FDA's advance notice of proposed rulemaking for OTC antigingivitis/antiplaque products excludes the combination of antigingivitis/antiplaque ingredients with other oral health care ingredients. The ¹ notice was published in the May 29 Federal Register.

Although some blends were endorsed by FDA's Dental Plaque Subcommittee, "the agency is not aware of any marketing history of such combination products eligible for the OTC drug review, nor were such combinations submitted to the subcommittee," the notice states. Therefore, "the agency is dissenting from these recommendations at this time."

Combinations of antigingivitis/antiplaque ingredients with anticaries and/or tooth desensitizer ingredients were designated as "rational" by the Plaque Subcommittee, which is part of the agency's Nonprescription Drugs Advisory Committee.

However, FDA states "data are needed to establish the safety and effectiveness of these combination products." Accordingly, "none of the combination products described above may be marketed OTC at this time under this advance notice of proposed rulemaking."

FDA will accept comments on the ANPR and submission of additional data until Aug. 27. Reply comments will be due Oct. 27. The final rule would be effective 12 months after it is published.

In other requests for input, the agency is seeking comments on the basis for allowing an antigingivitis ingredient that has not demonstrated effectiveness in reducing plaque to bear labeling statements relating to plaque reduction.

The agency also requests input on whether products that are solely antigingivitis agents, i.e., products that do not significantly reduce plaque, "constitute appropriate OTC drug products."

Such comments would address the agency's concern that "antigingivitis ingredients that work by a mechanism other than plaque reduction...may give consumers a false sense of security by masking symptoms of a more serious disease," the ANPR explains.

The ANPR includes the final report of the Dental Plaque Subcommittee. The subcommittee issued a draft version of the report in late 1998, following more than a dozen meetings from 1993 to 1998 that included FDA and industry.

In its report, the subcommittee proposes that "any reference to the control of dental plaque or its equivalents, with or without qualifications, should be interpreted as a drug claim."

The panel further agreed an OTC drug making any reference to reduction or prevention of plaque "also must demonstrate a clinically significant effect on gingivitis." Thus, "antiplaque claims should not stand alone."

The use of plaque-only claims qualified with "cosmetic benefits" was earlier suggested by dentifrice product developer WhiteHill Oral Technologies in comments on the draft version of the report (² Also see "FDA Allowance Of "Qualified" Plaque-Only Claims Urged By WhiteHill" - Pink Sheet, 8 March, 1999., p. 14).

The ANPR reaffirms two ingredients and one combination as Category I for antigingivitis/antiplaque products. The individual actives are cetylpyridinium chloride and stannous fluoride. The combination includes eucalyptol, menthol, methyl salicylate and thymol (see chart: " ³ Oral Care Ingredients Reviewed by FDA Dental Plaque Subcommittee ").

Cetylpyridinium chloride is safe and effective for use in mouthrinse formulations at concentrations of .045% to .1% with at least 72%-77% chemically available cetylpyridinium chloride, the subcommittee concludes.

Cetylpyridinium chloride .05% is the active ingredient in GlaxoSmithKline's Cepacol Antibacterial Mouthwash and Gargle Gold. Procter & Gamble's Scope also contains cetylpyridinium chloride.

Stannous fluoride is designated safe and effective in a compatible dentifrice base at a concentration of .454%, the notice points out. Recommended claims for the ingredient include: "helps interfere with harmful effects of plaque associated with gingivitis."

Because temporary tooth staining may be caused by stannous fluoride, the subcommittee also advised the additional labeling statement: "This product may produce surface staining of the teeth. Adequate tooth brushing may prevent these stains, which are not harmful or permanent and may be removed by a dentist."

P&G, which previously marketed stannous fluoride-containing Crest Gum Care , had urged the subcommittee to characterize the possible tooth staining as "mild to moderate (⁴ Also see "Stannous Fluoride "Mild" Staining Characterization Sought In Plaque Report" - Pink Sheet, 14 December, 1998., p. 6). Crest Gum Care was discontinued in 1999.

The combination of essential oil ingredients eucalyptol (.092%), menthol (.042%), methyl salicylate (.060%) and thymol (.064%) is considered safe and effective in a hydroalcoholic vehicle containing 21.6% to 26.9% alcohol in a mouthrinse, according to the ANPR.

Eucalyptol, menthol, methyl salicylate and thymol are the active components of Pfizer's Listerine Antiseptic mouthwash.

Based on proposals from industry, the subcommittee makes general recommendations on testing requirements for final product formulations. FDA notes it is also seeking "specific information" from interested parties on testing protocols, effectiveness criteria and statistical methods used to analyze data from such tests.

The subcommittee advises a single six-month rando-mized, controlled, clinical trial to demonstrate antigingivitis/antiplaque effectiveness of Category I ingredients formulated in dosage forms other than those reviewed by the panel.

The report further recommends final formulation testing on the individual product, a standard formulation and a negative control. The "criteria appropriate for these tests should be provided by the product manufacturers" during the rulemaking process, the subcommittee states.

In a discussion of inactive ingredients, the subcommittee reviews the current data on the safety of alcohol in oral health care products and mouthrinses. Based on the studies reviewed, the panel concludes the "available data do not support a causal relationship between the use of alcohol-containing mouthrinses and oral cancer."

However, the report adds, "because some studies did report a relationship between the use of high alcohol-content mouthrinses and oral/pharyngeal cancer, the subcommittee agrees that further studies should be conducted to determine the relationship."

The group advises mouthrinses declare the alcohol content in a percentage figure on the principal display panel.

Antigingivitis/Antiplaque Combination With Other Actives Excluded In ANPR

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