8 milliliter of antiseptic (for controls
use 0.8 milliliter of sterile water) with 9.0 milliliters of culture
medium containing an appropriate antiseptic neutralizer followed by the
addition of 0.2 milliliter of the test culture in 50 percent serum.
Incubate the mixture of cells, serum, antiseptic, and neutralizer at 37
deg.C for 10 minutes. Remove aliquots, dilute, and assay for surviving
bacteria by the plate-count assay method using diluting and plating
media containing appropriate neutralizers, if required. Results
obtained showing differences greater than 20 percent between test and
control cultures indicate that the neutralizer used to inactivate the
test antiseptic is ineffective. Reject results obtained from tests
employing ineffective neutralization procedures.
(ii) Neutralizer effect on bacteria viability test. Test the effect
of neutralizers used to inactivate antiseptic active ingredients on
cell viability by diluting aliquots of each test organism culture in
Medium A (without neutralizer), specified in paragraph (b)(1)(i) of
this section, and in the appropriate diluting fluid (neutralizing
medium), specified in paragraph (b)(2) of this section. Determine the
number of bacteria in aliquots of appropriate dilutions by the plate-
count assay method utilizing growth agar medium containing the same
neutralizer concentration as the diluting medium. Determine neutralizer
effects on cell viability by comparing the relative number of
microorganisms growing on Medium B, specified in paragraph (b)(1)(ii)
of this section, with and without added neutralizers. Results obtained
showing differences greater than 20 percent between cultures diluted in
medium with and without neutralizers indicate that, at the
concentration utilized, the antiseptic neutralizer alters the
determination of viable cells in the test cultures. Reject results
obtained from tests in which the neutralizer employed alters the
determination of viable cell numbers.
(c) Test organisms--(1) Use cultures of the following
microorganisms:
(i) Streptococcus mutans (ATCC No. 25175).
(ii) Actinomyces viscosus (ATCC No. 19246).
(iii) Candida albicans (ATCC No. 18804).
(2) Preparation of suspension. Maintain stock cultures on Medium B
agar slants by monthly transfers. Alternatively, cultures may be
lyophilized and stored at -70 deg.C. Incubate new stock transfers 2
days at 37 deg.C; then store at 2 to 5 deg.C. Incubate Streptococcus
mutans and Actinomyces viscosus anaerobically. Incubate Candida
albicans aerobically. From stock culture, inoculate tubes of Medium A
and make at least 4 but less than 30 consecutive daily transfers in
Medium A, incubating at 37 deg.C, before using the culture for
testing. Use a 16- to 18-hour culture of Streptococcus mutans and
Candida albicans and a 32- to 36-hour culture of Actinomyces viscosus
grown in Medium A at 37 deg.C for the test.
(3) Determination of cell number in broth cultures. Prepare serial
1:10 dilutions of each culture in Medium A and determine the number of
cells per milliliter of culture by the plate-count assay method. Do not
use cultures stored at 4 deg.C for more than 48 hours for assay. Do
not use cultures containing less than 109 cells per milliliter.
(4) Plate-count assay. For each culture to be assayed, pipet 1.0
milliliter of each prepared dilution into each of two sterile Petri
plates. To each plate, add 20 milliliters of sterile Medium B that has
been melted and cooled to 45 deg.C (if neutralizers are required, use
the corresponding agar growth medium with the appropriate neutralizer).
Mix the sample with the agar by tilting and rotating the plate and
allow the contents to solidify at room temperature. Invert the Petri
plates and incubate at 37 deg.C for 48 hours. Following incubation,
count the number of developing colonies. Use Petri plates containing
between 30 and 300 colonies in calculating the number of bacteria per
milliliter of original culture.
(5) Test organism antiseptic resistance test. To ensure that
antiseptic resistance properties of each organism have not changed
substantially, determine the susceptibility of each organism to the
active ingredient(s) being tested, in a suitable inactive medium, using
the testing procedures in this section. The organisms are satisfactory
if the number of organisms per milliliter are reduced by 3 log10
within 10 minutes at 37 deg.C in the presence of 10 percent serum.
(d) Test procedures--(1) Method 1--(i) Method validation. This test
is valid only for those antiseptics that are water soluble and/or
miscible and that can be neutralized by one of the subculture media
specified in paragraphs (b)(2)(i) and (b)(2)(ii) of this section or
that can be overcome by dilution.
(ii) Bactericidal assay procedure. Prewarm all test solutions by
incubating appropriate volumes at 37 deg.C in a water bath for 5
minutes. Pipet 1.0 milliliter of serum, 1.0 milliliter of appropriate
bacterial test culture, and 8.0 milliliters of the test antiseptic
product at its recommended use concentration into a medication tube and
mix well. Incubate at 37 deg.C for 10 minutes. Remove triplicate 1-
milliliter sample aliquots and dilute in Medium A containing
appropriate neutralizers. Determine the number of surviving organisms
per milliliter of test culture by the plate-count method using plating
media containing appropriate neutralizers, if required.
(iii) Bacteriostatic assay procedure. Prewarm all test solutions by
incubating appropriate volumes at 37 deg.C in a water bath for 5
minutes. Pipet 1.0 milliliter of serum, 1.0 milliliter of appropriate
bacterial test culture, and 8.0 milliliters of the test antiseptic
product at its recommended use concentration into a medication tube and
mix well. Pipet 1.0 milliliter aliquots of this test mixture into
triplicate medication tubes containing 100 milliliters of Medium A
without neutralizers and mix well. Incubate at 37 deg.C for 48 hours
and determine the number of organisms per milliliter of culture by the
plate-count method.
(2) [Reserved]
(e) Test modifications. The formulation or mode of administration
of certain products may require modification of the testing procedures
in this section. In addition, alternative assay methods (including
automated procedures) employing the same basic chemistry or
microbiology as the methods described in this section may be used. Any
proposed modification or alternative assay method shall be submitted as
a petition under the rules established in Sec. 10.30 of this chapter.
The petition should contain data to support the modification or data
demonstrating that an alternative assay method provides results of
equivalent accuracy. All information submitted will be subject to the
disclosure rules in part 20 of this chapter.
Dated: December 10, 1993.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2262 Filed 2-8-94; 8:45 am]
BILLING CODE 4160-01-F