Off-label Use of Fluoride Varnishes

Peter K. Domoto, D.D.S., M.P.H.
Professor and Chair
Department of Pediatric Dentistry
University of WashingtonIntroduction

The last half century in the US has demonstrated dramatic reductions in decay rates. While the causes of this reduction are multifactorial, it is clear that enormous benefits in caries reductions must be attributed to both systemic and topical mechanisms of fluoride ion. The efficacy of topical fluoride, both home and professional applications is well established. (1) In recent years as caries rates have gone down there has been a rise of mild to moderate dental fluorosis in permanent teeth. (1,2 ) Thus there are concerns regarding excessive ingestion of fluoride especially in children under the age of 3 years. (3-7)

At the same time, both national data and small area data indicate that some 20% of the population experiences 80% of the decay. (8,9) Clearly, the benefits of fluoride are essential for this high risk for caries group. The challenge for further reductions in caries lies in reducing the rates in these high risk groups.

Fluoride varnishes are a type of topical fluoride and have extensive evidence of efficacy as a caries preventive agent in Europe over the past three decades. (10-17) Fluoride varnishes appear to be comparable in efficacy to traditional fluoride gels currently used in dental practice. In spite of approval by the FDA as a device, fluoride varnishes are not used extensively in this country. The purpose of this paper is to suggest a rationale for the "off-label" use of fluoride varnish as a professionally applied topical for caries prevention.

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The FDA and Federal Law

The US Food and Drug Administration (FDA) administers the Federal Food, Drug and Cosmetic Act which requires manufacturers to demonstrate safety and effectiveness of all new drugs for their indications i.e., [the new drug] "will have the effect it purports or is represented to have under the conditions or use prescribed, recommended or suggested in the proposed labeling." (18) The FDA requires substantial evidence from adequate and well controlled investigations in order to approve a new drug for marketing. (18,19)

Fluoride varnishes became available in the United States in 1991 when the FDA approved DuraflorÆ. FluorProtectorÆ and DuraphatÆ are also currently approved. DuraflorÆ, DuraphatÆ and FluorProtectorÆ have FDA approval as root desensitizers or cavity varnishes, but not as a therapeutic topical fluoride. These three varnishes are considered by the FDA to fall into a category of drugs and devices that "present minimal risk and is (are) subject to the lowest level of regulation." (20) The FDA will not accept the extensive findings from European investigations as adequate evidence for approval for labeling as a caries preventive agent, primarily because European research compares the active drug to no treatment and not to a placebo.

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Off-label Use of Approved Drugs in Medicine

Use of approved fluoride varnishes for caries prevention therefore is an unapproved use or more commonly, "off-label" use, of an approved drug. Such use is not considered unlawful; indeed, the use of drugs off-label is common practice in medicine. Three fourths of the prescription drugs currently marketed in the US lack full pediatric approval. (18) Quoting from the recommendations of the Committee on Drugs of the American Academy of Pediatrics:

"Unapproved use does not imply an illegal use. The word unapproved is used merely to indicate lack of approval, not to imply disapproval or contraindication based on positive evidence of a lack of safety or efficacy." (Committee on Drugs, American Academy of Pediatrics 1996) (18)

The labeling of many drugs, "old and new," contain pediatric disclaimers and are being used extensively "off-label." The following are a few examples of commonly used "off-label" drugs with pediatric disclaimers:19
Albuterol (Ventolin)
Meperidine hydrochloride (Demerol) injection (PCA)
Ketorolac tromethamine (Toradol)
Morhphine (PCA)
Midazolam hydrochloride (Versed)

In addition, some drugs are used off-label when their use is not covered by the drugs labeling. (22) Some examples are as follows:

• Finasteride for benign prostatic hyperplasia. Off-label: male pattern baldness

• Fluoxethine (Prozac) for depression. Off-label uses: Anorexia nervosa, alcoholism, ADHD

• Mexiletine for refractory ventricular arrhythmias. Off-label: Paresthesia associated with diabetic neuropathy

• Triprolidine and Pseudoephedrine (Actifed) for bronchodilation. Off-label: Otitis Media
Both physicians and dentists assume the responsibility for justifying off-label use of approved drugs. If one considers that the application of topical fluoride for a patient who is at risk for caries is the standard of dental practice for his/her community then the selection of an approved fluoride varnish is a reasonable choice.

Justification for Off-label Use of Fluoride Varnish: Application of varnish is safe, effective, quick and easy

• Fluoride varnish is safe. FluorProtectorÆ is 0.9% fluor silane which yields a fluoride concentration approximately one half of conventional acidulated phosphate fluoride (APF). The fluoride concentration of DuraphatÆ and DuraflorÆ varnishes is twice that of APF gels, at 5% NaF, but the amount used per treatment is ten times less. For applications in the primary dentition 0.1 ml to 0.3 ml are utilized (2.3 to 6.8 mg of fluoride ion). (23) The toxic dose of fluoride varnish is reached with 10 times the normal dose. The toxic dose of APF gel is reached with about double the normal dose. In essence, we do not have any alternatives for use of a topical fluoride on very young children. Fluoride varnishes offer the safest topical fluoride available for the young, at risk child. An additional advantage of fluoride varnish is its slow release over time. APF gel is swallowed as a bolus, but varnish sets on the teeth and is swallowed over many hours.

Professionally applied topical fluorides actually present little risk for fluorosis. Burt found that dietary supplements, inadvertent swallowing of fluoride toothpaste, and increased fluoride in food and beverages are the most likely sources of increased fluoride ingestion. (25) In addition, Burt states that "...there is no evidence that swallowing of fluoride gels has been a factor in the increase in fluorosis among North American children." Since the amount of fluoride that is applied in the application of fluoride varnish is small and the varnish sticks to the tooth surface the risk for fluorosis is almost negligible. (24) Clark and Berkowitz in a longitudinal study of dental fluorosis in three Canadian communities concluded that while the prevalence of esthetic problems resulting from fluorosis is low in these communities, children's risk for esthetic problems increases when fluoride dentifrices, fluoride supplements, and fluoridated water are used in the third year of life. (25)

• Fluoride varnish is effective. Caries reductions have been shown to be in the range of 40% which is comparable to APF. (10-17) The principle of the varnish delivery system is based on contact of topical fluoride with the teeth over a sustained period of time. By the mid '70's the benefits of fluoride varnishes were accepted by the European dental community and were being used extensively.

By the early '90's almost 93% of all professionally applied topical fluorides in Scandinavia were varnishes. (27) In addition to the well accepted benefits for smooth surface caries prevention, there is some evidence that varnishes are more effective than other topical fluorides in reducing caries on fissured surfaces. (28)

• Fluoride varnishes offer several advantages over traditional topical fluoride such as speed and ease of application and a greater range of applications. Varnish can be safely and effectively applied to infants and toddlers, developmentally disabled patients, and patients with active gag reflexes. Varnish can be applied to at risk surfaces in a matter of seconds. An effective application is quick and easy. In addition, high risk for caries patients including adults with root caries and/or xerostomia benefit greatly from regular application of fluoride varnish.

Conclusions
Fluoride varnish provides a useful and effective means of delivering topical fluoride to the teeth of patients. As with any topical fluoride, the at risk for caries patient will benefit the most from periodic applications of this material. The fact that fluoride varnish as a caries preventive measure currently must be used "off-label" should not be a barrier to its use in clinical practice. The benefits of fluoride application far outweigh the risk for fluorosis in the at risk for caries patient. If a patient requires a professionally applied topical fluoride and is too young, too uncooperative, or too medically compromised for a four minute (or even one minute) APF treatment, fluoride varnish offers an efficacious and safe alternative.

Fluoride supplementation is not a substitute for topical fluorides in the child less than three years of age. Supplementation is prescribed for the infant and toddler in the form of drops or other liquid medium. There is no evidence that the high risk for caries child would receive any meaningful topical effect from this systemic method of fluoride supplementation. Since the caries preventive effect of supplements is primarily posteruptive it is reasonable to encourage a chewable tablet as soon as possible in order to exploit these topical benefits. (29)

The "off-label" use of drugs is a practice which is common in medicine with a number drugs that have multiple efficacious therapeutic uses. The literature is clear that the major benefit of the fluoride varnishes are their caries preventive properties. (10-17,28) The FDA requirements for substantial evidence from well controlled investigations should be met as soon as possible. Colleagues at the University of Washington are currently conducting controlled investigations designed to provide efficacy data on the use of a fluoride varnish in children under five years of age. An approved status from the FDA for one or more fluoride varnish products will greatly facilitate the use of effective caries preventive measures in both public and private programs.

Varnish is currently classified as a "device" but the FDA has ruled that it is a drug if it is used for caries prevention. There are, unfortunately, significant cost barriers for companies to support the investigations for full approval as a therapeutic agent. Full approval for new FDA labeling is a costly endeavor. It has been estimated that it would require at least half a million dollars for a company to fund the investigations necessary to meet the FDA requirements for new labeling. Dentistry is a small industry and an analysis of potential markets may not justify funded investigations in the minds of the fluoride varnish manufacturers. The reality is that dentistry may have to choose to use fluoride varnishes "off-label" for an extended time.

The Early Childhood Caries (ECC) Conference held on the NIH Campus in October 1997 addressed the etiology, implications and prevention of ECC. (30) It is clear that ECC is of epidemic proportions in many US minority populations. Unfortunately, an effective preventive regimen for high risk for ECC patients has not been developed. Much work remains to develop successful office and community based approaches to the prevention of ECC. In spite of the dearth of well controlled trials in the prevention of ECC, current knowledge of caries and its prevention yields some obvious guidance. The key to an effective primary prevention program with infants and toddlers is to deliver topical fluoride early and often to children at risk. At risk children include those with existing caries (including white spot lesions), family histories of moderate to severe dental disease, and congenital enamel defects. Other risk factors include high-risk pregnancy or complicated delivery and no systemic fluoride received.

Dental care providers and policy makers are encouraged to carefully review the existing data and practices involving the use of fluoride varnishes. A thorough assessment of the caries status of their patients and the potential risks and benefits of fluoride varnish application should result in the adoption of varnishes as a valid means of delivering fluoride to their patients teeth. Fluoride varnishes are safe, effective, and easily incorporated into both public and private programs of caries prevention.

REFERENCES
1. Ripa LW: A critique of topical fluoride methods in an era of decreased caries and increased fluorosis prevalence. J Public Health Dent 51:23-41, 1991.
2. Pendrys DG and Stamm JW: Relationship of total fluoride intake to beneficial effects and enamel fluorosis. J Dent Res 69 (Spec Iss):529-538, 1990.
3. Pang DT and Vann WF, Jr.: The use of fluoride-containing toothpastes in young children: The scientific evidence for recommending a small quantity. Pediatr Dent 14:384-387, 1992.
4. Levy SM, Maurice TJ and Jakobsen JR: A pilot study of preschoolers' use of regular-flavored dentifrices and those flavored for children. Pediatr Dent 14:388-391, 1992.
5. Levy SM, Maurice TJ and Jakobsen JR: Dentifrice use among preschool children. J Am Dent Assoc 124:57-60, 1993.
6. Stookey GK: Review of fluorosis risk of self-applied topical fluorides: dentifrices, mouthrinses and gels. Community Dent oral Epidemiol 22:282-286, 1994
7. Skotowski MC, Hunt RJ and Levy SM: Risk factors for dental fluorosis in pediatric dental patients. J Public Health Dent 55:154-159, 1995.
8. NIDR National survey of oral health in US school children 1986-87. Bethesda, MD: National Institute of Dental Research, 1992.
9. Leroux B, Maynard R, Domoto P, Zhu C, Milgrom P: The estimation of caries prevalence in small areas. J Dent Res 75:1947-1956, 1996.
10. Petersson LG: On topical application of fluorides and its inhibiting effect on caries; thesis University of Lund. Odont Rev 26(suppl 34) 1975.
11. Sepp L: Fluoride varnishes and enamel caries; thesis University of Groningen, 1987.
12. de Bruyn H and Arends J: Fluoride varnishes. J Biol Buccale 15:71-82, 1987.
13 Petersson LG, Arthursson L, ÷sterberg C, Jonsson G and Gleerup A: Caries-inhibiting effects of different modes of Duraphat varnish reapplication: A 3 year radiographic study. Caries 25:70-73, 1991.
14. Helfenstein U, Steiner M: Fluoride varnishes (Duraphat): A meta-analysis. Community Dent Oral Epidemiol 22:1-5, 1994.
15. Weinstein P, Domoto P, Koday M, and Leroux B: Results of a promising open trial to prevent baby bottle tooth decay: a fluoride varnish study. J Dent Child 61:338-341, 1994.
16. Twetman S, Petersson LG and Pakhomov GN: Caries incidence in relation to salivary mutans streptococci and fluoride varnish applications in preschool children from low- and optimal-fluoride areas. Caries Res30:347-353, 1996.
17. Twetman S and Petersson LG: Prediction of caries in pre-school children in relation to fluoride exposure. Eur J Oral Sci 104:523-528, 1996.
18. Committee on Drugs (Berlin CM, Jr., Chair) American Academy of Pediatrics. Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: Subject review. Pediatrics 98:143-145, 1996.
19. Cot CJ, Kauffman RE, Troendale GJ and Lambert GH: Is the "Therapeutic Orphan" about to be adopted? Pediatrics 98:118-123, 1996.
20. Code of the Federal Registry Part 130. Legal status of approved labeling for prescription drugs; prescribing for uses unproved by the Food and Drug Administration. Aug. 15, 1972.
22. Hom L: Off-label use of approved drugs. Pharmacy Newsletter 15:17-18, 1997.
23. Sepp L and Hanhijarvi H: Fluoride concentrations in whole and parotid saliva after application of fluoride varnishes. Caries Res 17:476-480, 1983.
24. Ekstrand J, Koch G, Petersson LG: Plasma fluoride concentration and urinary fluoride excretion in children following application of the fluoride containing varnish Duraphat. Caries Res 1980;14:185-189.
25. Burt BA: The changing patterns of systemic fluoride intake: J Dent Res 71(Spec Iss):1228-1237, 1992.
26. Clark CD and Berkowitz J: The influence of various fluoride exposures on the prevalence of esthetic problems resultuing from dental fluorosis. J Pub Health Dent 57:0144-149, 1997.
27. Moran R. and Saemundsson, S: Fluoride Varnish: An alternative to traditional topical fluoride therapy. Department of Pediatric Dentistry, University of North Carolina 1996.
28. Bravo M, Baca P, Llodra JC and Osorio E: A 24-month study comparing sealant and fluoride varnish in caries reduction on different permanent first molar surfaces. J Public Health Dent 57:184-186, 1997.
29. Clark CD: Appropriate use of fluorides in the 1990s. J Canad Dent Assoc 59:272-279, 1993.
30. Tinanoff N and O'Sullivan DM: Early childhood caries: Overview and recent findings. Pediatr Dent 19:12-15, 1997.


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