# Oral Health Care Drug Products for Over-the-Counter Human Use; Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3A03-12783 ## Record - **Collection:** Federal Register - **Document type:** Proposed Rule - **Published:** May 29, 2003 - **Citation:** 68 FR 32232 ## Text DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 356 [Docket No. 81N-033P] RIN 0910-AA01 Oral Health Care Drug Products for Over-the-Counter Human Use; Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph AGENCY: Food and Drug Administration, HHS. ACTION: Advance notice of proposed rulemaking. SUMMARY: The Food and Drug Administration (FDA) is issuing an advance notice of proposed rulemaking that would establish conditions under which over-the-counter (OTC) drug products for the reduction or prevention of dental plaque and gingivitis are generally recognized as safe and effective and not misbranded. This notice is based on the recommendations of the Dental Plaque Subcommittee of the Nonprescription Drugs Advisory Committee (NDAC) and is part of FDA's ongoing review of OTC drug products. DATES: Submit written or electronic comments by August 27, 2003. Submit reply comments by October 27, 2003. ADDRESSES: Submit written and reply comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. FOR FURTHER INFORMATION CONTACT: Robert L. Sherman, Center for Drug Evaluation and Research (HFD-560), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-2222. SUPPLEMENTARY INFORMATION: In accordance with part 330 (21 CFR part 330), FDA received on December 3, 1998, a report on OTC antigingivitis/antiplaque drug products from the Dental Plaque Subcommittee (the Subcommittee). FDA regulations (§ 330.10(a)(6)) provide that the agency issue in the Federal Register a proposed rule containing: (1) The monograph recommended by the Subcommittee, which establishes conditions under which OTC antigingivitis/antiplaque drug products are generally recognized as safe and effective and not misbranded; (2) a statement of the conditions excluded from the monograph because the Subcommittee determined that they would result in the drugs not being generally recognized as safe and effective or would result in misbranding; (3) a statement of the conditions excluded from the monograph because the Subcommittee determined that the available data are insufficient to classify these conditions under either (1) or (2) of this paragraph; and (4) the conclusions and recommendations of the Subcommittee. The unaltered conclusions and recommendations of the Subcommittee are issued to stimulate discussion, evaluation, and comment on the full sweep of the Subcommittee's deliberations. The report has been prepared independently of FDA, and the agency has not yet fully evaluated the report. The Subcommittee's findings appear in this document to obtain public comment before the agency reaches any decision on the Subcommittee's recommendations. This document represents the best scientific judgment of the Subcommittee, but does not necessarily reflect the agency's position on any particular matter contained in it. The Subcommittee was asked for its general recommendations on combination products in which antigingivitis/antiplaque ingredients are combined with other oral health care ingredients. The Subcommittee recommended the following as rational oral health care combination products: (1) An antigingivitis/antiplaque active ingredient combined with an anticaries active ingredient, (2) an antigingivitis/antiplaque active ingredient combined with a tooth desensitizer active ingredient, and (3) an antigingivitis/antiplaque active ingredient combined with an anticaries active ingredient and a tooth desensitizer active ingredient. However, 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. Therefore, the agency is dissenting from these recommendations at this time. 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. The agency invites supporting data and information demonstrating that these combination products can be generally recognized as safe and effective for OTC use. Based on proposals from industry, the Subcommittee also made general recommendations on testing requirements for final product formulations to be considered effective. The agency is seeking specific information from interested parties on testing protocols, effectiveness criteria, and statistical methods employed to analyze the data from these tests. The agency notes that the Subcommittee concluded that an active ingredient could be either an antigingivitis agent or an antigingivitis/antiplaque agent. While an ingredient may also be effective in reducing plaque, the Subcommittee stated that the therapeutic endpoint for both antigingivitis and antigingivitis/antiplaque active ingredients is a significant reduction in gingivitis, which can be measured using gingival index scores (see section II.C of this document). The Subcommittee concluded that there is an association between plaque and gingivitis. The Subcommittee agreed, however, that the exact relationship between plaque and gingivitis cannot be quantified. Because the data submitted to support the effectiveness of stannous fluoride in reducing plaque were inconclusive, the Subcommittee proposed an “antigingivitis” statement of identity for this ingredient. However, the Subcommittee's proposed indication for this ingredient includes a reference to plaque reduction. Although it did not require that antigingivitis ingredients also be effective in reducing plaque, the Subcommittee agreed that ingredients that work primarily by means other than plaque reduction would be inappropriate for use in OTC antigingivitis drug products because these products may mask the symptoms of a more serious condition and cause consumers to delay seeking the advice of a dentist. Because the Subcommittee believed that none of the submitted active ingredients acted other than by reducing plaque, this issue was not further discussed. Therefore, the agency is seeking comment on the basis for allowing an antigingivitis active ingredient that has not demonstrated effectiveness in reducing plaque to bear labeling statements relating to plaque reduction. More importantly, because of the safety concern that antigingivitis ingredients that work by a mechanism other than plaque reduction (e.g., anti-inflammatory) may give consumers a false sense of security by masking symptoms of a more serious disease, the agency is also seeking comment on whether products that are solely antigingivitis agents, i.e., products that do not significantly reduce plaque, constitute appropriate OTC drug products. After reviewing all comments submitted in response to this document, FDA will issue in the Federal Register a tentative final monograph (TFM) for OTC drug products for the reduction or prevention of dental plaque and gingivitis. Under the OTC drug review procedures, the agency's position and proposal are first stated in the TFM, which has the status of a proposed rule. Final agency action occurs in the final monograph, which has the status of a final rule. In accordance with § 330.10(a)(2), the Subcommittee and FDA have held as confidential all information concerning OTC drug products for the reduction or prevention of dental plaque and gingivitis submitted for consideration by the Subcommittee. All submitted information will be put on public display in the Dockets Management Branch ( see ADDRESSES ) after June 30, 2003, except to the extent that persons submitting it demonstrate that it falls within the confidentially provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or section 301(j) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 331(j)). Requests for confidentiality should be submitted to Robert L. Sherman, Center for Drug Evaluation and Research ( see FOR FURTHER INFORMATION CONTACT ). The agency advises that the conditions under which the drug products that are subject to this monograph would be generally recognized as safe and effective and not misbranded (monograph conditions) will be effective 12 months after the date of publication of the final monograph in the Federal Register . On or after that date, no OTC drug products that are subject to the monograph and that contain nonmonograph conditions, i.e., conditions 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 they are the subject of an approved new drug application (NDA) or abbreviated new drug application (ANDA). Further, any OTC drug products subject to this monograph that are 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 unless they are the subject of an NDA or ANDA. Manufacturers are urged to comply voluntarily with the monograph at the earliest possible date. A proposed review of the safety, effectiveness, and labeling of all OTC drugs by independent advisory review panels was announced in the Federal Register of January 5, 1972 (37 FR 85). The final regulations providing for this OTC drug review under § 330.10 were published and made effective in the Federal Register of May 11, 1972 (37 FR 9464). In accordance with these regulations, a request for data and information on all active ingredients used in OTC drug products bearing antiplaque and antiplaque-related claims was issued in the Federal Register of September 19, 1990 (55 FR 38560). These claims included the reduction or prevention of plaque, tartar, calculus, film, sticky deposits, bacterial buildup, gingivitis, diseased, inflamed, or swollen gums, pyorrhea, Vincent's disease, periodontal disease, and tooth-destroying acids. The Commissioner of Food and Drugs appointed the following members of the Dental Products Panel (the Panel) to review the information submitted and to prepare a report under § 330.10(a)(1) and (a)(5) on the safety, effectiveness, and labeling of those products: Paul B. Robertson, Chairperson Charles N. Bertolami (resigned March 24, 1997) William H. Bowen (term ended October 31, 1995) Carlos E. del Rio (resigned December 14, 1994) Julianne Glowacki (term ended October 31, 1994) Deborah Greenspan Richard D. Norman Burton Rosan Christine D. Wu The Subcommittee, comprised of two members from the Panel plus five nonvoting consultants to the Panel, was subsequently formed to evaluate the submitted data and report its findings on the safety and effectiveness of ingredients for the reduction or prevention of dental plaque and gingivitis. Each of the following was a voting member of the Subcommittee: William H. Bowen, Chairperson (term ended April 1995) Robert J. Genco, Chairperson (from April 1995 to December 3, 1998) Ralph D'Agostino Max A. Listgarten Shelia M. McGuire Eugene D. Savitt Stanley R. Saxe Jorgen Slots (resigned April 12, 1995) Christine D. Wu Several nonvoting liaison representatives served on the Subcommittee. P. Jean Frazier, served as the consumer liaison until June 6, 1996, followed by Susan Cohen, until May 1997, and Donald S. Altman, on May 27, 1998. Frederick A. Curro, served as industry liaison (drug) until October 31, 1995, followed by Lewis P. Cancro. Gerald N. McEwen, Jr., served as industry liaison (cosmetic) until October 31, 1996. On August 27, 1997, oversight of the Subcommittee was transferred from the Panel in the Center for Devices and Radiologic Health (CDRH) to the Nonprescription Drugs Advisory Committee in the Center for Drug Evaluation and Research (CDER). The following FDA employees assisted the Subcommittee: Carolyn Tollendi served as CDRH Executive Secretary to the Panel until June 7, 1996. Kennerly K. Chapman served as CDER Executive Secretary to the Subcommittee until December 17, 1996, followed by Andrea Neal until May 9, 1997, followed by Rhonda Stover (interim) until May 1998, followed by Kathleen Reedy. Jeanne L. Rippere served as CDER liaison to the Subcommittee until June 7, 1996, followed by Robert L. Sherman. Stephanie A. Mason served as special assistant to the Subcommittee until June 7, 1996. The Panel and the Subcommittee were first convened on August 2 and 3, 1993, for a joint organizational meeting. Working meetings of the Subcommittee were held on December 16 and 17, 1993; June 28 and 29, October 11, and December 5, 6, and 7, 1994; April 10, 11, and 12, August 14 and 15, and December 4 and 5, 1995; June 6 and 7, and December 16 and 17, 1996; October 29 and 30, 1997; May 27, 28, and 29, October 22, and December 2 and 3, 1998. Joint meetings of the Panel and the Subcommittee were held on August 2 and 3, 1993, and December 6, 1994. Minutes of most Subcommittee meetings are on public display in the Dockets Management Branch (see ADDRESSES ). The following individuals appeared before the Panel and/or the Subcommittee at their own or at the Panel's or Subcommittee's request to discuss drug products for the reduction or prevention of plaque and gingivitis: Gariela Adam-Rodwell, Sam Amer, Daniel M. Bagley, John E. Bailey, Michael L. Barnett, Robert D. Bartizek, Kenneth Baumgartner, William J. Blot, Nancy L. Buc, Gregory A. Burkhart, Lewis P. Cancro, James R. Cheever, Philip Cole, W. Greg Collier, Mark M. Crisanti, Catherine C. Davis, Phillip Derfler, John M. DeSesso, Harvey L. Dickstein, Jerry A. Douglass, Matthew J. Doyle, W. Gary Flamm, William E. Gilbertson, Brian F. Gillespie, David M. Graham, Robert Heller, Jane E. Henney, Ira D. Hill, Peter B. Hutt, Frederick N. Hyman, Eugene Kamper, Linda M. Katz, Bruce Kohut, Surinder Kumar, Anthony C. Lanzaiaco, Mark S. Leusch, Debbie L. Lumpkins, Milton V. Marshall, Stephanie A. Mason, Stephen F. McClanahan, Stephen H. McNamara, Jerome A. Merski, David Morrisson, Kevin P. Mulry, Anne J. Mustafa, Paul J. Okarma, C. Lee Peeler, Julie H. Rhee, David I. Richardson, Jeanne L. Rippere, Norman A. See, James M. Serafino, Samuel Shapiro, Robert L. Sherman, Chakwan Siew, Gregory Singleton, James Skiles, Thomas J. Slaga, R. William Soller, Steven D. Stellman, George K. Stookey, Howard Strassler, Stanley Tarka, Jr., John M. Treacy, Jack Vincent, Frank A. Volpe, Michael Weintraub, Clifford W. Whall, Jr., Donald J. White, Robert White, Charles Wiggins, David Williams, Gary M. Williams, Deborah Winn, Roy Witkin, and Patrice Wright. No person who so requested was denied an opportunity to appear before the Panel or Subcommittee. The Subcommittee has thoroughly reviewed the literature and data submissions, listened to additional testimony from interested persons, and considered all pertinent data and information submitted through December 3, 1998, in arriving at its conclusions and recommendations. The Subcommittee wishes to thank the American Dental Association's (ADA) Council on Scientific Affairs for its assistance in providing data, information, and testimony during the course of the Subcommittee's deliberations. The ADA also provided its “Guidelines for Acceptance of Chemotherapeutic Products for the Control of Supragingival Plaque and Gingivitis” to the Subcommittee for consideration in making its recommendations on the requirements for safe and effective OTC antigingivitis/antiplaque ingredients. In accordance with the OTC drug review regulations in § 330.10, the Subcommittee reviewed OTC drug products for the reduction or prevention of dental plaque and gingivitis with respect to the following three categories: Category I—Conditions under which OTC drugs for the reduction or prevention of dental plaque and gingivitis are generally recognized as safe and effective and are not misbranded. Category II—Conditions under which OTC drugs for the reduction or prevention of dental plaque and gingivitis are not generally recognized as safe and effective or are misbranded. Category III—Conditions for which the available data are insufficient to permit final classification at this time. I. Submission of Data and Information Under the notices published in the Federal Register of September 19, 1990 (55 FR 38650), and March 8, 1991 (56 FR 9915), the following firms made submissions regarding OTC drug products that the Panel/Subcommittee determined contained active ingredients or labeling associated with claims relating to the reduction or prevention of dental plaque and gingivitis. A. Submissions by Firms Table 1.— Firms and Submitted Products Firm Submitted Products American Xyrofin (Morgan, Lewis & Bockius) Washington, DC 20036 Xylitol All Natural Toothpaste, Xytol 32 Dental Cream. Amer Co., Montecito, CA 93150 Insadol Toothpaste, Pyoralene Toothpaste. Angus Chemical Co., Northbrook, IL 60062 Hexetidine solution. Chesebrough Pond's USA Co., Greenwich, CT 06836 CloseUp Antiplaque Toothpaste, Mentadent P Toothpaste. Church & Dwight Co., Inc., Princeton, NJ 08543 Arm & Hammer Dental Tooth Powder, Dentifrice, and Gel. CIBA-GEIGY Corp., Greensboro, NC 27419 Irgasan DP, Irgacare MP. Clinical Product Research, Inc., Shreveport, LA 71109 Prozyme Toothpaste, Anti-Plaquer Oral Rinse, Anti-Plaquer Toothpaste. Colgate-Palmolive Co., Piscataway, NJ 08855 Colgate Tartar Control Toothpaste, Gelkam Oral Care Rinse, Dentaguard Toothpaste. E. Merck, Frankfurter, Germany Thera-Med, Cholordont M. E. B. Michaels Research Associates, Inc., Milford, CT 06460 Therasol Brush & Rinse Antiplaque Oral Hygiene Solution, Therasol Brush & Rinse Liquid Dentifrice Oral Irrigant. Leaf, Inc., (Hyman, Phelps & McNamara) Washington DC 20005 Xylitol. Lion Corp. (America), Memphis, TN 38138 Check-Up Gingival Toothpaste. Madaus Medtech, Inc., (ACC Consulting Group, Inc.) Washington DC 20036 Parodontax Toothpaste. Pfizer Inc, New York, NY 10017 Plax Pre-Brushing Dental Rinse. Pierre Fabre, S.A., 81106 Castres Cedex, France Eligydium Toothpaste, Eludil Mouthwash. Prevention Laboratories (formerly 7-L Corp.), Harrisburg, IL 62947 Prevention Mouth Rinse. Procter & Gamble Co., Cincinnati, OH 45242 Crest Gum Care Toothpaste. SmithKline Beecham Consumer Brands (Marion Merrell Dow, Inc.), Parsippany, NJ 07054 Cepacol Gold and Mint Mouthwashes, Gly-oxide Liquid. Vipont Pharmaceuticals, Fort Collins, CO 80522 Viadent Toothpaste and Oral Rinses. Warner-Lambert Co., Morris Plains, NJ 07950 Listerine Antiseptic Mouthwash. WhiteHill Oral Technologies, Inc., Hazlet, NJ 07730 Omni-Med Brush-On Tooth Medication, Perio-Med Spray, Take-5 Plaque Fighter Brushless Dentifrice, Smokers Take-5 Plaque and Stain Fighter. Witkins, Roy T., Westport, CT 06880 Perimed Oral Hygiene Rinse. In categorizing ingredients as “active” and “inactive,” the advisory review panels relied upon their expertise and understanding of these terms. FDA has defined “active ingredient” in its current good manufacturing practice regulations in § 210.3(b)(7) (21 CFR 210.3(b)(7)) as: [Any] component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect. An “inactive ingredient” is defined in § 210.3(b)(8) as “any component other than an active ingredient.” B. Active Ingredients Submitted For Review Labeled Ingredients Contained in Marketed Products Submitted to the Subcommittee: Alkyl dimethyl amine oxide Alkyl dimethyl glycine Aloe vera Bromchlorophene Carbamide peroxide Cetylpyridinium chloride Chlorhexidine digluconate Dicalcium phosphate dihydrate Eucalyptol Hexetidine Hydrogen peroxide Menthol Methyl salicylate Peppermint oil Polydimethylsiloxane Poloxamer Povidone iodine Sage oil Sanguinaria extract Sodium bicarbonate Sodium citrate Sodium lauryl sulfate Soluble pyrophosphate Stannous fluoride Stannous pyrophosphate Thymol Triclosan Unsaponifiable fraction of corn oil Xylitol Zinc chloride Zinc citrate Some of these ingredients (bromchlorophene, chlorhexidine digluconate, hexetidine, soluble pyrophosphate, triclosan, unsaponifiable fraction of corn oil) were not marketed for a material time and to a material extent for antigingivitis/antiplaque use in the United States. (See 21 U.S.C. 321(p)(2).) Although the Subcommittee reviewed data to support the safety and effectiveness of these ingredients, they are not eligible for inclusion in the OTC drug review as part of this advance notice of proposed rulemaking and, therefore, are not discussed in this document. In addition, although xylitol was reviewed by the Subcommittee, the two firms that submitted data subsequently withdrew xylitol from consideration by the Subcommittee. Therefore, xylitol is not discussed. The nomenclature used by the Subcommittee for the ingredients reviewed in this document was the currently accepted terminology stated in the 1996 edition of “USAN and the USP Dictionary of Drug Names.” Names recommended by FDA were used for any ingredients which did not have USAN names. C. Referenced OTC Volumes All “OTC Volumes” cited throughout this document refer to submissions made by interested persons under the call-for-data notices published in the Federal Register of September 19, 1990, and March 8, 1991. The information included in these volumes, except for those deletions made in accordance with the confidentiality provisions in § 330.10(a)(2), will be put on public display after June 30, 2003, in the Dockets Management Branch (see ADDRRESSES ). II. General Statements and Recommendations A. Definitions The Subcommittee adopted the following definitions as its intended meaning of terms specifically used in this document concerning OTC drug products for the reduction or prevention of dental plaque and gingivitis. The Subcommittee was aware that some degree of variation with other definitions of the same term may exist. • Calculus . The hard concretions ( i.e., calcified plaque) that form on teeth, prostheses, and other hard surfaces. Calculus on teeth is clinically classified into supragingival calculus, which is located on surfaces not covered by the oral mucosa, and subgingival calculus, which is located apical (at the top) to the soft tissue margin of the gingiva. • Dental Plaque . Organized coherent gel-like or mucoid masses consisting of microorganisms in an organic matrix derived from saliva and extracellular bacterial products such as glucans, fructans, enzymes, toxins, and acids. Plaque also contains other cells (e.g., desquamated epithelial cells) and inorganic components such as calcium and phosphate. It adheres to the teeth and other surfaces of the oral cavity. It occurs at the orifice of the gingival crevices and in the periodontal pockets. Plaques may differ markedly in biochemical or microbial composition, and their localization. • Gingival Sulcus . The shallow groove between the tooth and the marginal gingiva. • Gingivitis . An inflammatory lesion of the gingiva that is most frequently caused by dental plaque. Gingivitis is characterized by tissue swelling and redness, loss of stippling (a normal state in which the surface of healthy gingiva is comprised of small lobes), glossy surface, and increased tissue temperature. The gingiva also may bleed upon gentle provocation such as toothbrushing or may bleed spontaneously. Gingivitis is usually not painful. • Oral Hygiene . Self-administered processes aimed at controlling microbial and other deposits in the oral cavity. • Pellicle . A thin, colorless, translucent film derived from bacterial products and saliva, which forms rapidly on tooth surfaces after natural cleansing or prophylaxis. A few hours after deposition, oral bacteria begin to adhere to the pellicle. These processes represent the earliest stages of plaque formation. • Periodontitis . A disease condition of the periodontium characterized by inflammation of the gingiva, increasing probing depth, and destruction of the periodontal ligament and the adjacent supporting alveolar bone. • Tartar . A synonymous term for calculus. B. Background and General Discussion of Terms 1. Background The Subcommittee was charged with the evaluation of the safety and effectiveness of ingredients or combinations of ingredients for the reduction or prevention of plaque and gingivitis as claimed in the labeling of OTC drug products in light of present-day knowledge and standards used in pharmacology, pharmacodynamics, therapeutics, and toxicology. In making its evaluation, the Subcommittee relied upon factual data found in standard textbooks and scientific articles published by independent investigators in medical, dental, and other scientific journals. Manufacturers included some of these scientific articles in their submissions to FDA to provide a scientific basis for claims made for the safety and effectiveness of their ingredients. Data supplied by manufacturers in unpublished reports of studies performed by private laboratories under contract to the manufacturer or in manufacturers' laboratories were also used by the Subcommittee in making judgments. The Subcommittee also gave due consideration to data from marketing experience and widespread clinical usage when in agreement with basic data from controlled studies and scientific facts. 2. Plaque Plaque, also known as dental plaque and/or microbial plaque, has been examined for several decades with most of the information explained in the past 25 years. Plaque has a critical etiological role in the development of dental caries, gingivitis, and periodontal disease. It is now clear that dental plaque is a variable biologic community made up of bacteria and a bacterially synthesized matrix. While dental plaque may be combined with other materials such as food particles and sloughed epithelial cells, the combination of these components is called materia alba and is no longer considered plaque. The precise genera and species of microorganisms in each dental plaque may differ from individual to individual, site to site in the same individual, and within a specific site over time. Plaque from sites of similar clinical health within individual subjects tends to be more similar in composition than plaque from sites in different subjects. Even though there is considerable variation within dental plaques, the composition of plaque is influenced by several factors. The composition of dental plaques is currently known to be affected by plaque age, dietary intake of sucrose and other foods, and other factors ( e.g., friction of mastication, oral health, and salivary flow). Plaque composition is also affected by its location above or below the gingiva. Dental plaques are subdivided into supragingival plaque and subgingival plaque. The distinction resides in the location of dental plaque as either coronal (toward the crown) or apical (toward the root tip) to the soft tissue margin. The microbial populations may differ in plaque from the two locations. The extracellular matrix synthesized by the bacteria is a significant component of plaque. Because the matrix provides plaque organisms with strong adhesive and cohesive properties, plaque is not easily removed. The tenacity of plaque to adhere to the surfaces of oral structures can be used to distinguish plaque from debris, in that plaque is not removed by flushing the mouth with water. Plaques differ not only quantitatively but qualitatively in their bacterial composition. For example, microorganisms found in dental plaque include Actinomyces species, Streptococcus sanguis , S. mutans , and other Streptococcus species, Spirochetes , Porphyromonas gingivalis , Bacteroides forsythus , and other Bacteroides species, Campylobacter recta , Peptostreptococcus micros , Eikenella corrodens , Actinobacillus actinomycetemcomitans , Eubacterium species, Fusobacterium species, Capnocytophaga species, and Prevotella species. This difference in bacterial composition has a major effect on its pathogenic potential both for periodontal diseases and caries. Some dental plaques are not pathogenic or associated with disease, whereas others are etiologic factors for caries and periodontal diseases. However, the two types of plaque cannot be distinguished visually. The pathogenic potential is dependent upon the microbial composition, including the metabolic products of microbes, dietary patterns, and the intrinsic resistance of the host. It may be prudent to treat all plaques as having pathogenic potential. 3. Calculus Calculus is a hard concretion that forms on the teeth or dental prostheses through deposition of mineral salts in dental plaques. Human calculus is essentially mineralized dental plaque, which is almost always covered on its external surface by vital, tightly adherent, nonmineralized soft plaque. There may also be loosely held materials associated with calculus such as materia alba, shed bacteria, desquamated epithelial cells, and blood cells. In germ-free animals, calcified deposits may occur in the absence of bacterial accumulation (Ref. 1). However, in humans, virtually all calculus seen clinically likely results from the deposition of calcium and phosphates within bacterial plaques. Calculus formation occurs in an orderly fashion, beginning after 1 or 2 weeks of plaque formation and resulting in full calcification of plaque after 2 to 4 weeks. The process occurs more rapidly in some persons than in others. Calculus may form subgingivally and is often stained and tenaciously attached to the crown and/or root of the tooth. Calculus may also form supragingivally, coronal (toward the crown) to the gingival margin. Supragingival calculus is found in greater amounts on tooth surfaces adjacent to the openings of the ducts of the major salivary glands. Both subgingival and supragingival calculus are often stained; supragingival calculus can be unsightly, particularly when formed in abundance on labial (facing the lips) surfaces. Although subgingival calculus is a contributing factor in the development of gingivitis, and can also be associated with the progression of gingivitis, periodontitis, and periodontal abscesses, the exact nature of the role of supragingival calculus in gingivitis is not clear. Supragingival calculus can accumulate plaque and act as a nidus (nest) for plaque formation, which can lead to gingivitis. Calculus facilitates the retention of dental plaque in close proximity to the periodontal tissues. It reduces the effectiveness of overall hygiene methods to control dental plaque accumulation. Subgingival calculus interferes with the regeneration of lost periodontal attachment. The removal of calculus is considered a basic step in the prevention and treatment of inflammatory periodontal diseases. The formation of supragingival calculus can be limited through mechanical or chemical methods. Preventing subgingival calculus formation, if possible, would not necessarily reduce gingivitis, because a surface currently free of calculus can still harbor plaque. Present methods do not allow for the predictable prevention of subgingival calculus. 4. Gingivitis Gingivitis, an inflammation of the gingiva, affects most of the population at one time or another. The signs of gingivitis are tissue swelling and redness, loss of stippling, glossy surface, and increased tissue temperature. The gingiva may also bleed upon gentle provocation, such as toothbrushing, or may bleed spontaneously. Some signs of gingivitis, such as bleeding, can be identified by lay persons. Gingivitis is a response to injury, often resulting in localization of tissue damage and neutralization of the effects of injurious agents. If the injurious agents cannot be adequately neutralized or eliminated, they may lead to chronic inflammation of the soft tissue and periodontitis. While most cases of periodontitis are believed to start with gingivitis, most cases of gingivitis do not progress to periodontitis. Histologically, gingivitis is characterized by inflammatory exudate or infiltrate, loss of collagen of the gingival connective tissue, and proliferation of the epithelium into the infiltrated tissue. Sometimes the epithelium lining the sulcus (crevice bounded by the tooth and free gingiva) may develop microulcerations. In gingivitis, the junctional epithelium usually is at or near the cementoenamel junction (junction of the tooth crown and root). Gingivitis, especially when severe, may be self-diagnosable because people can recognize some of the signs of gingivitis, such as bleeding, gingival discoloration, and swelling, which gives rise to pseudopockets (pocket-like structure caused by inflammation of the gingiva without effecting the sulcus base). In the early stages of gingivitis when there is little or no pseudopocket formation, only noncalcified plaque, and little or no calculus, thorough daily oral hygiene may resolve the disease. Under these conditions, self-treatment of gingivitis is appropriate. When OTC drug products for the prevention and control of plaque-associated gingivitis are used as part of a program of good oral hygiene, including regular dental checkups, they can help consumers maintain their gingival health. The most common form of gingivitis is termed marginal gingivitis and occurs in all individuals at some time. It is limited to the gingivae around the collar of the tooth. However, people are seldom easily able to detect sites with mild gingivitis because there may be no pain or bleeding. Plaque-associated gingivitis, an inflammation of the interdental and marginal gingiva, can be controlled or prevented by removal or inhibition of microbial plaque accumulation. Chemotherapeutic agents can enhance the benefits of traditional methods of oral cleansing by toothbrushing with a dentifrice and regular use of dental floss and other cleaning aids. Readily available OTC drug products for the prevention and control of plaque-associated gingivitis are intended to play a significant public health role. However, the effects of these products in periodontitis have not been determined in large scale studies. OTC drug products are useful adjuncts to, but do not replace, regular professional care. In the later stages of gingivitis with the formation of pseudopockets and calculus, it becomes more difficult for people to resolve the gingivitis. Therefore, self-treatment has limited potential for resolution of severe gingivitis, which should be treated as part of a regular professional care program. Gingivitis can progressively worsen and lead to the development of pockets that can be difficult for people to clean. 5. The Interrelationship Between Plaque and Gingivitis Dental plaque can be causally related to gingivitis. A critical plaque mass at the gingival margin for a particular length of time can initiate change. However, the Subcommittee has no knowledge of any studies where the volume, mass, or amount of plaque can be closely equated with the extent of gingival inflammation. There is a general, positive relationship between supragingival plaque levels and levels of gingivitis. For example, with little or no supragingival plaque accumulation, most often there is gingival health, whereas heavy levels of plaque accumulation, especially at the gingival margin, are often associated with gingivitis. Plaque forms readily on tooth surfaces in individuals with poor oral hygiene. It takes, histologically, about 3 to 4 days with no oral hygiene in periodontally healthy subjects to develop microscopic evidence of gingivitis. This evidence consists of infiltration of the gingival epithelium, especially the junctional epithelium, with inflammatory cells (including neutrophils), infiltration of the gingival connective tissue with lymphocytes, and beginning loss of collagen. The Subcommittee does not know how long plaque must be present before gingivitis spontaneously appears. When distinguishing between experimentally induced gingivitis and spontaneous gingivitis (developing under conditions of normal oral hygiene) the following are found: (1) Most subjects over a period of 1 to 3 weeks of cessation of oral hygiene developed gingivitis measurable with clinical indices, and (2) subjects must accumulate a certain level of plaque before clinical signs of gingivitis are apparent. In addition, mature plaque with complex flora appears to be correlated with gingivitis. However, mature plaque, comprised of a complex gram-positive and gram-negative flora with motile organisms, is often associated with spontaneous gingivitis. The Subcommittee accepts that gingivitis is associated with an accumulation of plaque along the gingival margin but is unaware of any evidence that shows that there is a close correlation between the amount of plaque and the induction of gingivitis, as can be assessed using present day methods. It should be noted that the relationship between the quantity of plaque present and the degree of gingivitis is sufficiently complex such that reductions in plaque mass alone are inadequate to conclude that a therapeutic effect on gingivitis could be expected. Therefore, gingivitis reductions must be measured directly. 6. Periodontitis Most cases of periodontitis are believed to start with gingivitis, although not all cases of gingivitis lead to periodontitis. Periodontitis is characterized clinically by gingivitis of varying severity, loss of periodontal attachment, increased probing depth, and radiographically detectable loss of alveolar and supporting bone. In advanced disease, the teeth may become increasingly mobile. Progression of gingivitis and the relationship of gingivitis to the onset of periodontitis are not well understood. However, one approach to addressing this relationship comes from human studies in which meticulous oral hygiene leading to excellent plaque control and control of gingivitis appears to prevent the onset of periodontitis (Ref. 2). It is not clear whether this prevention was due to reduction of supragingival plaque associated with gingivitis, or to meticulous oral hygiene, which also prevents colonization of the subgingival area by periodontal pathogens that are responsible for the onset of periodontitis. What is clear, however, is that in most instances meticulous plaque control appears to lead to reduction of gingivitis and suppression of the onset or rate of progression of periodontitis. Despite periodontal treatment, loss of periodontal attachment and loss of bone often persists. Moreover, people treated for periodontitis may suffer from recurrent gingivitis, root sensitivity, and increased susceptibility to root caries. Periodontitis appears to progress in alternating cycles of exacerbation, which are often asymptomatic and localized, followed by periods of remission. Population studies indicate that systemic conditions such as diabetes mellitus and neutrophil disorders, as well as smoking, increase the risk for developing periodontitis (Refs. 3 and 4). Histologically, the gingiva becomes inflamed, and the sulcus is deepened to form a pocket which is lined with a pathologically altered epithelial lining, the pocket epithelium. The junctional epithelium is displaced apically. The pocket is largely filled with a subgingival microbiota that is in contact with the adjacent denuded root surface or adherent subgingival calculus deposits. The alveolar process (portion of the upper and lower jaws that forms and supports the tooth sockets) shows evidence of destruction in a “horizontal” or “vertical” pattern with concomitant loss of the connective tissue attachment to the root. There are several variants of the disease, including adult periodontitis, early-onset periodontitis (which includes localized juvenile), periodontitis associated with systemic diseases, necrotizing ulcerative periodontitis, and refractory and recurrent periodontitis. Of these, adult periodontitis is the most common form of the disease, and it responds most predictably to scaling, root planing, and plaque control. 7. Oral Hygiene The Subcommittee's definition of oral hygiene in this document represents the self-administered processes aimed at controlling microbial and other deposits in the oral cavity. Regular oral hygiene, by interfering with plaque accumulation and maturation, favors facultative (able to grow or live with or without oxygen) over anaerobic (growing or living in the absence of oxygen) bacteria. In the process, regular oral hygiene promotes clean dentition and fresh breath, and decreases the risk of plaque-mediated inflammatory changes in the oral cavity. Today, mechanical plaque removal with assorted devices is the primary method for maintaining good oral hygiene. Chemical plaque control ( e.g., antiseptic or surfactant mouthrinses) is used primarily as an adjunct to mechanical methods and may be particularly useful for the treatment of surfaces that are not readily accessible to mechanical cleansing, for postsurgical plaque control, and for oral care of handicapped persons. Antibiotics may be used as adjuncts to oral hygiene to suppress or eliminate specific segments of the bacterial population not readily accessible to mechanical cleansing. C. Drug/Cosmetic Status The current statutory definitions of “drug” and “cosmetic” require some consideration when applying them to products for the reduction or prevention of plaque and gingivitis. According to the act, a “drug” includes any article “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,” or any article “intended to affect the structure or any function of the body * * * .” ( See 21 U.S.C. 321(g).) According to the act, a “cosmetic” includes an article or component thereof “intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance * * *.” ( See 21 U.S.C. 321(i).) Some products may not clearly fall under one definition or the other. Therefore, another consideration in classifying a product is the “intended use” of the product, which is largely dependent on the claims made for the product and the accompanying labeling. 1 In attempting to accurately describe a product's benefits, one of the guiding principles should be to avoid misleading the public with ambiguous claims. Unfortunately, in the case of mouthrinse products, it is easy to make claims that suggest a drug-like benefit, while staying within the guidelines for cosmetic products. Much of the controversy regarding the “drug” versus “cosmetic” issue for these products revolves around the use of the word “dental plaque” or its synonyms (plaque, bacterial deposits, etc.). 1 The legal opinions of this scientific panel in this area may not and do not necessarily reflect FDA's position. 1. Antiplaque Products It is the position of the ADA and the American Academy of Periodontology that the control of dental plaque is a therapeutic procedure basic to the prevention and treatment of caries and periodontal diseases, particularly the latter. The well-established association between dental plaque accumulation and gingivitis demands that effective control of gingivitis be accompanied by effective control of dental plaque. “Nonspecific” plaque control involves decreasing the entire microbial mass in a nonspecific manner, i.e., without any attempt at differentially removing or suppressing any particular bacterial species, although shifts in bacterial composition may occur. It is the primary therapy for preventing and controlling periodontal infections that may lead to periodontal inflammatory lesions. “Specific” plaque control implies the control of specific pathogens, using strategies that will preferentially suppress certain species or categories of microorganisms. This approach generally requires the use of antimicrobial agents, typically antibiotics, with a specific antimicrobial spectrum. Ideally, the microbial composition of the dental plaque should be assessed before and after treatment to insure that the antimicrobial agents used are appropriate and that the therapy has the desired effect. The nonspecific control of dental plaque needs to be thorough in order to achieve clinically significant therapeutic benefits. While some OTC oral health care products may be able to reduce the rate of plaque formation to a statistically significant degree, the inhibitory effect on plaque is often insufficient to be considered of therapeutic benefit. It is also highly unlikely that the marginal control of bacterial deposits has a significant relationship to most, if not all, of the cosmetic claims. Outcome variables such as taste and “feel” are more likely to be affected by flavoring agents and products that reduce surface tension than by minor variations in plaque accumulation. The claim that a product significantly reduces dental plaque (statistically speaking) may mislead people into thinking that the reduction is therapeutically significant. Thus, people may purchase a product with the mistaken notion that a therapeutic benefit may be derived from its use, instead of seeking effective care for potential signs and symptoms of disease. Therefore, 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. In addition, the Subcommittee proposes that an OTC drug product making any reference to the reduction or prevention of dental plaque also must demonstrate a clinically significant effect on gingivitis. Thus, antiplaque claims should not stand alone. 2. Tartar Products The Subcommittee proposes that any reference to supragingival tartar (calculus) be interpreted as a cosmetic claim. The Subcommittee did not make any reference to subgingival tartar. D. Labeling of Antigingivitis/Antiplaque Drug Products Having reviewed the submitted labels of antigingivitis/antiplaque drug products, the Subcommittee recommends that labeling include the following: 1. Ingredients Antigingivitis/antiplaque agents should contain only active ingredients plus such inactive ingredients as may be necessary for formulation. The label should state the name and quantity of each active ingredient in appropriate units as specified later in this document. For various reasons, including allergic reactions, safety concerns, and personal preference, individuals may wish to avoid using certain inactive ingredients. It is impossible to make a free choice in this regard unless all the components of drug products are listed on the labels. Therefore, the Subcommittee strongly recommends that all inactive ingredients be listed on the label in descending order of quantity. However, the product should not imply or claim that its inactive ingredients have a therapeutic benefit. The Subcommittee recognizes that although full disclosure of flavoring and coloring ingredients is desirable, this may be impractical and confusing because of the large number of ingredients that may be involved. Thus, flavoring and coloring ingredients may be listed in accordance with present regulations for labeling such ingredients in cosmetic products (21 CFR 701.3). 2. Statement of Identity The labeling must indicate the principal intended action of the active ingredient as well as the indication for use of the product. The Subcommittee recommends that the statement of identity for active ingredients that demonstrate an antigingivitis effect should be “antigingivitis.” The recommended statement of identity for active ingredients that also demonstrate an antiplaque effect should be “antigingivitis/antiplaque.” 3. Indications The indications for antigingivitis/antiplaque drug products should be simply and clearly stated, inform the user of the general pharmacological action of the product, and provide a reasonable expectation of results to be anticipated from use of the product. The indications should be specific and confined to the conditions for which the product is recommended. The labeling for any product that contains an active ingredient for which no claim is made would be misleading. a. For all antigingivitis products . The Subcommittee's recommended indication for OTC drug products containing antigingivitis active ingredients is: “helps (select one of the following: `control,' `reduce,' or `prevent') (select one or more of the following: `gingivitis,' `gingivitis, an early form of gum disease,' or `bleeding gums').” b. For antigingivitis products containing stannous fluoride . The Subcommittee's recommended indication for OTC antigingivitis drug products containing stannous fluoride is the statement in paragraph a. above and/or the following: “helps interfere with harmful effects of plaque associated with gingivitis.” c. For all antigingivitis/antiplaque products . The Subcommittee's recommended indication for OTC drug products containing antigingivitis/antiplaque active ingredients is: “helps (select one of the following: `control,' `reduce,' `prevent,' or `remove') plaque that leads to (select one or more of the following: `gingivitis,' `gingivitis, an early form of gum disease,' or `bleeding gums').” d. For antigingivitis/antiplaque products containing the fixed combination of eucalyptol, menthol, methyl salycilate, and thymol . The Subcommittee's recommended indication for OTC drug products containing the fixed combination of eucalyptol, menthol, methyl salycilate, and thymol is the statement in paragraph c. above and/or the following: “helps (select one of the following: `control,' `inhibit,' or `kill') plaque bacteria that contribute to the development of (select one or more of the following: `gingivitis,' `gingivitis, an early form of gum disease,' or `bleeding gums').” 4. Directions for Use The directions for use should be clear, direct, and provide sufficient information to permit safe and effective use of the product. The product labeling should include a clear statement of the smallest usually effective dose and, where applicable, maximum doses (or concentration if more appropriate) per time interval. If dosage varies by age, the directions should be broken down by age groups. The Subcommittee used directions from the supportive clinical trials as the basis for its recommended directions for use. a. For antigingivitis or antigingivitis/antiplaque dentifrice products . The directions for use for antigingivitis or antigingivitis/antiplaque dentifrice drug products should be consistent with the directions required in the final monograph for OTC anticaries drug products in 21 CFR 355.50(d)(1). b. For antigingivitis/antiplaque oral rinse products . “Adults and children 12 years of age and older: Vigorously swish 20 milliliters of rinse between your teeth twice a day for 30 seconds and then spit out. Do not swallow the rinse. Children 6 years to under 12 years of age: supervise use. Children under 6 years of age: do not use.” 5. Warnings Labeling of antigingivitis and antigingivitis/antiplaque products should include warnings against unsafe use, side effects, and adverse reactions. a. For all antigingivitis and antigingivitis/antiplaque products . “If more than used for brushing (rinsing) is accidentally swallowed, get medical help or contact a Poison Control Center right away. If gingivitis, bleeding, or redness persists for more than 2 weeks, see your dentist. See your dentist immediately if you have painful or swollen gums, pus from the gum line, loose teeth, or increasing spacing between the teeth. These may be signs or symptoms of periodontitis, a serious form of gum disease.” b. For antigingivitis products containing stannous fluoride . “Keep out of the reach of children under age 6.” 6. Additional Labeling Statements For stannous fluoride dentifrice drug products . In addition to warning statements, the following statements should appear on the label of antigingivitis dentifrice drug products containing stannous fluoride: “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.” E. Combination Drug Products 1. General Combination Policy The Subcommittee recognizes that there may be a reason for combining active ingredients in certain OTC drug products. However, such combinations must be based on a sound and logical scientific rationale. The Subcommittee applied the OTC drug review regulation in § 330.10(a)(4)(iv) in developing a combination policy for antigingivitis/antiplaque drug products. The Subcommittee believes that it is rational to combine oral health care ingredients that meet the regulatory requirements as well as the criteria adopted by the Subcommittee, together with suitable inactive ingredients, provided that: (a) Each active ingredient makes a contribution to the claimed effect, (b) the active ingredients are safe and effective and combining the ingredients does not decrease the effectiveness of any individual ingredient, (c) combining the ingredients does not decrease the safety of the combination compared to a single ingredient, (d) the inactive ingredients are safe and do not interact with or otherwise inhibit the effectiveness of the active ingredients, (e) there is a significant target population that can benefit from the use of the combination, and (f) the combination contains adequate directions for use and is labeled with adequate warnings against unsafe use. The Subcommittee concludes that the same general principles apply when an active ingredient from a different pharmacological class reviewed by another OTC drug advisory panel is combined with an active ingredient reviewed by this Subcommittee. The rationale for such combinations should be evaluated by FDA according to the combination policy set forth in the reports of both advisory panels and in accordance with the agency's regulations. 2. Criteria for Category I Combination Products The Subcommittee recommends that each claimed active ingredient in a combination product must make a significant contribution to the claimed effects of the product. Further, two Category I active ingredients from different pharmacological groups may be combined to treat different symptoms concurrently if each Category I active ingredient is present within its established dosage range, the combination is rational, there is a significant target population that suffers from the concurrent symptoms, and the combination is as safe and as effective as each individual active ingredient used alone. 3. Category I Combination Antigingivitis/Antiplague Drug Products The Subcommittee considers it rational to combine antigingivitis/antiplaque agents with an anticaries agent. It is also rational to combine antigingivitis/antiplaque agents with a tooth desensitizing agent. In addition, the Subcommittee considers it rational to combine an antigingivitis/antiplaque agent with an anticaries agent and a tooth desensitizer in a single drug product. Further, the Subcommittee believes that although it has been presented with no scientific basis to recommend the combination of two or more antigingivitis ingredients, two or more antigingivitis/antiplaque ingredients, or combinations of antigingivitis and antigingivitis/antiplaque ingredients, it is theoretically reasonable to combine such ingredients, provided it is demonstrated that each ingredient contributes to the claimed effect and does not decrease the safety or effectiveness of another active ingredient. F. Testing of Antigingivitis/Antiplaque Drug Products The Subcommittee concludes that the single active ingredients and the fixed combination of eucalyptol, menthol, methyl salicylate, and thymol placed in Category I have been shown through clinical trials to be safe and effective for OTC use in the control of gingivitis and plaque. However, because product formulation can have a significant impact on the effectiveness of these active ingredients, the Subcommittee recommends that OTC antigingivitis/antiplaque drug products demonstrate their effectiveness through the testing described below. Based on the varying mechanisms of action of the Category I active ingredients, the Subcommittee recommends testing specific to each of the Category I active ingredients to demonstrate their effectiveness in traditional dosage forms (dentifrice, gel, paste, or rinse). 1. Changes in Traditional Dosage Forms The Subcommittee recommends that drug products containing Category I active ingredients formulated in dosage forms other than those reviewed by the Subcommittee be required to demonstrate antigingivitis/antiplaque effectiveness by a single 6-month, randomized, controlled, clinical trial. 2. Final Formulation Testing The following testing should be conducted on the product formulation, a standard formulation with effectiveness documented by clinical trials, and a negative control. In general, for a product to be considered effective it must demonstrate that it is statistically substantially equivalent to the standard formulation and statistically superior to the negative control as assessed by reasonable statistical analyses. For validation of the study, the standard must be statistically superior to the negative control. However, during the rulemaking process, the criteria appropriate for these tests should be provided by the product manufacturers. a. Cetylpyridinium Chloride Rinse . • Determine the in vitro antimicrobial activity of the product against representative plaque organisms commonly associated with gingivitis. Representative organisms include, but are not limited to, typed stains of: Actinomyces viscosus , F. nucleatum , P. gingivalis , Prevotella intermedia , Bacteroides forsythus , Candida species, S. mutans , and gram negative enteric rods. Testing to determine a product's in vitro antimicrobial activity should include minimal inhibitory concentration (MIC) assays, or 30-second kill-time studies, as appropriate. • Demonstrate the availability of the active ingredient using a Disk Retention Assay (DRA). A suggested method for this assay is included in a submission to the Subcommittee (Ref. 5). • Demonstrate the biological activity of the formulation using an ex vivo Plaque Glycolysis and Regrowth Model (PGRM). A suggested protocol for this assay is included in a submission to the Subcommittee (Ref. 5). b. Stannous Fluoride Dentifrice . • An in vitro determination of antimicrobial activity against representative plaque organisms commonly associated with gingivitis (described in paragraph F.2.a. of this document) is recommended. Testing to determine a product's in vitro antimicrobial activity should include MIC assays, 30-second kill-time studies, or plaque biofilm assays, as appropriate. • Demonstrate the biological activity of the formulation using ex vivo PGRM (protocol for assay, Ref. 5). c. Fixed Combination of Eucalyptol (0.092 percent), Menthol (0.042 percent), Methyl Salicylate (0.060 percent), and Thymol (0.064 percent) Rinse . • Determine the in vitro antimicrobial activity using 30-second kill-time studies with both standard laboratory strains and wild-type organisms obtained from saliva sampling. Representative organisms are listed in paragraph F.2.a of this document. Conduct kill-time testing using an exposure time of 30 seconds in the presence of exogenous protein. Use an initial inoculum of 1-percent transmission. • Demonstrate the in vivo activity of the formulation through a short-term experimental gingivitis study of at least 2 weeks duration. A representative protocol, comparing the test product, a clinically tested standard, and a negative control, is included in a submission to the Subcommittee (Ref. 6). The criterion for study validation is statistically significant differences in plaque and gingivitis scores between the clinically tested standard and the negative control. To establish comparability to the standard mouthrinse in this test (or another generally accepted statistical test of clinical comparability), the new mouthrinse formulation must satisfy the “at least as good as” statistical criteria for both plaque and gingivitis scores, i.e., at least statistically significantly comparable or equivalent to the clinically tested standard. G. Inactive Ingredients 1. Alcohol in Oral Health Care Drug Products Many OTC mouthrinses contain alcohol (up to 26 percent or more). Concerns were raised when published reports and other information appeared to show a possible risk of developing oropharyngeal cancers from daily use of mouthrinses containing high concentrations of alcohol. After reviewing the available data, the Subcommittee has the following comments concerning high alcohol-content mouthrinses and cancer of the buccal cavity and pharynx (oral). a. Oral cancer . Based on the 1993 statistics for oral cancer in the United States (Ref. 7), the buccal cavity and pharynx are the eighth most common site of cancer, representing approximately 3 percent of all cancers reported. Approximately 30,000 people per year develop oral cancer. The ratio of men to women developing oral cancer is about 2 to 1. The 5-year survival rate for persons with oral cancer is about 33 percent for African-Americans and 50 percent for Caucasians. Alcohol consumption and tobacco smoking/chewing account for approximately three-fourths of oral cancers in the United States (Refs. 8 through 13). Other less clearly established causal factors include poor dental conditions, oral infections, nutritional deficiencies, and possibly high alcohol-content mouthrinses (Refs. 14 through 19). b. Adverse reactions associated with mouthrinses . A drug that ordinarily causes no adverse effects with short-term exposure may produce pathologic tissue changes after chronic usage. Prolonged usage of a drug and/or its metabolites combined with various compounds in the mouth may result in cumulative effects in oral tissues. Mouthrinses should be evaluated for chronic, long-term usage and resulting manifestations (Ref. 20). Mucous membranes of the mouth can absorb mouthrinse ingredients, which may pass systemically into the bloodstream. The literature describes local adverse reactions from mouthrinse usage, ranging in severity from irritancy and sensitization to cancer (Refs. 21, 22, and 23). Some case-control studies suggest a causal association between mouthrinse use and oral cancer risk, most recently in the largest study to date by the National Cancer Institute (Ref. 24). The cancer risk seems to be greater in females (60 percent) than in males (40 percent) and varies in proportion to dose, tending to increase with increasing duration and frequency of use and the alcohol concentration of the mouthrinse (Ref. 24). Other researchers have found no evidence of an increased cancer risk associated with mouthrinses (Refs. 25, 26, and 27). The reported risk of oral cancer pertains to mouthrinses with alcohol-contents of 25 percent or higher. However, since these mouthrinses also contain other active ingredients, such as essential oils with lipophilic, membranotropic effects, some high alcohol-content mouthrinses may affect tissues by a variety of mechanisms. Studies that have evaluated the potential for alcohol in mouthrinses to cause cancer have a number of shortcomings: (1) Investigations based on subject accounts without benefit of medical records or other written documentation, (2) unreliable classification of exposure to known risk factors such as alcohol and tobacco in study subjects, (3) lack of consistent dose-response relationships based on frequency and/or duration of mouthrinse use, and (4) combining cases of cancer of the buccal cavity and pharynx despite the fact that mouthrinses are in direct contact only with the mucosa of the buccal cavity. c. Alcohol and oral cancer . Although consumption of alcoholic beverages is a known risk factor for oral cancer, pure alcohol does not show a direct carcinogenic action in laboratory animals or humans. The cancer associated with alcoholic beverages is probably related to contaminating carcinogens. These include urethane produced from urea reacting with ethyl alcohol during yeast fermentation of fruit juices, and n-nitrosamine compounds catalyzed from precursor nitrite and amines, amides, or other nitrosatable agents. Commercial mouthrinses contain distilled ethanol free of these contaminating carcinogens. Other findings suggest an ability of ethanol to enhance the conversion of procarcinogens to mitogens, and of ethanol's metabolite acetaldehyde to produce deoxyribonucleic acid (DNA) abnormalities in human cells. Animal studies have indicated that ethanol may also function as a cocarcinogen, in association with other substances that are true carcinogens (Ref. 28). Alcohol may act by facilitating the penetration of carcinogens into the mucosa (Refs. 29 through 33). Weak carcinogenic nitrosamines and other compounds have been shown to have enhanced carcinogenicity in the presence of alcohol (Ref. 33). Alcohol may act directly on epithelial cells by altering intracellular metabolism and rendering cells more susceptible to carcinogens (Ref. 28). Based on these studies, the Subcommittee recommends that further studies on the possible cancer risk associated with high alcohol-content mouthrinses be conducted. These studies should include testing various components of the mouthrinse and pertinent dietary ingredients. d. Abuse and misuse of mouthrinses . Although some OTC mouthrinses contain alcohol, the potential for development of drug tolerance and addiction due to use of these products seems negligible. However, misuse of any mouthrinse product may occur if the product gives the user a false sense of security, diminishing the users's desire to seek professional advice. This problem may be particularly acute for mouthrinses that may subdue signs and symptoms of a gingivitis infection without resolving a more severe, underlying periodontitis infection. A label warning should alert the consumer to this danger. e. Alcohol as a facilitator . While the Subcommittee recognizes that the combination of alcohol and tobacco is associated with a marked increase in the incidence of oral cancer as compared to exposure to tobacco alone, it concludes that the mechanism of this synergism is unknown. Animal studies (Ref. 28) have shown that alcohol has a topical potentiating effect in the production of squamous cell carcinoma in animal cheek pouches treated with 7,12-dimethylbenz(a)-anthracene (DMBA). Decreased latency and larger tumors were observed as compared to controls. Other animal studies (Refs. 29, 30, 32, and 33) have demonstrated similar effects. These studies were older and implied a model that is not comparable to what happens in humans. Moreover, some carcinogens are extremely species-specific, and limited information is available on direct experiments performed on the human mucosa. If the synergistic effect of alcohol in causing an increased risk of oral cancer is attributed to a topical effect, as noted in the animal studies, then daily use of oral rinses containing a high concentration of alcohol may have a tissue altering effect. Whether this may be as significant as alcoholism in the epidemiology of oral cancer warrants continued investigation. One of the few mechanistic evidences for a local alcohol effect has been demonstrated by permeability studies. In the presence of nicotine, alcohol had a greater relative effect on penetration of carcinogens in and across the floor of the oral mucosa (floor of the mouth, oral mucosa) (Ref. 34). Also, pharmaceutical studies have demonstrated that the oral mucosa can have a reservoir effect, so that compounds are rapidly taken up and held in the oral epithelium, extending the duration of their effect (Ref. 35). This mechanism has recently been utilized in a formulation using alcohol to increase permeability, thereby obtaining systemic delivery of proprietary drugs after only a mucosa exposure. It is clear that further research is needed to investigate the role of alcohol as an enhancer of the penetration of carcinogens through the oral mucosa. In addition, the threshold of alcohol concentration necessary to achieve this phenomena needs to be investigated. 2. The Subcommittee's Conclusions and Recommendations Regarding Alcohol Content in Mouthrinses On June 6, 1996, the Subcommittee, along with other scientific experts (e.g., epidemiologists and statisticians) held a workshop (Ref. 36) to further consider whether alcohol-containing mouthrinses contributed to oral cancers. Although some studies have implicated high alcohol-content mouthrinses as a possible cause of oral/pharyngeal cancer, the relationship between high alcohol-content mouthrinses and oral/pharyngeal cancer is not clear. The findings of various studies are contradictory and do not show a consistent dose-response relationship. A major difficulty in deciding cause and effect in these studies is the possibility of confounding by known risk factors, such as high alcoholic beverage consumption and tobacco use. The Subcommittee reviewed new data consisting of a specificity analysis (Ref. 37) using data from the Winn et al. study (Ref. 24) and a preliminary analysis from an unpublished study of laryngeal, esophageal, and oral cancer (Ref. 38). In addition, the Subcommittee reviewed seven case-control studies, published between 1979 and 1991 (Refs. 12, 13, and 23 through 27), of the association between mouthrinse use and oral cancer. These studies are described below. Weaver et al. (Ref. 23) reported the use of alcohol-containing mouthrinses among 11 subjects with oropharyngeal cancer who indicated that they did not smoke or drink alcoholic beverages. These cases became part of a case-control study regarding an association between alcohol-containing mouthrinses and oropharyngeal cancer. Although the study was unevaluable, it generated the hypothesis that led to subsequent studies. A 1983 case-control study by Wynder et al. (Ref. 12) evaluated the relationship between mouthrinses and oropharyngeal cancer. No positive findings were reported for men. In women, the relative risk, unadjusted for smoking and alcoholic beverage consumption, was statistically significant for daily use of mouthrinses. However, there was no consistent relationship for duration or frequency of use. Further, a refined analysis using a multiple logistic model indicated no association between mouthrinse use and oropharyngeal cancer. The investigators concluded that, due to the absence of a dose-response relationship and the possibility of confounding by tobacco and alcoholic beverage use, it was not possible to attribute an association between daily mouthrinse use and oral cancer in women. A 1983 case-control study by Blot et al. (Ref. 13) included female subjects from a previous study of snuff use. A relative risk of 1.94 was reported for women who used a mouthrinse but did not use tobacco products. However, this was not statistically significant (confidence interval = 0.8 to 4.7), and there were no consistent dose-response relationships for years of use, frequency of use, time retained in the mouth, or concentration (i.e., diluted vs. full strength). Because dose-response relationships are important in considering whether there is an association between mouthrinse use and oral cancer, the Subcommittee concludes that this study does not support a causal association between alcohol-containing mouthrinses and oropharyngeal cancer. The Subcommittee reviewed three additional case-control studies published between 1985 and 1989 (Refs. 25, 26, and 27). One study by Kabat et al. (Ref. 26) is of particular interest because, although mouthrinses were not associated with increased oral cancer risk in terms of frequency or duration of use, cases were significantly more likely than controls to state that mouthrinses were used to disguise breath odors caused by alcoholic beverages or tobacco. In contrast, similar proportions of cases and controls reported using a mouthrinse to conceal food odors or for mouth infections or dental problems. The Subcommittee concludes that these findings indicate that mouthrinse use may be serving as a surrogate for underreported drinking and/or smoking. A 1991 study by Winn et al. (Ref. 24) was the largest case-control study among the seven published studies evaluating mouthrinses (866 cases and 1,249 controls). Odds-ratios for oropharyngeal cancer risk after adjusting for tobacco and alcoholic beverage use were 1.4 (confidence interval 1.0 to 1.8) in men and 1.6 (confidence interval 1.1 to 2.3) in women. Dose-response relationships, such as duration of use, frequency of use, and age when use started, were questionable, with no trend analysis of these relationships reported. This study also showed a decreased odds-ratio for dental X-rays. There is no biologically plausible reason to expect X-rays to be protective against oral cancer, and the negative association is likely a reflection of less frequent visits for dental care by cases versus controls. However, the negative association could not be eliminated by adjustment for factors that are relevant to quality of dental care (e.g., education). Thus, this study was capable of producing a statistically significant noncausal association that could not be eliminated by adjustment of the data. Further, regarding the odds ratio for mouthrinse use, confounding due to underreported use of tobacco and alcoholic beverages, both strong risk factors for oropharyngeal cancer, could result in an artificially elevated odds ratio. Such a false association can be produced even though the extent of underreporting is the same in both the case and control groups (Ref. 39). Information in the published literature indicates that especially drinking and sometimes smoking are underreported (Refs. 40 through 44). The Subcommittee concludes that these studies do not support a causal relationship between the use of alcohol-containing mouthrinses and oropharyngeal cancer. The Subcommittee reviewed unpublished new data that included a specificity analysis (Ref. 37) of the data from the Winn et al. study (Ref. 24). This analysis excluded 75 cases (38 men and 37 women) who did not have oropharyngeal cancer ( i.e., epithelial cell cancer of the mouth) based on evaluation of the International Classification of Diseases codes. The excluded cases consisted primarily of tumors of the minor salivary glands and sarcomas and lymphomas that happened to occur within the oral cavity. Excluding these cases left 535 and 256 cases of oropharyngeal cancer in men and women, respectively. Evaluation of smoking and alcoholic beverage use indicated that both of these risk factors were more strongly associated with the included cases than with the total number of cases (included plus excluded). Neither smoking nor alcoholic beverage use were associated with the excluded cases. This analysis indicated that the excluded cases may not have the same etiology as the included cases and, therefore, should not have been included in the original analysis conducted by Winn et al. (Ref. 24) to evaluate risk associated with mouthrinse use. When odds ratios for mouthrinse use in women were calculated for the included cases, they were decreased relative to the odds ratios for total cases originally reported by Winn et al. (Ref. 24). This was true for a number of subanalyses, including duration of use, frequency of use, age when use began, and alcohol concentration. Higher odds ratios for mouthrinse use among the excluded cases suggested that mouthrinse use was more strongly associated with excluded cases than with included cases. However, there is no biologically plausible explanation for this finding since the excluded cases represent a variety of tumor types whose origins cannot be presently explained by topical exposure to ethanol via mouthrinse use. In addition, the data were inconsistent with a dose-response with respect to duration of use, frequency of use and age when mouthrinse use started, which suggests that this finding may be related to information bias rather than a causal association. The specificity analysis among male cases was less informative than for females and supports neither a causal hypothesis nor information bias as the explanation for the weak association with mouthrinse use (odds ratio 1.4) originally reported by Winn et al. (Ref. 24). The limited value of the specificity analysis in males is likely related to the fact that: (1) The excluded male cases represented a smaller percentage of the total male cases and (2) the odds ratio for mouthrinse use in males is smaller than it is in females. Both of these factors make it difficult to detect any shifts in odds ratios. The Subcommittee concludes that, overall, the specificity analysis of the Winn et al. study (Ref. 24) indicates that this study does not support a causal association between mouthrinse use and oropharyngeal cancer (Ref. 37). Preliminary analyses from an unpublished case-control study of laryngeal, esophageal, and oral cancer (Ref. 38) showed that the odds ratio for mouthrinse use in males and females combined (adjusted for cigarette and alcoholic beverage use) was 1.4 (confidence interval 1.0 to 2.0). However, the analyses of frequency, duration, and age when use started showed inconsistencies that question a causal relationship. In addition, when the data were evaluated with respect to alcohol content, the highest odds ratio (unadjusted for smoking and alcoholic beverage use) was found among users of mouthrinses containing no alcohol (e.g., salt water, vinegar, baking soda in water). The Subcommittee concludes that this finding differs from the Winn et al. study (Ref. 24) results showing that odds ratios were elevated only for mouthrinses having the highest alcohol content and is inconsistent with the hypothesis of a causal association between alcohol-containing mouthrinses and oral cancer. An unpublished review of the literature concerning possible mechanisms of alcoholic beverage consumption and oral cancer risk was submitted to the Subcommittee (Ref. 45). Although alcoholic beverage consumption is a known risk factor for oral cancer and the literature on experimental mechanistic studies (e.g., in vitro and animal studies) raises speculations concerning how the biological effects of alcohol may modulate cancer risk, the Subcommittee concludes that the relevance of these studies to mouthrinse use in humans has not been established. Based on the studies reviewed, the Subcommittee concludes that the available data do not support a causal relationship between the use of alcohol-containing mouthrinses and oral cancer. The vote was unanimous with the Chairman abstaining. The Subcommittee acknowledges that epidemiologic research on oropharyngeal cancer will continue, and that the conclusion reached by the Subcommittee is based on the data available at the time of its deliberations. However, because some studies did report a relationship between the use of high alcohol-content mouthrinses and pharyngeal cancer, the Subcommittee agrees that further studies should be conducted to determine the relationship between high alcohol-content mouthrinses and oral/pharyngeal cancers. In addition, the Subcommittee recommends that all mouthrinses should be labeled in a readily readable manner with the alcohol concentration in percent, e.g., “Contains _ % alcohol” on the principal display panel. H. General Guidelines on Safety and Effectiveness 1. General Statement The Subcommittee arrived at its conclusions and recommendations regarding the safety and effectiveness of all active ingredients after considering all pertinent data and information submitted. The Subcommittee adopted the following general “points to consider.” These are not intended to restrict investigators, but are recommendations for studies recognized as desirable approaches to determine the safety and effectiveness of OTC antigingivitis/antiplaque active ingredients. In some cases, other methods may be equally applicable, or newer methods may be preferable. Also, these recommended studies may not produce all information necessary to determine that an ingredient is generally recognized as safe and effective. 2. Guidelines An OTC drug included in a monograph is described in § 330.10 as generally recognized among qualified experts as safe and effective for use and as not misbranded. Proof of the safety of an OTC drug ingredient consists of adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use. This proof shall include results of significant human experience during marketing. General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data. Proof of effectiveness of an OTC drug ingredient consists of controlled clinical investigations as defined in § 314.126(b) (21 CFR 314.126b)) by qualified experts to show that the drug provides clinically significant relief of the type claimed in its labeling. The latter requirement may be waived if it is not reasonably applicable to the drug in question or essential to the validity of the investigation and an alternative method of investigation is adequate to substantiate effectiveness. Effectiveness may be corroborated by partially controlled or uncontrolled studies, and reports of significant human experience during marketing. General recognition of effectiveness shall ordinarily be based upon published studies that may be corroborated by unpublished studies and other data. The characteristics of adequate and well-controlled studies have been developed over a period of years and are described in § 314.126. Studies supporting the safety and effectiveness of OTC drug ingredients should provide sufficient details of study design, conduct, and analysis to allow a critical evaluation of the data in relationship to the above characteristics. In several proposed and final monographs, the agency has stated that, in order for an active ingredient to be included in an OTC drug monograph, it is necessary that the ingredient be adequately characterized and that these standards be published in an official compendium such as the United States Pharmacopeia (USP) or the National Formulary (NF) (58 FR 28194 at 28284). Such specifications are necessary to assure the identity, strength, quality, and purity of the active ingredient. Therefore, the Subcommittee recommends that a full description of the ingredient, including its physical and chemical characteristics and stability, be provided, and that manufacturers contact and work with the USP to develop monographs for ingredients that are not currently included in that compendium. For ingredients that are currently included in an official compendium, reference to the current edition of the USP or the NF may satisfy this requirement. a. Safety . The Subcommittee's determination of the safety of single ingredients and ingredient combinations is based on the following criteria: (1) The incidence and risk of adverse reactions and significant side effects when the ingredient was used according to adequate directions in the labeling, (2) the margin of safety under conditions of normal use and the potential for harm that might result from abuse or misuse under conditions of widespread OTC availability, (3) the potential for inducing untoward effects on the oral tissues, including irritation, ulceration, inflammation, erosion, and minor effects such as discoloration of the teeth, restorations, and prostheses, etc., and (4) assessment of the benefit-to-risk ratio. The Panel further states that microbial safety should be determined through clinical evaluation of changes in representative oral microbial populations ( e.g., the possible emergence of opportunistic organisms or potential pathogens), in order to assure that there is no adverse change in the balance of the oral microflora under conditions of expected OTC use. i. Toxicological studies . A variety of toxicological data can be obtained to demonstrate that an active ingredient is safe. The Subcommittee recommends that manufacturers conduct the applicable studies discussed below and emphasizes that these recommendations do not preclude the use of alternative comparable methods that are currently available or better methods that may be developed in the future. The Subcommittee recommends that the following data be available for the active ingredient(s) intended for use on the mucous membranes of the mouth and throat. Testing the effects of various ingredients on animal subpopulations that can reflect human subpopulations should be considered (e.g., hyposalivation studies in nonsalivating animals). Adequate, acceptable, controlled in vivo studies of acute and chronic toxicity in several species of animals should be available. Such studies may include single-dose gavage studies, repeat-dose gavage studies, oral irritation studies, pharmacokinetic/biodistribution studies, and dermal sensitization studies. Information regarding the genetic, reproductive toxicologic, and carcinogenic potential should be considered for ingredients that are going to be used daily on a long-term basis. It is not necessary to determine the LD 50 (lethal dose for 50 percent of the test animals) of the ingredient. However, information about the minimal lethal dose would be useful. All or some of the recommended toxicological studies may not be necessary for all active ingredients. Some circumstances that might preclude an ingredient from the above testing are: (1) It is already generally recognized as safe, (2) it is a direct food additive, (3) it has been used previously in approved dental drug products, or (4) it is the subject of an OTC drug monograph with a different but similar or related use at a similar concentration and for a similar time period. Published articles may be considered in lieu of the testing recommended above. One of the Subcommittee's primary concerns regarding antigingivitis/antiplaque ingredients is whether or not swallowing the active ingredient presents a threat to the user. The Subcommittee recommends that gavage studies be used to address concerns about potential systemic toxicity unless applicable published or unpublished studies have been conducted using a dietary admixture mode of administration and comparable toxicokinetics can be shown between gavage and dietary modes of administration. Single administration gavage studies are typically performed using a limit-value test in the rat at a specified high dose to evaluate acute toxicity potential (Refs. 46, 47, and 48). In the absence of adequate dietary admixture studies, repeat dose gavage studies may be employed to evaluate systemic toxicity from multiple exposures. The test article is administered to rats on a number of consecutive days. Where there is a concern that antigingivitis/antiplaque active ingredients may induce untoward effects on the oral mucosa, the dosage to be used for these studies should be justified based on the concentration of human exposure levels. An appropriate dosage range may extend, for example, from a low dose comparable to swallowing a single dose of mouthrinse or the amount remaining following expectoration of a mouthrinse to a high dose that either causes dose-limiting toxicity or is several orders of magnitude greater than the clinical exposure levels. Such studies usually use four applications per day for a period of 28 consecutive days. The oral irritation should include both a negative and a positive control group. All test articles should be applied in an identical manner. A negative control group may consist of animals that are treated with either water or saline, and the positive control is a group of animals that are treated with the solution that is known to cause a minimal degree of irritation without being inhumane to the animals (e.g., 5-percent solution of sodium lauryl sulfate). The Subcommittee recommends that the study include abraded mucosa in order to determine whether the test ingredient delays or prevents the healing of oral lesions. The parameters to include are any gross observations of changes in the oral tissue, such as sloughing, ulceration, or bleeding. Following the sacrifice of each animal, the histopathology of oral tissues should be examined. ii. Studies in older adults . The Subcommittee is concerned that older adults might be at greater risk for potential systemic toxicity from the use of antigingivitis/antiplaque active ingredients. This is of particular concern because of the continually increasing size of the older adult population, who are retaining more natural teeth and becoming a significant population for use of antiplaque/antigingivitis products. Publications have described differences in drug responses in the elderly. Changes in pharmacokinetics have been reviewed (Ref. 49). Absorption can theoretically be altered by noted changes in gastrointestinal function, but the majority of studies have shown no difference in rate or extent of absorption of the drug examined. Distribution of a drug within the body is affected because fat content of body weight increases and intracellular water decreases. For example, albumin concentration is reduced and drugs which bind to albumin are more free to distribute to the rest of the body. Hepatic metabolism may be altered. Reduction of blood flow to the liver will decrease clearance of some drugs. Renal excretion is affected in some older adults by loss of renal mass and functional nephrons. Russell (Ref. 50) noted that despite numerous reports in the literature of impaired GI function with aging, most functions remain relatively intact because of the large reserve capacity of the intestine, pancreas, and liver. In a review critically analyzing available information on age-related changes in the digestive and absorptive GI physiology of lipids, data suggested lipid digestion and absorption are well-preserved in the aging. However, intercurrent illness or experimental stress may produce impairment in aging animals and humans that is not seen in younger controls (Ref. 51). Atillasoy and Holt (Ref. 52) noted that the GI tract represents an organ system characterized by rapid proliferation. Contrary to generally held prejudices, the authors write, a state of hyperproliferation, not hypoproliferation, occurs in the epithelial cells of the stomach, small intestine, and large intestine of stable-fed, aged rodents when compared to young adult rodents. In a gavage study (Ref. 53) Yamada et al. investigated renal ammoniagenesis in isolated nephron segments from control, acidotic senescent (exhibiting deteriorating teeth due to aging), and young adult rats. No significant difference was seen in glutamine-dependent ammonia production in the segments. However, ammonia production in glomeruli from old rats was significantly greater than in young rats. There appear to be no available consistent findings to warrant that additional gavage studies of antigingivitis/antiplaque active ingredients in older animals will produce more meaningful findings relative to older adults than the usual gavage studies in adult animals. This is due to the great diversity which exists in the health and fitness status of the elderly population. The Subcommittee considers a comment by Ahronheim (Ref. 54) appropriate: Although much has been written about age-related alterations in drug disposition, there is disagreement as to the extent and inevitability of these changes. Studies focusing on aged individuals suffer from several problems. Cross-sectional studies comparing young and old subjects sometimes compare young, healthy individuals with aged subjects gathered from hospitals or nursing homes. If the aged subjects are “healthy” they may nonetheless have subclinical disease, which can alter outcomes in studies that seek to determine a drug's disposition and effects. However, aged subjects that are truly healthy may represent an elite minority so that the study's results may not be applicable to the general elderly population. Longitudinal studies are almost impossible to complete and data is sparse, but recent findings indicate that the geriatric population is, indeed, heterogeneous. In addition to these pitfalls, it is not known how generalizations about aging physiology, even if they are true, can be applied to drug disposition, since most drugs have not been subjected to exhaustive age-specific testing and few conclusions can be reached based on pharmacokinetic data. Even less is known about pharmacodynamic changes because the study of age-related tissue receptor density, activity, and sensitivity is in its infancy. We must therefore rely on clinical observations to a large extent when drawing conclusions about efficacy and potential toxicity of various agents in use. The Subcommittee concludes that the results of the usual gavage studies are adequate. iii. Irritation and delayed contact sensitization studies in humans . Observations during adequate clinical studies are sufficient to demonstrate the irritation and sensitization potential of an ingredient or ingredient combination. However, if necessary, a number of methods embodying the use of patch testing have proven of value in determining skin irritancy and systemic sensitization. The Subcommittee recommends one of the following three methods of patch testing to address concerns of irritancy and sensitivity: • Draize testing . In the Draize human skin irritancy and sensitization tests or one of its various modifications (Ref. 55), the testing should be performed on the skin of the subject's back or arm. • Method of Shelanski and Shelanski . In this method (Ref. 56), the active ingredients or the formulation under study are applied at frequent intervals of 1 or 2 days to the test site for 3 or 4 weeks. After a rest period of 2 weeks, a single dose of the drug is applied as a challenge. The preliminary applications are made to detect primary skin irritants and provoke sensitization in susceptible individuals. The challenging dose detects whether or not the drug is a skin sensitizer. • Maximization procedure of Kligman . This procedure (Ref. 57) or one of its modifications uses an irritant applied over a desquamated test site. Desquamation is performed by using a rubbing technique that facilitates penetration, thereby hastening and accentuating the skin-sensitizing potential of the substance. Other validated human models may be used. iv. Microbiologic evaluation . The Subcommittee is concerned about the potential of antigingivitis/antiplaque ingredients with antimicrobial effects to allow emergence of opportunistic pathogens, induce resistance in oral microorganisms, or allow an oral overgrowth of inherently resistant potential pathogens. Representative microbial species and their relative proportion to the total cultivable microflora in supragingival plaque and saliva should be monitored over at least a 6-month period of continuous use of the antiplaque product to determine if a shift in the oral flora has occurred that might result in the proliferation of pathogenic microorganisms, which may include Candida species and other yeast, Staphylococcus aureus and other Staphylococcus species, beta-hemolytic Streptococci , and enteric gram-negative rods. Additionally, for those antigingivitis/antiplaque ingredients where the mechanism of action is suspected to be antimicrobial, an assessment of changes in microorganisms associated with gingival disease should be carried out. One determination should be made prior to the start of use, one at the conclusion of the study, and one at an intermediate time. In vitro minimum inhibitory concentrations should be assessed for representative species to determine the development of increased resistance after prolonged antimicrobial therapy. b. Effectiveness . The Subcommittee's determination of the therapeutic effectiveness of ingredients and combinations of ingredients for antigingivitis/antiplaque use is based on published and unpublished studies containing pharmacological data considered by the Subcommittee to be scientifically valid and pertinent. Clinical criteria for proof of effectiveness of a single ingredient or combination of ingredients were determined by evaluating data from valid controlled studies and by calling on the clinical expertise of the Subcommittee members. Proof of effectiveness of a single ingredient or combination of ingredients was determined by evaluating data from valid, well-controlled studies demonstrating a significant reduction of the symptoms or a therapeutic benefit for the stated indication in the labeling. Although the OTC drug review is an active ingredient review, not a product review, the Subcommittee recognizes that a final product must be formulated properly, according to accepted pharmaceutical manufacturing practices. If a product is not formulated properly, active ingredients may be present in less than the minimum effective dose, may be in a form that does not exert the intended therapeutic effect(s), or may not be bioavailable. Therefore, the Subcommittee considered it important whether or not inert ingredients or other active ingredients in a formulation might alter the effect of the product's principal active ingredient. The designation of a pharmaceutical necessity as an inactive ingredient does not necessarily mean that the ingredient is pharmacologically inactive. The Subcommittee considers its recommended “points to consider” acceptable current approaches for arriving at valid conclusions concerning the effectiveness of OTC antigingivitis/antiplaque drug products. These “points to consider” do not preclude the use of newer, more refined laboratory or clinical techniques to establish effectiveness. c. Clinical trials . Acceptable studies should state the specific objectives of the study, a review of pertinent literature, and present the scientific rationale for the use of the ingredient. The mode, frequency, and duration of application should be thoroughly described. The indices and variables selected for measuring effectiveness, the methods of measurement, and the rationale for such choices should be characterized. The Subcommittee believes that the effectiveness of an OTC antigingivitis ingredient, antigingivitis/antiplaque ingredient, or ingredient combination should be demonstrated by evidence of a clinically significant endpoint, specifically a reduction and/or prevention of gingivitis. In general, the Subcommittee would also expect a reduction of dental plaque mass and/or plaque virulence (degree of pathogenicity as indicated by the severity of the disease produced). However, the Subcommittee also believes that an ingredient can reduce gingivitis without a demonstrated reduction of plaque. Where possible, additional evidence for the effectiveness of the agent should be provided by demonstrating a shift in the plaque flora. i. Design . Studies should measure the difference between reduction or prevention of dental plaque and gingivitis resulting from the test ingredient as compared to a placebo. Examples of acceptable experimental designs include crossover, parallel, factorial, sequential, single-blind, and therapeutic equivalency studies. Preference should be given to using double-blind studies with a placebo control. The placebo is the formulation of the test agent without the active ingredient, or some other suitable placebo. ii. Subjects . A sufficient number of subjects should be used to permit statistical analysis for the data obtained. The number of subjects tested should be sufficient to eliminate examiner bias and bias introduced by the placebo effect, if applicable, and to allow for anticipated dropouts and estimated variability of effect. The subjects should be of both genders and within the age groups for which the active ingredient is intended. Specific exclusionary criteria should be given. iii. Conduct of the study . The study should be of sufficient duration to demonstrate effectiveness. The duration will depend upon the actual use, anticipated effect, potential sustained benefits, and any safety considerations. The Subcommittee believes that such studies should be at least 6 months in duration to provide sufficient time for an ingredient to exert an antigingivitis/antiplaque effect and for adverse events to manifest themselves. Six months will also provide time to investigate the possibility that an OTC oral ingredient used daily over an extended period of time might cause a shift in the oral flora that may result in the proliferation of pathogenic microorganisms. Scoring and oral health evaluations should be done at baseline, at completion, and at appropriate intervals during the study. Baseline demographic, medical, historical, and physical data for each subject should be obtained and recorded. Such data should include a medical history, a complete oral examination, laboratory studies, if indicated, and other pertinent data. The treatments should be performed on a random basis. The randomization procedure should be used so that variables not otherwise controlled balance out. The number and frequency of applications of the preparation should be in accordance with the method outlined in the indication for use and directions in the labeling. The clinical investigative team should monitor subjects during the study to detect any adverse events and take appropriate action. An evaluation of dose response and possible mechanism of action would enhance any submission. iv. Appropriate assessments . Appropriate assessments using validated or accepted techniques must be used. v. Interpretation of data . Investigative methods should be described in sufficient detail so that experiments can be repeated by another investigator to verify and confirm results. Methods of statistical analysis should be determined before starting the study. Positive evidence of effectiveness should be obtained from a minimum of two studies, each conducted by an independent investigative group. In addition to statistical significance, clinical importance should be addressed. Strength of effect and concern about statistically significant changes not being clinically significant reflect the importance of randomized controlled trials of longer duration to determine if individuals benefit from proposed agents and interventions. Statistical significance can be easily calculated using a nominal (categorical) scale such as gingival index scores. A large “N” offers scores with an approximately normal distribution so that parametric statistics can be used, as if using exact measures such as in an interval or ratio scale. The gingival index, however, is a nominal scale and the difference between 0 and 2 is not the same as the difference between 1 and 3. Slight differences exist in mean gingival index scores which are not clinically obvious and cannot be easily discerned in a subject. A product can produce a change in the response variable that is statistically significant, yet the question of clinical significance remains unanswered. III. Classification of Active Ingredients In addition to carefully reviewing the submitted data, the Subcommittee considered all pertinent data and information available in arriving at its conclusions and recommendations regarding the active ingredients. The following tables summarize the Subcommittee's recommended categorization of active ingredients: Table 2.— Categorization of Single Active Ingredients Active Ingredients Safety Efficacy Aloe vera III III Cetylpyridinium chloride I I Dicalcium phosphate dihydrate I III Hydrogen peroxide I III Sanguinaria extract I III Sodium bicarbonate I III Sodium lauryl sulfate I III Stannous fluoride (for gingivitis) I I Zinc citrate I III Table 3.— Categorization of Combinations of Active Ingredients Active Ingredient Combination Safety Efficacy Alkyl dimethyl amine oxide and alkyl dimethyl glycine III III Eucalyptol, menthol, methyl salicylate, and thymol I I Hydrogen peroxide and povidone iodine III III Hydrogen peroxide and sodium bicarbonate I III Hydrogen peroxide, sodium citrate, sodium lauryl sulfate, and zinc chloride I III Peppermint oil and sage oil I III Polydimethylsiloxane and poloxamer I III Stannous pyrophosphate and zinc citrate I III A. Category I Conditions The Subcommittee recommends Category I labeling for all Category I single antigingivitis/antiplaque active ingredients and combinations of active ingredients (see section II.D of this document). 1. Category I Single Active Ingredients Cetylpyridinium chloride (rinse) Stannous fluoride (dentifrice) a. Cetylpyridinium chloride (rinse) . The Subcommittee concludes that cetylpyridinium chloride at concentrations of 0.045 to 0.1 percent with at least 72 to 77 percent chemically available cetylpyridinium chloride is safe and effective for use in mouthrinse formulations as an OTC antigingivitis/antiplaque agent. Cetylpyridinium-containing mouthrinses have been used in the United States since 1940. Cetylpyridinium chloride 0.025 percent to 0.1 percent has been marketed nationally in several products. Products containing cetylpyridinium chloride have also been marketed internationally. The more than 55-year U.S. marketing history is significant with respect to the ingredient's safety. Cetylpyridinium chloride is a quaternary nitrogenous compound l-hexa-decyl pyridinium chloride with antimicrobial activity against many microorganisms, including viruses. Its chemical and physical properties are well described in the USP (Ref. 58). It is classified as a cationic surface-active agent and contains a cetyl radical substituted for hydrogen atom on position 1. In hydrochloric acid it forms a chloride salt. The cetyl radical renders the molecule lipophilic, contributing to the lipophilic/hydrophilic balance which is necessary for the antimicrobial activity of such quaternary nitrogenous compounds. The antimicrobial activity is dependent upon the positioning of the charged molecule with bacterial cells that carry a net negative charge. This positioning allows the hydrophilic portion of the cetylpyridinium chloride to interact with the cell membrane, resulting in leakage of cellular components, disruption of cellular metabolism, inhibition of cell growth, and cell death (Refs. 59 through 62). Because the positively charged hydrophilic region is critical to antimicrobial activity, any formulation that diminishes the activity of this cationic group or that competes with this group may inactivate the product. Therefore, it is essential to establish that the cetylpyridinium chloride in products is sufficiently biologically active to justify an antigingivitis claim. i. Safety . The Subcommittee believes there are sufficient safety data to permit final classification of the safety of cetylpyridinium chloride as an OTC antimicrobial agent for topical use in the oral cavity when used within the proposed dosage limits set forth below. The Subcommittee bases its conclusions on the safety of cetylpyridinium chloride mouthrinses used in animal and pharmacokinetic studies, assessment of adverse events in randomized, placebo-controlled clinical trials, and postmarket spontaneous adverse event data reported to the manufacturer and FDA. The LD 50 of cetylpyridinium chloride is 250 milligrams per kilogram (mg/kg) given subcutaneously, 6 mg/kg intraperitoneally, 30 mg/kg intravenously, and 200 mg/kg given orally as a pure compound (Ref. 63). The data (Ref. 64) show that the oral LD 50 values in the rat from a mouthrinse containing 0.05 percent cetylpyridinium chloride were 34 mg/kg to 48 mg/kg of the mouthrinse alone. This lower LD 50 with the rinse formulation as compared to cetylpyridinium chloride in solution is likely due to the other components of the mouthrinse, such as the alcohol. Subchronic toxicity studies of cetylpyridinium chloride administered orally at dose levels ranging from 5 to 500 mg/kg showed morbidity and death at 125, 250, and 500 mg/kg. At lower doses, the only significant finding in rats and dogs was gastric irritation at doses of 50 mg/kg per day and higher (Ref. 65). These studies are similar to studies conducted prior to 1950. Two chronic exposure safety studies of 6 months and 1 year were reported (Ref. 65). Doses administered daily by oral gavage ranged from 5 to 75 mg/kg. Significant decreases in body weight and weight gain were noted in 40- and 75-mg/kg animals of both sexes. At necropsy, GI irritation was manifested as thickening of the stomach mucosa observed at the 40- and 75-mg/kg level, and in some animals administered 15 mg/kg. Local irritation studies (Ref. 65) included eye irritation tests and dermal exposure. Evidence of eye irritation was observed at high concentrations but no dermal lesions were observed. Local irritation using cetylpyridinium chloride mouthrinse formulations was assessed in the canine oral mucosa irritation model (Ref. 65). A cotton plug saturated with cetylpyridinium chloride mouthrinse was applied to the gingival mucosa three to five times a day for 4 days. Mouthrinse formulations containing up to 0.45 percent cetylpyridinium chloride did not induce irritation after 20 applications. Lin et al. (Ref. 66) evaluated inhalation toxicity in rats and found clinical signs of toxicity, including respiratory difficulty, eye irritation, and nasal discharge at concentrations of approximately 0.1 mg cetylpyridinium chloride/liter and above. However, these nonlethal effects were reversible. A study of the effects of alcohol and cetylpyridinium chloride on the buccal mucosa of hamsters was reported (Ref. 67). Animals received daily applications of 0.05 percent cetylpyridinium chloride for 21 days on the everted hamster cheek pouch. Abrasion was also carried out. No significant differences were found between the control and study animals. Contact sensitization potential was assessed using a 25-percent concentration of cetylpyridinium chloride in petrolatum for sensitization and a 10-percent concentration for challenge. No evidence of sensitization was observed in any of the 24 participants (Ref. 65). Pharmacokinetic studies assessing absorption, distribution, and elimination of cetylpyridinium chloride were done in rats and dogs (Ref. 65). In the rat study, approximately 85 percent of a single dose of radiolabeled cetylpyridinium chloride was detected in the feces and about 10 percent in the urine. The dog study was inconclusive, since only 56.5 percent of the radiolabeled cetylpyridinium chloride administered was recovered from the urine, feces, case rinses, organs, and carcass. The safety data were systematically collected from several clinical trials (Refs. 68, 69, and 70). Adverse events did not differ between placebo and control except for tongue and tooth discoloration associated with cetylpyridinium chloride. In contrast, Lobene et al. (Ref. 71) found that approximately a quarter of the subjects using cetylpyridinium chloride reported a slight, transient irritation of the gingiva. In one short-term study (Ref. 72), more subjects in the cetylpyridinium chloride group were found to have aphthous ulcers than the placebo group. Gingival irritation and aphthous ulcers were not reported in other randomized controlled clinical trials of cetylpyridinium chloride-containing mouthrinses. Further studies of the mucosal irritancy potential of cetylpyridinium chloride, especially in those with hyposalivation, are warranted. Studies (Refs. 65 and 73) showed that there are no significant changes in the balance of the human oral flora or in the overgrowth of potential pathogens such as Candida . It appears that cetylpyridinium chloride has activity in the range of 0.12 to 8 micrograms per milliliter (μg/mL) in vitro against S. aureus , S. sanguis , E. corrodens , Neisseria , Veillonella parvula , P. gingivalis , F. nucleatum , and Candida albicans . Data on teratogenic and mutagenic effects are available from in vitro and in vivo animal studies (Ref. 65). However, long-term cumulative effects on metabolism and teratogenic effects are not available from controlled human studies. The FDA spontaneous adverse reaction reports and adverse events reports submitted suggest that clinical experience following long-term OTC use of the ingredient has not revealed overt toxic manifestations. Although the summarized FDA spontaneous adverse drug reaction report (Ref. 65) indicates that three deaths and six comas occurred after ingestion of cetylpyridinium chloride-containing mouthrinses, it is unclear to what extent the mouthrinses or other circumstances may have contributed to these severe adverse events. The Subcommittee notes that tooth and tongue staining, as well as oral irritation, may occur with the use of products containing cetylpyridinium chloride. In summary, the safety of cetylpyridinium chloride has been extensively evaluated in a variety of controlled, clinical and nonclinical studies. Based on this information, in addition to adverse event data collected during more than 55 years of U.S. marketing of mouthrinses containing cetylpyridinium chloride, the Subcommittee concludes that cetylpyridinium chloride is safe when used at concentrations of 0.045 percent to 0.1 percent in mouthrinse formulations. ii. Effectiveness . The Subcommittee concludes that cetylpyridinium chloride is effective as an OTC antigingivitis/antiplaque ingredient within the dosage limits proposed above. The Subcommittee evaluated six placebo-controlled, blinded, clinical efficacy trials (Ref. 65). In five of the six studies, a 15- to 27-percent reduction in supragingival plaque was obtained with cetylpyridinium chloride in concentrations ranging from 0.05 to 0.1 percent. The reduction seems to persist for 6 months. Four 6-month trials and several shorter trials were also submitted (Refs. 70 and 73). All of the studies demonstrated a significant reduction of supragingival dental plaque with the use of 0.045 to 0.1 percent cetylpyridinium chloride mouthrinse. This is a reproducible finding in both short-term and 6-month studies based on the data submitted and in the published literature (Ref. 74). The results of two 6-month studies (Refs. 68 and 69), a 2-month study (Ref. 75), and a 4-month study (Ref. 76) showed reductions in gingivitis (based upon gingival index) ranging from 15.7 to 41 percent. Although trends were noted, no clear-cut dose response in the antigingivitis effect was documented in any one study in that range. Data from four other 6-month studies (Ref. 70) (three of which were carried out by different research groups) did not demonstrate a statistically significant reduction in gingivitis. In the Ciancio study (Ref. 77), there was no statistically significant reduction in gingivitis, although there was a reduction in plaque. Similarly, in the Lobene study (Ref. 78), no differences in gingival index were seen at 4, 20, or 26 weeks, although there was a statistically significant reduction in gingival index at 8 weeks. In two studies (012-035 and 012-037) by Ackerman and DeGenero (Ref. 79), a mouthrinse containing cetylpyridinium chloride showed no effect on gingivitis at 6 months. In a 6-week study by Moran (Ref. 80), cetylpyridinium chloride in a mouthrinse had no effect on plaque or gingivitis. Although most of the formulations reduced plaque, the gingivitis results in these studies are not consistent. The Subcommittee believes that differences in the results of studies on the effectiveness of cetylpyridinium chloride mouthrinse are likely explained by the use of different formulations (Refs. 65, 70, and 81). Based on the data presented, the biological effectiveness and chemical availability of cetylpyridinium chloride in a mouthrinse appear to be greatly affected by the particular formulation. Cetylpyridinium chloride in mouthrinse formulations all at approximately 0.045 percent nominal concentrations were shown to vary markedly between 4 and 77 percent. Thus, it is clear that inactivation of cetylpyridinium chloride is likely based upon formulation. It is recommended that the bioavailability of cetylpyridinium chloride in each formulation be determined to reduce the possibility that the active ingredient is removed due to chemical reaction, complexing, micelle (a colloid particle formed by an aggregation of small molecules) formation, or other sources of deactivation. Assessment of mouthrinses containing cetylpyridinium chloride in formulations similar to those tested in the positive studies (Refs. 68, 69, 76, and 77) show that 72 to 76 percent of the cetylpyridinium chloride is available (Ref. 82). Therefore, it is reasonable to assume that formulations containing 72 to 76 percent available cetylpyridinium chloride are active in reducing gingivitis and plaque. At the request of the Subcommittee, the manufacturer conducted additional analyses demonstrating the effectiveness of cetylpyridinium chloride on a site and subject basis, relative to other oral healthcare practices, and on the basis of odds-ratio calculations. Specifically, using a minimum 33 percent reduction in bleeding criterion, results of 4 long-term studies were pooled to estimate an overall odds ratio for improvement relative to a placebo. After 3 months of product use, the odds ratio was 3.12 with a 95 percent confidence interval of 2.85 to 3.40. After 6 months, the odds ratio was 3.10 with a 95 percent confidence interval of 2.75 to 3.45. Based on the totality of the data, the Subcommittee concludes that cetylpyridinium chloride mouthrinse is safe and effective as an OTC antigingivitis/antiplaque agent. b. Stannous fluoride (dentifrice) . The Subcommittee concludes that stannous fluoride in a compatible dentifrice base at a concentration of 0.454 percent is safe and effective for OTC use as an antigingivitis active ingredient. i. Safety . Stannous fluoride has been used as an OTC caries-preventive agent in toothpastes in the United States since 1954. Since 1981, it has been largely replaced by sodium fluoride or sodium monofluorophosphate. However, during this 27-year period, it is estimated that at least 70 billion doses of stannous fluoride were sold in the United States. Thus, a long market history exists to support its safety. The toxicity of ingesting fluoride from toothpaste has been reviewed extensively (Ref. 83). Concern has been expressed over the need to supervise the use of fluoridated toothpaste by young children because of the potential risk of developing fluorosis (Ref. 84). Acute toxicity of stannous fluoride in the rat (LD 50 ) appears to range from 31 to 300 mg/kg. Thus, it appears to have an acute toxicity comparable to that of sodium fluoride (Refs. 85 and 86). Toxicity studies show that a dentifrice formulation containing stannous fluoride plus stannous chloride was comparable to other nationally marketed fluoride-containing dentifrices. Several subchronic toxicity tests of stannous fluoride dentifrice formulations h [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A03-12783. Public record. Not legal advice.