Anticaries Drug Products for Over-the-Counter Human Use; Final Monograph

[[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.

-----------------------------------------------------------------------

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

This text is long and has been trimmed here. Open the source document for the complete record.