[Federal Register Volume 60, Number 194 (Friday, October 6, 1995)]
[Rules and Regulations]
[Pages 52474-52510]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-24693]
[[Page 52473]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 310 et al.
Anticaries Drug Products for Over-the-Counter Human Use; Final
Monograph; Final Rule
Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules
and Regulations
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[[Page 52474]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 355, and 369
[Docket No. 80N-0042]
RIN 0910-AA01
Anticaries Drug Products for Over-the-Counter Human Use; Final
Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
in the form of a final monograph establishing conditions under which
over-the-counter (OTC) anticaries drug products (products that aid in
the prevention of dental cavities) are generally recognized as safe and
effective and not misbranded. FDA is issuing this final rule after
considering public comments on the agency's proposed regulation, which
was issued in the form of a tentative final monograph, and all new data
and information on OTC anticaries drug products that have come to the
agency's attention. This final monograph is part of the ongoing review
of OTC drug products conducted by FDA.
EFFECTIVE DATE: October 7, 1996.
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 March 28, 1980
(45 FR 20666), 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 anticaries drug products, together with the
recommendations of the Advisory Review Panel on OTC Dentifrice and
Dental Care Drug Products (the 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 June
26, 1980. Reply comments in response to comments filed in the initial
comment period could be submitted by July 28, 1980.
In accordance with Sec. 330.10(a)(10), the data and information
considered by the Panel, after deletion of a small amount of trade
secret information, were placed on display in the Dockets Management
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420
Parklawn Dr., Rockville, MD 20857.
The agency's proposed regulation, in the form of a tentative final
monograph, for OTC anticaries drug products was published in two
segments. The first segment was published in the Federal Register of
September 30, 1985 (50 FR 39854). It addressed general issues on OTC
anticaries drug products, the switch of prescription anticaries drug
products to OTC status, specific anticaries active ingredients, dosages
for anticaries active ingredients, and labeling of anticaries drug
products. Interested persons were invited to file by November 29, 1985,
written comments, objections, or requests for oral hearing on the
proposed regulation before the Commissioner of Food and Drugs (the
Commissioner). Interested persons were invited to file comments on the
agency's economic impact determination by January 28, 1986. New data
could have been submitted until September 30, 1986, and comments on the
new data until December 1, 1986.
The agency stated in the advance notice of proposed rulemaking that
the Panel's recommended Laboratory Testing Profiles (LTP's) represented
a new concept with many technical issues yet to be resolved. Thus, the
LTP's were not included in the first segment of the tentative final
monograph. The agency mentioned in the tentative final monograph (50 FR
39854) that an open public meeting was held on September 26 and 27,
1983, to discuss unresolved technical issues concerning the LTP's. The
LTP's were subsequently discussed in the second segment of the
tentative final monograph, published in the Federal Register of June
15, 1988 (53 FR 22430). This amendment of the tentative final monograph
addressed final formulation testing for monograph active ingredients in
dentifrice formulations and issues relating to this testing. Interested
persons were invited to file by October 13, 1988, written comments,
objections, or requests for oral hearing on the proposed regulation
before the Commissioner. Interested persons were invited to file
comments on the agency's economic impact determination by October 13,
1988. New data could have been submitted until June 15, 1989, and
comments on the new data until August 15, 1989.
In a notice published in the Federal Register of May 8, 1992 (57 FR
19823), the agency reopened the administrative record to include data
and information in support of a request to increase the package size
limitation for fluoride dentifrice drug products from not more than 260
milligrams (mg) of total fluorine per package to not more than 350 mg.
Interested persons were invited to submit written comments by July 7,
1992.
In the Federal Register of November 24, 1992 (57 FR 55199), the
agency also reopened the administrative record to obtain public comment
on whether the labeling of OTC fluoride-containing drug products should
include the quantity of fluoride, i.e., the specific amount of fluoride
present in the product. Interested persons were invited to submit
written comments by January 25, 1993. In the Federal Register of
January 26, 1993 (58 FR 6102), the agency extended the comment period
to March 26, 1993.
This final rule encompasses all of the above segments. Final agency
action on all OTC anticaries drug products occurs with the publication
of this final rule establishing a monograph for OTC anticaries drug
products.
The OTC drug procedural regulations (Sec. 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 is no longer using 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 Category II or III,
the term ``nonmonograph conditions'' is used.
As discussed in the proposed regulation for OTC anticaries drug
products (50 FR 39854), the agency advised that the conditions under
which the drug products that are subject to this monograph will be
generally recognized as safe and effective and not misbranded
(monograph conditions) will be effective 12 months after the date of
publication in the Federal Register. Therefore, on or after October 7,
1996, 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 or abbreviated application (hereinafter called
application). Further, any OTC drug product subject to this monograph
[[Page 52475]]
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 response to the proposed rule, the amended proposed rule, and
the two reopenings of the administrative record for OTC anticaries drug
products, 19 drug manufacturers, 2 drug manufacturers associations, 2
health care professionals, 1 health care professional society, and 3
academic institutions submitted comments. Copies of the comments are on
public display in the Dockets Management Branch (address above.)
Additional information that has come to the agency's attention since
the publication of the proposed rule, amended proposed rule, and
notices to reopen the administrative record is also on display in the
Dockets Management Branch.
All ``OTC Volumes'' cited throughout this document refer to the
submissions made by interested persons pursuant to the call-for-data
notice published in the Federal Register of August 9, 1972 (37 FR
16029) 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.
I. The Agency's Conclusions on the Comments-
A. General Comments on Anticaries Drug Products
1. One comment noted its continuing position that FDA could not
legally and should not, as a matter of policy, prescribe exclusive
lists of terms from which indications for use for OTC drug products
must be drawn.-The comment stated that FDA could not legally prohibit
alternative OTC indications for use in terminology that is otherwise
truthful and not misleading. The comment added that its views on this
subject were presented in oral and written testimony submitted to FDA
in connection with the September 29, 1982, FDA hearing on the
exclusivity policy. The comment noted that a proposed revision to the
exclusivity policy had been published on April 22, 1985 (50 FR 15810).
The comment mentioned that it had submitted its views in response to
that proposal and was incorporating those views into the rulemaking for
OTC anticaries drug products. A second comment strongly supported the
proposed revision of the exclusivity policy and discussed a number of
constitutional and policy concerns about the agency's labeling policies
for OTC drug products.
The agency notes that the comments in the current rulemaking were
submitted before the agency published a final rule changing its
labeling policy for stating the indications for use of OTC drug
products in the Federal Register of May 1, 1986 (51 FR 16258). The
comments' concerns were addressed by the agency's change in its
labeling policy for stating indications for use. Under the new policy
in Sec. 330.1(c)(2) (21 CFR 330.1(c)(2)), the label and labeling of OTC
drug products are required to contain in a prominent and conspicuous
location, either: (1) The specific wording on indications for use
established under an OTC drug monograph, which may appear within a
boxed area designated ``APPROVED USES''; (2) other wording describing
such indications for use that meets the statutory prohibitions against
false or misleading labeling, which shall neither appear within a boxed
area nor be designated ``APPROVED USES''; or (3) the approved monograph
language on indications, which may appear within a boxed area
designated ``APPROVED USES''; plus alternative language describing
indications for use that is not false or misleading, which shall appear
elsewhere in the labeling.
2. One comment contended that OTC drug monographs are interpretive,
as opposed to substantive, regulations. The comment referred to
statements on this issue submitted earlier to other OTC drug rulemaking
proceedings.
The agency addressed this issue in paragraphs 85 through 91 of the
preamble to the procedures for classification of OTC drug products,
published in the Federal Register of May 11, 1972 (37 FR 9464 at 9467
to 9472); in paragraph 3 of the preamble to the tentative final
monograph for OTC antacid drug products, published in the Federal
Register of November 12, 1973 (38 FR 31260); and in paragraph 1 of the
preamble to the tentative final monograph in the present proceeding (50
FR 39854 at 39855). FDA reaffirms the conclusions stated in those
documents. Court decisions have confirmed the agency's authority to
issue substantive regulations by informal rulemaking. (See, e.g.,
National Nutritional Foods Association v. Weinberger, 512 F.2d 688,
696-698 (2d Cir. 1975) and National Association of Pharmaceutical
Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980), aff'd, 637 F.2d
887 (2d Cir. 1981).)
3. One comment noted that interested persons must file new data
within 1 year after publication of a tentative final monograph per 21
CFR 330.10(a)(7)(iii). For this reason, the comment contended that it
is important that persons submitting comments or objections to the
tentative final monograph be provided with early feedback from FDA so
that sufficient time will remain to allow any necessary additional
testing or market research. The comment requested that the agency
provide feedback on requests no later than 6 months following the
submission of comments or objections to the proposed rule. The comment
also asked that the agency's regulations for the OTC drug review be
amended to contain this provision.
The agency is unable to make a specific commitment to provide
feedback on all comments and objections received in this and other OTC
drug rulemakings within a specific time frame, as requested by the
comment. Competing priorities and the constraints of limited resources
make this impossible to do. However, the agency does review all
comments and objections and tries to provide timely feedback as the
situation requires and as workloads permit.
4. The Public Health Service Ad Hoc Subcommittee on Fluoride of the
Committee to Coordinate Environmental Health and Related Programs (the
Subcommittee) discussed dental fluorosis resulting from fluoride intake
in its report entitled ``Review of Fluoride: Benefits and Risks'' (Ref.
1). The Subcommittee stated that dental fluorosis only occurs during
tooth formation and becomes apparent upon eruption of the teeth. Dental
fluorosis ranges from very mild (symmetrical whitish areas on teeth) to
severe (pitting of the enamel, frequently associated with brownish
discoloration). The Subcommittee recommended that manufacturers of
dental products explore whether the levels of fluoride in their
products can be reduced while preserving clinical effectiveness.
(However, the Subcommittee did not suggest an acceptable fluoride
exposure level.) In response to the Subcommittee's recommendation, the
agency asked a professional dental association and two manufacturers
associations (Refs. 2, 3, and 4) for information on dentifrices
containing low levels of fluoride, particularly for use by children 2
to under 6 years of age.
The dental association stated that it is not currently considering
a low fluoride toothpaste, but would evaluate such a product if one
were to be submitted.
[[Page 52476]]
The association indicated that such a product would be accepted if
clinical data demonstrating effectiveness were available.
The two manufacturers associations provided a joint response, in
which they reviewed the report and relevant clinical and
epidemiological literature, with the following conclusions: (1) There
is a lack of scientific support for a cause and effect relationship
between the ingestion of fluoride from dentifrice products and the
subsequent development of enamel fluorosis; (2) the reported increase
in enamel fluorosis, which ranges from very mild to mild, appears to be
a result of factors other than dentifrice use, while, importantly,
dentifrice use has been the principal contributor to the caries decline
over the past 20 years; and (3) manufacturing changes to reduce the
fluoride content of baby formulas, as well as cautionary advice to
physicians about the administration of fluoride supplements to young
children, are steps that have already been initiated and may well
counteract the increase of the very mild to mild forms of enamel
fluorosis that have been reported, as new epidemiologic data become
available in the future.
The manufacturers associations recommended that there be no
reduction in the 850- to 1,150-parts per million (ppm) theoretical
total fluorine levels proposed in the tentative final monograph for OTC
anticaries drug products, contending that any reduction in this range
could have serious public health consequences in terms of reducing the
current level of anticaries protection in young children. The
associations noted that data from studies evaluating low-potency (250
to 550 ppm) fluoride dentifrices were contradictory and very sparse in
children 2 to 6 years of age.
The agency agrees that there is not enough evidence available at
this time to support the safety and effectiveness of a low-fluoride
dentifrice for children 2 to under 6 years of age, or to determine an
appropriate fluoride concentration for a low-level dentifrice. As noted
by the Subcommittee, dental fluorosis does not compromise oral health
or tooth function as do dental caries. Therefore, the risk of dental
caries from inadequate fluoride protection is a greater health hazard
than the cosmetic detriment of fluorosis. Until adequate data become
available, the agency is not able to generally recognize a low-fluoride
dentifrice as safe and effective. If data become available, the agency
will consider them.
References
(1) Department of Health and Human Services, ``Review of
Fluoride Benefits and Risks: Report of the Ad Hoc Subcommittee on
Fluoride, of the Committee to Coordinate Environmental Health and
Related Programs,'' February, 1991, in OTC Vol. No. 08AFM, Docket
No. 80N-0042, Dockets Management Branch.
(2) Comment No. LET15, Docket No. 80N-0042, Dockets Management
Branch.
(3) Comment No. LET16, Docket No. 80N-0042, Dockets Management
Branch.
(4) Comment No. LET17, Docket No. 80N-0042, Dockets Management
Branch.
5. One comment stated that the proposed definitions for dentifrice,
treatment gel, and treatment rinse in Sec. 355.3(d), (g), and (h),
respectively, should be revised to exclude discussion of the ``cosmetic
function or nonfunction'' of these treatment categories. The comment
noted, for example, that the first sentence in the definition for
dentifrice, ``A substance used with a toothbrush to clean the
accessible surfaces of the teeth,'' refers to a cosmetic function and
should be deleted. The comment proposed modifying the definitions for
dentifrice and treatment gel to be consistent with the definition for a
treatment rinse as follows: A dentifrice is an abrasive-containing
dosage form for delivering an anticaries drug to the teeth, a treatment
gel is a gel dosage form for delivering an anticaries drug to the
teeth, and a treatment rinse is a liquid dosage form for delivering an
anticaries drug to the teeth. The comment suggested the following
alternative definition for the entire category of anticaries drug
products rather than defining individual dosage forms: ``an anticaries
drug product is one which aids in the prevention or treatment of dental
caries. It may be formulated as an abrasive-containing paste or powder,
nonabrasive-containing gel, liquid rinse, or other appropriate product
types.'' The comment concluded that this alternative definition more
clearly emphasizes the intended use of these products rather than
emphasizing the dosage form.
Another comment requested that some proposed definitions of OTC
anticaries dosage forms be revised to delete those terms that refer to
both therapeutic and cosmetic functions. The comment specifically
referred to the definitions in Sec. 355.3(a) (abrasive), (d)
(dentifrice), (g) (treatment gel), (h) (treatment rinse), (i)
(treatment rinse concentrated solution), (j) (treatment rinse
effervescent tablets), and (k) (treatment rinse powder). The comment
contended that the combination of therapeutic and cosmetic functions in
these definitions would be confusing and inappropriate. The comment
recommended that this section be revised to more clearly emphasize the
intended therapeutic function of these dosage forms. For example, ``an
anticaries drug product is one which aids in the prevention or
treatment of dental caries (decay, cavities) and may be formulated as
an abrasive-containing dentifrice, paste, or powder, nonabrasive gel,
liquid rinse, or effervescent powder or tablets.''
The agency has reviewed the Panel's evaluation of the definition of
different fluoride dosage forms and concludes that there is a
significant difference between dentifrices and nonabrasive dental gels
and rinses. A dentifrice formulation contains an abrasive that is
included in the formulation to clean the teeth (45 FR 20666 at 20671),
while nonabrasive dental gels and rinses do not (45 FR 20666 at 20671).
The agency agrees with the comments that OTC drug monographs should
not regulate cosmetic claims and are limited to only drug claims. The
monograph definitions are intended to refer to the therapeutic uses of
the dosage forms defined. Accordingly, the agency is deleting any
references to a ``cosmetic function'' (e.g., cleaning) from the
proposed definitions. In the definition for dentifrice, the first
sentence (``A substance used with a toothbrush to clean the accessible
surfaces of the teeth.'') is deleted. The second sentence is revised to
read ``An abrasive-containing dosage form for delivering an anticaries
drug to the teeth.'' In the definition for treatment gels, the words
``and are not intended for use in cleaning the teeth'' are deleted.
Other definitions mentioned by the comment (treatment rinse, treatment
rinse concentrated solution, treatment rinse effervescent tablets, and
treatment rinse powder) do not need to be revised because they do not
contain any ``cosmetic functions'' language.
6. One comment recommended that the definition of an ``anticaries
drug,'' proposed in Sec. 355.3(b) as ``a drug that aids in the
prevention of dental cavities (decay, caries),'' be revised to include
``treatment'' in addition to ``prevention'' of dental cavities. The
comment also requested that the definition of ``anticaries drug''
reflect the various product dosage forms by adding the following
sentence to the definition: ``It may be formulated as an abrasive-
containing paste or powder, nonabrasive-containing gel, liquid rinse,
or other appropriate product type.'' The comment indicated that the
expanded definition more clearly defines an anticaries drug and
encompasses the various product dosage forms.
[[Page 52477]]
The agency does not agree that the term ``treatment'' alone should
be added to the definition of an anticaries drug. In the context of
this definition, the word ``treatment'' alone implies that anticaries
drug products could treat an existing caries lesion rather than being
useful as a preventive treatment. The Panel recommended and the agency
previously proposed conditions under which OTC anticaries drug products
that aid in the prevention of dental cavities would be generally
recognized as safe and effective, and not misbranded (45 FR 20666 at
20690 and 50 FR 39854 at 39871). Treatment of dental cavities is
generally understood to be a process by which medical or dental
intervention in the management of cavities results in either repair or
stabilization of tooth decay. Neither the Panel nor the agency received
data indicating that fluoridated compounds included in the monograph
are effective in treating or stabilizing tooth decay. The fluoride
drugs included in the monograph are intended as preventive measures
against tooth decay and not as treatment modalities for the management
of existing dental cavities. However, if the term ``treatment'' is
expanded to read ``prophylactic treatment,'' the preventive nature of
such ``treatments'' would not necessarily imply treatment of an
existing caries lesion. Prophylactic treatment is generally described
as the act or manner of protection for or prevention of disease. Thus,
the agency is adding the term ``prophylactic treatment'' in the
definition for ``anticaries drug'' in Sec. 355.3(c) of this final
monograph.
The agency does not agree with the comment that the definition of
``anticaries drug'' should specify various dosage forms. The definition
is only included in the monograph to reflect the intended use of these
drug products.
The agency agrees with the comment that an ``anticaries drug'' can
be formulated in various dosage forms and has defined numerous dosage
forms in the final monograph (see Sec. 355.3(e) and (h) through (m)).
These dosage forms include those requested by the comment.
7. Two comments objected to the second sentence of the definition
for ``treatment gel'' in proposed Sec. 355.3(g), which reads:
``Treatment gels are formulated in an anhydrous glycerin base with
suitable thickening agents included to adjust viscosity.'' The comments
indicated that treatment gels, including 0.4-percent stannous fluoride
treatment gel, may be formulated in bases that do not contain any
anhydrous glycerin compound without compromising the safety or
effectiveness of the anticaries drug product. Therefore, the comments
recommended that the agency delete the second sentence of the
definition.
The agency does not agree that the second sentence of the
definition of a ``treatment gel'' should be deleted. The definition in
proposed Sec. 355.3(g) was based on the only formulation for this
dosage form that was submitted to the Panel for review. The Panel
stated that stannous fluoride is stable in anhydrous glycerin (45 FR
20666 at 20688) and defined ``dental gels'' as being ``formulated in an
anhydrous glycerin base with suitable thickening agents included to
adjust viscosity'' (45 FR 20690). The Panel (45 FR 20688) and the
agency have used this definition based on the results of laboratory and
clinical studies that supported the safety and effectiveness of a
specific formulation. For greater clarity, the agency is changing the
term ``treatment gel'' in Sec. 355.3(i) to ``preventive treatment gel''
to make it clear that the product's intended purpose is prevention of
dental cavities. Preventive treatment gels formulated in bases other
than anhydrous glycerin could be considered for inclusion in the
monograph provided that stability of the fluoride compound is
demonstrated and the available fluoride ion is not adversely affected
by the base used in the formulation. If such a formulation were found
acceptable, the definition of a preventive treatment gel could be
revised as necessary to describe such a formulation. However, the
agency currently has no data to support such formulations. Accordingly,
the agency is not revising the definition at this time.
8. One comment disagreed with the agency's suggestion in the
tentative final monograph (53 FR 22430 at 22432) that interested
persons may petition the agency to amend the anticaries monograph to
include specific organic fluorides as active ingredients for use in
dental formulations rather than file to obtain an approved new drug
application (NDA). The comment stated that allowing submission of a
petition to include organic fluorides in the monograph presupposes that
these active ingredients can be shown to be generally recognized as
safe and effective, and have been used for a material time and to a
material extent. The comment noted that although organic fluoride
formulations have been used outside the United States, they do not meet
the conditions for inclusion in the OTC drug review because they have
never been sold in this country. The comment therefore suggested that
the agency not allow the alternative of petitioning to amend the
monograph to include organic fluoride formulations, but instead require
filing an NDA.
The agency agrees with the comment that organic fluoride
formulations do not have a marketing history in the United States.
However, the agency is currently reevaluating whether foreign marketing
can satisfy the material time and extent criteria for inclusion of an
ingredient in the OTC drug review. The agency intends to address this
issue in a future issue of the Federal Register. In the meantime, it
would not be in the public interest to unduly delay publication of the
final monograph for OTC anticaries drug products while this matter is
being resolved.
Interested persons may submit a petition requesting amendment of
the final anticaries monograph to include an organic fluoride
formulation. Such a petition would be considered in the context of the
agency's reevaluation of the marketing history threshold criteria for
the OTC drug review. Alternatively, an NDA may be filed under part 314
(21 CFR part 314). With either procedure, the manufacturer must submit
adequate data showing the organic fluoride to be safe and effective for
its intended use.
B. Comments on Specific Anticaries Active Ingredients and Dosage Forms
9. One comment requested that the agency consider the anticaries
activities of both the stannous and the fluoride ions in 0.4 percent
stannous fluoride, as well as the combined anticaries effect of the
total compound, instead of considering the fluoride ions alone. The
comment contended that the stannous ions in 0.4 percent stannous
fluoride have significant anticaries properties, by reducing enamel
solubility and through antibacterial activity. However, the comment did
not submit any data to support its position.
The Panel reviewed extensive data on stannous fluoride dentifrices,
rinses, and gels (45 FR 20666 at 20684 to 20685 and 20687 to 20688) and
attributed effectiveness to the fluoride ion present in the product.
The agency is not aware of any data supporting anticaries activity of
stannous ions in stannous fluoride. Without data demonstrating this
activity, the agency has no basis to consider the stannous ions as
contributing to the anticaries effects of these drug products.
10. Several comments requested that the allowable upper limit of
fluoride concentration in a dentifrice marketed under the final
monograph be increased from 1,150 ppm theoretical total fluorine to
1,500 ppm. The comments stated that 850 to 1,150 ppm levels of fluoride
in dentifrice products were
[[Page 52478]]
established nearly 25 years ago. One comment mentioned that, at that
time, concentrations of fluoride were set arbitrarily low because of
concerns about fluoride toxicity. The comments indicated that there is
sufficient evidence that much higher fluoride concentrations are safe
and effective, based on widespread use of such concentrations in the
United States and Europe. With more toxicological data now available,
the comments suggested a higher dosage of fluorides in dentifrices
should be available for persons who reside in nonfluoridated areas or
who have a greater propensity to develop caries. The comments contended
that such a need has been acknowledged by the agency's approval of an
NDA for an ``extra-strength'' (1,500 ppm) fluoride dentifrice. One
comment indicated that it manufactures and distributes ``extra-
strength'' fluoride dentifrices in other countries and has received no
reports of ill effects from use of these products.
The comments submitted several clinical studies (Refs. 1, 2, and 3)
demonstrating that a dentifrice containing 1,500 ppm theoretical total
fluorine can provide greater anticaries protection than 850- to 1,150-
ppm levels. The first study (Ref. 1) was a 3-year, double-blind
clinical comparison of the anticaries effectiveness of a test
dentifrice containing 1.14 percent sodium monofluorophosphate (1,500
ppm theoretical total fluorine) with a control dentifrice containing
0.76 percent sodium monofluorophosphate (1,000 ppm theoretical total
fluorine). This study involved 2,415 children, primarily 8 to 11 years
of age, who resided in a nonfluoridated community. The children were
randomly assigned to one of the two groups. The children brushed
normally at home and participated in a daily supervised toothbrushing
exercise at school. Results of this study indicated that 48 percent of
the subjects who used the 1,000-ppm fluoride dentifrice remained caries
free and 57 percent of those who used the 1,500-ppm dentifrice remained
caries free. The study also suggested that the participants using the
1,000-ppm dentifrice would have projected a savings of 639 additional
surfaces and 344 teeth if they had received the 1,500-ppm dentifrice
during the 3-year trial.
The second study (Ref. 2) was also a 3-year, double-blind clinical
comparison of two sodium monofluorophosphate dentifrices, one
containing 1,500 ppm and the other containing 1,000 ppm theoretical
total fluorine. The study involved 1,913 children between 6 and 11
years of age. The subjects were randomly assigned to one of the two
groups. The children brushed in the same manner as in the first study.
Results of this study demonstrated that, even in an area with optimal
water fluoridation, a 1,500-ppm concentration provides greater
anticaries protection than a 1,000-ppm theoretical total fluorine
concentration.
The third clinical study (Ref. 3) compared the anticaries effect of
three dentifrices containing the following concentrations of
theoretical total fluorine: (1) 1,100 ppm (as sodium fluoride), (2)
2,800 ppm (as sodium fluoride ), and (3) 2,800 ppm (as sodium
monofluorophosphate). Approximately 4,500 school children between 7 and
15 years of age, whose community water supply contained less than 0.3
ppm fluoride, were assigned at random to brush unsupervised with one of
the three dentifrices. Results of the 3-year clinical study showed no
significant difference between the 2,800-ppm sodium monofluorophosphate
and the positive control (1,100 ppm as sodium fluoride). However, the
study demonstrated that the group assigned to brush with sodium
fluoride containing 2,800 ppm theoretical total fluoride received an
estimated 15 percent fewer cavities than those subjects who brushed
with the sodium fluoride dentifrice containing 1,100 ppm theoretical
total fluoride.
One comment noted that two of these clinical studies (Refs. 1 and
2) formed the basis for FDA approval of the 1,500-ppm ``extra-
strength'' dentifrice under an NDA. Based on these data, the comment
requested that the 1,500-ppm dentifrice be included in the monograph.
One comment requested that the agency specifically include higher
strength sodium fluoride dentifrice products (1,500 ppm) in the final
monograph. The comment stated its belief that consumers should be
permitted the widest possible choice of safe and effective OTC drugs
and that the monograph should be flexible to permit the use of
equivalent fluoride species.
Several other comments argued that increasing the fluoride
concentration to a level as high as 1,500 to 1,650 ppm would be unwise
without adequate scientific support to justify the increased risk of
developing fluorosis. One comment indicated that clinical trials using
higher strength fluoride-containing dentifrices have demonstrated no
adverse experiences or changes of any consequence with respect to soft
tissue aberrations in children 8 to 12 years of age. However, the
comment added that there has not been sufficient attention paid to the
potential risk of enamel fluorosis in children under 6 years of age
using such higher strength fluoride dentifrices, particularly if the
children live in an optimally-fluoridated community. Another comment
cited two reports (Refs. 4 and 5) indicating that the prevalence of
dental fluorosis in children residing in nonfluoridated areas has
increased appreciably during the past decade with more than 20 percent
of the children having mild fluorosis. The comment also cited another
study (Ref. 6) suggesting that the use of fluoride dentifrices prior to
2 years of age is a major risk factor for dental fluorosis. The comment
pointed out that modifying the monograph to permit the use of elevated
fluoride concentrations in dentifrices (i.e., 1,500 to 1,650 ppm) would
clearly increase the risk of children developing dental fluorosis. The
comment further stated that the modest increase in anticaries
effectiveness attributable to elevated fluoride levels in dentifrices
may not be adequate to justify the increased risk of developing
fluorosis. The comment concluded that the proposed increase of fluoride
in dentifrices to 1,500 ppm would affect the risk/benefit ratio
unfavorably. Accordingly, the comment urged the agency to reject the
proposed increase in the fluoride level in dentifrices to 1,500 to
1,650 ppm.
Another comment expressed similar concern for the potential risk of
enamel fluorosis in children under 6 years of age who may use
dentifrices containing the proposed higher levels of fluoride during
toothbrushing. The comment indicated that there exists ample
documentation that young children swallow a significant amount of
dentifrice. The comment submitted two published clinical studies (Refs.
7 and 8) evaluating the significance of fluoride dentifrices as a risk
factor in dental fluorosis. One study (Ref. 7) indicated that a portion
of the dentifrice introduced to the mouth and not expectorated, but
swallowed and absorbed, ranged from 0 to 100 percent. The study
suggested that inadequate control of the swallowing reflex by younger
children accounts for the excessive ingestion of fluorides,
particularly from dentifrices and mouthrinses. The other study (Ref. 8)
indicated that, on average, children used 0.662 gram (g) of dentifrice
and ingested 0.299 g per brushing. Results from this study indicated:
(1) The younger the children, the more likely they are to swallow a
greater proportion of dentifrice; and (2) young children who rinse
their mouths and expectorate properly after brushing ingest less
[[Page 52479]]
dentifrice. The comment predicted that if manufacturers are allowed to
market an increased level of fluoride without requiring an agency-
approved application, routine use of these extra strength dentifrices
would increase the potential risk of enamel fluorosis in younger
children. However, the comment did not indicate how or why the routine
use of NDA-approved extra strength dentifrice products would prevent an
increased risk of enamel fluorosis in younger children.
In the tentative final monograph for OTC anticaries drug products
(53 FR 22430 at 22432), the agency stated that a 1,500-ppm theoretical
total fluoride level is safe, but indicated that general recognition of
the effectiveness of this strength fluoride dentifrice must be based on
adequate published or publicly available medical and scientific data.
Two clinical studies (Refs. 1 and 2) that formed the basis of an agency
NDA approval of this strength sodium monofluorophosphate dentifrice
have now been included in the public record for this rulemaking by the
NDA holder. Results of these studies indicate an enhanced anticaries
benefit derived over a 3-year period from the use of the higher
fluoride sodium monofluorophosphate dentifrice (1,500 ppm) when
compared to the positive control fluoride dentifrice (1,000 ppm). The
studies also indicated that children who are at increased risk to
develop caries and those with erupting premolars and second molars may
derive more benefit from a 1,500-ppm dentifrice than a 1,000-ppm
dentifrice.
The agency has not received any clinical or available fluoride ion
data on any 1,500-ppm sodium fluoride dentifrice comparable to the
information for 1,500-ppm sodium monofluorophosphate dentifrice.
Therefore, the agency is not including higher strength (1,500 ppm)
sodium fluoride dentifrice drug products in this final monograph at
this time.
As noted above, comments expressed concern that an increase of
theoretical total fluorine to 1,500 ppm could increase the incidence of
dental fluorosis in children. The agency agrees that for children under
6 years of age a risk/benefit analysis indicates that levels of
fluoride in dentifrices should not exceed the currently accepted OTC
level of 1,150 ppm (see discussion of fluorosis in comment 23).
Although an NDA was approved in 1986 for an extra-strength fluoride
dentifrice (1,500 ppm) whose labeling allowed for use in children above
2 years of age, the agency recognizes that more recent data (Refs. 4
and 8) suggest that the incidence of fluorosis in children under 6
years of age is increasing in the United States. The agency does not
believe that the increased risk of fluorosis outweighs the benefit of
using an extra-strength fluoride dentifrice in children under 6 years
of age. The agency has determined from the results of the submitted
clinical studies that the enhanced benefit of using an extra-strength
dentifrice product does not present additional risk to children above 6
years of age and to adults, particularly for those with a greater
propensity to develop cavities or for those who live in communities
with nonfluoridated water. As discussed in the tentative final
monograph (50 FR 39854 at 39864), developing teeth of children under 6
years of age may show objectionable dental fluorosis from repeated
ingestion of excessive amounts of fluoride. However, epidemiological
and clinical findings indicate that the formative state of the teeth of
children 6 years of age and older (excepting third molars) is too
advanced to be affected by the amount and frequency of use of fluoride
dentifrices.
The agency is including sodium monofluorophosphate dentifrices that
contain 1,500 ppm theoretical total fluorine in this final monograph.
Because of concerns about dental fluorosis, the agency is requiring
that dentifrice products with these fluorine concentrations be clearly
labeled for use only by children above 6 years of age. Accordingly, the
agency is including the following directions in Sec. 355.50(d)(1)(ii):
Paste dosage form with a theoretical total fluorine
concentration of 1,500 ppm identified in Sec. 355.10(b)(2). Adults
and children 6 years of age and older: brush teeth thoroughly,
preferably after each meal or at least twice a day, or as directed
by a dentist or doctor. Instruct children under 12 years of age in
good brushing and rinsing habits (to minimize swallowing). Supervise
children as necessary until capable of using without supervision.
Children under 6 years of age: Do not use unless directed by a
dentist or doctor.
The agency believes that extra-strength fluoride dentifrice
products may be beneficial to consumers who have a greater propensity
to develop cavities, and that manufacturers may wish to promote these
products for this purpose. Therefore, the agency is expanding
Sec. 355.50(f)(2) to include an optional additional labeling statement
for these products as follows:
For dentifrice products containing 1,500 ppm theoretical total
fluorine. Adults and children over 6 years of age may wish to use
this extra-strength fluoride dentifrice if they reside in a
nonfluoridated area or if they have a greater tendency to develop
cavities.
Finally, the agency does not find that sufficient data exist to
support the safety and effectiveness of a theoretical total fluorine
level above 1,500 ppm. Accordingly, the agency is not including
dentifrices with such theoretical total fluorine levels in the
monograph.
References-
(1) Conti, J. A. et al., ``A 3-year Clinical Trial to Compare
Efficacy of Dentifrices Containing 1.14 Percent and 0.76 Percent
Sodium Monofluorophosphate,'' Community Dental Oral Epidemiology,
16:135-138, 1988.--
(2) Fogels, H. R. et al., ``A Clinical Investigation of a High-
Level Fluoride Dentifrice,'' Journal of Dentistry for Children,
55(3):210-215, 1988.---
(3) Lu, K. H. et al., ``A Three-year Clinical Comparison of a
Sodium Monofluorophosphate Dentifrice with Sodium Fluoride
Dentifrices on Dental Caries in Children,'' Journal of Dentistry for
Children, 54(4):241-244, 1987.
(4) Woolfolk, M. W. et al., ``Relation of Sources of Systemic
Fluoride to Prevalence of Dental Fluorosis,'' Journal of Public
Health Dentistry, 49:78-82, 1989.
(5) Leverett, D. H., ``Fluorides and the Changing Prevalence of
Dental Caries,'' Science, 217:26-30, 1982.
(6) Osuji, O. O. et al., ``Risk Factors for Dental Fluorosis in
a Fluoridated Community,'' Journal of Dental Research, 67(12):1488-
1492, 1988.
(7) Whitford., G. M., D. W. Allmann, and A. R. Shahed, ``Topical
Fluorides: Effects on Physiologic and Biochemical Processes,''
Journal of Dental Research, 66(5):1072-1078, 1987.
(8) Simard, P. L. et al., ``The Ingestion of Fluoride Dentifrice
by Young Children,'' Journal of Dentistry for Children, 56:177-181,
1989.
11. One comment (from the holder of the only approved NDA for a
1,500-ppm fluoride dentifrice) provided data indicating that the lowest
available fluoride ion concentration measured during the 3-year
clinical trial of its 1,500-ppm sodium monofluorophosphate dentifrice
product was 1,295 ppm, with an analytical variability of
20 ppm (Refs. 1 and 2).
Based on the available fluoride ion data for this product, the
agency has determined at this time that all 1,500-ppm sodium
monofluorophosphate dentifrices must provide an available fluoride ion
concentration equal to or greater than 1,275 ppm. Accordingly, the
agency is including higher strength (1,500 ppm) sodium
monofluorophosphate dentifrice products in Sec. 355.10(b)(2) of this
final monograph as follows:
Dentifrices containing 1,500 ppm theoretical total fluorine in a
paste dosage form. Sodium monofluorophosphate 1.153 percent with an
available fluoride ion concentration (consisting of PO3F=
and F- combined) gr-thn-eq 1,275 ppm.
[[Page 52480]]
References
(1) Comment LET18, Docket No. 80N-0042, Dockets Management
Branch.
(2) Comment LET20, Docket No. 80N-0042, Dockets Management
Branch.
12. One comment requested that the active ingredient listings for
sodium fluoride treatment rinses in proposed Sec. 355.10(b)(3), (b)(4),
and (b)(5) be combined as follows: ``Sodium fluoride 0.02 to 0.05
percent in a final solution with a pH of approximately 7.'' The comment
stated that this would provide a range of allowable concentrations for
these rinses without affecting the technical accuracy of the monograph.
The agency disagrees with the comment. The active ingredient
listings in Sec. 355.10(b)(3), (b)(4), and (b)(5) specify particular
concentrations for sodium fluoride in a rinse dosage form. The
monograph is not intended to provide a range of concentrations for
these products. The 0.02- and 0.05-percent sodium fluoride
concentrations were included in the monograph based on separate,
independent clinical studies, as discussed for the 0.05-percent
concentration in the Panel's report (45 FR 20666 at 20686) and for the
0.02-percent concentration in the agency's tentative final monograph
(50 FR 39854 at 39863). More importantly, the directions for 0.02
percent sodium fluoride in a neutral dental rinse (pH of approximately
7) are for use twice daily and for 0.05 percent sodium fluoride rinse
are for use only once a day. These dosage regimens are each supported
by separate, independent clinical data. There are no data to support
directions for other concentrations. Accordingly, there is no basis to
combine the active ingredient listings for the sodium fluoride
treatment rinses included in this final monograph.
13. One comment requested that sodium fluoride/sodium bicarbonate
powdered dentifrices be included in the final monograph for OTC
anticaries drug products. In response to the agency's concerns
discussed in the tentative final monograph (53 FR 22430 at 22443) about
the safety and effectiveness of powdered fluoride dentifrices, the
comment submitted several analytical and biological studies (Ref. 1).
The comment contended that these studies demonstrate the effectiveness
and comparable bioavailability of a powdered fluoride dentifrice with a
toothpaste containing a similar abrasive system and an equivalent
concentration of theoretical total fluorine.
The comment submitted several animal studies (Refs. 2, 3, and 4)
that determined the anticaries effect of a sodium fluoride/sodium
bicarbonate powdered dentifrice in rats that were infected with highly
virulent strains of cariogenic bacteria. In one study (Ref. 2), a group
of rats infected with Streptococcus sobrinus that was treated topically
with sodium fluoride/sodium bicarbonate powdered dentifrice experienced
42 percent fewer caries lesions than a control group treated only with
distilled water. Rats exposed to either the tooth powder or 10 ppm
fluoridated drinking water produced similar reduction in caries (42 and
47 percent, respectively).
In another study (Ref. 3), rats infected with S. mutans were
treated with a 1:2 part slurry of sodium bicarbonate-based powdered
dentifrice containing 0.22 percent sodium fluoride (1,000 ppm) in water
for 1 minute daily for 3 weeks. Results indicated a 51-percent caries
reduction in infected rats treated with the tooth powder as compared to
the group of rats treated with distilled water. Rats treated with an
equal concentration of sodium fluoride aqueous solution without other
inactive ingredients developed a 36-percent reduction in cavities as
compared to the control group. The data also indicated that no
significant difference in the incidence of cavities was observed in the
group of rats treated topically with sodium fluoride/sodium bicarbonate
powdered dentifrice and the group of rats receiving no other treatment
except 10 ppm fluoride in their drinking water (51 percent versus 54
percent).
In another animal study (Ref. 4), rats infected with S. sobrinus
were treated with an undiluted sodium bicarbonate-base powdered
dentifrice containing 0.22 percent sodium fluoride. Results of this
study indicated a 47-percent reduction in cavities as compared to the
control group. This reduction in cavities was not statistically
different from the 43-percent reduction in total cavities obtained by
topical treatment with an undiluted sodium bicarbonate-based toothpaste
containing the same level of sodium fluoride.
The comment also submitted several clinical studies that evaluated
the anticaries effectiveness of fluoridated and nonfluoridated powdered
dentifrices. However, the studies involving nonfluoridated powdered
dentifrices were not related to and do not support the effectiveness of
the comment's dentifrice product that contains sodium fluoride as the
active ingredient.
The comment submitted a 1-year clinical study (Ref. 5) that
demonstrated the anticaries effectiveness of tooth powders containing
fluorapatite (essentially calcium fluoride). Although the powdered
dentifrice used in this study contained an active ingredient
(fluorapatite) different than the active ingredient found in the
comment's sodium fluoride dentifrice product, the study supported the
anticaries effectiveness of a powdered dentifrice dosage form. In this
study, 150 medical students brushed daily with one of three dentifrices
containing: (1) 71.4 percent fluorapatite, (2) an ion-free ``synthetic
apatite'' consisting of hydroxyapatite with a surface layer of
fluorapatite (total fluorine content, 0.25 percent), or (3) a control
powdered dentifrice not containing fluoride. Results of this study
indicated that the group that brushed with the fluorapatite powder and
the group that bushed with the ``synthetic apatite'' paste developed an
average of 38 and 67 percent fewer cavities, respectively, than those
students who brushed with the nonfluoride tooth powder.
Another study (Ref. 6) compared human enamel uptake of fluoride
from a sodium fluoride/sodium bicarbonate dentifrice in a powdered and
a paste dosage form. In this study, human enamel was ground and
polished flat to provide a uniform surface and then demineralized to
create a simulated white-spot caries lesion. Several enamel slabs were
exposed continuously for 30 minutes at body temperature to a tooth
powder (with a poured-bulk density of 1.0 to 1.2 g/milliliter (mL) and
available fluoride ion concentration equal to or greater than 850 ppm)
and a toothpaste containing sodium fluoride/sodium bicarbonate with an
available fluoride ion concentration equal to or greater than 650 ppm.
Results of this study indicated that both the powder and paste dosage
forms demonstrated comparable enamel uptake of fluoride ions.
The comment concluded by stating that the data demonstrate the
safety and effectiveness of a powdered dentifrice containing sodium
fluoride and show that such a product can provide effectiveness
equivalent to a toothpaste containing a similar abrasive system. The
comment urged the agency to include sodium fluoride/sodium bicarbonate
powdered dentifrices in the final monograph for OTC anticaries drug
products.
The agency has reviewed the data provided by the comment and
determined that sufficient data have been provided to generally
recognize as safe and effective powdered dentifrices containing sodium
fluoride with a sodium bicarbonate abrasive. However, the agency points
out that several of the studies submitted measured the anticaries
effectiveness of dentifrices containing active agents (fluorapatite,
carbamide-urease, and fluoridated table
[[Page 52481]]
salt) different than the active ingredient contained in the comment's
tooth powder (sodium fluoride). Although the data from one study
provide some indication of cariostatic effectiveness of a fluorapatite
dentifrice, the agency does not find these studies pertinent to the
determination of the safety and effectiveness of the comment's sodium
fluoride/sodium bicarbonate powdered dentifrice.
The agency considers the biological studies submitted by the
comment as demonstrating that the bioequivalence and bioavailability of
fluoride ions are comparable for sodium fluoride/sodium bicarbonate
powdered and paste dentifrices containing the same concentration of
theoretical total fluorine. Results of several well-designed animal
caries studies (Refs. 2, 3, and 4) demonstrate that rats inoculated
with cariogenic bacteria and fed a caries promoting diet developed 42
to 51 percent fewer cavities when treated with a topical application of
sodium fluoride/sodium bicarbonate powdered dentifrice than rats in a
control group. In addition, the agency concludes that the results of
the submitted human enamel uptake study (Ref. 6) indicate that the
measured human enamel uptake of fluoride from a powder containing
sodium fluoride/sodium bicarbonate with a fluoride ion concentration of
1,000 ppm was better than the fluoride uptake of a similar dentifrice
paste formulation. Although the agency does not believe that this
system is comparable to real-life development of early dental caries or
that a one-time exposure of enamel slabs continually for 30 minutes at
37 deg.C simulates real-life conditions of short, intermittent
exposures during a month's usage, the agency does believe that fluoride
uptake is a marker of potential anticaries effectiveness and considers
the two fluoride dosage forms at least equivalent.
Accordingly, the agency is including sodium fluoride/sodium
bicarbonate powdered dentifrices in Sec. 355.10(a)(2) of this final
monograph as follows:
Dentifrices containing 850 to 1,150 ppm theoretical total
fluorine in a powdered dosage form: Sodium fluoride 0.188 to 0.254
percent with an available fluoride ion concentration of
gr-thn-eq 850 ppm for products containing the abrasive sodium
bicarbonate and a poured-bulk density of 1.0 to 1.2 grams per
milliliter.
References-
(1) Comment No. C00066, Docket No. 80N-0042, Dockets Management
Branch.
(2) Tanzer, J. M. et al., ``Effects of Bicarbonate-based Dental
Powder, Fluoride, and Saccharin on Dental Caries and on
Streptococcus sobrinus Recoveries in Rats,'' Journal of Dental
Research, 66(3):791-794, March, 1987.
(3) Tanzer, J. M. et al., ``Bicarbonate-based Dental Powder,
Fluoride, and Saccharin Inhibition of Dental Caries Associated with
Streptococcus mutans Infection of Rats,'' Journal of Dental
Research, 67(6):969-972, June, 1988.---
(4) McMahon, T. et al., ``Caries Inhibition by Bicarbonate-based
Dental Powder in S. mutans 10449S-infected Rats,'' Journal of Dental
Research, 67:343, 1988.
(5) McClendon, J. F., and W. C. Foster, ``Prevention of Dental
Caries by Brushing The Teeth With Powders Containing Fluorapatite,''
Journal of Dental Research, 26:233-239, 1947.--
(6) Letter from J. J. Hefferren, J. J. Hefferren Resources,
Inc., to T. Winston, Church & Dwight Co., Comment No. C00066
(Attachment 1), Docket No. 80N-0042, Dockets Management Branch.
14. One comment responded to the agency's concern expressed in the
tentative final monograph (53 FR 22430 at 22444) that several possible
methods of applying a powdered dosage form to a toothbrush may lead to
significant variations of fluoride ion delivered to the teeth. The
comment agreed that directions for using powdered products have been
varied. However, the comment indicated that this is not a reason to
determine that a sodium fluoride powdered dentifrice would not be safe
and effective. The comment added that after several years of marketing
a powdered dentifrice, it has found that pouring a powdered dentifrice
from a container with a flip-top spout provides a cleaner and simpler
application of the product with a uniform dosage of fluoride.
The comment claimed that the available fluoride ion obtained from
two applications of a tooth powder containing a minimum of 850 ppm
soluble (available) fluoride ion will be equal to or greater than the
Panel's recommended 650 ppm available fluoride ion for sodium fluoride
dentifrices. The comment based the need for two applications of tooth
powder on its recommendation that sodium fluoride/sodium bicarbonate
powdered dentifrices have a poured-bulk density of 1.0 to 1.2 g/mL and
an available fluoride ion concentration equal to or greater than 850
ppm. The comment responded to several concerns raised by the agency in
the tentative final monograph (53 FR 22430 at 22443). These concerns
involved previous recommendations that two poured-bulk density ranges
(0.5 to 0.99 g/mL and 1.0 to 1.7 g/mL) were necessary for powdered
fluoride dentifrices and that two applications per brushing with a
powdered dentifrice in the lower poured-bulk density range would
provide an appropriate dose of fluoride. The comment stated that the
two poured-bulk density ranges were based on the assumption that equal
volumes of tooth powder and toothpaste are applied in a single
application to the brush; however, that assumption may no longer be
correct because of the difference in consistency of the two dosage
forms. The comment mentioned that more toothpaste than tooth powder can
be applied to a brush without falling off; thus, the level of fluoride
delivered to the teeth in one application is greater with a toothpaste
than with a tooth powder, assuming comparable theoretical total
fluorine.
The comment submitted a study (Ref. 1) that measured the weight of
tooth powder and toothpaste applied in a single application to a tooth
brush. Subjects were instructed to generously pour tooth powder onto a
wet toothbrush so that the bristles were completely covered. The
subjects were also instructed to apply to a similar size brush an
amount of toothpaste they would normally use during brushing. The
weight of dental powder in a single application was determined by
weighing the toothbrush (plus a piece of paper used to catch spillage)
before and after application; whereas the weight of the toothpaste was
determined by weighing the package before and after applying a single
dose to a toothbrush. The results of this study indicated that
consumers applied an average of 0.8 g of powdered dentifrice and 1.46 g
of paste to the same type of toothbrush. Results of this study
indicated that two applications of a powdered dentifrice product of
poured-bulk density 1.1 g/mL provides a level of fluoride comparable to
a single application of a fluoridated toothpaste containing the same
fluoride concentration.
The data were further analyzed (Ref. 2) to determine what dosage of
fluoride would be provided if two applications of tooth powder with an
available fluoride concentration of 850 to 1,100 ppm were placed on a
toothbrush. The comment stated that, assuming two applications of tooth
powder and one of toothpaste, the extrapolated amount of available
fluoride ion delivered to the teeth by the tooth powder is comparable
to the amount of soluble fluoride ion provided by a toothpaste. Based
on these data, the comment recommended that the directions specify two
applications of fluoride powder dentifrices containing 850 to 1,100 ppm
theoretical total fluorine and a poured-bulk density range of between
1.0 and 1.2 g/mL.
One comment discussed directions for use of powdered fluoride
dentifrices by children under 12 years of age. In the
[[Page 52482]]
tentative final monograph (53 FR 22430 at 22444), the agency had stated
that children under 12 years of age may require greater manual
dexterity to properly use a powdered dentifrice than is needed to
correctly use a toothpaste. The agency expressed concern about the
potential for young children to accidentally consume a toxic amount of
fluoride when using a tooth powder compared to a toothpaste. The
comment contended that powdered dentifrices do not pose any greater
risk over pastes for accidental overdoses by children. The comment
added that, while it believes that children between 6 and 12 years of
age can use a powdered dentifrice properly, it has no objection to the
monograph providing that powdered dentifrices not be labeled for use by
children under 6 years of age and requiring labeling that states use by
children 6 to under 12 years of age should be only with adult
supervision. However, the comment expressed concern that such labeling
might give the false impression that there is an inherent unsafe
quality with the product, rather than merely a difficulty for children
to use the product properly. The comment suggested the monograph
include the following directions and labeling for powdered fluoride
dentifrices to prevent any such false impressions: ``Since a powdered
fluoride dentifrice may be difficult for children to use, this product
is not recommended for children under 6. Children between the ages of 6
and 12 should use this product under adult supervision.''
The agency has reviewed the data (Refs. 1 and 2) and determined
that the directions for use of fluoride powdered dentifrices with a
poured-bulk density of 1.0 to 1.2 g/mL and an available fluoride ion
concentration equal to or greater than 850 ppm must specify two
applications to deliver a comparable amount of fluoride as a fluoride
toothpaste of the same strength. One study (Ref. 1) showed that in a
single application 45 percent less tooth powder than toothpaste was
applied to a similar size brush. Because spillage that occurred during
the weighing procedure was included in the final applied weight of
powder, even less tooth powder than toothpaste was actually placed on
the brush. Thus, the agency agrees with the comment that consumers who
use two applications of a fluoride tooth powder with a poured-bulk
density of 1.0 to 1.2 g/mL containing 850 to 1,100 ppm available
fluoride ion receive an amount of fluoride ion comparable to using a
single application of a sodium fluoride toothpaste with an available
fluoride ion concentration equal to or greater than 650 ppm.
Accordingly, the agency is including directions in this final monograph
that provide for two applications of fluoride powdered dentifrices. The
agency is also including in the LTP tables a poured-bulk density range
of 1.0 to 1.2 g/mL for powdered dentifrices (see section I.F., comment
37 of this document).
Regarding the use of powdered fluoride dentifrices by children, the
agency does not believe that powdered fluoride dentifrices pose a
greater threat for accidental ingestion than fluoride toothpaste. Also,
the agency does not believe that children 6 years of age and older are
likely to consume a toxic amount of fluoride from a dentifrice powder.
In most instances, such products will be used under adult supervision.
Further, existing regulations (Sec. 310.201(a)(10)(iv)) establish
package size limitations for sodium fluoride preparations.
The agency agrees with the comment that these products should not
be labeled for use by children under 6 years of age, and should be
labeled for use with adult supervision by children 6 to under 12 years
of age. Accordingly, the agency is adding the following directions for
powdered dentifrices in Sec. 355.50(d)(1)(iii):
Powdered dosage form with a theoretical total fluorine
concentration of 850 to 1,150 ppm identified in Sec. 355.10(b)(2).
Adults and children 6 years of age and older: Apply powder to a wet
toothbrush; completely cover all bristles. Brush for at least 30
seconds. Reapply powder as before and brush again. Rinse and spit
out thoroughly. Brush teeth, preferably after each meal or at least
twice a day, or as directed by a dentist or doctor. Instruct
children under 12 years of age in good brushing and rinsing habits
(to minimize swallowing). Supervise children as necessary until
capable of using without supervision. Children under 6 years of age:
Do not use unless directed by a dentist or doctor.
The agency believes that these directions will not give consumers a
false impression that there is any inherent unsafe quality with these
products.
References-
(1) J. Ross Associates, ``A Dentifrice Use Test,'' draft of
unpublished study, Comment No. C00066 (Attachment I, Exhibit 5),
Docket No. 80N-0042, Dockets Management Branch.
(2) J. Ross Associates, ``A Dentifrice Use Test,'' draft of
unpublished study, Comment No. C00066 (Attachment I, Exhibit 7),
Docket No. 80N-0042, Dockets Management Branch.
15. One comment agreed with the agency's concern expressed in the
tentative final monograph (53 FR 22430 at 22444) that proper packaging
is important to prevent moisture contamination of a powdered
dentifrice, particularly in areas where the humidity is high due to
showering and bathing. The comment indicated that its powdered
dentifrice product is sold in a plastic bottle with a flip top cap and,
therefore, quite effectively prevents moisture contamination.
As discussed in the tentative final monograph (53 FR 22444), the
agency agrees with the comment that powdered fluoride dentifrices would
probably remain more stable for a longer period of time than the paste
form because there would be less interaction between dry ingredients
during storage of the dentifrice. However, the agency recognizes that
the storage conditions of a powdered fluoride dentifrice would have a
significant impact on whether the product would remain stable longer
than the paste form. Storage of the powdered product in areas where the
humidity is high due to showering and bathing would require that the
container be resistant to moisture contamination.
A ``tight container,'' as defined in the United States Pharmacopeia
(U.S.P.), would meet this criterion. The U.S.P. defines a ``tight
container'' (Ref. 1) as a container that ``protects the contents from
contamination by extraneous liquids, solids, or vapors, from loss of
the article, and from efflorescence, deliquescence, or evaporation
under the ordinary or customary conditions of handling, shipment,
storage, and distribution, and is capable of tight re-closure.''
In addition, Sec. 211.94 (21 CFR 211.94) of the FDA current good
manufacturing practice (GMP) regulations addresses drug product
containers and closures. Section 211.194(a) states: ``Drug product
containers and closures shall not be reactive, additive, or absorptive
so as to alter the safety, identity, strength, quality, or purity of
the drug beyond the official or established requirements.'' Section
211.194(b) states: ``Container closure systems shall provide adequate
protection against foreseeable external factors in storage and use that
can cause deterioration or contamination of the drug product.''
Therefore, based on Sec. 211.94 of the FDA GMP regulations and the
U.S.P. standard for a ``tight container,'' the agency is adding a new
paragraph in Sec. 355.20(b) that reads: ``Tight container packaging. To
minimize moisture contamination, all fluoride powdered dentifrices
shall be packaged in a tight container, which is defined as a container
that protects the contents from contamination by extraneous liquids,
solids, or vapors, from loss of the article, and from efflorescence,
deliquescence,
[[Page 52483]]
or evaporation under the ordinary or customary conditions of handling,
shipment, storage, and distribution, and is capable of tight
reclosure.''
Reference-
(1) The United States Pharmacopeia 23--The National Formulary
18, United States Pharmacopeial Convention, Inc., Rockville, MD, p.
10, 1994.
C. Comments on Labeling of OTC Anticaries Drug Products
16. One comment responded to the agency's question whether
consumers would benefit in having OTC fluoride-containing drug products
labeled to state their fluoride levels. The comment objected to
fluoride level labeling for OTC anticaries drug products and provided
the results of a consumer survey as support (Ref. 1). The survey was
conducted in shopping malls in eight different geographic areas and
included a sample of 200 women between the ages of 18 and 49. The women
routinely purchased dentifrice products for their households. In
addition, 150 women with children between 1 and 5 years of age were
interviewed to determine the habits and practices of women with
children regarding the use of fluoride dentifrices. The comment stated
that the results of the survey indicate that: (1) Consumers believe
that fluoride in dentifrice products is important in preventing
cavities, (2) regardless of the unit of measurement, e.g., ppm,
percent, or milligrams per inch (mg/in), used to label the fluoride
concentration, consumers believe ``more is better'' when choosing a
dentifrice because they consistently selected dentifrices labeled with
the higher net fluoride, indicating that consumers believe that there
are differences in the effectiveness of fluoride dentifrice products,
(3) most consumers know how to use fluoride dentifrices, (4) most
consumers are aware of the fluoride ingredient in the toothpaste, and
(5) most parents take an interest in and supervise their children's
brushing habits. Based on these results, the comment concluded that
labeling fluoride-containing products to state their fluoride levels is
not useful to consumers and could be misleading. The comment
recommended that such labeling not be required for OTC fluoride drug
products.
The agency has evaluated the consumer survey and determined that it
has some methodology deficiencies. The major deficiency is an
inadequate respondent sample size. In order to generalize the findings
of this study to the general population, it would be necessary to have
a larger number of respondents. Further, the survey involved only women
between the ages of 18 and 49 years of age. There were no men in the
survey nor women above 49 years of age; these people might also have
reasons for wanting to know the fluoride content. In addition, the
survey did not attempt to assess the relative understanding by the
respondents of the various methods of expressing quantities of
fluoride. Contextual material could have been used to clarify the
meaning of the measures used, making it more likely that consumers
could make use of the information provided, regardless of the type of
measurements used.
Nonetheless, the survey provides some useful information. It
demonstrates that more consumers chose a dentifrice labeled with the
higher net fluoride content, based on the concept that ``more fluoride
is better.'' Rather than emphasizing fluoride concentration numbers,
the agency believes that labeling would be more beneficial if it
informs consumers who have a greater propensity to develop cavities of
the need to use a higher strength fluoride dentifrice. Therefore, in
this final rule, the agency is including in Sec. 355.50(f)(2) the
following optional additional labeling statement for dentifrice
products containing 1,500 ppm theoretical total fluorine: ``Adults and
children over 6 years of age may wish to use this extra-strength
fluoride dentifrice if they reside in a nonfluoridated area or if they
have a greater tendency to develop cavities.'' Because of concerns
about dental fluorosis occurring in children under 6 years of age, the
agency is requiring extra-strength fluoride dentifrice products to
state in their labeling that the product should not be used by children
under 6 years of age unless directed by a doctor or dentist. (See
section I.B., comment 10 of this document.)
In conclusion, no comments, data, or information were submitted in
support of fluoride level labeling. Accordingly, this final monograph
does not contain a requirement that fluoride-containing dentifrice
products label the quantity of fluoride. However, it does provide an
optional additional labeling statement that manufacturers may use for
these products.
Reference-
(1) Comment No. C0097, Docket No. 80N-0042, Dockets Management
Branch.
17. One comment objected to the inclusion of the term ``treatment''
as the single recommended term in the proposed statement of identity in
Sec. 355.50(a). The comment stated that the terms ``treatment'' and
``dental'' are both appropriate statements of identity for various
anticavity product dosage forms and that other equally truthful and
nonmisleading identifiers are also appropriate. The comment made two
recommendations: (1) The term ``treatment'' be retained as an optional
statement of identify for gels, rinses, concentrated rinses, rinse
powders, or rinse effervescent tablets, and (2) the term ``dental''
also be listed as optional, such as in connection with a professionally
promoted ``dental treatment gel.'' The comment concluded that its
suggested revisions to Sec. 355.50(a) would provide for truthful and
accurate statements of identity.
Another comment suggested that the agency delete the term
``treatment'' from the statement of identity and permit ``anticavity
dental rinse'' or ``fluoride dental rinse'' as a statement of identity,
because the term ``treatment'' does not appropriately describe the
activity of these products. The comment stated that these rinse
products provide their anticaries benefits primarily through a
prophylactic mode of action and are perceived by consumers as
preventive prophylactic measures rather than therapeutic treatments.
The mechanism of fluoride action is well recognized in the scientific
community and was addressed in the Panel's report (45 FR 20666 at
20672). According to the comment, the Panel noted that fluoride
increases enamel resistance to acid solubility, making the teeth less
susceptible to plaque acid attack, thereby producing its cariostatic
effect. The comment concluded this is primarily a preventive mode of
action as contrasted to a therapeutic action. The comment thus proposed
that the agency delete the term ``treatment'' from the statement of
identity and permit ``anticavity dental rinse'' or ``fluoride dental
rinse'' as a statement of identity. The comment concluded that these
statements of identity are more descriptive and meaningful to consumers
and more accurately define the therapeutic benefit of an anticaries
drug product.
The agency discussed the use of the term ``treatment'' as part of
the statement of identity for nonabrasive gels and rinses in the
tentative final monograph (50 FR 39854 at 39866) in response to a
comment that pointed out that some current dentifrice (abrasive-
containing) products are transparent or translucent and are called gels
by manufacturers and consumers. Two other comments also expressed
concern that the use of the term ``gel'' alone for a nonabrasive 0.4-
percent stannous fluoride product could be confusing to
[[Page 52484]]
the consumer in distinguishing between abrasive and nonabrasive
fluoride gels; these comments suggested the term ``nonabrasive dental
gel.'' The agency agreed with the comments that it is important to
provide labeling that would allow consumers to easily distinguish
between a nonabrasive and an abrasive-containing fluoride gel, but
stated that the term ``nonabrasive'' may not be meaningful for
consumers. The agency also stated that because nonabrasive fluoride
gels had not been widely marketed, consumers were not familiar with the
use of the term ``dental gel'' to identify such products, particularly
in the context of widely marketed abrasive-containing fluoride
dentifrices labeled as gels. Thus, the agency proposed that the term
``treatment'' be included in the statement of identity for all
nonabrasive OTC fluoride products to clearly distinguish between a
dentifrice and a nonabrasive fluoride product.
The agency agrees with the comment that the term ``treatment'' can
be optional for fluoride dental rinses, but disagrees with making this
term optional for nonabrasive fluoride gels. As discussed in section
I.A., comment 7 of this document, the agency has added the word
``preventive'' to the definition of a ``treatment gel.'' The comments
did not discuss the possibility that consumers could be confused in
distinguishing a nonabrasive fluoride treatment gel from an abrasive-
containing dentifrice gel. The comment also did not explain how such
labeling would distinguish a nonabrasive fluoride gel from an abrasive
fluoride dentifrice. In order for consumers to be better able to make
this distinction, the agency is requiring that the term ``preventive
treatment'' be included in the statement of identity for nonabrasive
fluoride gels. Because a distinction is not needed for fluoride dental
rinses, the agency is providing that the phrase ``preventive
treatment'' be optional in the statement of identity for these
products. The statement of identity for OTC anticaries drug products in
Sec. 355.50(a) of this final monograph reads as follows:
The labeling of the product contains the established name of the
drug, if any, and identifies the product as the following:
``anticavity fluoride'' (select one of the following as appropriate:
``dentifrice,'' ``toothpaste,'' ``tooth polish,'' ``tooth powder;''
(optional: ``dental'') ``preventive treatment gel;'' or (optional:
``preventive treatment'' or ``dental'')) (select one of the
following: ``rinse,'' ``concentrated solution,'' ``rinse powder,''
or ``rinse effervescent tablets''). The word ``mouthwash'' may be
substituted for the word ``rinse'' in this statement of identity if
the product also has a cosmetic use, as defined in section 201(i) of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
321(i)).
18. One comment requested revisions in the proposed statement of
identity for fluoride-containing products in Sec. 355.50(a). The
comment contended that a fluoride-containing liquid product labeled
both to prevent cavities and to freshen the breath should be identified
as an ``anticavity or fluoride mouthwash,'' whereas a fluoride rinse
that makes no cosmetic claims should properly be identified as an
``anticavity or fluoride rinse.''
Several other comments requested that the statement of identity for
anticaries drug products include the terms ``tooth powder'' and ``tooth
polish.'' The comments stated that these terms are commonly recognized
and have been used in dentifrice product labeling for many years.-
The agency agrees that a fluoride-containing liquid product
represented both to prevent cavities and to freshen the breath can
properly be identified as an ``anticavity or fluoride mouthwash.''
Further, the agency agrees that a fluoride rinse with no cosmetic
claims in its labeling is appropriately identified as a ``rinse.'' The
agency also agrees that the terms ``tooth polish'' and ``tooth powder''
are suitable for use as part of the statement of identity for
anticaries drug products. The word ``tooth'' indicates the site of
usage; ``powder'' is a dosage form; and ``polish'' has been used in
labeling of these products for many years without consumer confusion.
The word ``polish'' indicates a cosmetic usage. As discussed in comment
19, the agency's OTC drug regulations do not prohibit placing a
cosmetic statement of identity of a drug/cosmetic product on the
principal display panel. Accordingly, the agency is including the terms
``mouthwash'' (if the product also has a cosmetic use), ``tooth
polish,'' and ``tooth powder'' in Sec. 355.50(a) in this final rule.
(For further discussion of the statement of identity, see section I.C.,
comments 17 and 19 of this document.)
19. Two comments noted that many anticaries drug products also
properly contain cosmetic ingredients and include cosmetic labeling.
The comments contended that manufacturers must be permitted to label
such products with statements of identity that include truthful drug/
cosmetic terminology. For example, the comments stated that the same
product may be used both as an anticaries dentifrice and as a cleaning
and breath freshening toothpaste. The comment maintained that such a
product should be able to truthfully declare in its statement of
identity what it is and what it does.
One comment maintained that the agency's labeling policy set forth
in a proposal to amend the statement of identity requirements for OTC
drugs published in the Federal Register of April 17, 1986 (51 FR
13023), along with the agency's exclusivity and label separation
policies, make it impossible for a manufacturer to comply with both the
drug and cosmetic labeling requirements set forth in the statute and
regulations. The comment pointed out that existing FDA regulations
require that the statement of identity for both drug and cosmetic
products appear on the principal display panel of the product. The
comment contended that the effect of the agency's drug-cosmetic label
separation policy is that the cosmetic statement of identity may not be
placed on the principal display panel.
The comment argued that cosmetic terminology should be allowed
anywhere in the labeling of an anticaries dentifrice that is also a
cosmetic product so long as it does not render the product's labeling
false or misleading. The comment argued that consumers would not be
misled by the inclusion of both kinds of labeling on an anticaries drug
product. On the contrary, the comment stated that consumers would more
likely be misled if the drug and cosmetic statements of identity and
other claims were to appear on entirely different portions of the
label. The comment concluded that there is no legal or policy
justification for this label separation policy.
If a product covered by this rulemaking is marketed for both drug
and cosmetic use, it must conform to the requirements of the final OTC
drug monograph and bear appropriate labeling for cosmetic uses in
accord with section 602 of the act (21 U.S.C. 362) and the provisions
of 21 CFR parts 701 and 740.
Sections 201.61 and 701.11 of the CFR require that the statement of
identity for OTC drug and cosmetic products each appear on the
principal display panel of the product. The agency's OTC drug
regulations do not prohibit placing the cosmetic statement of identity
of a drug/cosmetic product on the principal display panel. However, in
accordance with the revised labeling requirements for OTC drug
products, cosmetic claims may not appear within the boxed area
designated ``APPROVED USES.'' (See section I.A., comment 1 of this
document.) As discussed in the final rule on the agency's ``exclusivity
policy'' (51 FR 16258 at 16264 (paragraph 14)), cosmetic terminology is
[[Page 52485]]
not reviewed and approved by FDA in the OTC drug monographs and
therefore can not be placed in the boxed portion of the label. Cosmetic
terminology can, however, be placed outside the box and on the
product's principal display panel. In addition, 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 other than
in the product's indications section, such claims should be
appropriately described so that consumers will be readily 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 sections 502(a) and 602(a) of the act (21 U.S.C. 352(a) and
362(a)).
20. One comment objected to the first portion of the agency's
proposed additional labeling statement for fluoride dental rinses in
Sec. 355.50(e)(2), which states: ``This is a(n)'' (select one or both
of the following: ``anticavity'' or ``fluoride'') ``treatment rinse,
not a mouthwash. Read directions carefully before using.'' The comment
contended that a properly formulated and labeled product could be
legally and accurately promoted as both an anticavity dental rinse and
a cosmetic mouthwash. The comment added that requiring the ``not a
mouthwash'' statement on fluoride dental rinses is not consistent with
the agency's well-established policy regarding OTC drugs that claim
both therapeutic and cosmetic benefits. The comment stated that dual
drug/cosmetic labeling is permitted in other product categories (e.g.,
antiperspirants, dentifrices, and antidandruff shampoos), and that the
agency does not require similar labeling statements for such products.
The comment contended that requiring an anticavity dental rinse/
mouthwash product to display the ``not a mouthwash'' labeling statement
is inconsistent with agency policy for these other OTC products and
could be confusing to consumers who have been receiving both benefits
from previous use of these products.
The comment argued that the agency's proposal would adversely
affect the truthful promotion of OTC anticavity dental rinses, and that
consumers desiring both anticavity and breath freshening activity would
have to purchase two separate products (i.e., an anticavity dental
rinse and a cosmetic mouthwash) instead of purchasing one product that
would provide both benefits. The comment requested the agency to delete
the statement in proposed Sec. 355.50(e)(2) that says ``This is a(n)''
(select one or both of the following: ``anticavity'' or ``fluoride'')
``treatment rinse, not a mouthwash.''
In the tentative final monograph for OTC anticaries drug products,
the agency expressed concern that, because fluoride dental rinses and
cosmetic mouthwashes are similar in appearance, consumers might confuse
such products (50 FR 39854 at 39869). The agency stated that proper
labeling is an important aid to preventing consumer confusion as to the
use of these products. Therefore, the agency proposed labeling,
including the labeling statement ``* * * not a mouthwash * * *'' in
Sec. 355.50(e)(2), to minimize confusion and to help consumers
distinguish between dental rinses and cosmetic mouthwashes.
The agency sees no reason why an appropriately labeled OTC fluoride
rinse cannot also be used for freshening the breath. Such a product can
properly be identified as an anticavity or fluoride rinse or mouthwash
(see section I.C., comment 18 of this document). However, the agency
believes that proper labeling of OTC fluoride rinses is an important
factor in helping to ensure the safe and effective use of these
products.
The agency is concerned that, based upon familiarity with cosmetic
mouthwash use, a consumer might overuse and/or misuse an OTC fluoride
rinse. For example, directions for use of fluoride rinses are notably
different from directions for use of cosmetic mouthwashes. Cosmetic
mouthwashes are often labeled for multiple use during the day (e.g.,
``first thing in the morning, after meals, and before social
engagements'') (Ref. 1). Fluoride rinses are labeled for use once or
twice a day (Sec. 355.50(d)(2)). Cosmetic mouthwash labeling directs
consumers to ``rinse or gargle 30 seconds'' (Ref. 1). The directions
for use of fluoride rinses state that consumers should ``* * * swish *
* * between your teeth for 1 minute * * * Do not eat or drink for 30
minutes after rinsing'' (Sec. 355.50(d)(2)).
Based on the above discussion, the agency has determined that the
``not a mouthwash'' statement need not be required labeling for OTC
fluoride rinses. Accordingly, the agency is not including proposed
Sec. 355.50(e)(2) in this final monograph. However, in order to
maximize the safe and effective use of OTC fluoride rinses, the agency
concludes that these products must contain labeling that clearly
instructs consumers to read the directions. The agency also believes
that this information should be displayed on the principal display
panel. Therefore, the agency is including in this final monograph new
Sec. 355.55 as follows: ``Principal display panel of all fluoride rinse
drug products. In addition to the statement of identity required in
Sec. 355.50, the following statement shall be prominently placed on the
principal display panel: `IMPORTANT: Read directions for proper use'.''
Reference-
(1) Labeling for Scope, OTC Vol. 08AFM, Docket No.
80N-0042, Dockets Management Branch.
21. One comment disagreed that the heading ``Indication'' proposed
in Sec. 355.50(b) was needed in the labeling of OTC fluoride dentifrice
products. The comment contended that the function of a fluoride
toothpaste is generally known, and consumers have safely and correctly
used these products for years without the heading ``Indication'' in the
labeling of these products. The comment added that the consuming public
probably does not consider fluoride toothpaste to be a drug in the same
sense as other common OTC drug products; thus, consumers could be
confused by this new labeling requirement. The comment suggested that
Sec. 355.50(b) be revised to make use of the heading ``Indication''
optional.
The agency does not agree that the heading ``Indication(s)'' should
be optional. All OTC drug monographs in parts 331 through 358 (21 CFR
331 through 358) have been promulgated with a standard ``Indications''
paragraph requiring that the labeling of the product state its FDA
approved use(s) under the heading ``Indication(s).'' However, two
general OTC drug product labeling provisions, which were promulgated
after the comment was submitted, provide alternatives. Section
330.1(c)(2)(i) provides that, at the option of the manufacturer, the
``Indications'' may be designated ``APPROVED USES'' or given a similar
designation as permitted in that paragraph of the regulations. Section
330.1(i)(8) provides that ``indications'' or ``uses'' may be used
interchangeably.
Although the comment claims that consumers may not be accustomed to
reading such information on dentifrice product labels, the agency
believes that consumers should be aware that these products are drugs.
This same principle would apply to other OTC products that consumers
might not consider to be drugs because they have not contained such
labeling in the past, e.g., antiperspirants and sunscreens. The comment
did not provide any evidence that consumers would be confused by
[[Page 52486]]
reading this type of labeling, which has appeared for years on many
widely used OTC drug products. The agency finds that informative
headings such as ``Indications'' or ``Uses'' (as well as ``Warnings''
and ``Directions'') are useful to consumers and provide uniformity to
OTC drug product labeling. Therefore, the agency is not making use of
the heading ``Indication(s)'' optional.
22. One comment noted that Sec. 330.1(g) (21 CFR 330.1(g)) requires
that all drugs, unless exempted, be labeled with the warning ``Keep
this and all drugs out of the reach of children.'' The comment stated
that OTC anticaries dentifrices and rinses obviously should not be
subject to the general warning because they bear directions for use by
children. The comment requested that OTC anticaries drug products be
exempted from the requirement to bear this warning.
The agency agrees, in part, with the comment. The agency recognizes
that fluoride dentifrices are generally kept within the reach of
children to encourage use on a regular basis. The agency is concerned
that the general warning ``Keep this and all drugs out of the reach of
children'' could discourage or inhibit parents from keeping fluoride
dentifrices within easy reach of children 6 years of age and older who
are able to use dentifrice products safely and effectively. However,
these products should not be within easy reach of children under 6
years of age, who should be supervised and instructed in the proper use
of these products and who are vulnerable to dental fluorosis. Thus, in
Sec. 355.50(c) of this final monograph, the agency is modifying the
Sec. 330.1(g) warning to read as follows for fluoride dentifrice
products: ``Keep out of the reach of children under 6 years of age.''
The agency disagrees with the comment with respect to fluoride
rinses and gels. The agency believes that these dosage forms should not
be within easy reach of any children. These products are not indicated
for use in children under 6 years of age on an OTC basis. For children
6 to under 12 years of age, the products must be labeled for use under
the supervision of an adult. These fluoride dosage forms are
potentially more toxic than fluoride dentifrice products because they
do not contain an abrasive that can bind some the fluoride ion and
because a child under 6 is more likely to drink a flavored liquid than
eat large amounts of toothpaste, which may contain up to 40 percent by
weight of inert abrasive ingredients.
The agency has reviewed its adverse reaction data base covering the
period from 1985 to 1992 for reports related to fluoride rinses, gels,
and dentifrices (Ref. 1). In the 0- to 9-year age group, there were 22
reports for fluoride rinses and gels, but no reports for fluoride
dentifrice products. In addition, the agency has reviewed available
data concerning exposures to fluoride toothpastes and fluoride rinses
(mouthwash) in annual reports of the American Association of Poison
Control Centers for the years 1989 to 1991 (Refs. 2, 3, and 4). For
children under 6 years of age, the number of accidental exposures
averaged approximately 1,200 per year for fluoride toothpastes and
almost 1,000 per year for fluoride rinses. However, fluoride toothpaste
usage is estimated to be 300 times that of fluoride rinses. Thus, the
accidental ingestion rate for fluoride toothpaste is much lower than
for fluoride liquid products. Therefore, the available data strongly
support a requirement that fluoride rinses and gels be labeled in
accord with the general warning in Sec. 330.1(g), without any
modifications. This requirement appears in Sec. 355.50(c)(2) of this
final monograph.
References-
(1) Food and Drug Administration, Center for Drug Evaluation and
Research, Adverse Reaction Summary Listing for Fluoride Rinses,
Gels, and Dentifrices for years 1985 to 1992, OTC Vol. O8AFM, Docket
No. 80N-0042, Dockets Management Branch.
(2) Litovitz, T. L. et al., ``1989 Annual Report of the American
Association of Poison Control Centers National Data Collection
System,'' The American Journal of Emergency Medicine, 8:421, 1990.
(3) Litovitz, T. L. et al., ``1990 Annual Report of the American
Association of Poison Control Centers National Data Collection
System,'' The American Journal of Emergency Medicine, 9:488, 1991.
(4) Litovitz, T. L. et al., ``1991 Annual Report of the American
Association of Poison Control Centers National Data Collection
System,'' The American Journal of Emergency Medicine, 10:480, 1992.
23. Two comments disagreed with the directions proposed in
Sec. 355.50(d)(1) for anticaries dentifrices, which state: ``Adults and
children 2 years of age and older: brush teeth thoroughly at least once
daily or as directed by a dentist or doctor. Children under 6 years of
age should be supervised in the use of this product.'' The comments
disagreed in two major areas: (1) The agency's reference to brushing at
least once daily may be misinterpreted by the public as being adequate
and, therefore, may lead to less brushing and poor oral health care.
The comments indicated that there is no clear consensus within the
dental profession as to the number of times teeth should be brushed
each day. Many dentists recommend brushing after each meal, and, for
reasons of practicality, brushing at least twice a day--after breakfast
and in the evening. The comments indicated that they are unaware of any
data that suggest brushing once a day is adequate, and therefore urged
the agency not to refer to any minimum number of times for brushing.
(2) The contraindication for the use of fluoride dentifrices by
children under 2 years of age is unwarranted because children that age
have many teeth requiring anticaries protection. The comments stated
that early instruction of children regarding dental care minimizes the
risk of fluorosis due to ingestion of fluoride dentifrice and
encourages good oral health care habits.
The Panel reviewed several clinical studies that showed fluoride-
containing dentifrices effectively increase resistance to enamel
solubility and therefore reduce dental decay when applied to the teeth
at least once a day (Refs. 1, 2, and 3). Radike (Ref. 3) describes
three 1-year clinical studies with a similar design conducted to
determine whether the frequency of application affects the
anticariogenic effect of a stannous fluoride dentifrice. Each study
used similar stannous fluoride dentifrices, but the subjects (school
children) were assigned one of three different brushing procedures: (1)
Unsupervised brushing, (2) supervised brushing once-a-day after the
noon meal, and (3) supervised brushing three times a day (after
breakfast and dinner and before retiring). Each brushing regimen was
assigned approximately the same number of control subjects as test
subjects. Subjects in a control group assigned to a specific brushing
procedure brushed with a nonfluoride-containing dentifrice. In the
study in which no toothbrushing instructions were given and the
subjects were allowed to follow their usual brushing habits, the
fluoride dentifrice subjects developed 23 percent fewer new caries than
those in the control group. In the study with one supervised brushing
in the school room after the noon meal, the fluoride dentifrice
subjects developed 34 percent fewer caries than those in the control
group. In the third study with supervised brushing three times a day
(after breakfast and dinner and before retiring), the fluoride
dentifrice subjects developed 57 percent fewer new caries than those in
the control group. The results from these studies clearly suggest that
simply cleansing the teeth with an abrasive containing nonfluoridated
dentifrice is not as effective in reducing the incidence of caries as
brushing with a fluoride-
[[Page 52487]]
containing dentifrice. The data also show that more frequent topical
applications of fluoride significantly enhance anticaries protection.
Supervised brushing with a fluoride dentifrice once-a-day after the
noon meal resulted in 33 percent fewer cavities than unsupervised
brushing. Further, subjects who brushed three times a day with a
fluoride dentifrice experienced: (1) 40 percent fewer new cavities than
those who brushed with a fluoride dentifrice only once-a-day, even
under supervision, and (2) 60 percent fewer cavities than those whose
brushing was unsupervised. The results of these three studies indicate
that fewer caries occur as frequency of supervised brushing and
brushing after meals is increased.
Several additional studies (Refs. 4 through 7) also indicate that
brushing immediately after meals is the most favorable time to reduce
the number of cariogenic bacteria from all tooth surfaces. Two review
studies (Refs. 4 and 6) discussed the role nutrition plays in the
etiology of dental disease. Both studies concluded that one
preventative measure to effectively reduce the number of cariogenic
bacteria present in the mouth is to brush thoroughly after each meal
with a fluoride-containing dentifrice. Forty years ago, another study
(Ref. 7) indicated that many dentists and health workers strongly
recommend that toothbrushing be performed immediately after the
ingestion of sugar-containing food if brushing is to be effective in
reducing dental cavities. The study also included a clinical
investigation evaluating the effectiveness of reducing dental cavities
by brushing the teeth with one of three types of nonfluoridated
dentifrices immediately after the ingestion of food. This report (Ref.
7) dealt with only one of the dentifrices, the neutral paste. Subjects
in the experimental group were instructed individually to brush their
teeth thoroughly within 10 minutes after each ingestion of food or
sweets and, when brushing was not possible, to rinse the mouth
thoroughly with water. Toothbrushes and dentifrice were supplied to all
experimental subjects. Subjects in the control group were not supplied
with dentifrices or brushes, but were instructed to continue their
customary oral hygiene habits of brushing only on arising and before
retiring, rather than after the ingestion of food. When this study was
conducted in 1950, fluoridated toothpastes were not available in the
marketplace; thus, the control subjects would not have used a
fluoridated dentifrice as a part of their customary oral hygiene
habits. Clinical results after 1 year indicated that brushing
thoroughly immediately after the ingestion of food resulted in a 63-
percent reduction in caries activity in the experimental group when
compared to the control group.
A more recent 1982 study (Ref. 8) reviewed the prevention control
of oral diseases and recommended at least two daily brushings with a
fluoride dentifrice as effective in reducing the incidence of dental
cavities. The study further stated that because toothbrushing is
intended to remove food debris and dental plaque from the teeth,
brushing after meals and sweet snacks is commonly recommended in dental
health messages to the public.
The agency agrees with the comments and with many dentists that
brushing properly and thoroughly more often than once daily will
promote better oral health care. Reducing cariogenic activity by
brushing more often than once a day, particularly after meals, can be
explained by the synergistic effect of the antienzymatic properties of
fluoride (45 FR 20666 at 20672) along with the mechanical removal of
food debris. The Panel recognized that three factors are necessary for
caries to occur (45 FR 20666 at 20672): (1) The teeth must be
susceptible to caries, (2) acid-producing bacteria of the mouth must
colonize on the teeth, and (3) a substrate must be present for bacteria
to proliferate and to produce acid for demineralization of the teeth.
Effective anticaries protection is achieved by exposing the tooth
enamel to fluoride ions and by the mechanical removal of dental plaque
and food debris from tooth surfaces and gingival tissue areas. Both
objectives are better accomplished by toothbrushing more often than
once daily, preferably after meals. The mechanical removal of food
debris from teeth and gingival areas decreases the availability of
metabolized carbohydrate sources, which are required for caries
development.
The agency agrees with the Panel that brushing with a fluoride-
containing dentifrice at least once daily effectively renders the teeth
less susceptible to dental cavities. The agency also recognizes,
however, that anticaries protection could be enhanced by brushing more
than once a day, preferably after each meal to remove the food
particles that provide the substrate necessary for bacteria to
proliferate and produce acid in the development of dental caries (Ref.
3). Therefore, the agency is revising part of the directions for all
OTC fluoride dentifrices to read: ``* * * brush teeth thoroughly,
preferably after each meal or at least twice a day, or as directed by a
dentist or doctor.''
The agency disagrees with the comments suggesting that the
contraindication for children under 2 years of age is unwarranted. Very
young children cannot be expected to rationally interpret and
consistently follow the instructions involving proper toothbrushing;
nor do they have the manual dexterity to use the fluoride dentifrice
product properly. Children under 2 years of age do not have control of
their swallowing reflex and do not have the skills to expectorate the
toothpaste properly (50 FR 39854 at 39867). Although the prevalence of
dental caries is decreasing, some reports suggest the incidence of mild
fluorosis (a permanent, mottled discoloration of the teeth) in young
children is increasing in the United States due to the increase of
fluoride in our food chain (Ref. 9). Excessive ingestion of fluoride by
young children increases the risk of fluorosis during the critical time
of anterior teeth development and can interfere with the successful
development of other emerging teeth (Ref. 10). Toothbrushing for
children under 2 years of age when teeth are first emerging may also
cause minor injury to the soft tissue in the mouth. The agency
recognizes that young children are most susceptible to mild fluorosis
as a result of improper use and swallowing of a fluoride dentifrice
product. Based on the above, the agency concludes that it is
appropriate to include in the labeling of fluoride dentifrice drug
products containing 1,000 ppm theoretical total fluorine the following
sentence: ``Children under 2 years of age: Consult a dentist or
doctor.'' The agency is including this sentence in the directions in
Sec. 355.50(d)(1)(i) of this final monograph. The agency is also
including a similar statement in the directions for dentifrices
containing 1,500 ppm theoretical total fluorine for children under 6
years of age (see section I.B., comment 10 of this document).
References-
(1) Council on Dental Therapeutics, Accepted Dental
Therapeutics, 37th ed., American Dental Association, Chicago, p.
303, 1977.
(2) Council on Dental Therapeutics, ``Evaluation of Super Stripe
Toothpaste,'' Journal of the American Dental Association, 71:930-
931, 1966.
(3) Radike, A. W., ``Current Status of Research on the Use of a
Stannous Fluoride Dentifrice,'' in OTC Vol. 080099.
(4) Massler, M., ``Nutrition and Dental Decay,'' Food and
Nutrition News, 39:1-4, 1968.
(5) Nikiforuk, G., and J. B. MacDonald, ``An Evaluation of
Dentifrices in the Prevention of Dental Caries and Gingivitis,''
Journal of the
[[Page 52488]]
Canadian Dental Association, 21:557-565, 1955, Abstracted in Dental
Abstracts, 1(4):227, 1956. -
(6) Finn, S. B., and R. B. Glass, ``Sugar and Dental Decay,''
World Review of Nutrition and Dietetics, 22:318-320, 1975.
(7) Fosdick, L. S., ``The Reduction of the Incidence of Dental
Caries. 1. Immediate Tooth-Brushing with a Neutral Dentifrice,'' The
Journal of the American Dental Association, 40(2):133-143, 1950.
(8) Council on Dental Therapeutics, Accepted Dental
Therapeutics, 39th ed., American Dental Association, Chicago, pp.
335-337, 1982.--
(9) Leverett, D. H., ``Fluorides and the Changing Prevalence of
Dental Caries,'' Science, 217:26-30, 1982.--
(10) Simard, P. L. et al., ``The Ingestion of Fluoride by Young
Children,'' Journal of Dentistry for Children, 56:177-181, 1989.
24. Three comments objected to the directions proposed in
Sec. 355.50(d)(1) for anticaries products marketed in a dentifrice
dosage form (containing 1,000 ppm theoretical total fluorine), which
states: ``Children under 6 years of age should be supervised in the use
of this product.'' The comments contended that this is the type of
language that is customarily used for products or activities that are
dangerous, thus the language is needlessly alarmist. The comments
explained that ``supervision'' in this usage connotes watchfulness to
prevent any action by the child that could lead to harm. The comments
claimed that a parent reading this direction for use might infer that
toothpaste has some dangerous hidden toxicity. The comments emphasized
that the important point is that children should be trained how to
brush their teeth so that they will obtain the desired benefit of
toothbrushing without swallowing excessive amounts of toothpaste, which
would increase their risk of fluorosis. One comment stated that the
proposed labeling implies that even after good brushing habits are
acquired, every toothbrushing event until age 6 should be supervised by
a parent. The comments requested that the directions be revised to
read: ``Instruct children under 6 years of age in good brushing and
rinsing habits as recommended by your dentist.'' The comments argued
that implicit in the concept of instruction is supervision until the
parent is satisfied that the child can follow the instruction
correctly. The comments concluded that the term ``instruction'' rather
than ``supervision'' provides the correct emphasis, provides useful
guidance adequate to deal with the concern about fluorosis, and does so
without stimulating unwarranted parental concern.
Another comment did not object to the term ``supervised'' in the
direction for dentifrices containing 1,000 ppm theoretical total
fluorine, but requested the agency to expand Sec. 355.50(d)(1) to read:
``To prevent swallowing, children under 6 years of age should be
supervised in the use of toothpaste (mouthrinse).'' The comment stated
that young children should be educated in the proper manner of
toothbrushing so as to help enhance proper brushing technique as well
as appropriate product use (i.e., using small portions and spitting the
dentifrice out after use, rather than ingestion). The comment stated
that the Council on Dental Therapeutics of the American Dental
Association (ADA) has recently adopted this statement and directed its
use on all labeling for Council-accepted fluoride-containing
dentifrices and mouthwashes.
The agency agrees with the comments. The Panel recommended that
fluoride dentifrices be labeled to indicate that children under 6 years
of age should be supervised in the use of these products. In the
tentative final monograph for OTC anticaries drug products (50 FR 39854
at 39867), the agency interpreted the Panel's statement to mean that
all children under 6 years of age should be properly instructed and
supervised in the use of a dentifrice, but the amount of supervision
may vary depending on a child's skills. If a child has fairly good
toothbrushing skills, parents may allow unsupervised brushing, but may
wish to check the child's toothbrushing techniques periodically. The
agency did not intend that every toothbrushing event until age 6 should
be supervised. As the comments suggested, the important point is for
parents to assure themselves that their children are learning the
proper use of dentifrices, and once they are assured of this,
supervision is no longer required. The agency agrees that the labeling
should make this point without being unnecessarily overcautious or
alarmist.
Regarding the request to expand Sec. 355.50(d)(1) to include the
language ``To prevent swallowing * * * ,'' the agency agrees that the
objective of instruction and supervision is to avoid excessive
ingestion of the dentifrice. However, the agency believes that the word
``prevent'' may be too strong a term and that prevention of some
swallowing of dentifrices is unachievable in young children. The amount
of dentifrice ingested varies with the age and skill of the child. The
Panel reviewed a study (Ref. 1) involving children 2 to 6 years of age
that showed large individual variations in expectorated volumes after
mouthrinsing with water. Only a few of the children between 2 and 3
years of age could perform mouthrinsing without swallowing the fluid.
The 3- and 4-year-old children could, as a rule, keep the fluid in
their mouths for 30 seconds. The 5- and 6-year-old children could all
perform the rinse for 1 minute; these children had considerably less
individual variation in expectorated volumes. Based on these data, the
agency finds that suggesting to parents that swallowing can be
prevented may cause unnecessary alarm when they observe a young child
swallow small amounts of dentifrice during the learning process.
Accordingly, the agency is using the word ``minimize'' instead of
``prevent'' in this final monograph. The revised direction statement in
Sec. 355.50(d)(1)(i) reads: ``Instruct children under 6 years of age in
good brushing and rinsing habits (to minimize swallowing). Supervise
children as necessary until capable of using without supervision.''
Reference-
(1) Ericsson, Y., and B. Forsman, ``Fluoride Retained from
Mouthrinses and Dentifrices in Preschool Children,'' Caries
Research, 3:290-299, 1969.
25. One comment objected to the part of the proposed directions in
Sec. 355.50(d)(2)(i) for anticaries products marketed for use as
treatment rinses, which states: ``Children under 12 years of age should
be supervised in the use of this product.'' The comment stated that the
Panel recommended that children under 6 years of age be supervised in
the use of fluoride dentifrices (45 FR 20666 at 20673), but did not
mention children above 6 years of age. The comment suggested that the
Panel's recommendation was made in order to limit daily fluoride
ingestion and thereby avoid possible dental fluorosis. The comment
cited the Panel's discussion of epidemiological and clinical findings
that indicated that teeth of children 6 years of age and older are
``(excepting third molars) * * * too advanced to be affected by
excessive daily fluoride ingestion.'' The comment mentioned the Panel's
discussion (45 FR 20666 at 20673) that children 6 years of age and
older have developed control of their swallowing reflexes and are able
to rinse for 1 minute and expectorate properly. The comment stated that
if the agency is concerned that children between 6 and 12 years of age
using the product for the first time may not be able to follow label
directions without instruction from a parent or other adult, then
limited directions about supervision might be useful. However, the
comment expressed concern that continuing
[[Page 52489]]
supervision each time the product is used did not appear warranted and
that this unnecessarily overcautious labeling could discourage use of
these products.
The agency agrees. As discussed in comment 24, the agency
interpreted the Panel's statement to mean that children under 6 years
of age should be properly instructed and supervised in the use of a
dentifrice, not because of any particular hazard, but to ensure that
the child is developing adequate toothbrushing skills and is using the
product correctly. Instruction and supervision serve the same purpose
for fluoride rinses (i.e., to assure proper use of these products) and
are not intended to discourage use of fluoride rinses by children. Once
the parent is certain that the child is using the product correctly,
unsupervised use may be allowed. Therefore, the agency is revising part
of the directions statement to read: ``Instruct children under 12 years
of age in good rinsing habits (to minimize swallowing). Supervise
children as necessary until capable of using without supervision.''
26. One comment disagreed with the agency's proposal to include the
following statement in Sec. 355.50(c) as a warning for concentrated
treatment rinse solutions, powders, and effervescent tablets: ``Do not
use before mixing with water. Read the directions carefully.'' The
comment stated that neither the Panel in the advance notice of proposed
rulemaking (45 FR 20666) nor the agency in the tentative final
monograph for OTC anticaries drug products identified a compelling
safety hazard that warrants including the information in the warnings
section rather than in the directions for use. The comment contended
that the safe use of these concentrated products is amply ensured by
including the quoted language in the directions for use. The comment
requested that this information be included in the directions section
only, because it concerns proper use of a product rather than
cautioning to prevent possible dangers of misuse.
In the tentative final monograph, the agency stated that, in order
to alert consumers that dental rinse products in concentrated form
(solutions, powders, and effervescent tablets) must be diluted or
dissolved in water before using, the agency is proposing the warning
stated above for these dosage forms. The agency agrees with the comment
that consumers could equally be alerted if this information appeared in
the directions for use section. Accordingly, in this final monograph,
the agency is moving the statement ``Do not use before mixing with
water.'' from the warnings to the directions for use section. This
statement is to appear as the first statement under the directions for
use for concentrated treatment rinse solutions, powders, and
effervescent tablets. It should then be followed by the proper
directions for preparing the diluted rinse product. The part of the
proposed warning that stated ``Read the directions carefully.'' is not
needed when this revised labeling format is used.
27. Several comments objected to the agency's proposed labeling
statement in Sec. 355.50(e)(3) for OTC stannous fluoride-containing
dentifrices, treatment gels, and treatment rinses, which states: ``This
product may produce surface staining of the teeth. Adequate
toothbrushing may prevent these stains which are not harmful or
permanent and may be removed by your dentist.'' In support of their
objections to this statement, one comment cited five published studies
(Refs. 1 through 5) and another comment submitted an unpublished study
of the incidence of stained teeth in school children who used a
stannous fluoride dentifrice (Ref. 6). Stating that the evidence
regarding the propensity of stannous fluoride products to stain teeth
is equivocal, another comment argued that the labeling statement should
be required only on those stannous fluoride products that have been
scientifically proven to cause substantial and discernible staining on
the teeth of users. The comment urged the agency to abandon or strictly
limit its proposal to require a teeth staining labeling statement on
OTC stannous fluoride dentifrice products.
Three comments noted that the Panel specifically stated in its
discussion of stannous fluoride dentifrice drug products (45 FR 20666
at 20685) that ``* * * the frequency and intensity of staining with the
level of tin present in these formulations does not appear to present
any significant problem; therefore, no labeling statement on staining
shall be required for stannous fluoride dentifrice formulations * *
*.'' Two of the comments stated that the agency failed to offer any new
evidence that would make the findings of the expert panel
inappropriate. One of the comments asserted that all the studies cited
by the agency in support of the proposed labeling statement for
stannous fluoride dentifrice products (50 FR 39854 at 39865 and 39866)
were cited previously by the Panel as support for its conclusion that
no labeling statement about tooth staining was necessary (45 FR 20666
at 20685). Another comment mentioned extensive experience with the
first stannous fluoride dentifrice formulation marketed in the United
States. This comment stated that no incidence of surface staining was
found that would justify such a labeling statement.
One comment suggested that the tendency of stannous fluoride
products to cause staining of the teeth is directly related to a number
of factors. It may be highly dependent on the formulation of the
product and/or the brushing habits of the user. The comment stated that
the stability of the fluoride and the stannous ions in a product have
an effect on whether or not the product causes tooth staining. For
example, a product that contains a high level of stannous ions may be
more likely to stain teeth than a product that is stabilized and,
therefore, does not contain many stannous ions. The comment asserted
that stable stannous fluoride products (e.g., dental gels) are not
likely to cause discernible staining. The comment concluded that the
labeling statement about tooth staining should not be imposed
indiscriminately on all stannous fluoride products without regard to
the stability of the product.
One comment contended that requiring the labeling statement about
tooth staining on stannous fluoride dentifrice products would cause
undue concern among consumers. The comment was concerned that the
proposed warning would cause users to avoid safe and effective stannous
fluoride products in favor of other products that do not bear such a
warning. Another comment stated that requiring such a labeling
statement without reliable scientific support is damaging to consumers
who may place undue emphasis on the possibility of some transient
staining. The first comment added that requiring the labeling statement
regardless of whether or not a product caused staining of the teeth
would handicap stannous fluoride products that could be shown not to
cause a greater amount of staining than any other fluoride product.
Another comment contended that the data used by the agency to
support the tooth staining labeling statement (50 FR 39854 at 39865 and
39866) are flawed and do not support the agency's decision to require
this statement on stannous fluoride products. Stating that none of the
studies attempted to relate the incidence of staining to any element of
the dentifrice other than stannous fluoride, the comment asserted that
interaction between the polishing agent (abrasive) and the fluoride
moiety may be responsible for any staining observed. The comment noted
that the polishing agent in the stannous fluoride dentifrices in some
studies was sodium
[[Page 52490]]
metaphosphate. The comment maintained that it is impossible to know
whether similar results would have occurred if a different polishing
agent had been used. The comment concluded that these data show that
stannous fluoride contained in a dentifrice base of sodium
metaphosphate can cause mild staining in some subjects when analyzed by
investigators in blind, controlled settings.
The comment added that the studies used by the agency to support
the proposed staining statement (50 FR 39854 at 39865 and 39866) did
not compare the reported incidence of tooth staining with consumer
perception of such staining. The comment maintained that these studies
demonstrate that tooth staining caused by stannous fluoride products is
barely perceptible by consumers and is of little importance to the vast
majority of people under normal conditions of daily use. The comment
and another comment mentioned a study by Ness, Rosekrans, and Welford
(Ref. 5) that also demonstrates that staining is barely perceptible and
not important to consumers.
One comment agreed with the Panel that a labeling statement about
tooth staining is unnecessary for stannous fluoride dentifrices.
However, the comment asserted that, if the agency determines that such
a labeling statement is necessary, the data support only a limited
labeling statement for stannous fluoride dentifrice products in which
sodium metaphosphate is the polishing agent. In addition, the comment
requested that this labeling statement be modified to reflect the
underlying data as follows: ``This product may occasionally produce
minor temporary surface staining of teeth. Adequate toothbrushing will
prevent these stains and they may be easily removed by your dentist.''
The agency does not believe that the studies submitted by the
comments support eliminating the labeling statement regarding tooth
staining from stannous fluoride dentifrice products. Although two of
the six studies submitted do not show significant staining caused by
stannous fluoride dentifrice products (Refs. 5 and 6), four of the six
studies (Refs. 1 through 4) demonstrate that test groups using stannous
fluoride dentifrice products had significantly more tooth staining than
groups using dentifrice products without fluoride. Three of these
studies (Refs. 1, 2, and 4) used a dentifrice with calcium
pyrophosphate as the abrasive agent. Sodium metaphosphate was the
abrasive agent used in the other study (Ref. 3). These studies do not
indicate that tooth staining is related to any individual polishing
agent. However, based on the information available from the studies,
the agency is unable to determine if staining is a formulation specific
problem. The agency believes that the information submitted clearly
demonstrates that stannous fluoride dental products (i.e., dentifrices,
nses, and gels) have the potential to produce surface staining of the
teeth. The agency is not aware that such staining results from the use
of any other commonly utilized fluoride ingredients.
The agency reaffirms its conclusion that a labeling statement
regarding tooth staining should be required on all stannous fluoride
products. The agency believes that: (1) Consumers should be advised
that staining of the teeth may be caused by stannous fluoride products,
including dentifrices, and (2) that adequate brushing or dental
prophylaxis may prevent the stains. The agency does not believe that
one comment's suggested labeling statement about tooth staining has any
advantage over the statement proposed by the agency in the tentative
final monograph. The comment's suggested statement uses words like
``occasionally'' and ``minor'' and is more ambiguous than the agency's
proposed statement. The agency's statement conveys a more meaningful
message using the phrase ``may produce surface staining.'' In addition,
the agency's statement advises the consumer that the staining is not
harmful or permanent. The agency considers its proposed statement to be
more informative than the comment's suggested statement and more
helpful to consumers. Therefore, the agency is including its proposed
labeling statement in Sec. 355.50(e)(2) of this final monograph.
References--
(1) Jackson, D., and P. Sutcliffe, ``Clinical Testing of a
Stannous Fluoride-Calcium Pyrophosphate Dentifrice in Yorkshire
School Children,'' British Dental Journal, 123:40-48, 1967.
(2) James, P. M. C., and R. J. Anderson, ``Clinical Testing of a
Stannous Fluoride-Calcium Pyrophosphate Dentifrice in
Buckinghamshire School Children,'' British Dental Journal, 123:33-
39, 1967.
(3) Naylor, M. N., and R. D. Emslie, ``Clinical Testing of
Stannous Fluoride and Sodium Monofluorophosphate Dentifrices in
London School Children,'' British Dental Journal, 123:17-23, 1967.
(4) Slack, G. L. et al., ``Clinical Testing of a Stannous
Fluoride-Calcium Pyrophosphate Dentifrice in Essex School Girls,''
British Dental Journal, 123:26-33, 1967.
(5) Ness, L., D. L. Rosekrans, and J. F. Welford, ``An
Epidemiological Study of Factors Affecting Extrinsic Staining of
Teeth in an English Population,'' Community Dentistry and Oral
Epidemiology, 5:55-60, 1977.
(6) Katayama, T., ``Incidence of Stained Teeth on School
Children Who Have Used Stabilized SnF2 Toothpaste for Three
Years,'' unpublished study in Comment No. C63, Docket No. 80N-0042,
Dockets Management Branch.
28. One comment requested that the professional labeling in
Sec. 355.60 be modified to require that only dental rinse formulations
composed of ingredients suitable for swallowing be used as fluoride
supplements intended for ingestion in areas where the water supply is
nonfluoridated. The comment stated that this section, as proposed, does
not mention that fluoride rinses promoted to health professionals and
not offered to the general public are specially formulated with
ingredients suitable for ingestion. These products are intended to be
swallowed. The comment mentioned that dental rinse products not
intended to be swallowed are formulated differently and contain other
ingredients.
The agency agrees that further explanation of the term
``supplement'' would help to reduce possible confusion. Therefore, the
agency is modifying the introductory language in the professional
labeling in Sec. 355.60 as follows: ``The labeling for anticaries
fluoride treatment rinses identified in Sec. 55.10 that are specially
formulated so they may be swallowed (fluoride supplements) and are
provided to health professionals (but not to the general public) may
contain the following additional dosage information: * * *.'' Also, the
agency is including a definition of fluoride supplement in Sec. 355.3
as follows: ``Fluoride supplement. A special treatment rinse dosage
form that is intended to be swallowed, and is promoted to health
professionals for use in areas where the water supply contains 0 to 0.7
parts per million fluoride ion.''
D. Comments on the Switch of Prescription Anticaries Drug Products to
OTC Status
29. One comment objected to the proposed prescription-to-OTC switch
of 0.4 percent stannous fluoride gel products for economic and labeling
reasons. The comment indicated that currently only small manufacturers
make and market these products on a prescription basis. The comment
asserted that OTC status would disadvantage these small companies by
forcing them into the OTC marketplace with obvious competitive and
marketing expenses. According to the comment, promoting its products
through health-care professionals is less costly than promoting the
products to the general
[[Page 52491]]
public on an OTC basis. The comment contended that OTC status creates a
labeling problem that does not exist when these products are marketed
as prescription drugs. The comment identified this problem as
a``negative statement'' required in the product's labeling, i.e., ``not
a toothpaste.'' The comment concluded by suggesting that the interests
of the consuming public and ``small'' entities are best served by not
including 0.4 percent stannous fluoride gel in the OTC drug monograph
and by continuing its prescription status.
The agency does not agree with the comment. The Panel recommended
that certain fluoride dental rinses and gels, which had previously been
restricted to prescription use, be made available OTC provided that
they conform to package size limitations and proper labeling to avoid
misuse (45 FR 20666 at 20666, 20674, and 20691). (Package size
limitations are discussed in section I.G., comment 46.) The Panel
reviewed four published studies on stannous fluoride dental gels
containing 0.4 percent stannous fluoride in an anhydrous glycerin gel
(45 FR 20682) and concluded that these studies provide sufficient
documentation of the safety and effectiveness of this dental gel dosage
form for OTC use. In the tentative final monograph (50 FR 39854 at
39858), the agency concurred with the Panel's recommendation that 0.4
percent stannous fluoride in an anhydrous glycerin gel be switched to
OTC status and labeled with proper directions for use (45 FR 20688).
The agency is aware that the change of 0.4 percent stannous
fluoride dental gels from prescription-to-OTC status will lead to
different marketing strategies and promotional activities. However, the
agency has determined that such a product can be generally recognized
as safe and effective and marketed as an OTC product. This OTC status
does not prevent a manufacturer from continuing to promote the use of
such products through health-care professionals, who then would
instruct their patients to purchase and use the products.
In response to the comment's objection to the proposed labeling of
its product with the statement ``This is not a toothpaste,'' the agency
indicated in the tentative final monograph (50 FR 39869) that a
nonabrasive dental gel packaged in a conventional tube can be confused
with a conventional abrasive-containing dentifrice. There is also a
safety concern because dentifrices contain an abrasive, while these
dental gels do not. This safety concern is discussed in section I.G.,
comment 46 of this document. The agency considers the statement for
dental gel products to be important to their safe OTC use.
The agency concludes that the OTC availability of 0.4 percent
stannous fluoride dental gel products provides benefit to consumers and
poses very little risk of misuse when the products are packaged and
labeled properly. Therefore, the agency is including 0.4 percent
stannous fluoride dental gel products in this final monograph.
30. One comment objected to the 120-mg package size limitation for
fluoride treatment gels proposed in Sec. 55.20. The comment requested
that a 7-ounce (oz) package size for 0.4 percent stannous fluoride
preventive treatment gels (containing 192 mg total fluorine) remain in
the marketplace, at least as a prescription drug product for use under
the supervision and direction of the dental profession. The comment
noted that its decision to market a 7-oz package size of 0.4 percent
stannous fluoride treatment gel was partially based on the 7-oz package
size of 0.4 percent stannous fluoride dentifrice products marketed at
the time its product was introduced into the marketplace. The comment
noted that, in the tentative final monograph (50 FR 39854 at 39857),
the agency cited the position and experience since 1958 of the ADA
concerning package size limitations for OTC rinses and gels in support
of the proposal in Sec. 355.20 to limit package sizes for dental rinses
and gels.
The comment mentioned over 10 years of safe prescription marketing
of its 7-oz product with a child-proof safety closure. The comment
contended that consumer use is different with regard to the safe
handling of prescription drug products, as compared to OTC drug
products. The comment noted that the agency concluded in the tentative
final monograph that a toxic dose of fluorine via a dentifrice drug
product could not be ingested without vomiting, although the agency did
not address the effect of glycerin (which is used in the treatment gel)
with regard to vomiting. The comment stated that the 7-oz package size
of this product represents over 50 percent of its dollar volume and its
discontinuance would represent a hardship. The comment requested
reconsideration of the OTC status of the 7-oz package size for its 0.4-
percent stannous fluoride treatment gel. The comment stated that, at a
minimum, allowing this product to remain in the marketplace on a
prescription basis would best serve the interests of the dental
profession and small businesses in the stannous fluoride industry
without endangering public safety.
In the tentative final monograph (50 FR 39854 at 39857), the agency
concurred with the Panel's recommendation that the package size of OTC
preventive treatment gel products be limited to 120 mg total fluorine
because of possible safety concerns. The Panel was concerned about the
significant differences in the amount of fluorine available for
pharmacological or toxicological action between dentifrices (abrasive-
containing) and nonabrasive treatment gels and rinses. Available
fluoride in a dentifrice is dependent upon the chemical reactivity of
the fluoride ion with the abrasive (45 FR 20675 to 20677), while all of
the fluoride ion in the nonabrasive preventive treatment gel is
available. There are potential safety concerns (i.e., ingestion of an
entire package that could cause serious effects, particularly for a
small child) when the 120-mg total fluorine package size limitation for
a preventive treatment gel is exceeded. This package size limitation
appears in Sec. 355.20 of this final monograph. Although the package
size will vary depending on the concentration of the fluoride
ingredient in the product, the maximum OTC package size of a 0.4-
percent stannous fluoride preventive treatment gel product is 4.375 oz.
The agency has no objection to larger size packages being available as
prescription drug products. However, if a manufacturer wishes to market
a 0.4-percent stannous fluoride preventive treatment gel product in a
larger package size on a prescription basis, the manufacturer must
obtain an approved NDA under section 505 of the act (21 U.S.C. 355) and
part 314 of the regulations.
The comment provided no data or information in support of its
contention that the general public handles prescription drugs
differently than OTC drugs. The agency believes that more potent
prescription drug products generally are handled differently than most
OTC drugs. However, the agency is unaware of any data that suggest that
consumers handle prescription anticaries gels and treatment rinses
differently than OTC anticaries fluoride mouthwashes and rinses.
The agency indicated in the tentative final monograph (50 FR 39857)
that the safety of dentifrice pastes containing up to 260 mg fluoride
can be attributed to: (1) The decreased amount of fluoride actually
available for absorption because of the reactivity of fluoride with the
abrasive in dentifrice pastes; and (2) the likelihood that the amount
of dentifrice that contains a toxic dose of fluoride
[[Page 52492]]
could not be ingested without vomiting. The comment provided no
information or data on the effect of glycerin in a dental gel with
regard to vomiting in support of its contention that larger package
sizes be allowed for the gel dosage form. Without data, the agency
cannot determine glycerin's role on vomiting if large amounts of a
dental gel were to be ingested. In conclusion, the agency does not
consider the comment's arguments supportive of its requests that 0.4
percent stannous fluoride gels remain prescription drugs or that the
120-mg package size be increased for such products marketed on an OTC
basis.
E. Comments on Combination Anticaries Drug Products
31. One comment submitted new data and information to support the
safety and effectiveness of a combination drug product containing 0.05
percent sodium fluoride and 1.5 percent hydrogen peroxide. The comment
stated that this combination drug product, which was not considered in
the tentative final monograph for OTC anticaries drug products, is
targeted for once-daily use in an orthodontic population. The comment
contended that this combination of ingredients provides rational,
concurrent therapy as an oral cleanser and anticaries agent for
orthodontic patients for two reasons: (1) Orthodontic appliances
occasionally cause minor irritation or injury to the oral mucosa and
the product cleanses these irritations or injuries, and (2) the
configuration of the orthodontic appliance and its duration of use may
cause decalcification of teeth in orthodontic patients and the product
reduces tooth decalcification.
The comment stated that the safety of the 0.05-percent sodium
fluoride component of the product was recognized by FDA in the
tentative final monograph for OTC anticaries drug products (50 FR 39854
at 39872). The comment submitted data (Ref. 1) from an enamel
solubility reduction test and an enamel fluoride uptake test to support
the effectiveness of the sodium fluoride in the combination product.
The comment also submitted a clinical study of the combination product
to support the safety of daily exposure of the oral mucosa to 1.5
percent hydrogen peroxide for an 18-month period (Ref. 1). The comment
added that the effectiveness of up to 3 percent hydrogen peroxide as an
oral cleanser was established in the tentative final monograph for OTC
oral health care drug products published in the Federal Register of
January 27, 1988 (53 FR 2436). Based on these data, the comment
requested that the agency include this combination product in the final
monograph for OTC anticaries drug products.
The agency agrees that 0.05 percent sodium fluoride and 1.5 percent
hydrogen peroxide may be a rational combination for concurrent therapy
in orthodontic patients. However, as the agency discussed in the
tentative final monograph for OTC oral health care drug products, the
Advisory Review Panel on OTC Oral Health Care Drug Products (Oral
Cavity Panel) was concerned about the chronic use of hydrogen peroxide
in products such as antimicrobial mouthwashes (53 FR 2436 at 2446 and
2447). The agency further stated in this discussion that the effects of
long-term OTC use of hydrogen peroxide would be considered as part of
the antiseptic segment of the oral health care drug products
rulemaking.
After that tentative final monograph was published, the agency
published a call-for-data for OTC antiplaque drug products in the
Federal Register of September 19, 1990 (55 FR 38560). The data
submitted to the agency as a result of this call-for-data will be
evaluated by the Dental Products Panel. That Panel will consider, among
other things, the safety of the long-term oral use of hydrogen peroxide
solutions. The agency believes that the Dental Products Panel is the
appropriate forum to consider whether a combination product containing
0.05 percent sodium fluoride and 1.5 percent hydrogen peroxide can be
generally recognized as safe and effective for long-term OTC use in the
oral cavity. The agency has informed the manufacturer that it considers
the combination product to be a new drug that may not be introduced or
delivered for introduction into interstate commerce without an approved
NDA (Ref. 2). The agency has deferred this product to the Dental
Products Panel and will address the submitted data as part of the OTC
oral health care rulemaking applicable to antiplaque drug products.
References
(1) Comment No. C80, Docket No. 80N-0042, Dockets Management
Branch.
(2) Letter from R. J. Chastonay, FDA, to R. Finn, Chesebrough-
Pond's USA Co., in OTC Vol. 08AFM, Docket No. 80N-0042, Dockets
Management Branch.
32. Two comments requested the agency to include the combination of
sodium fluoride with sodium monofluorophosphate in a dentifrice in the
final monograph. The comments contended that the combination of two
Category I fluoride ingredients, particularly sodium fluoride and
sodium monofluorophosphate, provides a rational combination that has an
enhanced therapeutic effect and satisfies the agency's combination
policy in Sec. 30.10(a)(4)(iv) (21 CFR 330.10(a)(4)(iv)).
One comment submitted two clinical studies (Refs. 1 and 2) to
support the combination of two fluoride ingredients in a dentifrice.
The first study (Ref. 1) was a 3-year double-blind, randomized clinical
study involving 799 children 14 to 15 years old. Two combination
dentifrices, each containing 0.76 percent sodium monofluorophosphate
(1,000 ppm theoretical total fluorine) and 0.10 percent sodium fluoride
(455 ppm theoretical total fluorine) (to provide a theoretical total
fluorine level of 1,455 ppm) were compared with a fluoride-free control
dentifrice and with a positive control 0.76 percent sodium
monofluorophosphate dentifrice (1,000 ppm theoretical total fluorine).
One of the two experimental combination fluoride dentifrices had an
alumina abrasive system. The other had a dicalcium phosphate abrasive
system. The combination dentifrices reduced the incidence of dental
caries by approximately 26 percent compared with the fluoride-free
placebo dentifrice, and by approximately 15 percent compared with the
positive control 0.76 percent sodium monofluorophosphate dentifrice
with an alumina abrasive system.
The second study (Ref. 2) was a 3-year clinical trial that involved
school children who resided in an area with nonfluoridated water. Two
combination dentifrices containing sodium monofluorophosphate and
sodium fluoride, either 1,450 or 2,000 ppm theoretical total fluorine,
were compared to a sodium monofluorophosphate dentifrice containing
1,000 ppm theoretical total fluorine. Results indicated that after 3
years of unsupervised brushing, the children who used either the 1,450-
or 2,000-ppm fluoride dentifrice combinations developed fewer cavities
than those who brushed with the 1,000-ppm sodium monofluorophosphate
dentifrice. No significant difference in caries reduction between the
1,450-ppm and 2,000-ppm fluoride dentifrices was reported.
Another comment submitted laboratory and clinical data (Ref. 3) to
support the safety and effectiveness of a dentifrice containing sodium
fluoride (1,000 ppm) and sodium monofluorophosphate (420 ppm). In one
study, enamel specimens exposed for 24 hours to a suspension of sodium
monofluorophosphate alone or in combination with sodium fluoride had
[[Page 52493]]
greater fluoride uptake with the combination fluorides than with sodium
monofluorophosphate alone. In another study, a nearly three-fold
reduction in enamel solubility was shown with the combination of sodium
fluoride and sodium monofluorophosphate compared to sodium
monofluorophosphate alone. The comment also provided a graph of enamel
solubility reduction data from dentifrices containing sodium fluoride
or sodium monofluorophosphate alone or various combinations of sodium
monofluorophosphate and sodium fluoride. The comment noted that a
combination containing 75 percent sodium fluoride and 25 percent sodium
monofluorophosphate would be optimal. The comment contended that this
combination produces twice as much reduction in enamel solubility as
either of the ingredients alone at comparable fluoride concentrations.
The comment included an animal study in which male rat pups were
inoculated with streptococci (strain not provided) and placed on a
standard cariogenic diet for 3 weeks. During this period, the teeth
were brushed with a sodium monofluorophosphate/sodium fluoride
dentifrice combination or a control fluoride dentifrice (active
ingredient and strength not specified). The results of this study
indicated that the combination of sodium fluoride and sodium
monofluorophosphate was significantly more ``cariostatic'' than the
single fluoride dentifrice.
The comment also mentioned a 3-year clinical study involving 573
school children. This study was designed to determine the anticaries
effect of a dentifrice containing a sodium monofluorophosphate/sodium
fluoride combination (1,420 ppm) with a comparable control toothpaste
containing only sodium monofluorophosphate (1,315 ppm). After 2 and 3
years of unsupervised brushing, the number of new decayed, missing, or
filled (DMF) surfaces was 12 to 50 percent lower in the combination
fluoride group than in the sodium monofluorophosphate control group.
Based on the results of this study, the comment concluded that the
combination of sodium fluoride and sodium monofluorophosphate is
significantly more effective than sodium monofluorophosphate alone in
reducing the incidence of dental cavities.
The comment acknowledged that combinations of fluoride active
ingredients have not been marketed in the United States. The comment
stated, however, that the combination of sodium fluoride and sodium
monofluorophosphate has been widely available in the United States for
many years. The comment stated that this combination occurs as a result
of the hydrolysis of sodium monofluorophosphate during contact with the
tooth surface and during the aging process of the fluoride dentifrice
formulation itself. The comment indicated that as the dentifrice ages,
sodium monofluorophosphate undergoes hydrolysis resulting in a
significant increase of sodium fluoride within the sodium
monofluorophosphate formulation. The comment added that in the oral
environment sodium fluoride may represent more than 50 percent of the
hydrolyzed fluoride species in contact with the tooth surface as a
result of the hydrolysis of sodium monofluorophosphate alone. The
comment included several studies showing that sodium
monofluorophosphate undergoes rapid hydrolysis in saliva and even more
rapid hydrolysis in the presence of plaque microorganisms. In one study
(Ref. 3), during a short period of toothbrushing, the levels of
fluoride ions in saliva were initially much lower with the sodium
monofluorophosphate dentifrice than with the comparable sodium fluoride
preparation. However, after 10 minutes in saliva, both dentifrice
formulations provided almost similar levels of fluoride ions. The
comment stated that the uncontrolled hydrolysis of the two fluoride
agents results in an important, but suboptimal, increase in the
bioavailability of fluoride ions. The comment indicated that a
combination of fluoride ingredients may provide greater product
stability if the agency allows manufacturers the opportunity to control
the ratio of these two fluoride ingredients in the dentifrice
formulation. According to the comment, this would be better than
relying on the unpredictable chemical process of hydrolysis to create a
fluoride combination product. The comment asserted that its dentifrice
product controls the process of hydrolysis by providing a combination
fluoride dentifrice with a fluoride ingredient ratio of 3 to 1 (sodium
fluoride to sodium monofluorophosphate), thereby enhancing the
therapeutic effect of the anticaries product. However, the comment did
not indicate how it proposed to control the hydrolysis of the one-
quarter proportion of sodium monofluorophosphate in its product. This
information is particularly significant if the hydrolysis of sodium
monofluorophosphate occurs as rapidly in the mouth as the comment
indicated.
The comment maintained that the fluoride ion is the effective
anticaries moiety, and it is irrelevant whether the fluoride ion comes
from one fluoride salt or a combination of two fluoride salts, as long
as the fluoride ion is present in safe and effective quantities. The
comment concluded that these data demonstrate the safety and
effectiveness of the combination of sodium fluoride and sodium
monofluorophosphate in a dentifrice product. The comment urged the
agency to include the combination of sodium fluoride with sodium
monofluorophosphate in a 3 to 1 ratio as a dentifrice in the final
monograph.
The agency has reviewed the available data and concludes that they
do not support the comments' claims. The data do not demonstrate the
cariostatic superiority of combination dentifrices containing sodium
fluoride and sodium monofluorophosphate compared to conventionally
formulated 0.76 percent sodium monofluorophosphate dentifrices. The
data do not show that the effect of the sodium fluoride/sodium
monofluorophosphate combination is greater than the effect achieved by
the individual active ingredients alone at comparable fluoride ion
concentrations.
A combination drug product containing Category I active ingredients
from the same therapeutic category must satisfy the criteria in
Sec. 330.10(a)(4)(iv). The ``General Guidelines for OTC Drug
Combination Products, September 1978'' give clarifying examples
regarding the combination policy (Ref. 4). Paragraph 3 of these
guidelines states:
Category I active ingredients from the same therapeutic category
that have the same mechanism of action 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. They 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.
The agency has not received sufficient data to conclude that the use of
a combination fluoride product has an advantage over or is more
effective in controlling the incidence of dental caries than a product
containing a single fluoride active ingredient at comparable fluoride
ion concentrations.
In the clinical studies submitted by the comment, there was no
comparison of a combination and single ingredient product at comparable
fluoride concentrations. The agency notes that
[[Page 52494]]
the higher levels of fluoride concentration in the combination
dentifrices, 1,455 ppm (Ref. 1) and 1,450 or 2,000 ppm (Ref. 2), as
compared to the fluoride levels in the positive control single fluoride
ingredient dentifrice (1,000 ppm), most likely account for the enhanced
effectiveness of the combination products. Because of these higher
concentrations, the presence of two sources of fluoride ions may be
unrelated to the observed increase in effectiveness.
The agency has also evaluated two other clinical studies (Refs. 6
and 7) that compared comparable fluoride concentrations (1,000 ppm) for
a single-ingredient sodium monofluorophosphate dentifrice and a
combination containing sodium fluoride and sodium monofluorophosphate.
In these studies, the two dentifrices were comparably effective. One
study (Ref. 6) was a 31-month, double-blind clinical study involving
1,027 school-aged children. The anticaries effectiveness of a single
fluoride ingredient dentifrice containing sodium monofluorophosphate
(1,000 ppm theoretical total fluorine) was compared with a combination
fluoride dentifrice containing sodium fluoride and sodium
monofluorophosphate (1,000 ppm theoretical total fluorine, with 500 ppm
contributed by each fluoride ingredient). During this study, the
children brushed daily in school under supervision and were clinically
and radiologically examined annually. After 31 months of use, no
statistically significant difference in the incidence of dental caries
was observed between children in the two dentifrice groups.
In the second study (Ref. 7), the effectiveness of three
dentifrices was compared over a 2-year period. The study involved 2,769
children; a nearly equal number did unsupervised brushing at home with
one of the following dentifrices: (1) Sodium monofluorophosphate (1,000
ppm), (2) a combination of sodium fluoride and sodium
monofluorophosphate containing equimolar amounts of each active
ingredient (theoretical total fluorine of 1,000 ppm), or (3) a
combination of sodium fluoride and sodium monofluorophosphate
containing equimolar amounts of each active ingredient (theoretical
total fluorine of 2,500 ppm). The results of this study indicated no
significant differences in caries inhibition among the dentifrices
tested.
In most of the in vitro studies submitted (Ref. 3), exposure times
of the tooth enamel surface to suspensions of dentifrice were for
lengthy periods of time ranging from 30 minutes to 24 hours. The agency
questions the relevancy of a 24-hour exposure time when the exposure
time to a dentifrice formulation in the mouth during actual
toothbrushing is a few minutes only. In the animal study measuring the
effect of three dentifrices on the incidence of caries in rats, no
details were given regarding the active ingredients or the fluoride
concentrations in the dentifrices tested. Regarding hydrolysis during
the aging process of sodium monofluorophosphate products, the Panel
stated that sodium monofluorophosphate exists in water in dynamic
equilibrium with sodium fluoride, and with the various ions produced by
the hydrolysis of the compound (45 FR 20666 at 20674). The agency does
not consider this reaction as producing a combination drug product. The
agency considers the sodium monofluorophosphate compound as a single
active ingredient, even though it is aware that the compound always
contains some amounts of sodium fluoride.
In conclusion, the agency has determined that the submitted
information and data do not demonstrate the cariostatic superiority of
combination dentifrices containing sodium fluoride and sodium
monofluorophosphate relative to single-ingredient fluoride dentifrices
with a comparable fluoride ion concentration. Accordingly, these
fluoride combinations are not included in this final monograph.
References
(1) Hodge, H. C. et al., ``Caries Prevention by Dentifrices
Containing a Combination of Sodium Monofluorophosphate and Sodium
Fluoride,'' British Dental Journal, 149:201-204, 1980.
(2) Diodati, R. R. et al., ``Clinical Anticaries Effect of
Various Fluoride Dentifrices,'' Abstract No. 258, Journal of Dental
Research, 65:198, 1986.
(3) Comment No. C00059, Docket No.80N-0042, Dockets Management
Branch.
(4) Food and Drug Administration ``General Guidelines for OTC
Drug Combination Products, September 1978,'' Docket No. 78D-0322,
Dockets Management Branch.
(5) Conti, A. J. et al., ``A 3-Year Clinical Trial to Compare
Efficacy of Dentifrices Containing 1.14 Percent and 0.76 Percent
Sodium Monofluorophosphate,'' Community Dental Oral Epidemiology,
16:135-138, 1988.
(6) Juliano, G. F. et al., ``Clinical Study Comparing the
Anticaries Effect of Two Fluoride Dentifrices,'' Abstract No. 131,
Journal of Dental Research, 64:189, 1985.-
(7) Ripa, L. W. et al., ``Clinical Comparison of the Caries
Inhibition of Two Mixed NaF-Na2PO3F Dentifrices Containing
1,000 and 2,500 ppm F Compared to a Conventional Na2PO3F
Dentifrice Containing 1,000 ppm F: Results after Two Years,'' Caries
Research, 21:149-157, 1987.
F. Comments on Testing Guidelines
33. One comment agreed with the agency's conclusion that laboratory
test data are not adequate to establish comparative claims of
effectiveness for anticaries active ingredients (53 FR 22430 at 22446).
However, the comment contended that the agency should recognize the
possibility that, in certain cases, claims of superior performance in a
laboratory test may be desirable. As a hypothetical example, the
comment stated that it may be important to a dental professional that
(1) one active ingredient provides more rapid fluoride uptake than
another and (2) this performance could promote hardening of enamel in
certain instances. The comment suggested that such claims could be made
in professional labeling without needing clinical studies for support.
The agency reiterates its conclusion that the extension of
laboratory test data to a comparative evaluation of effectiveness
between different fluoride products or fluoride active ingredients is
inappropriate (53 FR 22446). In general, the agency does not believe
that claims of superior performance in a laboratory test are
appropriate for use in either the consumer or professional labeling of
OTC anticaries drug products unless that superior performance has been
shown to have clinical significance. However, the agency will evaluate
any such laboratory test data submitted on a case-by-case basis.
34. One comment (from an agency dental reviewing officer) objected
to the use of Laboratory Testing Profiles (LTP's) for final formulation
testing for Category I active ingredients in fluoride dentifrice
formulations. The comment expressed unawareness of any data submitted
to the agency demonstrating that the results from the biological test
requirements in the LTP's were correlated with adequate and well-
controlled anticaries clinical studies. The comment did not submit any
data demonstrating that the LTP's do not correlate with clinical
studies.
Two comments (from manufacturers) concurred with the agency's
proposal that the LTP's be used to ensure the effectiveness of
abrasive-containing fluoride drug products. One of the comments
contended that, based on the current state of dental research, it is
not necessary to do clinical studies to verify anticaries performance
except in certain situations, such as the introduction of a new
anticaries active ingredient.
Regarding the comment questioning whether the LTP's were correlated
with
[[Page 52495]]
adequate and well-controlled clinical testing, the agency notes that
the Panel based its recommendations on the results of actual biological
tests performed on fluoride dentifrices that had been shown to be
clinically effective in preventing caries (45 FR 20666 at 20677). Thus,
the Panel's recommendations were based on the correlation of laboratory
testing results with clinical results.
The agency considers the LTP final formulation test requirements in
this final monograph to be adequate to ensure the safety and
effectiveness of dentifrices containing fluoride active ingredients
included in the monograph. In the tentative final monograph (53 FR
22430 at 22433), the agency stated reasons why it concurred with the
Panel's recommended laboratory testing requirements, as set forth in
the Panel's LTP tables (45 FR 20666 at 20679 to 20681) for Category I
fluoride ingredient/abrasive combinations. Thus, the agency concludes
that lengthy clinical trials are not necessary to ensure the safety and
effectiveness of dentifrices containing monograph fluoride ingredients.
35. One company asked whether the monograph would preclude FDA's
accepting valid clinical trials in lieu of LTP's. The comment noted the
agency's statement in the tentative final monograph that the use of
LTP's to establish efficacy should not in any way preclude the option
of clinical testing as a final demonstration of efficacy for those
companies that prefer to use this method (53 FR 22430 at 22434).
The monograph does not preclude manufacturers from performing
clinical testing to ensure the effectiveness of a fluoride dentifrice.
However, the regulatory requirement for all fluoride dentifrice drug
products marketed pursuant to the monograph is that the product must
meet the final formulation test requirements (LTP's) included in
Sec. 355.70.
36. One comment stated that all toothpaste advertised as containing
fluoride should be tested for stannous fluoride concentration, per unit
volume or weight. The comment contended that this is necessary to
ensure that the concentration of stannous fluoride is not being
reduced.
There are a number of requirements applicable to fluoride
dentifrices that will ensure the fluoride concentration of the product.
While toothpastes can contain one of several different fluoride
ingredients, the LTP's included in the final monograph are intended to
ensure available fluoride ion in the final products. The aged minimal
fluoride ion values in the LTP tables are used to determine the
product's expiration date. This date provides consumers relevant
information regarding use of the product. In addition, Sec. 211.166 of
the agency's current good manufacturing practice regulations (21 CFR
211.166) contains stability testing requirements for drug products,
including toothpastes. Accordingly, these requirements address the
comment's concern.
37. Two comments requested that the agency revise LTP Table 3 to
include corrected test values submitted by the industry for stannous
fluoride dentifrices (45 FR 20666 at 20681). One comment noted that the
agency's revisions in the LTP tables discussed in the tentative final
monograph (53 FR 22430 at 22435 and 22436) omitted a correction
mentioned in an earlier comment concerning stannous fluoride that was
made to this rulemaking. The comment requested that the agency revise
Table 3 under ``II. Soluble Stannous Ion,'' by inserting a statement
indicating that the test dilution for the silica abrasive should remain
1:10 as stated in the tentative final monograph (45 FR 20666 at 20681).
The second comment indicated that the appropriate values for soluble
fluoride should discriminate between dentifrices using insoluble sodium
metaphosphate and silica abrasives. The comment indicated that in Table
3 for stannous fluoride dentifrices (45 FR 20681) under ``I. Soluble
Fluoride Ion,'' the test values for fluoride ion listed for the silica
abrasive formulation should be 600 ppm for the fresh value and 500 ppm
for the aged minimal value with a test dilution of 1:10, rather than
700 ppm for the fresh value and 650 ppm for the aged minimal value. The
comment stated that this revision would discriminate between
dentifrices using insoluble sodium metaphosphate and those using silica
abrasives.
The agency recognizes that the data the Panel used to establish the
LTP tables were developed by industry and submitted to the Panel to
provide a basis for the LTP tables. The agency has reviewed the
industry's corrections of the LTP tables as noted above and agrees that
these corrections should be made. However, the agency does not find it
necessary to insert an additional clarification statement in the
corrected LTP tables as requested by one comment. Instead, the agency
has revised the LTP tables to reflect the changes made to the tables in
the tentative final monograph (53 FR 22435 and 22436) and in this final
monograph (see section I.B., comments 10, 13, 14, and 15 of this
document, and section I.F., comments 38, 39, and 42 of this document)
as follows:
TABLE 1.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Sodium Fluoride Dentifrices in a Paste Dosage Form
I. Soluble Fluoride Ion (F-)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Abrasive Fresh F- value1 Aged minimal F- value 1,2 Test dilution (w/w)
--------------------------------------------------------------------------------------------------------------------------------------------------------
High-beta-phase calcium
pyrophosphate 648 ppm 403 ppm 1:3
--------------------------------------------------------------------------------------------------------------------------------------------------------
II. Hydrogen Ion Concentration (pH)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Abrasive Test value Test dilution (w/w)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
High-beta-phase calcium pyrophosphate 6.5 to 8.0 1:3
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.
\2\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.
[[Page 52496]]
TABLE 2.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Sodium Monofluorophosphate Dentifrices
in a Paste Dosage Form
I.-Soluble Fluoride Ions (PO3F= and F-)1
----------------------------------------------------------------------------------------------------------------
Aged
Abrasive Ion Fresh value2 minimal Test dilution (w/w)
value2,3
----------------------------------------------------------------------------------------------------------------
Applicable to all abrasives PO3F= 650 ppm4 Half 1:10
total
(PO3F=
and F-)
value
F- 10 to 150 ppm 10 ppm to 1:10
PO3F=
value
Total 800 ppm 600 ppm 1:10
(PO3F=
and F-)
----------------------------------------------------------------------------------------------------------------
II.-Hydrogen Ion Concentration (pH)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Abrasive Test value Test dilution (w/w)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Alumina 6.4 to 9.0 1:10
Calcium carbonate 7.0 to 10.0 1:10
Calcium pyrophosphate 5.0 to 5.4 1:10
Dicalcium phosphate 6.3 to 7.6 1:10
Insoluble sodium metaphosphate 5.6 to 6.9 1:10
Silica 5.5 to 7.4 1:10
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ For the compound sodium monofluorophosphate in a dentifrice formulation, fluoride ion exists as a combination of the ions PO3F= and F-. Values are given for each of these ions as well as the ``Total'': combination of PO3F= plus F-.
\2\ Values listed are parts of the measured substance per million parts of the whole dentifrice.
\3\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.
\4\ Soluble PO3 is derived either by direct analytical measurement or by subtracting soluble fluoride ion (F-) from total soluble available fluoride (PO3F= plus F-).
TABLE 3.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Stannous Fluoride Dentifrices in a Paste Dosage Form
I. Soluble Fluoride Ion (F-)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Abrasive Fresh F- value1 Aged minimal F- value1,2 Test dilution (w/w)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Insoluble sodium metaphosphate 700 ppm 650 ppm 1:3
Silica 600 ppm 500 ppm 1:10
Calcium pyrophosphate 288 ppm 108 ppm3 1:3
--------------------------------------------------------------------------------------------------------------------------------------------------------
II. Soluble Stannous Ion (Sn++)
----------------------------------------------------------------------------------------------------------------
Aged minimal Sn++
Abrasive Fresh Sn++ value1 value1,2 Test dilution (w/w)
----------------------------------------------------------------------------------------------------------------
Insoluble sodium 2,000 ppm Qualitatively 1:10
metaphosphate detectable
Silica Qualitatively detectable Qualitatively 1:10
detectable
Calcium 900 ppm Qualitatively 1:3
pyrophosphate detectable
----------------------------------------------------------------------------------------------------------------
III. Hydrogen Ion Concentration (pH)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Abrasive Test value Test dilution (w/w)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Insoluble sodium metaphosphate 4.2 to 5.4 1:4
Silica 4.6 to 5.1 1:4
Calcium pyrophosphate 4.4 to 5.1 1:3
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.
\2\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.
\3\ Value corresponds to that of aged product found clinically effective.
TABLE 4.--Acceptable Test Values for all OTC Fluoride Dentifrices in a Paste Dosage Form
I.- Theoretical Total Fluorine1
[[Page 52497]]
A. 850 to 1,150 ppm for all active ingredients
B. 1,500 ppm for sodium monofluorophosphate
----------------------------------------------------------------------------------------------------------------
II. Available Fluoride Ion Concentration1
Active Ingredient Minimum Available Fluoride Ion1
A. For 850 to 1,150 ppm Dentifrices:
Sodium fluoride 650 ppm
Sodium monofluorophosphate 800 ppm (consisting of PO3F= and F- combined)
Stannous fluoride/calcium pyrophosphate 290 ppm
Stannous fluoride/with abrasive other than 700 ppm
calcium pyrophosphate
B. For 1,500 ppm Dentifrices:
Sodium Monofluorophosphate 1,275 ppm (consisting of PO3F= and F- combined)
----------------------------------------------------------------------------------------------------------------
III. Total Fluorine in Milligram Per Milliliter Dentifrice
A. For 850 to 1,150 ppm Dentifrices:
0.935 to 1.955
B. For 1,500 ppm Sodium Monofluorophosphate Dentifrices:
1.650 to 2.550
----------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.
TABLE 5.--Acceptable Test Values for Sodium Fluoride/Sodium Bicarbonate Powdered Dentifrices Containing 1,000
PPM Theoretical Total Fluorine
I. Theoretical Total Fluorine1
850 to 1,150 ppm
II. Minimum Available Fluoride Ion1
850 ppm
III. Poured-bulk Density Range in Gram Per Milliliter Dentifrice
1.0 to 1.2
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.
TABLE 6--Biological Testing Requirements for all Dentifrices in Paste and Powder Dosage Forms
I. Animal Caries Reduction
and,
II. One of the Following Tests:
A. Enamel Solubility Reduction
B. Fluoride Enamel Uptake
38. One comment concurred with the agency's statement (53 FR 22430
at 22435) that measurements such as specific gravity, pH, stannous ion
content, maximum test dilution, and lower limit of available fluoride
at the expiration date should not be included in the final monograph.
The comment agreed that these measurements are adequately addressed in
the current good manufacturing practices (CGMP) regulations. The
comment stated that the CGMP regulations in part 211 (21 CFR part 211)
provide for acceptable outcomes of the performing, validating,
recording, and reporting of procedures in drug manufacturing, but the
CGMP regulations do not provide test methods or acceptable values of
measurement.
The comment provided the following example: If control of pH is
important in manufacturing a dentifrice, the CGMP regulations provide
that it is necessary to institute and document procedures for ensuring
accurate recording, control of pH during the process, and acceptable
checking of equipment. However, the comment stated that the regulations
do not specify equipment, measurements, or the proper pH range. The
comment contended that one could reasonably conclude that omission of
pH, specific gravity, stannous ion concentration, or maximum test
dilutions from the provisions of the monograph means that manufacturers
may set these specifications as they see fit.
However, the comment added that there are other statements in the
agency's discussion of LTP's that cast doubt on the above
interpretation. As an example, the comment cited the phrase ``the
allowable range for specific gravity (1.1 to 1.7) and theoretical total
fluoride (850 to 1,150 ppm) * * *'' (53 FR 22430 at 22437). The comment
noted that, even though these ranges are given
[[Page 52498]]
equal force in this discussion, theoretical total fluoride is specified
in proposed Sec. 355, while specific gravity is not. The comment also
mentioned the Panel's recommendations regarding specific pH guidelines
(53 FR 22443) and the agency's statement that ``* * * manufacturers
should use the aged minimal fluoride ion limits provided in the LTP
Tables * * * to determine the expiration dates for fluoride dentifrices
* * *'' (53 FR 22445). The comment added that the third agency change
in the Panel's recommendations states that the agency is proposing the
LTP values of pH and specific gravity (but not stannous ion levels,
maximum test dilutions, or aged minimal fluoride levels) as guidelines
of appropriate testing limits. The comment requested that the agency
clarify its position on these matters.
The agency's proposal (53 FR 22430 at 22434 and 22435) states that
fluoride dentifrices shall: (1) Meet or exceed the soluble fluoride ion
level specified for each particular fluoride ingredient listed in the
monograph, and (2) meet the requirements for biological testing. The
agency included these criteria in the proposed monograph. Furthermore,
the agency is including requirements pertaining to available fluoride
content and biological testing in this final monograph. (See section
I.F., comment 40 of this document.) These requirements must be
satisfied for an anticaries dentifrice to be considered generally
recognized as safe and effective.
The agency stated in the tentative final monograph (53 FR 22430 at
22435) that certain recommended requirements in the LTP tables are
adequately addressed in the CGMP regulations (21 CFR part 211) and need
not be specifically addressed in the monograph. These included
parameters such as specific gravity and pH, which relate to inactive
ingredients and appropriate manufacturing procedures. The CGMP
regulations require establishing and following test methods and
specifications that are appropriate and scientifically sound. These
required methods and specifications may be found in a variety of
sources (e.g., the United States Pharmacopeia/National Formulary or
codified monographs).
The discussion about testing parameters not specifically included
in the monograph (such as pH, specific gravity (w/v), stannous ion
concentration, aged minimal fluoride ion values, and test dilution) was
intended as guidance only. While these parameters are important to the
manufacturer's product, only those requirements specifically set out in
the final monograph are considered essential by the agency and must be
met. In the preamble to the tentative final monograph (53 FR 22435 and
22436), the agency revised the Panel's recommended testing guidelines
for a number of testing parameters. The agency intended that these
testing values be used solely as guidance for fulfilling CGMP
requirements.
In this document, the agency has further revised the proposed
testing guidelines for parameters other than available fluoride ion and
biological test requirements (see section I.F., comments 35 and 39 of
this document). These revised parameters are also intended only as
guidance, e.g., for use in determining expiration dating. The agency is
including a revised LTP chart in the preamble of this document for
informational purposes (see section I.F., comment 37 of this document).
39. One comment stated its approval of the agency's proposed
modification of the Panel's recommended ranges for theoretical total
fluorine. The proposal set out a range of 0.935 to 1.955 mg theoretical
total fluorine per mL for dentifrices with a specific gravity lower
than 1.1 or higher than 1.7 (53 FR 22430 at 22438). The comment
indicated that the proposed modification reflects the dynamic nature of
dental research and provides innovation without compromising the
required amount of fluoride ion available to the teeth with each
brushing. The comment added that this single required range of
theoretical total fluorine values more accurately defines the amount of
fluoride ions available to the teeth during each brushing. For that
reason, the proposed range is more descriptive of products that have
been proven clinically effective. The comment suggested that a single
theoretical total fluorine range would be better than the two previous
proposed ranges of specific gravity and theoretical total fluorine. The
comment contended that a single range would ensure consumers that the
active ingredient in dentifrice products delivers the required
concentration of fluoride ion, thus providing the desired anticaries
effect.
In the tentative final monograph for OTC anticaries drug products
(53 FR 22430 at 22437), the agency proposed a range of 850 to 1,150 ppm
for theoretical total fluorine and a specific gravity range of 1.1 to
1.7. This range of values was intended to accommodate the newer, less
dense abrasive systems without compromising the effectiveness of
fluoride dentifrices. The agency indicated that these ranges are
intended for formulation purposes and not as a variation for quality
control purposes. The agency also acknowledges that changes in specific
gravity result in a corresponding change in the amount of fluoride
contained in a given volume of dentifrice if the concentration of the
fluoride is expressed as a weight-to-weight measurement, such as ppm.
The agency also indicated that a fluoride range of 0.935 to 1.955
mg per mL of dentifrice might be appropriate. These weight-to-volume
measurements correspond directly to allowable ranges for specific
gravity (1.1 to 1.7) and theoretical total fluorine (850 to 1,150 ppm).
The agency presented the following guidelines for dentifrices: The
lower limits of 850 ppm theoretical total fluorine and a specific
gravity of 1.1 convert to a lower limit of 0.935 mg fluorine per mL
toothpaste. The upper limits of 1,150 ppm theoretical total fluorine
and a specific gravity of 1.7 convert to an upper limit of 1.955 mg
fluorine per mL toothpaste. This provides a range of 0.935 to 1.955 mg
fluorine per mL toothpaste. This range ensures that fluoride
dentifrices with different specific gravities, due to changes in the
abrasive system, will contain the same range of total fluoride per
volume of dentifrice as specified in the LTP tables. This fluoride
range also will provide flexibility to accommodate the development of
new abrasive systems.
The agency indicated in an earlier comment (see section I.B.,
comment 10 of this document) that it is including extra-strength sodium
monofluorophosphate dentifrices (1,500 ppm) in this final monograph as
generally recognized as safe and effective dentifrice products.
Therefore, the agency is also providing a range of 1.65 to 2.55 mg per
mL of dentifrice for higher strength dentifrices (1,500 ppm). This
range corresponds directly to the allowable ranges for specific gravity
(1.1 to 1.7).
The agency concludes that fluoride ranges of 0.935 to 1.955 mg (for
all 850 to 1,150 ppm dentifrices) and 1.6 to 2.55 mg (for 1,500 ppm
sodium monofluorophosphate dentifrices) theoretical total fluorine per
mL toothpaste are appropriate for these Category I fluoride dentifrice
formulations, irrespective of their specific gravity. The agency is
including these ranges in the revised LTP tables. (See also section
I.F., comment 37 of this document.)
40. Several comments addressed the use of LTP's, rather than
clinical trials, to predict the anticaries effectiveness of monograph
fluoride dentifrices formulated with ``new'' abrasive systems or with
anticalculus agents. One comment (from a professional
[[Page 52499]]
dental association) objected to the agency's proposal in the tentative
final monograph (53 FR 22430 at 22442) to allow LTP's for this testing.
The comment contended that all fluoride-containing dentifrice products
should either be clinically tested or should be equivalent to
clinically tested products. The comment stated that the agency's
proposed LTP's would permit marketing of any dentifrice product
containing an established fluoride agent regardless of whether or not
the abrasive system had been clinically tested. The comment argued
that, because of the very limited nature of the monograph LTP's, there
is no assurance of the availability of fluoride ions during the time of
brushing. The comment added that abrasives can play a very critical
role in the rate of release/availability of the active ingredient.
Furthermore, the comment stated that the LTP's proposed in the
tentative final monograph assess the steady state level of release of
the active species. This value, according to the comment, has no
meaning in examining the potential efficacy of fluoride dentifrice
products. The comment maintained that only clinically tested fluoride/
abrasive systems should be eligible for review under the OTC drug
monograph system. The comment added that any fluoride dentifrice with
an untested abrasive system should be required to supply clinical data
demonstrating effectiveness. The comment stated that its association
had established testing guidelines designed to demonstrate equivalency
of fluoride agents provided that the formulations have a fluoride/
abrasive system similar to a clinically effective product.
The comment also contended that fluoride dentifrices containing
agents that inhibit calculus formation, thus influencing the
calcification/decalcification process associated with caries, should be
required to submit a more extensive LTP than the agency had proposed in
the tentative final monograph (53 FR 22430 to 22448). The comment
recommended that either animal caries or remineralization studies be
required for these products. The comment stated that such studies would
evaluate the potential inactivation of the fluoride agent by a
secondary nontherapeutic additive.
A comment from a manufacturers' association objected to the first
comment's position, contending that no data or other information were
submitted to rebut the agency's LTP proposal. The comment also
disagreed with the dental association's contention that calculus
inhibiting agents can influence the calcification/decalcification
process associated with caries. The comment submitted three clinical
studies (Refs. 1, 2, and 3) to demonstrate that the inclusion of
anticalculus agents in fluoride-containing dentifrices does not
interfere with the anticaries effectiveness of these products. The
comment noted that three clinically proven anticalculus agents
(pyrophosphate salts, zinc chloride, and zinc citrate) are currently
marketed in dentifrices in the United States. According to the comment,
these agents have been shown not to adversely affect fluoride activity
in three biological tests that were included in the tentative final
monograph (53 FR 22430 at 22447). The comment objected to the dental
association's position concerning the validity of using LTP's to
predict the anticaries effectiveness of fluoride dentifrices with an
anticalculus agent, contending that the dental association's concern is
not warranted by existing scientific data. The comment indicated that
it would be a waste of scarce resources and funds to require further
clinical testing when laboratory tests can accurately determine whether
or not anticalculus agents interfere with fluoride efficacy. The
comment requested that the agency continue to require only LTP's as set
forth in the tentative final monograph (53 FR 22430 at 22434).
The agency recognizes that inactive ingredients, such as abrasives
and anticalculus agents, can play an important role in the rate of
release/availability of fluoride from a fluoride compound during the
time period of toothbrushing. Although the analytical tests do not
directly measure the availability of fluoride ions during the time of
toothbrushing, the biological tests indicate that the fluoride ion is
active in preventing dental caries. In addition, one of the biological
tests, the animal caries reduction, directly measures the anticaries
effectiveness of a fluoride dentifrice product in an animal model in
vivo after a limited brushing time. The severity of caries in each
group is computed, and a favorable result for the test sample indicates
that the fluoride ion has activity. The test sample is compared with a
U.S.P. fluoride dentifrice reference standard that has been proven
effective in clinical studies.
In the tentative final monograph (53 FR 22430 at 22433 and 22440,
comments 4 and 11), the agency discussed why lengthy clinical trials
are no longer warranted. The comments did not provide any new data or
information to alter that conclusion. The agency determined that
appropriate laboratory testing, including biological testing, is
adequate to ensure the effectiveness of dentifrices containing
monograph fluoride ingredients. The agency indicated that the Panel
based its development of LTP's on laboratory testing results from
studies on fluoride dentifrice formulations that had actually been
clinically tested and found effective. The agency agreed with the
Panel's view that a monograph fluoride ingredient/abrasive system in a
dentifrice formulation not specifically reviewed by the Panel, must
contain an amount of available fluoride ion equal to or greater than
the highest available fluoride ion value recommended for the specific
fluoride ingredient. This requirement applies to fluoride dentifrices
that contain a monograph fluoride ingredient and either (1) a new
abrasive ingredient (not previously included in marketed dentifrices)
or (2) an abrasive ingredient included in previously marketed
dentifrices in a combination not specifically reviewed by the Panel (53
FR 22430 at 22441). The agency proposed that fluoride dentifrices must
meet or exceed the soluble fluoride ion level specified for each
particular fluoride ingredient listed in the monograph and meet the
test requirements of any two of the following biological tests: (1)
Enamel solubility reduction (ESR), (2) fluoride uptake by enamel, and/
or (3) animal caries reduction (53 FR 22430 at 22434).
The agency does not agree that one of the clinical studies (Ref. 1)
submitted by one comment adequately demonstrates whether or not an
anticalculus additive affects the anticaries effectiveness of a
dentifrice. The study did not include a positive control (Category I)
fluoride toothpaste in the experimental design. Instead, a fluoride/
anticalculus dentifrice was compared to a negative control toothpaste
(not containing either fluoride or anticalculus agent). However, the
two other studies (Refs. 2 and 3) submitted by the comment clearly
indicate that the anticaries effectiveness of the dentifrice
formulations tested was not adversely affected by the anticalculus
agents used in the studies. In one study (Ref. 2), three dentifrices
containing 1,000, 1,500, or 2,500 ppm fluoride (as sodium
monofluorophosphate) and an anticalculus agent (0.5 percent zinc
citrate trihydrate) were compared with dentifrices that contained the
same fluoride concentrations but no anticalculus agent. At the
conclusion of the 3-year study, no clinically significant difference
was observed between the fluoride dentifrices with or without the
anticalculus agent. However, a dose-response effect was
[[Page 52500]]
observed at varying fluoride concentrations. In the other clinical
study (Ref. 3), three dentifrices containing 1,000 or 1,100 ppm of
fluoride (as sodium fluoride and sodium monofluorophosphate) and
different anticalculus ingredients (3.3 percent soluble pyrophosphate,
2 percent zinc chloride, and 1.25 percent unspecified zinc compound)
were evaluated. The three dentifrices produced anticaries protection
similar to a control sodium monofluorophosphate toothpaste containing
1,000 ppm fluoride, but without an anticalculus ingredient. These two
clinical studies corroborate that these anticalculus agents do not
interfere with the anticaries effectiveness of the fluoride active
ingredients sodium fluoride and sodium monofluorophosphate.
The agency is concerned that newer abrasives and anticalculus
agents may reduce the availability of fluoride ions, and that this
reduction may not be detected by the chemical tests suggested in the
LTP's. These chemical tests may not always reflect the true anticaries
effectiveness of fluoride dentifrices with or without additives in situ
when diluted in the mouth by saliva or exposed to the subtle reactions
between dentifrice ingredients and salivary components. Although these
in vitro tests may show positive results that are predictive of
anticaries activity, during actual use in the mouth the product may not
provide the same expected level of anticaries effectiveness. The
limitations of in vitro tests are particularly significant in
evaluating fluoride toothpastes that contain additives that may affect
fluoride ion availability under in situ conditions. For that reason,
the agency considers them to be only markers of potential
effectiveness, not actual proof.
During one study (Ref. 4), several laboratory tests (including ESR,
enamel uptake of fluoride, and animal caries reduction tests) were
investigated as indicators of the compatibility of an abrasive system
and a fluoride source. Dentifrices containing 1,000 ppm of fluoride (as
sodium fluoride, stannous fluoride, or sodium monofluorophosphate) were
formulated with abrasives known either to interact or not interact with
particular fluorides. The in vitro tests measured fluoride uptake for a
considerably longer time period than would be experienced during actual
intermittent use. The authors claimed that the in vitro tests provide
valuable information. They also stated that the results of the ESR test
did not correlate well with the animal caries assay results.
Furthermore, the authors noted that the sodium monofluorophosphate
dentifrices provided high levels of available active fluoride ions but
produced only small reductions in enamel solubility. Thus, this study
indicated that the animal caries reduction studies gave the most
complete assessment of effectiveness of the dentifrices tested compared
with the test results from the two in vitro tests (ESR and enamel
uptake of fluoride). Therefore, the agency concludes that both animal
and human studies provide a more complete assessments of anticaries
effectiveness.
The agency has thoroughly reviewed the comments, the clinical
studies involving anticalculus agents added to dentifrice products
containing monograph fluoride ingredients, and data comparing the
results of in vitro biological tests with in vivo animal caries tests.
Based on this evaluation, the agency concludes that biological testing
is necessary for all clinically untested dentifrice products to ensure
fluoride ion availability. Therefore, the agency is revising the
biological testing requirements in this final monograph to require that
all OTC anticaries dentifrice drug product formulations not
specifically reviewed by the Panel be tested in an animal caries
reduction test. This type of biological test will be required rather
than optional, as proposed in the tentative final monograph (53 FR
22430 at 22434). Based upon a review of all the available data, the
agency still concludes that long-term clinical trials are not needed
for different or new dentifrice products containing a monograph
fluoride ingredient/abrasive system, including untested abrasive
systems or new additives. The agency considers fluoride availability as
well as ESR and fluoride uptake studies to be good predictors of
potential effectiveness of a fluoride toothpaste. However, the in vivo
animal caries reduction test provides further assurance that the
dentifrice is active against dental caries. The biological portion of
the recommended testing provides an important assurance that, in
addition to being chemically available as demonstrated by the
analytical portion of the testing recommendations, the fluoride is also
bioavailable in that it will alter tooth structure in the biological
tests to make the tooth resistant to caries.
Accordingly, the agency is revising the first sentence in
Sec. 355.70 of the testing procedures for fluoride dentifrice drug
products to read: ``A fluoride dentifrice drug product shall meet the
biological test requirements for animal caries reduction and one of the
following tests: Enamel solubility reduction or fluoride enamel
uptake.''
Although the agency encourages the development of additional
testing procedures, such as remineralization tests, the agency
considers the three biological tests recommended by the Panel as
sufficient at this time to demonstrate anticaries effectiveness.
Demineralization/remineralization studies in humans may also be
predictive of anticaries effectiveness. However, the agency has not
received sufficient data to correlate specifically the results of
remineralization tests with clinical studies that demonstrate
anticaries effectiveness of fluoride dentifrices. The agency would
consider such tests as an option to animal caries reduction tests if
adequate data were submitted to the agency in the form of a petition to
amend the monograph.
References-
(1) Lu, K. H. et al., ``The Effect of a Fluoride Dentifrice
Containing an Anticalculus Agent on Dental Caries in Children,''
Journal Of Dentistry For Children, 52(6):449-451, 1985. -
(2) Stephen, K. W. et al., ``A 3-Year Oral Health Dose-Response
Study of Sodium Monofluorophosphate Dentifrices with and without
Zinc Citrate: Anti-Caries Results,'' Community Dentistry and Oral
Epidemiology, 16:321-325, 1988.
(3) Triol, C. W. et al., ``A Clinical Study of the Anticaries
Efficacy of Three Fluoride Dentifrices Containing Anticalculus
Ingredients: One and Two Year Results,'' The Journal of Clinical
Dentistry, 1(2):48-50, 1988.
(4) Pader, M. et al., ``The Evaluation of Fluoride
Dentifrices,'' Journal of the Society of Cosmetic Chemistry, 28:681-
694, 1977.
41. One comment stated that it is unclear what the reference
standards will be for the required analytical and biological testing of
fluoride dentifrices. The comment contended that it is difficult to
comment on the whole program without knowing what the standards are.
The comment suggested that an additional period of time be permitted to
allow interested groups to comment on the acceptability of the actual
United States Pharmacopeia (U.S.P.) reference standards when they are
established.
In the tentative final monograph, the agency stated that it was
coordinating establishment of the fluoride dentifrice reference
standard formulations with the United States Pharmacopeial Convention
(U.S.P.C.) (53 FR 22430 at 22439). Since then, industry has worked with
the U.S.P.C. to establish reference standards, through the joint
Nonprescription Drug Manufacturers Association and Cosmetic, Toiletry
and Fragrance Association task force. Information about the reference
standards was made public in U.S.P.'s Pharmacopeial Forum in 1990 (Ref.
1),
[[Page 52501]]
and interested parties had an opportunity to comment at that time.
Reference standards have been available from U.S.P.C. since 1990.
Based on the public availability and use of these U.S.P. fluoride
dentifrice reference standards by the industry since 1990, the agency
concludes that it is not necessary to provide an additional comment
period.
Reference-
(1) The United States Pharmacopeial Convention, Inc.,
``Headquarters Column,'' Pharmacopeial Forum, 16:3-4, 1990.
42. Two comments requested that the agency refrain from mandating
specific biological test procedures in the final monograph for OTC
anticaries drug products. Instead, the two comments requested that the
biological test procedures proposed in Sec. 355.70 be considered as
guidelines only. The comments agreed with the agency that the
substitution of a new test, such as remineralization, for one of the
three qualifying biological tests should require a petition for FDA
approval. However, the comments strongly disagreed with the need for a
petition for minor modifications in the biological testing protocols
when the results are at least as valid, reliable, and accurate as the
current test procedures. One comment added that, without this
flexibility, the acceptance by the agency of even minor changes may
take an inordinate period of time without helping to protect the
dentifrice user from an ineffective product. The comment suggested that
if the agency continues to maintain control over changes in test
procedures, approval of the changes should be timely and a list of
criteria should be provided so that manufacturers can be assured that
changes will be accepted by the agency.
The second comment indicated that mandating specific test protocols
tends to discourage scientific experimentation and the application of
advanced technology in method development. The comment noted that
advances in technology alone will result in changes in test protocols
and the precision, sensitivity, and accuracy of various measurements.
Therefore, the comment requested that the agency designate the
biological testing procedures as guidelines only and explicitly
indicate that other valid, reproducible methods are acceptable. The
comment indicated that requiring a petition to modify and improve a
procedure would not only be time consuming, but also would be expensive
and thus not in the interest of consumers. The comment concluded that
companies should have the opportunity to make minor modification to
test methods as long as the changes are scientifically validated and
produce accurate and reliable results.
The agency does not agree that the specific biological testing
procedures for fluoride dentifrices should be considered as test
guidelines only. The agency indicated in the tentative final monograph
(53 FR 22430 at 22443) that the availability of the fluoride ion in a
dentifrice formulation and meeting the biological testing requirements
are the most important testing criteria for predicting the
effectiveness of a fluoride dentifrice product. The agency considers
demonstration of the bioavailability of the fluoride ion in the
biological tests listed in Sec. 355.70 as necessary to ensure the
anticaries effectiveness of fluoride dentifrices. The agency points out
that the required biological tests are based on the results of actual
biological testing procedures performed on fluoride dentifrices that
had been shown to be clinically effective in preventing caries. These
testing procedures are a regulatory standard that supports general
recognition of the safety and effectiveness of fluoride dentifrices.
The agency has had a similar petition procedure for many years for
modifications to the in vitro test for OTC antacid drug products (see
21 CFR 331.29). The agency has processed these petitions in a timely
manner. Accordingly, the agency is including the biological testing
procedures in Sec. 355.70 as required tests for any fluoride dentifrice
drug product marketed pursuant to this monograph.
The agency finds no basis to agree with the comment's suggestion
that requiring these specific biological testing procedures interferes
with the advancement of science and technology. The agency does not
intend for the testing procedures to preclude the application of new,
advanced technology in testing fluoride dentifrices. The agency agrees
with the two comments that as technology continues to evolve,
modifications to the existing testing procedures may result in more
sensitive, reliable, and accurate measurements. However, there should
be a consensus in the scientific community that these new procedures
are generally accepted. The agency encourages the development of new
testing technology and methods for fluoride dentifrices and has
provided in the monograph the opportunity for interested persons to
propose modifications or alternative testing procedures through the
petition process in 21 CFR 10.30. Any petition should contain
sufficient data to support the modification and to demonstrate that the
alternative testing procedure provides results that are equivalent to
the currently required biological test methods.
43. Two comments objected to fluoride dentifrice reference
standards being provided through the U.S.P.C. The comments suggested
that exact specifications for these reference standards (including
levels of ingredients, source of raw materials, product specifications,
and detailed production directions) be provided as part of the U.S.P.
monograph system so that manufacturers could prepare their own fresh
reference standards when needed. One comment contended that, given
sufficient detailed specifications, manufacturers would certainly be as
qualified to produce properly prepared standards as the U.S.P.C.
Following publication of the tentative final monograph, FDA and
industry developed procedures for introduction of new or modified
commercial dentifrice formulations without full clinical testing,
provided that bioavailability/bioequivalence of the formulation was
demonstrated against an appropriate reference standard (Ref. 1). Six
U.S.P. fluoride dentifrice reference standards were initially
established for use in the biological testing of fluoride dentifrices:
(1) Sodium fluoride-calcium pyrophosphate (high beta-phase), (2) sodium
fluoride-silica, (3) sodium monofluorophosphate-calcium carbonate, (4)
sodium monofluorophosphate-dicalcium phosphate, (5) sodium
monofluorophosphate-silica, (6) stannous fluoride-silica (Ref. 2).
These reference standards are prepared by manufacturers of dentifrice
drug products and provided to the U.S.P.C. for distribution. Thus, the
agency agrees with one comment that manufacturers are qualified to
produce these reference standards. Based on the development of these
reference standards by manufacturers of OTC dentifrice drug products,
neither the agency nor the U.S.P.C. sees a need to include exact
specifications for these reference standards in the U.S.P. monograph
system. Furthermore, the U.S.P. monograph system does not include exact
specifications for other reference standards the U.S.P.C. provides.
The agency had a meeting with U.S.P.C. and industry representatives
on May 20, 1993 (Ref. 3), to discuss the existing U.S.P. program for
dentifrice reference standards and to determine if any changes were
needed once the final monograph for OTC anticaries drug products is
issued. Additional procedures to assure continued
[[Page 52502]]
availability of these dentifrice reference standards from the U.S.P.C.
were developed. The U.S.P.C.'s current supply of dentifrice reference
standards were subsequently tested to monitor stability (Refs. 4
through 7). Manufacturers of each reference standard have committed to
retest stability every 18 months and to make every effort to resupply
the U.S.P.C. with additional reference standards when supplies are
depleted (Ref. 3). This should occur within 1 to 2 months after the
U.S.P.C. makes a request. The U.S.P.C. will provide information
concerning the reference standards' stability profile (including total
fluoride, available fluoride ions, pH, and specific gravity) that is
provided by each manufacturer to any purchaser upon written request.
The agency believes that the availability of this information
adequately addresses the comments' concerns about specifications for
these dentifrice reference standards. Other information of concern,
such as source of raw materials and detailed production directions, are
considered confidential commercial information or trade secret
information. The agency concludes that distribution of dentifrice
reference standards by the U.S.P.C. is appropriate.
References-
(1) The United States Pharmacopeial Convention, Inc.,
``Headquarters Column,'' Pharmacopeial Forum, 16:3-4, 1990.
(2) The United States Pharmacopeial Convention, Inc.,
``Reference Standards Catalog,'' Pharmacopeial Forum, 17:2458, 1991.
(3) Minutes of meeting between FDA, U.S.P.C., and industry
representatives, May 20, 1993, identified as MM6, Docket No. 80N-
0042, Dockets Management Branch.
(4) Comment No. RPT4, Docket No. 80N-0042, Dockets Management
Branch.
(5) Comment No. RPT5, Docket No. 80N-0042, Dockets Management
Branch.
(6) Comment No. RPT6, Docket No. 80N-0042, Dockets Management
Branch.
(7) Comment No. RPT7, Docket No. 80N-0042, Dockets Management
Branch.
44. Two comments suggested that several U.S.P. reference standards
for dentifrices should be provided for each Category I fluoride
ingredient and abrasive combination for which clinical proof of
effectiveness has been submitted. The comments stated that the types
and sources of abrasives and other ingredients present in dentifrice
reference standards could have a significant effect on the results of
bioavailability tests. As an example, the comments suggested that
U.S.P. dentifrice reference standards for sodium fluoride products
should include sodium fluoride/calcium pyrophosphate, sodium fluoride/
silica, and sodium fluoride/sodium bicarbonate combinations, all of
which have been proven effective in clinical trials. According to one
comment, providing all of these standards would ensure the exclusion of
ineffective combinations without unfairly excluding dentifrices that
are effective but fail to meet the performance of an inappropriate
standard.
The agency agrees with the comments that the availability of
appropriate U.S.P. reference standards is essential to conduct the
biological testing included in this final monograph for OTC anticaries
drug products. In the tentative final monograph (53 FR 22430 at 22439),
the agency stated that it was coordinating with U.S.P.C. to establish
fluoride dentifrice reference standards that would be made available to
manufacturers interested in manufacturing fluoride dentifrices.
Subsequently, U.S.P. fluoride dentifrice reference standards have been
established for Category I fluoride ingredient/abrasive combinations
that had been reviewed by the Panel and determined by clinical trials
to be effective anticaries drug products. These reference standards
include the fluoride dentifrice combinations suggested by the comments,
i.e., sodium fluoride/calcium pyrophosphate and sodium fluoride/silica,
as well as sodium monofluorophosphate/calcium carbonate, sodium
monofluorophosphate/dicalcium phosphate, sodium monofluorophosphate/
silica, and stannous fluoride/silica (see section I.F., comment 43 of
this document). A list of U.S.P. reference standards available as of
the date of this final rule is on file in the Dockets Management Branch
(Ref. 1).
The U.S.P. reference standards that have been established include
only those dentifrice formulations that have been demonstrated to be
clinically effective and that were reviewed by the Panel. At the time
of the Panel's deliberation, no clinical data supporting the
effectiveness of a sodium fluoride/sodium bicarbonate dentifrice were
submitted for review. Consequently, a U.S.P. reference standard for
this dentifrice formulation has not been established.
The agency indicated in the tentative final monograph (53 FR 22430
at 22443) that any Category I fluoride compound formulated with an
appropriate abrasive can be marketed provided the dentifrice meets the
biological testing requirements in Sec. 355.70 and contains the amount
of available fluoride ion stated in Sec. 355.10. The particular
fluoride ingredient contained in the chosen reference standard must be
the same as the fluoride ingredient in the dentifrice formulation being
tested; however, it is not necessary that the abrasive be the same as
the abrasive contained in the reference standard. The agency is aware
that several manufacturers use the U.S.P. reference standards, sodium
fluoride/calcium pyrophosphate or sodium fluoride/silica, in the
biological testing of their sodium fluoride/sodium bicarbonate
dentifrice products (Ref. 2). A manufacturers' association has recently
informed the agency that a new supply of one of the U.S.P. reference
standards, sodium fluoride/calcium pyrophosphate (high-beta phase),
will not be manufactured when the current supply at U.S.P.C. is
exhausted (Ref. 3). When this sodium fluoride/calcium pyrophosphate
dentifrice reference standard is no longer available, manufacturers
should use the sodium fluoride/silica dentifrice reference standard in
its place to conduct the biological tests. Thus, in response to the
comment's suggestion that a reference standard be established for a
sodium fluoride/sodium bicarbonate dentifrice, it is sufficient that
the formulation meet the biological testing requirements using a
reference standard containing sodium fluoride, and the available
fluoride ion concentration of the dentifrice be equal to or greater
than 650 ppm.
References-
(1) OTC Vol. 08BTPRS, Docket No. 80N-0042, Dockets Management
Branch.
(2) Memoranda of telephone conversations between C. Martin, FDA,
and W. Cooley, Procter & Gamble Co., dated February 8, 1993; P.
Okarma, Colgate-Palmolive Co., dated February 9, 1993; and D.
Worrell, Church & Dwight Co., dated February 17, 1993, OTC Vol.
08AFM, Docket No. 80N-0042, Dockets Management Branch.
(3) Comment No. RPT4, Docket No. 80N-0042, Dockets Management
Branch.
G. Comments on Package Size Limitation
45. One comment requested that the agency increase the fluoride
dentifrice package size limitation from 260 mg of total fluorine per
package to 350 mg to accommodate the increased amount of fluoride
contained in dentifrices containing 1,500 ppm. The comment noted that
dentifrice products marketed pursuant to the proposed OTC drug
monograph contain less than 1,150 ppm fluoride and are marketed in 9-oz
package sizes to adhere to the 260-mg total fluorine package size
limitation. The comment indicated that FDA had obviously reconsidered
the 260-mg dentifrice package size limitation in approving an NDA for
an OTC dentifrice
[[Page 52503]]
product containing 1,500 ppm fluoride. According to the comment, the
NDA fluoride dentifrice is marketed in 8.2 and 6.4 oz package sizes
that contain 350 and 272 mg theoretical total fluorine, respectively.
The comment added that these package sizes do not have any special
cautionary labeling concerning the additional fluoride and do not have
child-resistant closures. The comment contended that consumers would
not be able to differentiate the amount of fluoride contained in
packages of the 1,150-ppm and the 1,500-ppm products, and thus would
not treat or use the products differently. The comment remarked that
there appears to have been no concern at all that ingestion of the
entire package of dentifrice was a real public safety risk. The comment
concluded that consumers would benefit from an increase in the package
size fluorine limitation because of the added convenience of a larger
package size and more economical products on a cost per oz basis.
The comment stated that the issue in establishing a package size
limitation is to prevent acute toxicity that may result from a single
individual ingesting the entire contents of a fluoride dentifrice
package on a single occasion, rather than to prevent the long-term
adverse effects of fluoride ingestion. The comment submitted a list of
21 published animal toxicology studies (Ref. 1) that were submitted in
support of the NDA for the 1,500-ppm fluoride dentifrice product. The
comment stated that a review of its marketing experience records over
an 18-month period (during which tubes as small as 1.4 oz were
marketed) indicated that no one in the United States had ingested an
entire tube of toothpaste regardless of size during that period of
time. The comment added that it has marketed a 1,450-ppm fluoride
(theoretical total fluorine) dentifrice extensively outside the United
States in tube sizes that exceed the proposed monograph package size
limitations without any special warnings or closures. The comment
stated that no incidents or issues have been raised with respect to the
safety of such package sizes. The comment concluded that the proposed
260-mg package size limitation is unnecessary to protect the safety or
health of the American public and that the limitation should be raised
to 350-mg.
After the tentative final monograph was published in 1985, the
agency evaluated and approved an NDA (19-518) for an OTC fluoride
dentifrice containing 1,500-ppm theoretical total fluoride (Ref. 2). As
part of that evaluation, the agency reconsidered, as noted by the
comment, the package size limitation of 260 mg total fluorine that had
been recommended by the Panel and proposed by the agency in the
tentative final monograph. The agency approved marketing of a 6.4 oz
(actually containing 276 mg total fluorine) and a 8.2 oz (containing
350 mg total fluorine) package size. Since that time, the agency has
reviewed the confidential sales distribution data submitted under the
NDA for the extra-strength dentifrice. The data indicate extensive
marketing experience for the 6.4 oz package size and limited marketing
of the 8.2 oz package size. Furthermore, the manufacturer of the extra-
strength dentifrice has discontinued marketing the 8.2 oz package size
(Ref. 3). The agency concludes that it has insufficient marketing
experience and an inadequate safety profile to support general
recognition of an 8.2 oz package size containing 350 mg total fluorine
per package. The agency has sufficient data to support the 6.4 oz
package size of 1,500 ppm dentifrice (containing 276 mg total
fluorine). Therefore, the agency is limiting monograph dentifrices to a
package size containing no more than 276 mg total fluorine per package.
References-
(1) Comment No. CP4, Docket No. 85N-0554, Dockets Management
Branch.
(2) Copy of FDA-approved Labeling from NDA 19-518, OTC Vol.
08AFM, Docket No. 80N-0042, Dockets Management Branch.
(3) Memorandum of telephone conversation between C. Martin, FDA,
and L. Cancro, Consultant to Chesebrough-Pond's Co., dated August 9,
1993, OTC Vol. 08AFM, Docket No. 80N-0042, Dockets Management
Branch.
46. One comment requested that the proposed package size
limitations for dentifrices, treatment rinses, and treatment gels in
Sec. 355.20(a) and (b) not be limited to 260 mg (dentifrices) and 120
mg (rinses and gels) total fluorine per package when the products are
intended for professional use. Noting that the package size limitations
were proposed because of potential toxicity that might be caused by
accidental ingestion of these products, the comment contended that
these package size restrictions are inappropriate for professional
packages used by dental practitioners in their practice. The comment
stated that dentists routinely administer these products to their
patients as part of their treatment and, thus, require a larger
container than the proposed OTC package sizes. The comment concluded
that professional package sizes would have limited distribution, would
not be available to consumers and, therefore, would not be a safety
concern.
The package size limitations established for OTC fluoride
dentifrices, treatment rinses, and preventive treatment gels in
Sec. 355.20 of this final monograph are intended for products used by
the general public and not for products used only under professional
supervision. The agency does not believe that safety problems will
occur when a larger package size is distributed for professional office
use only, provided the package is not intended to be distributed by the
dentist to the consumer for home use. A product marketed in this manner
would present potential safety problems similar to an OTC product.
Therefore, the agency is not limiting the package size for dentifrices,
treatment rinses, and preventive treatment gels labeled for
professional office use only. The agency is including in Sec. 355.60 of
the monograph (professional labeling) the following statements for
products marketed to health professionals in package sizes larger than
those specified in Sec. 355.20: ``For Professional Office Use Only''
and ``This product is not intended for home or unsupervised consumer
use.'' For clarity, the agency is adding paragraph (a)(3) to
Sec. 355.20 as follows: ``Package size limitations do not apply to
anticaries drug products marketed for professional office use only and
labeled in accord with Sec. 355.60.''
II. Summary of Significant Changes From the Proposed Rule
A. Summary of Ingredient Categories
The agency has reviewed all claimed active ingredients submitted to
the Panel and to the tentative final monograph, as well as other data
and information available at this time. For the convenience of the
reader, the following table is a summary of the agency's categorization
of OTC anticaries active ingredients.
----------------------------------------------------------------------------------------------------------------
Anticaries Active
Ingredients Monograph (M) Nonmonograph (NM)
----------------------------------------------------------------------------------------------------------------
Hydrogen fluoride:........
[[Page 52504]]
Rinse--In an appropriate
formulation with 0.02
percent fluoride ion... NM
Phosphate preparations:...
Calcium sucrose
phosphate.............. NM
Dicalcium phosphate
dihydrate.............. NM
Disodium hydrogen
phosphate.............. NM
Phosphoric acid......... NM
Sodium dihydrogen
phosphate.............. NM
Sodium dihydrogen
phosphate monohydrate.. NM
Sodium phosphate........ NM
Sodium phosphate,
dibasic anhydrous
reagent................ NM
Sodium bicarbonate...... NM
Sodium fluoride:..........
Dentifrice--paste: 0.188
to 0.254 percent (with
650
available fluoride ion) M
Dentifrice--powder: 0.188
to 0.254 percent (with
850 ppm
available fluoride ion
and poured-bulk density
of 1.0 to 1.2 g/mL)...... M
Rinse--0.05 percent..... M
Rinse--0.02 percent..... M
Rinse--Acidulated
phosphate fluoride with
0.02 percent fluoride
ion.................... M
Rinse--Acidulated
phosphate fluoride with
0.01 percent fluoride
ion.................... M
Sodium fluoride and
hydrogen fluoride:.......
Rinse--Acidulated
phosphate fluoride with
1.23 percent fluoride
ion.................... MN
Sodium monofluorophosphate
(850 to 1,150 ppm):......
Dentifrice: 0.654 to
0.884 percent (with 800 ppm
available fluoride ion
as PO3F= and F-
combined).............. M
Rinse--6.0 percent...... NM
Sodium monofluorophosphate
(1,500 ppm):............. NM
Dentifrice--1.153
percent (with 1,275 ppm available
fluoride ion as PO3F=
and F- combined)....... M .........................................
Stannous fluoride:........
Dentifrice--0.351 to
0.474 with an available
fluoride ion
concentration of:......
700 ppm
for products
containing abrasive
other than calcium
pyrophosphate........ M
or....................
290 ppm
for products
containing the
abrasive calcium
pyrophosphate........ M
Rinse--0.1 percent...... M
Gel--0.4 percent in an
anhydrous glycerin gel. M
----------------------------------------------------------------------------------------------------------------
B. Summary of the Agency's Changes
1. The agency is revising the definitions proposed for anticaries
drug, dentifrice, and treatment gel in Sec. 355.3(c), (e), and (i),
respectively. The agency is adding a definition for anhydrous glycerin
in Sec. 355.3(b), as used in Sec. 344.3(a) (21 CFR 344.3(a)) of the
final monograph for OTC topical otic drug products. Also, in
Sec. 355.3(h), the agency is adding a definition for a fluoride
supplement that is intended to be swallowed. Because of these
additions, proposed Sec. 355.3(b) through (f) have been redesignated as
paragraphs (c) through (g), and Sec. 355.3(g) through (k) have been
redesignated as paragraphs (i) through (m), respectively, in this final
monograph. (See section I.B., comments 5, 6, and 7 of this document.)
2. The agency is including fluoride dentifrices that contain 1,500
ppm theoretical total fluorine in Sec. 355.10(b)(2) of this final
monograph. Because of concerns about dental fluorosis, the agency is
requiring that dentifrices containing these fluorine concentrations be
clearly labeled for use only by children 6 years of age and older and
is including directions for adults and children 6 years of age and
older in Sec. 355.50(d)(1)(ii) of this final monograph. The agency is
also including an optional additional labeling statement that will
inform consumers of the benefits of these products. (See section I.B.,
comment 10 of this document.)
3. The agency is adding sodium fluoride/sodium bicarbonate powdered
dentifrices in Sec. 355.10(a)(2) of this final monograph. Directions
for these products appear in Sec. 355.50(d)(1)(iii). (See section I.B.,
comments 13 and 14 of this document.)
4. The agency is increasing the package size limitations in
Sec. 355.20(a) for dentifrice (toothpastes and tooth powders) packages
up to 276 milligrams total fluorine per package. The agency is also
adding a new paragraph in Sec. 355.20 for fluoride powdered dentifrices
that provides for tight container packaging in accordance with the
definition in the U.S.P. (See section I.B., comment 15 and section
I.G., comment 45 of this document.)
5. The agency notes that there is a U.S.P. monograph for Sodium
Fluoride and Phosphoric Acid Topical Solution (Ref. 1). This monograph
applies to acidulated phosphate sodium fluoride topical solutions
having a pH between 3.0 and 4.0. Therefore, this monograph
[[Page 52505]]
would apply to the aqueous solution of acidulated phosphate fluoride
described in Sec. 355.10(a)(3)(ii) of the final monograph for OTC
anticaries drug products and could apply to the aqueous solution of
acidulated phosphate fluoride described in Sec. 355.10(a)(3)(i) if the
pH range of the U.S.P. monograph were to be expanded to 4.5. The agency
and an interested manufacturer (Ref. 2) are working with U.S.P. to
develop a revision in the compendial monograph for these rinse
products. The agency anticipates that this revision will be completed
before this final monograph for OTC anticaries drug products becomes
effective. In accord with Sec. 355.50(a) of the final monograph,
manufacturers marketing these products should include the compendial
name, Sodium Fluoride and Phosphoric Acid Topical Solution, as the
established name in the labeling of such products.
References-
(1) The United States Pharmacopeia 23--The National Formulary
18, United States Pharmacopeial Convention, Inc., Rockville, MD, p.
1423, 1994.
(2) Memorandum of telephone conversation between C. Martin, FDA,
and P. Okarma, Colgate-Palmolive Co., dated December 9, 1993, OTC
Vol. 08AFM, Docket No. 80N-0042, Dockets Management Branch.-
6. The agency is redesignating several paragraphs and is providing
the following table of changes for the convenience of the reader:
------------------------------------------------------------------------
Paragraph number in this Paragraph number in the tentative final
final mongraph monograph
------------------------------------------------------------------------
355.3(b)................. .............................................
355.3(c) through (g)..... 355.3(b) through (f)
355.3(h).................
355.3(i) through (m)..... 355.3(g) through (k)
.......................
355.10(a)(2)............. .............................................
355.10(a)(3)(i).......... 355.10(b)(1)
355.10(a)(3)(ii)......... 355.10(b)(2)
355.10(a)(3)(iii)........ 355.10(b)(3)
355.10(a)(3)(iv)......... 355.10(b)(4)
355.10(a)(3)(v).......... 355.10(b)(5)
355.10(b)(1)............. 355.10(a)(2)
355.10(b)(2)............. .............................................
355.10(c)(1)(i).......... 355.10(a)(3)
355.10(c)(1)(ii)......... 355.10(a)(4)
355.10(c)(2)............. 355.10(c)
355.10(c)(3)............. 355.10(b)(6)
.......................
355.20(a)(1)1............ 355.20(a)
355.20(a)(2)............. 355.20(b)
355.20(a)(3)............. .............................................
355.20(b)................ .............................................
355.50(d)(1)(i).......... 355.50(d)(1)(i)
355.50(d)(1)(ii)......... .............................................
355.50(d)(2)(i).......... 355.50(d)(2)
355.50(d)(2)(ii)......... .............................................
355.50(d)(2)(iii)........ 355.50(d)(2)(ii)
355.50(d)(5)............. .............................................
355.50(e)(2)............. 355.50(e)(3)
355.50(f)(1)2............ 355.50(f)
355.50(f)(2)............. .............................................
....................... 355.50(g)
------------------------------------------------------------------------
\1\ Because Sec. 355.20(b) has been revised, the heading of Sec.
355.20 has been changed to ``Packaging conditions.''
\2\ Because Sec. 355.50(f)(2) has been added, the word ``statement'' in
the heading of Sec. 355.50(f) has been changed to ``statements.''
7. The agency is revising and expanding Sec. 355.50(a) to provide
the option of using the additional terms ``mouthwash,'' ``tooth
powder,'' and ``tooth polish'' in the statement of identity. The agency
is also requiring that the term ``preventive treatment'' be included in
the statement of identity for nonabrasive fluoride gels. The agency is
providing that the word ``treatment'' be optional in the statement of
identity for fluoride rinse products. (See section I.C., comments 17
and 18 of this document.)
8. The agency has moved the statement ``Do not use before mixing
with water'' from the warnings in proposed Sec. 355.50(c) to the
directions for use in Sec. 355.50(d)(5) of this final monograph. This
statement is to be the first sentence of the directions for
concentrated treatment rinse solutions, powders, and effervescent
tablets. (See section I.C., comment 26 of this document.)
9. The agency is modifying the general warning in Sec. 330.1(g),
which states: ``Keep this and all drugs out of the reach of children,''
to read as follows for fluoride dentifrice drug products: ``Keep out of
the reach of children under 6 years of age.'' This warning appears in
Sec. 355.50(c)(1) of this final monograph. However, in
Sec. 355.50(c)(2), the agency continues to require the general warning
in Sec. 330.1(g) for all other OTC anticaries drug products. (See
section I.B., comment 22 of this document.)
10. The agency is revising the directions for anticaries dentifrice
drug products proposed in Sec. 355.50(d) and is including the revised
directions in Sec. 355.50(d)(1)(i), (d)(1)(ii), and (d)(1)(iii)
[[Page 52506]]
of this final monograph. The agency is also revising the directions for
use of anticaries preventive treatment gels by children in
Sec. 355.50(d) to read: ``Instruct children under 12 years of age in
the use of this product (to minimize swallowing). Supervise children as
necessary until capable of using without supervision.'' The agency is
including the revised directions in Sec. 355.50(d)(4) in this final
monograph.
11. The agency is revising the directions for use of anticaries
treatment rinses by children, proposed in Sec. 355.50(d)(2)(i), to
read: ``Instruct children under 12 years of age in good rinsing habits
(to minimize swallowing). Supervise children as necessary until capable
of using without supervision.'' The agency is including the revised
directions in Sec. 355.50(d)(2)(i) and (d)(2)(ii) in this final
monograph. (See section I.C., comment 25 of this document.)
12. The agency is not including proposed Sec. 355.50(e)(2) in this
final monograph. In its place, the agency is including new Sec. 355.55,
as follows: ``Principal display panel of all fluoride rinse drug
products. In addition to the statement of identity required in
Sec. 355.50, the following statement shall be prominently placed on the
principal display panel: 'IMPORTANT: Read directions carefully before
using'''. Because proposed Sec. 355.50(e)(2) is not included in this
monograph, the agency is redesignating proposed Sec. 355.50(e)(3) as
Sec. 355.50(e)(2) in this final monograph. (See section I.C., comment
20 of this document.)
13. The agency is not including proposed Sec. 355.50(g) (which
states: ``The word 'physician' may be substituted for the word 'doctor'
in any of the labeling statements in this section.'') in this final
monograph because the agency has amended Sec. 330.1 to permit the
interchangeability of certain terms, including ``physician'' and
``doctor,'' in all OTC drug monographs. (See 59 FR 3998, January 28,
1994.)
14. The agency is modifying the introductory language in the
professional labeling in Sec. 355.60 to read: ``The labeling for
anticaries fluoride treatment rinses identified in Sec. 355.10(b) that
are specially formulated so they may be swallowed (fluoride
supplements) and are provided to health professionals (but not to the
general public) may contain the following additional dosage
information: * * *.'' (See section I.C., comment 28 of this document.)
15. The agency is including in Sec. 355.60 (professional labeling)
the following statements for products marketed to professionals in
package sizes larger than those specified in Sec. 355.20: ``For
Professional Office Use Only'' and ``This product is not intended for
home or unsupervised consumer use.'' The agency is also amending
Sec. 355.20 by revising paragraph (b) to read: ``Package size
limitations do not apply to anticaries drug products marketed for
professional office use only and labeled in accord with Sec. 355.60.''
(See section I.G., comment 46 of this document.)
16. The agency is revising the biological testing requirements in
this final monograph to require that all OTC anticaries dentifrice drug
product formulations be tested in an animal caries reduction test
rather than allowing this type of biological test to be optional as
proposed in the tentative final monograph (53 FR 22430 at 22434).
Accordingly, the first sentence in Sec. 355.70 of the testing
procedures for fluoride dentifrice drug products reads: ``A fluoride
dentifrice drug product must meet the biological test requirements for
animal caries reduction and one of the following tests: Enamel
solubility reduction or fluoride enamel uptake.'' The agency has
further revised the proposed testing guidance for parameters other than
available fluoride ion and biological test requirements and is citing
these revised parameters as testing intended as guidance, e.g., for use
in determining expiration dating. The agency is including a revised LTP
chart in the preamble of this document for informational purposes. (See
section I.F., comments 37, 39, and 40 of this document.)
17. The agency is revising the testing procedures in Sec. 355.70 to
include information about the available U.S.P. fluoride dentifrice
reference standards. (See section I.F., comments 43 and 44 of this
document.)
III. The Agency's Final Conclusions on OTC Anticaries Drug Products
Based on available evidence, the agency is issuing a final
monograph establishing conditions under which OTC anticaries drug
products (aid in the prevention of dental cavities) are generally
recognized as safe and effective and not misbranded. Specifically, the
agency has determined that the following active ingredients meet
monograph conditions: Sodium fluoride, sodium monofluorophosphate, and
stannous fluoride. All other ingredients considered in this rulemaking
have been determined to be nonmonograph conditions. Four of these
ingredients are presently listed in Sec. 310.545(a)(2) (21 CFR
310.545(a)(2)) as not generally recognized as safe and effective for
anticaries use, i.e., hydrogen fluoride, sodium carbonate, sodium
monofluorophosphate (6 percent rinse), and sodium phosphate. In this
final rule, the agency is amending Sec. 310.545(a)(2) by adding the
ingredients calcium sucrose phosphate, dicalcium phosphate dihydrate,
disodium hydrogen phosphate, phosphoric acid, sodium dihydrogen
phosphate, sodium dihydrogen phosphate monohydrate, and sodium
phosphate, dibasic anhydrous reagent to this list of nonmonograph
conditions. These ingredients appear in new Sec. 310.545(a)(2)(ii),
while previous Sec. 310.545(a)(2) is redesignated
Sec. 310.545(a)(2)(i).
The agency is removing the existing warning and caution statement
required in Sec. 369.21 (21 CFR 369.21) and exemptions for certain
drugs limited by NDA's to prescription sale in Sec. 310.201(a)(10) and
(a)(15) (21 CFR 310.201(a)(10) and (a)(15)) for anticaries drug
products because most portions of those regulations are superseded by
the anticaries final monograph (21 CFR part 355). The items being
removed include: (1) Sec. 310.201(a)(10)(i) through (a)(10)(vi); (2)
Sec. 310.201(a)(15)(i) through (a)(15)(vi); and (3) paragraphs in
Sec. 369.21 applicable to sodium fluoride dentifrice powder and sodium
monofluorophosphate dentifrice solution. The agency is reserving
paragraphs (a)(10) and (a)(15) in Sec. 310.201 for future use.
Any drug product labeled, represented, or promoted for use as an
OTC anticaries drug product that contains any of the ingredients listed
in Sec. 310.545(a)(2) or that is not in conformance with the monograph
(21 CFR part 355) may be considered a new drug within the meaning of
section 201(p) of the act (21 U.S.C. 321(p)) and misbranded under
section 502 of the act (21 U.S.C. 352) and may not be marketed for this
use unless it is the subject of an approved application or abbreviated
application under section 505 of the act (21 U.S.C. part 355) and part
314 of the regulations (21 CFR part 314). In appropriate circumstances,
a citizen petition to amend the monograph may be submitted under 21 CFR
10.30 in lieu of an application. Any OTC anticaries drug product
initially introduced or initially delivered for introduction into
interstate commerce after the effective dates of Sec. 310.545(a)(2) or
the effective date of this final rule that is not in compliance with
the regulations is subject to regulatory action.
An analysis of the cost and benefits of this regulation, conducted
under
[[Page 52507]]
Executive Order 12291, was discussed in the tentative final monograph
of September 30, 1985 (50 FR 39854) and in the amendment of the
tentative final monograph of June 15, 1988 (53 FR 22430). No comments
were received in response to the agency's request for specific comment
on the economic impact of this rulemaking (50 FR 39854 at 39871 and 53
FR 22430 at 22447), and the substance of that analysis has not changed.
Executive Order 12291 has been superseded by Executive Order 12866. FDA
has examined the impacts of the final rule under Executive Order 12866
and the Regulatory Flexibility Act (Pub. L. 96-354). Executive Order
12866 directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and, thus, is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. All major anticaries drug products already contain
monograph ingredients, and no reformulations should be necessary. This
final rule will require some relabeling for these products.
Manufacturers will have 1 year to implement this relabeling.
Accordingly, the agency certifies that the final rule will not have a
significant economic impact on a substantial number of small entities.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required.
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.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 355
Labeling, Over-the-counter drugs.
21 CFR Part 369
Labeling, Medical devices, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR
chapter I is amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
Sec. 310.201 [Amended]
2. Section 310.201 Exemption for certain drugs limited by new-drug
applications to prescription sale is amended by removing and reserving
paragraphs (a)(10) and (a)(15).
3. Section 310.545 is amended by redesignating the text of
paragraph (a)(2) as paragraph (a)(2)(i); by adding new (a)(2)(i)
heading and paragraphs (a)(2)(ii) and (d)(24); and by revising
paragraph (d) introductory text and paragraph (d)(1) to read as
follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(2) Anticaries drug products--(i) Approved as of May 7, 1991. * * *
(ii) Approved as of October 7, 1996.
Calcium sucrose phosphate
Dicalcium phosphate dihydrate
Disodium hydrogen phosphate\1\
\1\ These ingredients are nonmonograph except when used to
prepare acidulated phosphate fluoride treatment rinses identified in
Sec. 355.10(a)(3) of this chapter.
---------------------------------------------------------------------------
Phosphoric acid1
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent1
* * * * *
(d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction into interstate commerce after the
dates specified in paragraphs (d)(1) through (d)(24) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(2)(i), (a)(3) through (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7)
(except as covered by paragraph (d)(3) of this section), (a)(8)(i),
(a)(9) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv), (a)(14)
through (a)(15)(i), and (a)(16) through (a)(18)(i) of this section.
* * * * *
(24) October 7, 1996, for products subject to paragraph (a)(2)(ii)
of this section.
4. Part 355 is added to read as follows:
PART 355--ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
Subpart A--General Provisions
Sec.
355.1 Scope.
355.3 Definitions.
Subpart B--Active Ingredients
355.10 Anticaries active ingredients.
355.20 Packaging conditions.
Subpart C--Labeling
355.50 Labeling of anticaries drug products.
355.55 Principal display panel of all fluoride rinse drug
products.
335.60 Professional labeling.
Subpart D--Testing Procedures
355.70 Testing procedures for fluoride dentifrice drug products.
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).
Subpart A--General Provisions
Sec. 355.1 Scope.
(a) An over-the-counter anticaries drug product in a form suitable
for topical administration to the teeth is generally recognized as safe
and effective and is not misbranded if it meets each condition in this
part and each general condition established in Sec. 330.1 of this
chapter.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise
noted.
Sec. 355.3 Definitions.
As used in this part:
(a) Abrasive. Solid materials that are added to dentifrices to
facilitate mechanical removal of dental plaque, debris, and stain from
tooth surfaces.
(b) Anhydrous glycerin. An ingredient that may be prepared by
heating glycerin U.S.P. at 150 -C for 2 hours to drive off the moisture
content.
(c) Anticaries drug. A drug that aids in the prevention and
prophylactic treatment of dental cavities (decay, caries).
[[Page 52508]]
(d) Dental caries. A disease of calcified tissues of teeth
characterized by demineralization of the inorganic portion and
destruction of the organic matrix.
(e) Dentifrice. An abrasive-containing dosage form for delivering
an anticaries drug to the teeth.
(f) Fluoride. The inorganic form of the chemical element fluorine
in combination with other elements.
(g) Fluoride ion. The negatively charged atom of the chemical
element fluorine.
(h) Fluoride supplement. A special treatment rinse dosage form that
is intended to be swallowed, and is promoted to health professionals
for use in areas where the water supply contains 0 to 0.7 parts per
million (ppm) fluoride ion.
(i) Preventive treatment gel. A dosage form for delivering an
anticaries drug to the teeth. Preventive treatment gels are formulated
in an anhydrous glycerin base with suitable thickening agents included
to adjust viscosity. Preventive treatment gels do not contain
abrasives.
(j) Treatment rinse. A liquid dosage form for delivering an
anticaries drug to the teeth.
(k) Treatment rinse concentrated solution. A fluoride treatment
rinse in a concentrated form to be mixed with water before using to
result in the appropriate fluoride concentration specified in the
monograph.
(l) Treatment rinse effervescent tablets. A fluoride treatment
rinse prepared by adding an effervescent tablet (a concentrated solid
dosage form) to water before using to result in the appropriate
fluoride concentration specified in the monograph.
(m) Treatment rinse powder. A fluoride treatment rinse prepared by
adding the powder (a concentrated solid dosage form) to water before
using to result in the appropriate fluoride concentration specified in
the monograph.
Subpart B--Active Ingredients
Sec. 355.10 Anticaries active ingredients.
The active ingredient of the product consists of any of the
following when used in the concentration and dosage form established
for each ingredient:
(a) Sodium fluoride--(1) Dentifrices containing 850 to 1,150 ppm
theoretical total fluorine in a paste dosage form. Sodium fluoride
0.188 to 0.254 percent with an available fluoride ion concentration
650 parts per million (ppm).
(2) Dentifrices containing 850 to 1,150 ppm theoretical total
fluorine in a powdered dosage form. Sodium fluoride 0.188 to 0.254
percent with an available fluoride ion concentration of 850
ppm for products containing the abrasive sodium bicarbonate and a
poured-bulk density of 1.0 to 1.2 grams per milliliter.
(3) Treatment rinses. (i) An aqueous solution of acidulated
phosphate fluoride derived from sodium fluoride acidulated with a
mixture of sodium phosphate, monobasic, and phosphoric acid to a level
of 0.1 molar phosphate ion and a pH of 3.0 to 4.5 and which yields an
effective fluoride ion concentration of 0.02 percent.
(ii) An aqueous solution of acidulated phosphate fluoride derived
from sodium fluoride acidulated with a mixture of sodium phosphate,
dibasic, and phosphoric acid to a pH of 3.5 and which yields an
effective fluoride ion concentration of 0.01 percent.
(iii) Sodium fluoride 0.02 percent aqueous solution with a pH of
approximately 7.
(iv) Sodium fluoride 0.05 percent aqueous solution with a pH of
approximately 7.
(v) Sodium fluoride concentrate containing adequate directions for
mixing with water before using to result in a 0.02-percent or 0.05-
percent aqueous solution with a pH of approximately 7.
(b) Sodium monofluorophosphate--(1) Dentifrices containing 850 to
1,150 ppm theoretical total fluorine in a paste dosage form. Sodium
monofluorophosphate 0.654 to 0.884 percent with an available fluoride
ion concentration (consisting of PO3F= and F- combined)
800 ppm.
(2) Dentifrices containing 1,500 ppm theoretical total fluorine in
a paste dosage form. Sodium monofluorophosphate 1.153 percent with an
available fluoride ion concentration (consisting of PO3F= and
F- combined) 1,275 ppm.
(c) Stannous fluoride--(1) Dentifrices containing 850 to 1,150 ppm
theoretical total fluorine in a paste dosage form. (i) Stannous
fluoride 0.351 to 0.474 percent with an available fluoride ion
concentration 700 ppm for products containing abrasives
other than calcium pyrophosphate.
(ii) Stannous fluoride 0.351 to 0.474 percent with an available
fluoride ion concentration 290 ppm for products containing
the abrasive calcium pyrophosphate.
(2) Preventive treatment gel. Stannous fluoride 0.4 percent in an
anhydrous glycerin gel, made from anhydrous glycerin and the addition
of suitable thickening agents to adjust viscosity.
(3) Treatment rinse. Stannous fluoride concentrate marketed in a
stable form and containing adequate directions for mixing with water
immediately before using to result in a 0.1-percent aqueous solution.
Sec. 355.20 Packaging conditions.
(a) Package size limitation. Due to the toxicity associated with
fluoride active ingredients, the following package size limitations are
required for anticaries drug products:
(1) Dentifrices. Dentifrice (toothpastes and tooth powders)
packages shall not contain more than 276 milligrams (mg) total fluorine
per package.
(2) Preventive treatment gels and treatment rinses. Preventive
treatment gel and treatment rinse packages shall not contain more than
120 mg total fluorine per package.
(3) Exception. Package size limitations do not apply to anticaries
drug products marketed for professional office use only and labeled in
accord with Sec. 355.60.
(b) Tight container packaging. To minimize moisture contamination,
all fluoride powdered dentifrices shall be packaged in a tight
container as defined as a container that protects the contents from
contamination by extraneous liquids, solids, or vapors, from loss of
the article, and from efflorescence, deliquescence, or evaporation
under the ordinary or customary conditions of handling, shipment,
storage, and distribution, and is capable of tight reclosure.
Subpart C--Labeling
Sec. 355.50 Labeling of anticaries 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 the
following: ``anticavity fluoride'' (select one of the following as
appropriate: ``dentifrice,'' ``toothpaste,'' ``tooth polish,'' ``tooth
powder;'' (optional: ``dental'') ``preventive treatment gel;'' or
(optional: ``treatment'' or ``dental'')) (select one of the following:
``rinse,'' ``concentrated solution,'' ``rinse powder,'' or ``rinse
effervescent tablets''). The word ``mouthwash'' may be substituted for
the word ``rinse'' in this statement of identity if the product also
has a cosmetic use, as defined in section 201(i) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 321(i)).
(b) Indication. The labeling of the product states, under the
heading ``Indication,'' the following: ``Aids in the prevention of
dental (select one of the following: ``cavities,'' ``decay,'' ``caries
(decay),'' or ``caries (cavities)''). Other truthful and nonmisleading
statements, describing only the
[[Page 52509]]
indication for use that has been established and listed in this
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2) of
this chapter, subject to the provisions of section 502 of the Federal
Food, Drug, and Cosmetic Act (the act) relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) Warning. The labeling of the product contains the following
warning under the heading ``Warning'':
(1) For all fluoride dentifrice (toothpastes and tooth powders)
products. ``Keep out of the reach of children under 6 years of age.''
This warning shall be used in place of the first general warning
statement required by Sec. 330.1(g) of this chapter.
(2) For all fluoride rinse and gel products. The first general
warning statement in Sec. 330.1(g) of this chapter shall be used.
(d) Directions. The labeling of the product contains the following
statements under the heading ``Directions'':
(1) For anticaries dentifrice products--(i) Paste dosage form with
a theoretical total fluorine concentration of 850 to 1,150 ppm
identified in Sec. 355.10(a)(1), (b)(1), and (c)(1). Adults and
children 2 years of age and older: Brush teeth thoroughly, preferably
after each meal or at least twice a day, or as directed by a dentist or
doctor. Instruct children under 6 years of age in good brushing and
rinsing habits (to minimize swallowing). Supervise children as
necessary until capable of using without supervision. Children under 2
years of age: Consult a dentist or doctor.
(ii) Paste dosage form with a theoretical total fluorine
concentration of 1,500 ppm identified in Sec. 355.10(b)(2). Adults and
children 6 years of age and older: Brush teeth thoroughly, preferably
after each meal or at least twice a day, or as directed by a dentist or
doctor. Instruct children under 12 years of age in good brushing and
rinsing habits (to minimize swallowing). Supervise children as
necessary until capable of using without supervision. Children under 6
years of age: Do not use unless directed by a dentist or doctor.
(iii) Powdered dosage form with a theoretical total fluorine
concentration of 850 to 1,150 ppm identified in Sec. 355.10(a)(2).
Adults and children 6 years of age and older: Apply powder to a wet
toothbrush; completely cover all bristles. Brush for at least 30
seconds. Reapply powder as before and brush again. Rinse and spit out
thoroughly. Brush teeth, preferably after each meal or at least twice a
day, or as directed by a dentist or doctor. Instruct children under 12
years of age in good brushing and rinsing habits (to minimize
swallowing). Supervise children as necessary until capable of using
without supervision. Children under 6 years of age: Do not use unless
directed by a dentist or doctor.
(2) For anticaries treatment rinse products--(i) For acidulated
phosphate fluoride solution containing 0.02 percent fluoride ion,
sodium fluoride 0.05 percent, sodium fluoride concentrate, and stannous
fluoride concentrate identified in Sec. 355.10(a)(3)(i), (a)(3)(iv),
(a)(3)(v), and (c)(3). Adults and children 6 years of age and older:
Use once a day after brushing your teeth with a toothpaste. Vigorously
swish 10 milliliters of rinse between your teeth for 1 minute and then
spit out. Do not swallow the rinse. Do not eat or drink for 30 minutes
after rinsing. Instruct children under 12 years of age in good rinsing
habits (to minimize swallowing). Supervise children as necessary until
capable of using without supervision. Children under 6 years of age:
Consult a dentist or doctor.
(ii) For acidulated phosphate fluoride solution containing 0.01
percent fluoride ion and sodium fluoride 0.02 percent aqueous solution
identified in Sec. 355.10(a)(3)(ii) and (a)(3)(iii). Adults and
children 6 years of age and older: Use twice a day after brushing your
teeth with a toothpaste. Vigorously swish 10 milliliters of rinse
between your teeth for 1 minute and then spit out. Do not swallow the
rinse. Do not eat or drink for 30 minutes after rinsing. Instruct
children under 12 years of age in good rinsing habits (to minimize
swallowing). Supervise children as necessary until capable of using
without supervision. Children under 6 years of age: consult a dentist
or doctor.
(3) For stannous fluoride treatment rinse products. (i) ``Use
immediately after preparing the rinse.''
(ii) For powder or effervescent tablets used to prepare treatment
rinses. ``Do not use as a rinse until all the'' (select one of the
following: ``powder'' or ``tablet'') ``has dissolved.''
(4) For anticaries preventive treatment gel products. Adults and
children 6 years of age and older: Use once a day after brushing your
teeth with a toothpaste. Apply the gel to your teeth and brush
thoroughly. Allow the gel to remain on your teeth for 1 minute and then
spit out. Do not swallow the gel. Do not eat or drink for 30 minutes
after brushing. Instruct children under 12 years of age in the use of
this product (to minimize swallowing). Supervise children as necessary
until capable of using without supervision. Children under 6 years of
age: consult a dentist or doctor.
(5) For all concentrated treatment rinse solutions, powders, and
effervescent tablets. The following statement shall appear as the first
statement under directions: ``Do not use before mixing with water.''
(e) Additional labeling statements for anticaries drug products.
The following statements need not appear under warnings, but are
required to appear on the label of anticaries drugs products as
applicable.
(1) For all preventive treatment gels. ``This is a(n)'' (select one
or both of the following: ``anticavity'' or ``fluoride'') ``preventive
treatment gel, not a toothpaste. Read directions carefully before
using.''
(2) For all stannous fluoride treatment rinse, preventive treatment
gel, and dentifrice products. ``This product may produce surface
staining of the teeth. Adequate toothbrushing may prevent these stains
which are not harmful or permanent and may be removed by your
dentist.''
(f) Optional additional labeling statements--(1) For fluoride
treatment rinses and preventive treatment gels. The following labeling
statement may appear in the required boxed area designated ``APPROVED
USES'': ``The combined daily use of a fluoride preventive treatment''
(select one of the following: ``rinse'' or ``gel'') ``and a fluoride
toothpaste can help reduce the incidence of dental cavities.''
(2) For dentifrice products containing 1,500 ppm theoretical total
fluorine. ``Adults and children over 6 years of age may wish to use
this extra-strength fluoride dentifrice if they reside in a
nonfluoridated area or if they have a greater tendency to develop
cavities.''
Sec. 355.55 Principal display panel of all fluoride rinse drug
products.
In addition to the statement of identity required in Sec. 355.50,
the following statement shall be prominently placed on the principal
display panel: ``IMPORTANT: Read directions for proper use.''
Sec. 355.60 Professional labeling.
(a) The labeling for anticaries fluoride treatment rinses
identified in Sec. 355.10(a)(3) and (c)(3) that are specially
formulated so they may be swallowed (fluoride supplements) and are
provided to health professionals (but not to the general public) may
contain the following additional dosage information: Children 3 to
under 14
[[Page 52510]]
years of age: As a supplement in areas where the water supply is
nonfluoridated (less than 0.3 parts per million (ppm)), clean the teeth
with a toothpaste and rinse with 5 milliliters (mL) of 0.02 percent or
10 mL of 0.01 percent fluoride ion rinse daily, then swallow. When the
water supply contains 0.3 to 0.7 ppm fluoride ion, reduce the dose to
2.5 mL of 0.02 percent or 5 mL of 0.01 percent fluoride ion rinse
daily.
(b) The labeling for products marketed to health to health
professionals in package sizes larger than those specified in
Sec. 355.20 shall include the statements: ``For Professional Office Use
Only'' and ``This product is not intended for home or unsupervised
consumer use.''
Subpart D--Testing Procedures
Sec. 355.70 Testing procedures for fluoride dentifrice drug products.
(a) A fluoride dentifrice drug product shall meet the biological
test requirements for animal caries reduction and one of the following
tests: Enamel solubility reduction or fluoride enamel uptake. The
testing procedures for these biological tests are labeled Biological
Testing Procedures for Fluoride Dentifrices; these testing procedures
are on file under Docket No. 80N-0042 in the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857, and are available on request to that office.
(b) The United States Pharmacopeia fluoride dentifrice reference
standards along with reference standard stability profiles (total
fluoride, available fluoride ion, pH, and specific gravity) required to
be used in the biological tests are available to any purchaser upon
written request to the United States Pharmacopeial Convention, Inc.,
1260 Twinbrook Parkway, Rockville, MD 20852.
(c) Alternative testing procedures may be used. Any proposed
modification or alternative testing procedures shall be submitted as a
petition in accord with Sec. 10.30 of this chapter. The petition should
contain data to support the modification or data demonstrating that an
alternative testing procedure provides results of equivalent accuracy.
All information submitted will be subjected to the disclosure rules in
part 20 of this chapter.
PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND
DEVICES FOR OVER-THE-COUNTER SALE
4. The authority citation for 21 CFR part 369 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371).
Sec. 369.21 [Amended]
5. Section 369.21 Drugs; warning and caution statements required by
regulations is amended by removing the entries for ``SODIUM FLUORIDE
DENTIFRICE POWDER'' and ``SODIUM MONOFLUOROPHOSPHATE DENTIFRICE
SOLUTION.''
Dated: September 18, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-24693 Filed 10-5-95; 8:45 am]
BILLING CODE 4160-01-F
