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Introduction

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Generic Name(s):

Fluoride increases resistance to dental caries and therefore is referred to as a cariostatic agent; fluoride also desensitizes dentin.

Uses

[Section Outline]

Prevention of Dental Caries !!navigator!!

Fluoride is used to reduce the incidence of dental caries and to slow or reverse the progression of existing dental lesions.107,109 Exposure to small amounts of oral and topical fluoride on a daily basis will reduce the risk for dental caries in all age groups.109,110 It was previously hypothesized that fluoride inhibited dental caries by a preeruptive effect (i.e., incorporation into developing dental enamel), but further laboratory and clinical research now indicates that the predominant effect is posteruptive, making consistent maintenance of a small amount of fluoride in saliva and dental plaque important.109,113

Combined use of fluoridated dentifrices and fluoridated water has been found to provide greater protection against dental caries than either source alone.109 The US Centers for Disease Control and Prevention (CDC) recommends that adults and children at low risk for dental caries drink water with an optimal fluoride concentration and brush their teeth twice daily with a fluoridated dentifrice to prevent and control dental caries;109 those at higher risk for dental caries may require additional exposure to fluorides (e.g., mouth rinses, dietary supplements, preparations applied by dental personnel).109

For adults, adolescents, and children 6 years of age or older who are at increased risk for dental caries, the American Dental Association (ADA) recommends use of the following prescription-strength or professionally applied fluorides: professional application of a varnish containing 2.26% fluoride ion or an acidulated phosphate fluoride gel containing 1.23% fluoride ion at least every 3-6 months or in-home use of a prescription-strength gel or paste containing 0.5% fluoride ion twice daily or rinsing solution containing 0.09% fluoride ion at least weekly (or daily for prevention of root caries in adults).136 The American Academy of Pediatric Dentistry (AAPD) also recognizes the efficacy of these preparations in reducing dental caries and states that children at risk for dental caries should receive a professional fluoride treatment at least every 6 months.134 The ADA and AAPD recommend the 2.26% varnish as the only professionally applied fluoride preparation for use in at-risk children younger than 6 years of a in-home prescription-strength topical fluoride preparations (e.g., gels, pastes, rinsing solutions) are not recommended for this age group.134,136 However, the ADA states that clinicians may consider use of these other preparations on the basis of individual patient factors that may alter the risk-benefit balance.136

Because many infants and young children do not receive regular dental care, the American Academy of Pediatrics (AAP) and the US Preventive Services Task Force (USPSTF) state that fluoride varnish is recommended in the primary care setting for all infants and young children beginning at tooth eruption and continuing until the establishment of dental care.131,137 Although dental experts recommend that use of fluoride varnish be limited to children at increased risk for dental caries, the USPSTF states that existing tools for assessment of caries risk have not been validated in the primary care setting and it is not known whether use of these tools by primary care clinicians will accurately and consistently identify children who will develop dental caries.137

For children at low risk for dental caries, AAP recommends that use of fluoridated dentifrice and fluoride varnish (applied professionally every 3-6 months) be initiated at tooth eruption; if the water supply is not fluoridated, all potential sources of fluoride should be assessed and dietary fluoride supplements considered accordingly.131 For children at high risk for dental caries, AAP recommends use of nonprescription fluoride-containing mouth rinse starting at 6 years of age (if the child can reliably swish and expectorate the rinse) in conjunction with the recommendations made for low-risk children.131

Patients at increased risk for dental caries include those with low socioeconomic status or low levels of parental education, those who do not seek regular dental care, and those without dental insurance or access to dental services.109 Additional risk factors include a high incidence of dental caries in older siblings or caregivers, root surfaces exposed by gingival recession, high levels of infection with cariogenic bacteria, impaired ability to maintain oral hygiene, malformed enamel or dentin, reduced salivary flow (because of medications, radiation, or disease), low salivary buffering capacity (i.e., decreased ability of saliva to neutralize acids), and wearing of space maintainers, orthodontic appliances, or dental prostheses.109 The risk of dental caries can increase if these risk factors are combined with dietary practices conducive to dental caries (i.e., frequent consumption of refined carbohydrates).109 The dental or health-care provider must periodically evaluate the individual's risk for dental caries, current fluoride sources, and potential for enamel fluorosis before recommending supplemental fluoride therapy.109

Community Water Fluoridation

The most effective means of providing optimal levels of fluoride to large segments of the population is fluoridation of public water supplies. There is good evidence to support fluoridation of the public water supply to prevent and control dental caries.109,130,131,132,133 The US Public Health Service (PHS) currently recommends an optimal fluoride concentration of 0.7 ppm (mg/L) in public water supplies to provide protection from dental caries while limiting the risk of dental fluorosis.130 Prior to this 2015 recommendation, PHS had recommended an optimal concentration range of 0.7-1.2 ppm (mg/L) depending on the annual mean maximum daily temperature of the area, and stated that concentrations should be at the lower end of the range in warm climates where more water is likely to be ingested.106,109,130 The change in recommendation was prompted by newer data indicating that children's water intake is not correlated with outdoor air temperature, that the incidence of dental fluorosis (mostly very mild or mild) has increased since the 1980s, and that other fluoride sources (e.g., fluoride-containing dentifrices, rinsing solutions, professionally applied preparations, commercial beverages, and foods) account for an increasing proportion of total fluoride exposure in the US.130 It is estimated that implementation of the newer recommendation will result in a reduction of fluoride ingestion from drinking water alone of about 25% and a reduction in total fluoride intake of about 14%.130

The National Academy of Sciences (NAS) states that the Adequate Intake (AI) of fluoride to prevent dental caries in children older than 6 months of age and in adults is 0.05 mg/kg daily, which coincides with the average dietary intake by US infants and children since 1980 in areas with optimally fluoridated water.107 Average dietary intakes for adults living in US communities with fluoridated water have ranged from 1.4-3.4 mg daily (0.02-0.05 mg/kg daily for a 70-kg person).107

In some communities where fluoridation of the water supply was not possible (e.g., rural areas), fluoridation of the school's water supply (at a concentration of 4.5 times the optimal concentration to compensate for the more limited consumption of fluoridated water outside the school) was promoted to provide a source of fluoride for children in the community.109 Although studies evaluating the effects of school water fluoridation reported a 40% reduction in dental caries in school children, the trials were not blinded and lacked concurrent controls. 109 Therefore, CDC states that the appropriateness of this practice is limited and alternative fluoride sources should be considered.109

Because consumption of commercially available beverages (including bottled water) in the US and Canada is displacing the consumption of tap or well water, the relative importance of fluoridation of local community water on fluoride intake may be affected.107 Some evidence indicates that more than 50-75% of fluid intake in children and adolescents may be from commercially available beverages.107,109 Thus, the fluoride concentration of water used in the preparation of these commercial beverages is an important factor affecting fluoride intake in the US and Canada.107 Despite this, however, current recommendations for fluoride supplementation in children continue to be based on the fluoride concentrations in local drinking water.107,131,134,135

Some community water supplies naturally contain fluoride at concentrations exceeding 2 ppm (mg/L), a concentration associated with an increased risk for development of enamel fluorosis in children 8 years of age or younger. 109,131 In communities where the concentration of fluoride in the water supply exceeds 2 ppm, an alternative source of drinking water should be used for children 8 years of age or younger.109,131,135

In areas where naturally occurring concentrations of fluoride in drinking water are inadequate and community water fluoridation programs are not available or feasible, daily administration of individualized fluoride supplements is used in children to provide adequate levels of fluoride ion to protect against dental caries.

Oral Fluorides

Sodium fluoride oral solutions and chewable tablets are used as dietary supplements for the prevention of dental caries in children in areas where the concentration of fluoride ion in drinking water is less than optimal.109,131,134,135,138 While the ADA, AAPD, and CDC state that dietary fluoride supplements should be considered only for children in such areas who are at high risk for dental caries, the AAP states that dietary fluoride supplements also may be considered for lower-risk children.109,131,134,135,138 Dosage is based on the concentration of fluoride in the drinking water and the child's age.109,110,131,134,135 Consideration also must be given to sources of fluoride other than the child's primary drinking water (e.g., other water supplies in the home, childcare settings, or school; bottled water or processed beverages; infant formula or prepared foods; dentifrice or mouth rinse) before selecting the dosage of fluoride to be prescribed.109,110,131,134,135 Commonly used home carbon-filter-based water purification systems do not remove fluoride from water; however, other water treatment systems (e.g., reverse osmosis, distillation) can effectively remove fluoride.131 Beginning in 1979, infant formula manufacturers in the US began to uniformly manufacture ready-to-use and liquid concentrate formulas with defluoridated water so that these preparations contain low fluoride concentrations (less than 0.3 ppm [mg/L]); therefore, fluoride concentrations in infant formulas that require reconstitution depend on the amount of fluoride added locally as fluoridated water prior to use.100,101,102,107

Oral fluoride supplements should not be used in areas where the fluoride content of drinking water exceeds 0.6 ppm (mg/L). The CDC states that there is good evidence to support the use of oral fluoride supplements in children 6-16 years of age who are at increased risk for dental caries and whose primary drinking water has a low fluoride concentration.109 However, clinical trials conducted in children younger than 6 years of age have been flawed in design and conduct, and there are no clinical studies to confirm the effectiveness of oral fluoride supplements in controlling dental caries in adults and children older than 16 years of age.109,185

The ADA, AAPD, and AAP state that in areas where oral fluoride supplements are necessary, children should receive fluoride supplements daily from 6 months of age until approximately 16 years of age to provide maximum benefit to both deciduous and permanent teeth. The ADA, AAPD, and AAP currently recommend that children 6 months to younger than 3 years of age receive 0.25 mg of oral fluoride daily in areas where the concentration of fluoride ion in drinking water is less than 0.3 ppm (mg/L); children 3 to younger than 6 years of age should receive 0.5 or 0.25 mg of oral fluoride in areas where the concentration of fluoride ion in drinking water is less than 0.3 or 0.3-0.6 ppm (mg/L), respectively.107,131,134,135 Children 6-16 years of age should receive 1 or 0.5 mg of oral fluoride in areas where the concentration of fluoride ion in drinking water is less than 0.3 or 0.3-0.6 ppm (mg/L), respectively.107,131,134,135

Although fluoride is distributed into milk, concentrations generally are less than 0.05 ppm (mg/L) and infants who are solely breast-fed ingest considerably less fluoride than infants receiving formula diluted with fluoridated drinking water. In the past, the ADA, AAP, and most clinicians have stated that oral fluoride supplements should be considered for infants who are solely breast-fed (i.e., those not receiving water, juice, or solid foods), especially those breast-fed for more than 6 months. However, the ADA, AAPD, and AAP currently do not recommend oral fluoride supplements in infants younger than 6 months of age,107,131,134,135 since limited evidence (based on caries rates between solely breast-fed infants not receiving fluoride supplements and infants receiving formula diluted with fluoridated water) suggests that fluoride supplementation may not be necessary for solely breast-fed infants living in areas with adequately fluoridated water.101,102,107

Sodium fluoride is commercially available in multivitamin or multivitamin/iron preparations for use as oral fluoride supplements in infants and children. However, the fixed proportion of fluoride contained in these combination preparations makes it difficult to appropriately adjust the amount of fluoride needed in areas where drinking water contains substantial but inadequate concentrations of fluoride.

Sodium fluoride has been administered orally to pregnant women to prevent caries in the deciduous teeth of their children. However, there is evidence that fluoride supplements administered orally to pregnant women do not provide caries prevention benefit for their children.107,109,143

Topical Fluorides

Sodium fluoride, acidulated phosphate fluoride (sodium fluoride and phosphoric acid), and stannous fluoride are applied directly to the surfaces of teeth in the form of solutions, foams, creams, gels, or varnishes for the prevention of dental caries in children and adults. The effectiveness of topically applied fluoride varies according to the concentration of fluoride ion in the preparation and the method and frequency of application; efficacy also may depend on the duration of use.

For the prevention of dental caries, use of fluoridated dentifrice is recommended beginning at tooth eruption.131,135,139 Sodium fluoride 1.1% gel (containing 0.5% fluoride ion); acidulated phosphate fluoride gel containing 0.5% fluoride ion; sodium fluoride 0.02, 0.05, or 0.2% oral rinsing solutions (containing 0.009, 0.02, or 0.09% fluoride ion, respectively); oral rinsing solutions of acidulated phosphate fluoride containing 0.02% fluoride ion; stannous fluoride 0.4% gel;114,115,116,119,158,171,181 and oral rinsing solutions containing 0.63% stannous fluoride (following dilution to form a 0.1% solution) are used to provide additional anticaries benefits in adults and pediatric patients 6 years of age and older.103,117,169 Sodium fluoride 2% gel, foam, or oral rinsing solution (containing 0.9% fluoride ion); sodium fluoride 5% varnish (containing 2.26% fluoride ion); or acidulated phosphate fluoride gel or foam containing 1.23% fluoride ion may be applied by dental personnel for additional anticaries benefits.120,136,160,162,172,173 When recommended by a clinician, some rinsing solutions (e.g., Phos-Flur® acidulated phosphate fluoride rinse) can be used as a rinsing solution and then swallowed to provide topical and systemic fluoride in children 3 years of age and older who live in areas where the fluoride content in drinking water is less than optimal.

Intake from fluoridated dental products such as dentifrices and mouth rinses adds considerable fluoride, often approaching or exceeding that from diet, particularly in young children who have poor control of the swallowing reflex.107 Although exposure from professionally applied products (e.g., rinses and gels with high fluoride concentrations) occurs less frequently, such products also contribute to fluoride intake.107

Efficacy of Topical Fluorides in Preventing Dental Caries

Evidence supports the use of topical fluorides (rinses, gels, varnish) in patients at increased risk for dental caries.109,141,142,144

Meta-analysis of 13 randomized clinical trials comparing fluoride varnish (most commonly sodium fluoride varnish containing 2.26% fluoride ion applied to the teeth semiannually) with placebo or no treatment in children and adolescents with permanent teeth indicated that those receiving fluoride varnish had, on average, a 43% reduction in decayed, missing, and filled tooth surfaces, while meta-analysis of 10 randomized clinical trials in children with primary teeth suggested that fluoride varnish resulted in a 37% reduction in decayed, missing, and filled tooth surfaces.141

The ADA states that there is high-level evidence that a prescription-strength gel or paste containing 0.5% fluoride ion results in substantially more arrest of root caries lesions compared with a nonprescription dentifrice.140 Meta-analysis of 25 randomized clinical trials comparing fluoride gel (various types and concentrations, most commonly acidulated phosphate fluoride gel containing 1.23% fluoride ion, typically applied via trays and administered no more than 4 times per year by dental personnel or self-administered 5 or more times per year under supervision) with placebo or no treatment in children and adolescents with permanent teeth indicated that those receiving fluoride gel had, on average, a 28% reduction in decayed, missing, and filled tooth surfaces; meta-analysis of 3 randomized clinical trials in children with primary teeth suggested that fluoride gel resulted in a 20% reduction in decayed, missing, and filled tooth surfaces.144

For fluoride mouth rinses, the ADA states that there is strong evidence supporting use in children at increased risk for dental caries and low-level evidence of benefit for prevention of root caries in adults.140 Daily use of oral rinsing solutions containing 0.05% sodium fluoride (0.02% fluoride ion) or once-weekly use of rinsing solutions containing 0.2% sodium fluoride (0.09% fluoride ion) reportedly results in a 30-40% reduction in the incidence of dental caries in children who live in areas without fluoridated drinking water and also has been shown to provide additional anticaries benefits in children who live in areas with optimally fluoridated drinking water. Preliminary data indicate that there is no substantial difference in effectiveness between daily and weekly use of sodium fluoride oral rinsing solutions. Meta-analysis of 35 clinical trials comparing regular use of fluoride mouth rinse (generally 0.05% sodium fluoride administered daily or 0.2% sodium fluoride administered once every 1 or 2 weeks) with placebo or no mouth rinse in school-age children and adolescents indicated that those receiving fluoride mouth rinse had, on average, a 27% reduction in decayed, missing, and filled tooth surfaces in permanent teeth.142 The analysis indicated that benefit from fluoride mouth rinse is likely even in children using fluoridated dentifrice or living in communities with water fluoridation.142 Analysis of 13 clinical trials indicated, on average, a 23% reduction in decayed, missing, and filled permanent teeth (rather than tooth surfaces) in children and adolescents receiving fluoride mouth rinse compared with those receiving placebo or no mouth rinse.142

Topical application of sodium fluoride solutions (usually a 2% solution) has been reported to result in a 30-40% reduction in the incidence of dental caries in children 6-12 years of age. In more recent studies, semiannual application of fluoride preparations by dental personnel reportedly resulted in an average reduction of 26% in the incidence of dental caries in the permanent teeth of children residing in areas without fluoridated water.109

The CDC states that there is good evidence obtained from one or more properly conducted randomized clinical trials to support the use of fluoridated dentifrices in all individuals.109 Meta-analysis of 70 clinical trials comparing fluoridated dentifrice with placebo indicated that children and adolescents who brushed their teeth at least once daily with fluoridated dentifrice had a 24% reduction in decayed, missing, and filled permanent teeth; the effect was greater in patients with higher baseline levels of caries and with higher fluoride concentration, more frequent (e.g., twice daily) use, and supervised brushing, but was not influenced by exposure to fluoridated water.145 Some data suggest that use of fluoridated dentifrice may reduce the incidence of caries in children and adolescents by an amount ranging from 16% per tooth to 31% per tooth surface.140

The beneficial effects of topical fluorides (e.g., dentifrices, gels, rinses) have not been adequately studied in adults; however, teeth remain susceptible to caries throughout life, and administration of topical fluoride could be effective in preventing dental caries at any age.109

ADA-recommended Prescription and Professionally Applied Topical Fluoride Therapy

For adults, adolescents, and children 6 years of age or older who are at increased risk for dental caries, the ADA recommends use of the following prescription-strength or professionally applied topical fluorides: professional application of a varnish containing 2.26% fluoride ion or an acidulated phosphate fluoride gel containing 1.23% fluoride ion at least every 3-6 months or in-home use of a prescription-strength gel or paste containing 0.5% fluoride ion twice daily or rinsing solution containing 0.09% fluoride ion at least weekly (or daily for prevention of root caries in adults).136 For at-risk children younger than 6 years of age, 2.26% fluoride varnish is recommended.134,136 Experts state that in patients at increased risk for dental caries, the recommended frequency for application of topical fluorides by dental personnel is at least every 3-6 months.109,134,136 Patients at low risk for dental caries may not require any topical fluorides in addition to fluoridated water and fluoridated dentifrice.136

Although 5% sodium fluoride varnish (containing 2.26% fluoride ion) is regulated as a medical device and is not FDA-labeled as an anticaries agent,146,159,166 the ADA states that the benefits of professionally applied 2.26% fluoride varnish for prevention of dental caries outweigh potential harms in all age groups at increased risk for dental caries.136 The ADA states that evidence from multiple randomized and nonrandomized clinical trials conducted in various populations (mostly pediatric patients with various levels of dental caries, primary or permanent dentition, and various other exposures to fluoride) favors providing fluoride varnish at least semiannually as an option for dental caries prevention in pediatric patients (up to 18 years of age) at increased risk for dental caries with a moderate level of certainty; the ADA recommendation supporting use of 2.26% fluoride varnish as an option for preventing dental caries in adults at increased risk for dental caries has a low level of certainty and is based largely on extrapolation of data from pediatric patients.136 Because of the low risk of harm associated with use of unit-dose packages of 2.26% fluoride varnish, this preparation is the only prescription-strength or professionally applied topical fluoride preparation recommended by the ADA for children younger than 6 years of age.136 Although varnishes containing 0.1% fluoride ion also may be commercially available, the ADA states that they provide no benefit for dental caries prevention when applied semiannually in children younger than 6 years of age or 3 times yearly in children and adolescents 6-18 years of age.136

Evidence from multiple randomized and nonrandomized clinical trials conducted in various populations (mostly school-age children with permanent teeth) favors use of professionally applied acidulated phosphate fluoride gels containing 1.23% fluoride ion as an option for dental caries prevention in pediatric patients 6-18 years of age who are at increased risk for dental caries with a moderate level of certainty and as an option for preventing dental caries in adults at increased risk for dental caries with a low level of certainty.136 The ADA states that there is no demonstrated anticaries benefit from semiannual use of acidulated phosphate fluoride foams containing 1.23% fluoride in children and adolescents 6-18 years of age.136 Although professionally applied acidulated phosphate fluoride gels or foams containing 1.23% fluoride ion may provide benefit for children younger than 6 years of age, the ADA states that the potential for harm, including swallowing the gel or foam, outweighs the benefit.136 The ADA also states that there is no demonstrated anticaries benefit from semiannual professional application of fluoride pastes in pediatric patients up to 18 years of age.136

The ADA states that evidence from multiple randomized and nonrandomized clinical trials conducted mostly in school-age children with permanent teeth favors in-home use of prescription-strength rinsing solutions containing 0.09% fluoride ion as an option for dental caries prevention in pediatric patients 6-18 years of age who are at increased risk for dental caries with a moderate level of certainty; the ADA recommendation supporting use of these rinsing solutions as an option for preventing dental caries in adults at increased risk for dental caries has a low level of certainty.136 In children younger than 6 years of age, the benefit from rinsing solutions containing 0.09% fluoride ion is unknown and is outweighed by the potential for harm, including swallowing the mouth rinse.136

The ADA recommendations supporting in-home use of prescription-strength gels or pastes containing 0.5% fluoride ion as an option for preventing dental caries in adults and pediatric patients 6-18 years of age who are at increased risk for dental caries have a low level of certainty.136 These recommendations are based largely on randomized and nonrandomized clinical trials evaluating fluoride gels or pastes in pediatric patients 2-15 years of age.136 Although in-home use of prescription-strength gels or pastes containing 0.5% fluoride ion may provide benefit for children younger than 6 years of age, the ADA states that the potential for harm, including swallowing the gel or paste, outweighs the benefit.136

Special Populations

Topical fluorides are used to prevent early stages of dental caries, appearing as decalcified white lesions, around fixed orthodontic appliances.131,178,179 Because use of fluoridated dentifrice alone is not sufficient in many patients with fixed orthodontic appliances, use of additional fluoride preparations (e.g., gels, mouth rinses, varnish) has been recommended.178,179 However, additional studies are needed to determine the optimal means for delivering topical fluorides to individuals undergoing orthodontic treatment.179 Limited data indicate that fluoride varnish can reduce the risk of decalcified white lesions.179

Acidulated phosphate fluoride gels or solutions containing 0.5-1.23% fluoride ion have been effective when used topically to control dental decay that frequently follows xerostomia-producing radiation therapy of tumors of the head and neck; these preparations are often used in conjunction with a saliva substitute (e.g., Xero-Lube®) in patients with this condition. Gels containing 0.4% stannous fluoride also have been used to protect against postirradiation caries.

Desensitizing Dentin !!navigator!!

Sodium fluoride, acidulated phosphate fluoride, and stannous fluoride are used topically to desensitize exposed root surfaces of teeth. Hypersensitivity is thought to result from dentin exposure and fluid movement through the exposed dentinal tubules, which activates nerve fibers in the pulp.148,175 Pain occurs when the exposed root surfaces are exposed to various thermal, tactile, evaporative, acidic, or other stimuli.175 The number of exposed tubules is thought to correlate with sensitivity.148,175 Thus, treatment may consist of therapies that contribute to occlusion of the open tubules (e.g., fluorides, oxalates, sealants or bonding agents, laser therapy) and/or inhibit neural transmission (e.g., potassium nitrate).148,175,176 Evidence regarding the relative efficacy of various therapies or combinations of therapies is limited.176 Fluoride therapy may include use of fluoridated dentifrices and fluoride gels or rinses supplemented as required with professionally applied fluoride varnish, gel, or rinse.124,148,156,166,168,169,175,177 It has been suggested that the effectiveness of topical fluoride therapy for this condition may be increased by concomitant iontophoresis,147,148 but the efficacy of this procedure has not been fully established.147

Bone Diseases !!navigator!!

Sodium fluoride has been used orally to increase bone density and relieve bone pain in the treatment of various metabolic (osteoporosis, corticosteroid-induced osteoporosis) and neoplastic bone diseases (bone lesions in multiple myeloma, bone pain associated with metastatic prostatic carcinoma). Although fluoride stimulates formation of new bone, the quality of the bone mass developed is uncertain and the evidence that fluoride reduces fracture risk is conflicting and controversial.150,184 Other therapies (e.g., calcium, vitamin D, bone resorption inhibitors) currently are preferred for these metabolic and neoplastic bone diseases.108,149,150,151,152,153

Dosage and Administration

[Section Outline]

Fluorides are administered orally as sodium fluoride or topically directly onto teeth as sodium fluoride, acidulated phosphate fluoride, sodium monofluorophosphate, or stannous fluoride.

To minimize the risk of fluorosis and the amount of fluoride swallowed and absorbed systemically, children younger than 12 years of age should be instructed and/or supervised carefully regarding proper techniques for use of topical fluoride preparations.100,101,103 When using fluoride-containing dentifrices in children 3-6 years of age, only a pea-sized amount (approximately 0.25 g) of dentifrice should be applied to the toothbrush twice daily, and the child should be instructed not to swallow the toothpaste.131,139 When using fluoride-containing dentifrices in younger children (from eruption of the first tooth up to 3 years of age), only a smear (approximately 0.1 g; about the size of a grain of rice) of dentifrice should be applied to the toothbrush twice daily, and the child should be supervised to ensure that the correct amount of dentrifice is used and to minimize swallowing of the dentifrice.131,139 The American Academy of Pediatrics (AAP) states that young children should not rinse with water after brushing their teeth with fluoridated dentifrice because their instinct is to swallow; expectorating without rinsing reduces the amount of fluoride swallowed and leaves some fluoride in saliva, where it is available for uptake into plaque.131 Unless a fluoride rinsing solution also is being used to provide oral fluoride supplementation, rinsing solutions should not be swallowed after administration but should be expectorated once rinsing is complete.103

Patients receiving fluoride powders or concentrated rinsing solutions should be advised that the preparation must be reconstituted and/or diluted as directed prior to use.103 Patients receiving fluoride treatment gels or rinsing solutions for self-administration should be advised that these preparations are to be used as directed and should not be used as dentifrices or mouthwashes/gargles, respectively.103

Oral Fluorides !!navigator!!

To provide protection against dental caries, fluoride preferably should be provided by fluoridation of public water supplies. Oral fluoride supplements should be administered only when community fluoridation programs are not available or feasible and when the fluoride ion concentration in drinking water is 0.6 ppm (mg/L) or less.

Sodium fluoride is administered orally as solutions or chewable tablets. Sodium fluoride oral solutions may be administered undiluted or mixed with water or other nondairy liquids.131 Chewable tablets should be dissolved in the mouth or chewed before swallowing and should preferably be administered at bedtime after brushing the teeth. Mixing of fluoride solutions with milk or formula or ingestion of dairy products within 1 hour of oral administration of fluoride supplements is not recommended since fluoride absorption may be impaired.131,155

Dosage of sodium fluoride is expressed in terms of fluoride ion. Dosage of oral fluoride supplements varies according to the age of the child. To avoid dental fluorosis, dosage also must be adjusted in proportion to the amount of fluoride ion provided in drinking water. Other sources of fluoride also should be considered.109,110

The usual oral dosage of fluoride ion for children who live in areas where the fluoride ion concentration in drinking water is less than 0.3 ppm (mg/L) is 0.25 mg daily from 6 months to younger than 3 years of age, 0.5 mg daily for children 3 to younger than 6 years of age, and 1 mg daily for children 6-16 years of age.107,109,131,134,135 The usual oral dosage for children who live in areas where the fluoride ion concentration in drinking water is 0.3-0.6 ppm (mg/L) is 0.25 mg daily for children 3 to younger than 6 years of age and 0.5 mg daily for children 6-16 years of a oral fluoride supplements are unnecessary in children younger than 3 years of age who live in areas where the fluoride ion concentration in drinking water is 0.3-0.6 ppm (mg/L).107,109,131,134,135

As recommended by the National Academy of Sciences (NAS), the estimated adequate daily dietary intake of fluoride is 3.1-3.8 mg in adults 19 years of age and older and 0.01 and 0.5 mg in infants up to 6 months of age and 7-12 months of age, respectively. The estimated safe and adequate daily dietary intake of fluoride is 0.7, 1.1, 2 and 2.9-3.2 mg in children 1-3, 4-8, 9-13, and 14-18 years of age, respectively.107 The NAS states that the upper level for the dietary intake of fluoride should not be routinely exceeded, since the amount of fluoride necessary to produce acute toxicity may be only slightly greater than recommended adequate intakes.104,107 Because of the risk of dental fluorosis, tolerable upper intake levels recommended by NAS are 0.7, 0.9, 1.3, and 2.2 mg daily for children 0-6 months, 7-12 months, 1-3 years, and 4-8 years of age, respectively.107 For older children and adults in whom dental fluorosis usually is unlikely, including pregnant or lactating women, the tolerable upper limit recommended by NAS is 10 mg daily, since clinically apparent skeletal fluorosis can occur in this age group at such daily intakes over several years.107 The risk of skeletal fluorosis may be increased in malnourished individuals living in hot climates or tropical areas.107

Topical Fluorides !!navigator!!

Sodium Fluoride

Sodium fluoride is applied topically to teeth as a 0.02, 0.05, or 0.2% rinsing solution (containing 0.009, 0.02, or 0.09% fluoride ion, respectively); 1.1% gel (containing 0.5% fluoride ion); 2% gel, foam, or rinsing solution (containing 0.9% fluoride ion); or 5% varnish (containing 2.26% fluoride ion).115,116,120,158,160,162,164,165 Sodium fluoride also is applied topically to teeth in appropriately formulated prescription or nonprescription dentifrices (generally containing 0.5 or 0.1-0.15% fluoride ion, respectively).135,165 Depending on the fluoride concentration, topical fluoride preparations may be applied once daily, twice daily, or once weekly;103,115,116,158 professionally applied topical fluorides generally are applied at least every 3-6 months for prevention of dental caries.109,134,136

In adults and children 6 years of age or older, rinsing solutions containing 0.02% (10 mL) or 0.05% (10 mL) of sodium fluoride generally are self-administered twice or once daily, respectively, after thoroughly brushing the teeth.116,158 In adults and children older than 6 years of age, rinsing solutions containing 0.2% sodium fluoride (10 mL) are administered once weekly, preferably at bedtime, after thoroughly brushing the teeth.115 The solutions should be rinsed around and between the teeth for 1 minute and then expectorated. Patients should be instructed not to swallow the solution. For maximum benefit, patients should not eat or drink for at least 30 minutes after using the rinsing solution.116,158

In adults and children 6 years of age or older, gels containing 1.1% sodium fluoride generally are administered once daily, unless otherwise instructed by a clinician, preferably at bedtime after brushing and flossing the teeth.119,164 The gel should be applied in a thin ribbon to the teeth using a toothbrush or mouth trays for at least 1 minute and then expectorated.119,164 Patients should be instructed not to swallow the gel.119,164 Children 6-16 years of age should be instructed to rinse their mouth thoroughly after expectorating.119 For maximum benefit, adults should not eat, drink, or rinse their mouth for at least 30 minutes after using the gel.119,164

Sodium fluoride 2% gel or foam can be applied topically to teeth by dental personnel by means of trays.120,160,161 The trays may be filled with gel (one-third full) or with foam and then inserted into the patient's mouth.120,160,161 For maximum benefit, the patient should be instructed to bite down lightly for 4 minutes;120,134,160,161,182 the trays should then be removed and the patient instructed to expectorate the excess gel or foam.120,160,161 Patients should not eat, drink, or rinse their mouth for 30 minutes after application.120,160,161

In adults and children (starting at the age of primary tooth eruption), varnishes containing 5% sodium fluoride (2.26% fluoride ion) can be applied topically to teeth by dental personnel (or by other primary care clinicians prior to the establishment of dental care) for dental caries prevention .131,134,135,136,137,159,166 The varnish is applied to tooth surfaces in a thin layer by means of an applicator brush and hardens on contact with saliva;135,159,166 the coating wears off over a period of hours.135,159,166 Patients should be advised to eat only soft foods and avoid hot drinks for several hours after application, and also should be instructed to refrain from flossing or brushing the teeth for at least 4 hours and preferably for 24 hours.159,167 A typical application requires 0.2-0.5 mL.135 For sensitivity relief, fluoride varnish frequently is applied every 6 months, but may be used safely 4 times yearly in patients 6 years of age or older.166 Other prescription-strength topical fluoride preparations should be avoided for 24 hours after application, and use of fluoride dietary supplements should be suspended for several days after treatment.159,166

Rinsing solutions containing 2% sodium fluoride (10 mL) may be administered by dental personnel; some manufacturers state that the rinse procedure may be repeated with an additional 10 mL of solution for maximum benefit.162 Alternatively, dental personnel may apply 2% sodium fluoride rinse with a cotton tip applicator to teeth isolated with cotton rolls.162 Although application of sodium fluoride 2% solutions to the teeth by dental personnel previously was commonly employed, particularly for administration in school or other public health programs, such use generally has been replaced by use of other topical fluoride preparations.100,136

Acidulated Phosphate Fluoride

Acidulated phosphate fluoride is applied topically to the teeth in the form of rinsing solutions, foams, or gels.

In adults and children 6 years of age or older, acidulated phosphate fluoride gels containing 0.5% fluoride ion generally are administered once daily, unless otherwise instructed by a clinician, preferably at bedtime after thoroughly brushing the teeth.171 The gel should be applied in a thin ribbon to the teeth using a toothbrush or mouth trays for at least one minute and then expectorated.171 Patients should be instructed not to swallow the gel.171 Children 6-16 years of age should be instructed to rinse their mouth thoroughly after expectorating.171 For maximum benefit, adults should not eat, drink, or rinse their mouth for at least 30 minutes after using the gel.171

Acidulated phosphate fluoride rinsing solutions containing 0.02% fluoride ion are self-administered after thoroughly brushing the teeth. The usual dosage of acidulated phosphate fluoride rinsing solution containing 0.02% fluoride ion is 10 mL once daily for adults and children 6 years of age or older, preferably at bedtime. The solution should be rinsed around and between the teeth for 1 minute and then expectorated. The patient should be instructed not to eat or drink for 30 minutes after using the rinsing solution,114 and should be instructed not to swallow the rinse unless advised to do so by a dental or medical professional.170

Acidulated phosphate fluoride topical gels or foams containing 1.23% fluoride ion can be applied to the teeth by dental personnel by means of trays. The trays may be filled with gel (one-third full) or with foam and then inserted into the patient's mouth.172,173,174 For maximum benefit, the patient should be instructed to bite down lightly for 4 minutes;134,136,172,174 the trays should then be removed and the patient instructed to expectorate the excess foam or gel.172,173,174 Patients should not eat, drink, or rinse their mouth for at least 30 minutes following application.172,173

Stannous Fluoride

In adults and children 6 years of age and older, 0.4% stannous fluoride gels are self-administered once daily after brushing the teeth for prevention of dental caries.181 The gel should be applied to the toothbrush; the patient should brush thoroughly, allow the gel to remain on the teeth for 1 minute, and then expectorate.181 For sensitivity relief in adults and children 12 years of age or older, 0.4% stannous fluoride gel should be self-administered twice daily (morning and evening) after brushing and flossing the teeth, or as recommended by a clinician.124 After shaking the toothbrush to remove excess water, the gel should be applied to cover the bristles; the patient should brush thoroughly, allow the gel to remain on the teeth for 1 minute, and then expectorate.124 The patient should use a toothbrush or cotton swab to make certain that all sensitive areas are covered with the gel.124 Patients should be instructed not to swallow stannous fluoride gel.124 Patients also should be advised not to eat, drink, or rinse their mouth for 30 minutes after using the gel.124

In adults and children 6 years of age or older, 0.63% stannous fluoride rinsing solutions are self-administered once daily, or as directed by the patient's clinician, following regular brushing of the teeth.117,169,183 The usual dosage of 0.1% rinsing solution should be prepared from the concentrate by pouring the concentrated rinse (0.63%) to the 1/8-oz mark (3.75 mL) of the mixing vial and adding water (26.25 mL) to the 1-oz mark; the resulting solution should be mixed and used immediately.103,117,169 One-half of the solution (15 mL) should be rinsed around and between the teeth for 1 minute and then expectorated.117,183 This rinsing procedure should be repeated with the remaining solution (15 mL).117,183

Stannous fluoride gels and rinsing solutions should not be self-administered for dental sensitivity for periods exceeding 4 weeks without consulting a dentist.124,169

Stannous fluoride also is self-administered topically to teeth in appropriately formulated dentifrices.

Cautions

[Section Outline]

Effects on Teeth !!navigator!!

Prolonged daily ingestion of excessive amounts of fluoride during the period of tooth development results in varying degrees of dental fluorosis; children approximately 15 months to 3 years of age appear to be most vulnerable to fluorosis of the permanent teeth. Dental fluorosis, or mottled enamel, is characterized by markings of hypocalcification or hypocalcification and hypoplasia, and the extent of fluorotic changes is dose dependent. Fluorosed enamel has a high protein content, resulting in increased porosity; in moderate to severe forms of fluorosis, the teeth eventually become stained and pitted.107 Milder forms of fluorosis are characterized by opaque striations that run horizontally across the tooth surface; the striations may become confluent, resulting in white opaque patches, and such changes often are most apparent on the incisal edges of anterior teeth or cusp tips of posterior teeth (“snow capping”).107 Mild fluorosis has no effect on tooth function and actually may render the enamel more resistant to caries.107,138 Even in more advanced forms of enamel fluorosis, the adverse effect generally has been considered cosmetic rather than functional.107 However, the degree of cosmetic change can be extensive, presenting in moderate to severe forms as aesthetically objectionable changes in tooth color and surface irregularities.107 Some experts now question whether the pitting associated with severe fluorosis, which constitutes enamel loss, should be considered only a cosmetic effect since tooth enamel protects the dentin and pulp from decay and infection and the structural changes caused by severe fluorosis may compromise this protective function.184 The vast majority of cases of dental fluorosis in the US are very mild or mild; however, the prevalence increased from the 1980s to the early 2000s, possibly because of greater exposure to sources of fluoride.130,131,138

When the fluoride ion content of drinking water is 1 ppm (mg/L) or less, faint white flecks on the teeth may occasionally occur. Brownish spots develop on many teeth in most individuals when the fluoride ion content of drinking water is greater than 2 ppm (mg/L), and the enamel has a darker discoloration and loses its smoothness when the fluoride ion content of drinking water is greater than 2.5 ppm (mg/L). Dental fluorosis is the most sensitive index of chronic fluoride poisoning. Dental fluorosis generally does not occur when oral or topical fluoride supplements are administered in the recommended dosages or when excessive amounts of fluoride are ingested after the teeth have developed. Therefore, because the preeruptive maturation of crowns of anterior permanent teeth is complete by 8 years of age, the risk of enamel fluorosis is of greatest concern in children younger than 8 years of age.107

Staining or pigmentation (e.g., yellow, brown, brown-black) of the teeth resulting from topical application of concentrated solutions or gels of stannous fluoride has been reported, particularly in patients with poor oral hygiene. The pigmentation, which is probably stannous sulfide, is generally associated with a carious lesion or a hypocalcified area of the enamel or with plaque or accumulated debris, or occurs at the margin of a silicate restoration. Staining also has occurred with stannous fluoride-containing dentifrices, but the risk of staining with these dentifrices appears to be less than that with stannous fluoride-containing solutions or gels because the latter preparations do not contain abrasives, they are in contact with teeth for longer periods of time after application, and the mouth is not rinsed with water after application. To minimize the risk of staining, individuals receiving stannous fluoride-containing preparations should be advised of the importance of good oral hygiene (e.g., adequate brushing).103,124,169 These individuals also should be advised that such staining is not harmful or permanent and can be removed by a dentist or dental hygienist.103,124,169

Sensitivity Reactions !!navigator!!

Allergic rash and other idiosyncratic reactions have been reported with oral and topical sodium fluoride preparations. Urticaria, exfoliative dermatitis, atopic dermatitis, eczema, headache, weakness, gastric distress, stomatitis, and GI and respiratory allergic reactions may occur rarely. Dyspnea has occurred rarely in asthmatic children receiving fluoride varnish.159 Edematous swelling also has been reported rarely after application of fluoride varnish, particularly when applied to extensive surfaces.159 If intolerance to the varnish occurs, the coating may be removed by brushing and rinsing.159

In patients with mucositis, gingival tissue may be hypersensitive to alcohol or other ingredients contained in some oral or topical sodium fluoride preparations.

Skeletal Fluorosis !!navigator!!

The principal adverse functional effect of excess fluoride intake is skeletal fluorosis.107 Prolonged intake of drinking water that contains a fluoride ion concentration of 4-8 ppm (mg/L) infrequently has resulted in an increase in the density of bone mineral to a degree detectable by radiographic studies, and apparent fluoride osteosclerosis has been reported. In one study, however, such intake resulted in 23 cases of osteosclerosis but no evidence of skeletal fluorosis in 170,000 surveyed radiographs.107 In tropical areas, relatively marked osteofluorotic changes have been associated with drinking water fluoride concentrations of only 3 ppm (mg/L) and were attributed to poor nutrition, hard manual labor, and high levels of water intake.107 Therefore, the risk of skeletal fluorosis may be increased in malnourished individuals living in hot climates or tropical areas.107

In the asymptomatic, preclinical stage, skeletal fluorosis manifests as slight radiographically detectable increases in bone mass, bone ash fluoride concentrations ranging from 3.5-5.5 g/kg, and bone fluoride concentrations that are 2-5 times higher than those of life-long residents of communities with optimally fluoridated water supplies.107 Stage 1 skeletal fluorosis is characterized by occasional joint stiffness or pain and some pelvic and vertebral osteosclerosis; bone ash concentrations usually range from 6-7 g/kg.107 In stages 2 and 3, potentially crippling changes may include dose-related calcification of ligaments, osteosclerosis, exostoses, possibly osteoporosis of long bones, muscle wasting, and neurologic defects secondary to vertebral calcification; bone ash concentrations exceed 7.5-8 g/kg.107

The risk of developing skeletal fluorosis is related directly to the extent and duration of fluoride exposure, and crippling skeletal fluorosis is extremely rare in the US.107 Manifestations of milder forms of skeletal fluorosis generally require a fluoride intake of at least 10 mg daily for at least 10 years.107 At least one case of severe joint pain and stiffness was attributed to fluoride intake of about 50 mg daily for 6 years.107

Other Adverse Effects !!navigator!!

Laboratory tests indicate that use of acidulated phosphate fluoride may cause dulling of porcelain and ceramic restorations; therefore, use of neutral sodium fluoride preparations may be recommended for patients with these restorations.

Adverse GI effects including GI bleeding, nausea, and vomiting have been reported in patients receiving 40-65 mg of sodium fluoride daily for the treatment of osteoporosis. When large doses of sodium fluoride are used, nausea may be reduced by administering the drug with or immediately following meals.

Adverse rheumatic effects such as synovitis and a plantar fascial syndrome characterized by diffuse pain and tenderness of the plantar portion of one or both feet have been reported in patients receiving an oral sodium fluoride dosage of 40-65 mg daily.

Precautions and Contraindications !!navigator!!

Because prolonged ingestion of high doses of fluoride may result in dental fluorosis and osseous changes, the recommended dosage of oral and topical fluoride preparations should not be exceeded, and dosage should be adjusted in proportion to the amount of fluoride ion present in drinking water. In addition, proper techniques for applying topical fluoride preparations should be followed to minimize the amount of fluoride that is swallowed and absorbed systemically.100,101,103

Sodium fluoride and acidulated phosphate fluoride oral solutions and sodium fluoride oral chewable tablets are contraindicated for use as dietary supplements when the fluoride ion concentration in drinking water is greater than 0.6 ppm (mg/L). Sodium fluoride oral solution should not be used in infants younger than 6 months of age.154 Sodium fluoride chewable tablets containing 0.25 mg of fluoride ion should not be used in children younger than 3 years of a 180 the chewable tablets containing 0.5 mg of fluoride ion should not be used in children younger than 3 years of age and should not be used in those younger than 6 years of age when the fluoride ion concentration in drinking water is 0.3 ppm (mg/L) or greater;180 and the chewable tablets containing 1 mg of fluoride ion should not be used in children younger than 6 years of age and are contraindicated when the fluoride ion concentration in drinking water is greater than 0.3 ppm (mg/L).180

Young children usually cannot perform the rinse process necessary with oral rinsing solutions, and they are more likely to swallow some or all of topical fluoridated dental preparations (e.g., dentifrices).107,131 Potential risks from swallowing topical fluoride preparations in young children include nausea and vomiting and, with repeated ingestion, dental fluorosis.136 Because systemic exposure to fluoride is thought to be lower with sodium fluoride varnish containing 2.26% fluoride ion than with other professionally applied fluoride preparations, the 2.26% varnish is the only professionally applied fluoride preparation recommended for use in children younger than 6 years of age.134,136,137 Fluoride gels and mouth rinses generally should not be used in this age group unless otherwise instructed by a dentist or medical professional.114,116,119,131,135,136,158,169,171,181 In-home use of prescription-strength topical fluoride preparations (e.g., gels, pastes, mouth rinses) is not recommended by the American Dental Association (ADA) or American Academy of Pediatric Dentistry (AAPD) for use in children younger than 6 years of age.134,136 Children younger than 6 years of age should be instructed and/or supervised carefully regarding the proper use of fluoridated dentifrices to ensure that the correct amount is used and to minimize swallowing of the dentifrice.103,131,139 Those 6-12 years of age also should be instructed and supervised as necessary regarding proper techniques for use of topical fluoride preparations (e.g., rinsing solutions, gels, dentifrices).103

Oral or topical fluoride preparations are contraindicated in individuals who are hypersensitive to fluoride. Some manufacturers state that topical fluorides (e.g., gels, foams, rinsing solutions) are contraindicated in patients with dysphagia.115,120,164,172 Sodium fluoride varnish is contraindicated in patients with ulcerative gingivitis or stomatitis,159,166 and some preparations should not be used in patients with known hypersensitivity to colophony/rosin.166

Other Information

[Section Outline]

Acute Toxicity

Pathogenesis !!navigator!!

Acute toxicity is not likely to result from the small amounts of fluoride present in drinking water but is possible when concentrated fluoride solutions or tablets containing fluoride are ingested. Most cases of acute fluoride toxicity have occurred following accidental ingestion of insecticides or rodenticides containing fluoride salts. To minimize the risk of acute toxicity, it has been recommended that no more than 264 mg of sodium fluoride (120 mg of fluoride ion) be dispensed at one time for use as a dietary supplement. In addition, the US Consumer Product Safety Commission states that child-resistant containers are not required for preparations containing 50 mg or less of fluoride ion.126 The oral dose of sodium fluoride that may be fatal is not known but is estimated to be about 5-10 g (70-140 mg/kg) in untreated adults and 500 mg in children.

Manifestations !!navigator!!

Symptoms of acute fluoride overdosage include hypersalivation, a salty or soapy taste, epigastric pain, nausea, vomiting, burning or crampy abdominal pain, diarrhea, dehydration, thirst, localized or generalized urticaria, muscle weakness, tremors, and, rarely, transient epileptiform seizures. Shock may occur and is characterized by pallor, weak and thready pulse which may be irregular, wet cold skin, dilated pupils, cyanosis, shallow unlabored respiration, and weak heart sounds. Death may result from cardiac failure, respiratory arrest, or shock and usually occurs within 2-4 hours following ingestion; if a victim survives the first 24 hours, the prognosis is good. When death is delayed, paralysis of the muscles of deglutition, carpopedal spasm, and spasm of the extremities may occur.

Treatment !!navigator!!

In acute oral overdosage of fluoride, the manufacturers and some clinicians recommend treatment based on the estimated amount of fluoride ingested per unit of body weight.115,119,121,127 If less than 5 mg of fluoride per kg of body weight has been ingested, calcium (e.g., milk) should be administered orally to relieve GI symptoms and the patient should be observed for 2-4 hours.115,119,121,127 If more than 5 mg of fluoride per kg of body weight has been ingested, vomiting should be induced, an orally soluble form of calcium (e.g., milk, 5% calcium gluconate, calcium lactate solution) should be administered, and medical assistance should be sought immediately; if more than 15 mg of fluoride per kg of body weight has been ingested, vomiting should be induced and medical assistance should be sought immediately.115,119,121,127 Other clinicians state that patients who become symptomatic following ingestion of more than 8 mg of fluoride per kg of body weight or following ingestion of an unknown amount of fluoride should be provided supportive and symptomatic treatment, including gastric lavage if emesis has not occurred.127 Serum electrolytes, especially calcium and magnesium, should be monitored carefully, and appropriate therapy to correct any imbalances should be initiated if required.127 Milk, calcium salts, or aluminum- and/or magnesium-containing antacids should be given orally.127 Hemodialysis may be beneficial in patients with severe intoxication or in those with impaired renal function.

Pharmacology

The mechanisms of action of orally and topically administered fluorides in reducing tooth decay are not fully understood. However, several mechanisms may be involved.109,111,112,113,128 Fluoride ions are incorporated into and stabilize the apatite crystal of teeth and bone. Deposition of fluoride in tooth enamel increases resistance to acid dissolution and formation of dental caries. Fluoride also promotes remineralization of decalcified enamel and inhibits the cariogenic microbial process in dental plaque. Fluoride is incorporated into teeth by occupying sites otherwise occupied by hydroxyl and/or carbonate anions in the apatite structure of the tooth enamel. This reaction results in the formation of fluorapatite which is less soluble in an acid medium than is hydroxyapatite and therefore increases resistance of tooth enamel to acid.

Orally administered fluoride apparently exerts its anticaries effect preeruptively while teeth are developing and posteruptively, and both mechanisms are thought to be necessary to attain maximum protection against caries. Prior to tooth eruption, fluoride is incorporated into tooth enamel while teeth are being formed. After calcification is completed, deposition of fluoride in the external surface enamel continues during the preeruptive period; diffusion of fluoride from the surface inward is apparently restricted. However, a high fluoride concentration in sound enamel alone does not support a marked reduction in dental caries; the prevalence of dental caries in a population is not inversely related to the concentration of fluoride in enamel.109,113 Therefore, the principal effect of orally administered fluorides is most likely related to the availability of fluoride in plaque and saliva.109,113

After eruption, the cariostatic effect of fluoride on teeth in children and adults results from combined effects on bacterial metabolism in plaque and on the dynamics of enamel demineralization and remineralization during an acidogenic challenge.107 Fluoride concentrations in plaque are related to concentrations in and frequency of exposure to the ion in water, beverages, foods, and dental products.107 Fluoride can be deposited in plaque from direct uptake from these sources as well as from saliva and gingival crevicular fluid following ingestion and GI absorption.107 The effects of fluoride on plaque bacteria involve inhibition of several enzymes, with resultant limitations on bacterial glucose uptake and reductions in acid production and secretion into extracellular plaque fluid.107 As a result, the usual decline in plaque pH and resultant severity of acidic challenge to the enamel are attenuated.107

When fluoride is applied topically to teeth, calcium fluoride as well as fluorapatite is formed and a part of the calcium fluoride is converted slowly to additional fluorapatite. Uptake of fluoride is facilitated by thorough cleaning prior to topical application of fluoride preparations. The effects of fluoride on enamel demineralization and remineralization in erupted teeth include a reduction in acid solubility of enamel; promotion of remineralization of incipient enamel lesions, which develop at the ultrastructural level throughout the day according to the frequency of eating and drinking foods and beverages containing carbohydrates that can be metabolized by plaque bacteria; an increase in the deposition of mineral phases in plaque, which under acidic conditions produced during plaque metabolism provide a source of mineral ions (calcium, phosphate, and fluoride) that retard demineralization and promote remineralization; and a reduction in the net rate of transport of minerals out of the enamel surface by inducing a reprecipitation of fluorapatite within the enamel.107 These mechanisms underlying the protective effects of fluoride on erupted teeth in children and adults require frequent exposure to fluoride throughout life in order to achieve and maintain adequate plaque and enamel concentrations of the ion.107

Acidification of sodium fluoride solutions increases fluoride uptake by dental enamel and the addition of phosphate to sodium fluoride solutions protects enamel from demineralization by suppressing the formation of calcium fluoride and favoring deposition of fluoride as fluorapatite. When stannous fluoride is applied topically to teeth, a highly adherent surface coating composed mainly of tin phosphate and smaller amounts of calcium fluoride and a tin hydroxyorthophosphate is formed on enamel.

The mechanism by which fluoride decreases sensitivity of exposed dentin is thought to be related to the formation of calcium-phosphorus precipitates, calcium fluoride, and fluorapatite, which may occlude exposed dentinal tubules and thereby reduce fluid movement through the tubules.175 Fluid movement through exposed tubules activates nerve fibers in the pulp resulting in pain in response to various stimuli.148,175

Fluoride ions also increase skeletal density and bone mass; however, large doses can cause skeletal fluorosis and osteomalacia. Some evidence suggests that long-term ingestion of fluoride at concentrations slightly exceeding those required for cariostatic effects may increase the quality of the human skeleton and thus might potentially decrease the risk of osteoporosis.107 Compared with low-fluoride intake, perimenopausal women who had consumed fluoridated water (1-1.2 mg of fluoride/L) for 10 years or longer exhibited slight increases in vertebral but not femoral neck bone mineral density (BMD); however, there was no difference between the groups in the prevalence of self-reported bone fractures, and other evidence indicates that consumption of fluoridated water is inadequate to prevent bone fractures or improve bone densities.107 Normal age-related increases in bone fluoride concentrations do not appear to affect the compressive strength or ash density of vertebra.107 However, some observational data suggest an increased risk for fractures in populations exposed to a fluoride concentration of 4 mg/L in drinking water; thus, under certain conditions, fluoride may weaken bone and increase the risk of fractures.184

Some evidence indicates that fluoride can inhibit the calcification of soft tissues, including the aorta, and that the standardized mortality rates secondary to ischemic heart disease may be reduced in cities with optimally fluoridated water compared with those with low fluoride concentrations in water, but data currently are insufficient to affect recommendations for fluoride intake.107

Pharmacokinetics

Absorption !!navigator!!

Sodium fluoride and other soluble fluoride salts are readily and almost completely absorbed from the GI tract. The absorption of fluoride from ingested toothpaste containing sodium fluoride or sodium monofluorophosphate (MFP) also appears to be almost complete.107 A substantial portion of an oral dose of soluble fluoride may be absorbed in the stomach, and the rate of absorption may depend on gastric pH.100 If fluoride is administered orally as a less soluble salt (e.g., calcium fluoride) or as bone meal, absorption of fluoride is slow and variable. Oral absorption of fluoride may be decreased by simultaneous ingestion of magnesium or aluminum hydroxide. Simultaneous ingestion of calcium also may decrease absorption of large doses of fluoride since calcium fluoride, which is poorly absorbed, may be formed in the GI tract. However, simultaneous ingestion of dairy products containing calcium probably has little effect on absorption of the low concentrations of fluoride present in drinking water. In the absence of high dietary concentrations of calcium and certain other cations, 80% or more of a dose of soluble fluoride probably is absorbed from the GI tract.107 When administered concomitantly with milk, infant formula, or foods, especially those with high concentrations of calcium or certain other divalent or trivalent cations that form insoluble fluoride salts, absorption of fluoride may be reduced by 10-25%.107 Although some studies suggested that oral bioavailability of fluoride may increase with concomitant administration of caffeine or other methylxanthines, other studies failed to confirm this finding.107

Normal total plasma fluoride concentrations have been reported to range from 0.14-0.19 mcg/mL, of which 15-20% is ionized. Ionic fluoride is the physiologically important form in plasma.100 The source(s), physiologic importance, and fate of nonionic fluoride (e.g., perfluoro-octanoic acid) present in plasma is not known, but conversion of nonionic to ionic fluoride in plasma does not appear to occur.100

Distribution !!navigator!!

Following absorption, fluoride is stored in bones and developing teeth. Skeletal tissue has a high storage capacity for fluoride ions and a storage-mobilization mechanism in skeletal tissue maintains a low level of fluoride in the body which may be important in providing a constant supply of fluoride for developing teeth. Although body and tissue concentrations of fluoride are proportional to the chronic level of intake, they are not homeostatically controlled.107 Because of their small mass, teeth serve as storage sites for only a small fraction of fluoride retained in the body; however, fluoride deposited in teeth is not readily released. The highest concentration of fluoride in dental enamel is present in the outer surface, with the next highest concentration occurring at the dentinoenamel junction.100

Although fluoride has been detected in all organs and tissues, very little fluoride accumulates in noncalcified tissues. About 99% of total body fluoride is strongly but not irreversibly bound in calcified tissues.107 Bone fluoride appears to exist in both a rapidly and slowly exchangeable pool.107 The rapidly exchangeable bone pool is located in the hydration shells of bone crystallites, where fluoride may be exchanged isoionically or heteroionically with ions in the surrounding extracellular fluid.107 Mobilization from the slowly exchangeable pool results from resorption associated with bone remodeling.107 Fluoride concentrations in parotid and submandibular ductal saliva are about 70-90% those in plasma, and concentrations in whole saliva exceed those in ductal saliva.100 Small amounts of fluoride are distributed into sweat, tears, and hair.

Fluoride crosses the placenta and is distributed into milk. Fluoride concentrations in milk are reported to range from less than 0.05 ppm (mg/L) to 0.13 ppm (mg/L) and generally remain constant regardless of the fluoride concentration in the woman's serum or drinking water. In one study, the concentration of fluoride in milk ranged from 2-8 ng/mL prior to and up to 2 hours after oral administration of a single 1.5-mg dose of sodium fluoride. However, fluoride concentration in milk may be increased when the daily dose of fluoride is greater than 1.5 mg.

Elimination !!navigator!!

Fluoride is rapidly excreted principally in urine, although small amounts are excreted in feces. About 90% of fluoride is filtered by the glomerulus and is reabsorbed to a variable degree by the renal tubules; it is not known if tubular secretion of fluoride occurs. The extent of renal tubular reabsorption of fluoride is inversely related to tubular fluid pH.107 The renal clearance of fluoride in adults is about 30-40 mL/minute.107 The clearance of fluoride from plasma is about 75 mL/minute in healthy adults, which is approximately equivalent to the sum of renal and calcified tissue clearances of the ion.107

The fractional retention or balance of fluoride depends on age-dependent quantitative characteristics of absorption and excretion.107 Under most dietary conditions, fluoride balance is positive.107 However, when fluoride intake is inadequate to maintain or gradually increase plasma fluoride concentrations, fluoride excretion can exceed the amount ingested secondary to mobilization from calcified tissues.107 For healthy young or middle-aged adults, about 50% of absorbed fluoride is retained by uptake in calcified tissues, with the remainder being excreted in urine.107 In young children, up to 80% of absorbed fluoride can be retained secondary to increased uptake by developing teeth and bone.107 Based on bone mineral dynamics, it is likely that the fraction of absorbed fluoride that is excreted exceeds the fraction retained in older adults.107

Chemistry and Stability

Chemistry !!navigator!!

Fluoride, the ionic form of fluorine, is a normal component of body fluids and tissues that reduces the incidence of dental caries and reverses the progression of existing tooth decay.107,109,110 Fluorine is a halogen and the most electronegative element in the periodic table; it is ubiquitous in nature.107 Fluoride combines reversibly with hydrogen, forming the acid hydrogen fluoride, and much of the physiologic behavior of fluoride (e.g., GI absorption, distribution between extracellular and intracellular fluids, renal clearance) results from the diffusion of hydrogen fluoride.107 Because of fluoride's high affinity for calcium, the ion is associated principally with calcified tissues in the body.107

Fluoride is commercially available as sodium fluoride for oral administration and as sodium fluoride, acidulated phosphate fluoride, sodium monofluorophosphate, or stannous fluoride for topical application directly to the teeth.

Sodium Fluoride

Sodium fluoride (NaF) contains about 45% fluoride ion. Sodium fluoride occurs as a white, odorless powder and is insoluble in alcohol and has a solubility of approximately 40 mg/mL in water at 25°C. Aqueous solutions of sodium fluoride generally have a neutral pH; although actual pH may vary somewhat, for labeling purposes, neutral solutions of sodium fluoride are considered to have a pH of approximately 7.103 Sodium fluoride is commercially available as chewable tablets or solutions for oral administration and in dentifrices or as oral gels, foams, or rinsing solutions for topical administration.

Acidulated Phosphate Fluoride

Acidulated phosphate fluoride (sodium fluoride and phosphoric acid, APF) is sodium fluoride and/or hydrogen fluoride that has been acidified with phosphoric acid (orthophosphoric acid). Acidulated phosphate fluoride is commercially available for topical administration as oral gels, foams, or rinsing solutions. Commercially available acidulated phosphate fluoride topical gels and foams containing 1.23% fluoride ion generally have a pH of 3-4; gels containing 0.5% fluoride ion generally have a pH of 5-6. Commercially available rinsing solutions containing 0.02% fluoride ion generally have a pH of 3-4.5.103

Stannous Fluoride

Stannous fluoride (SnF2, tin fluoride) contains about 24% fluoride ion and is prepared by reacting moist stannous oxide with hydrofluoric acid or by reacting powdered tin with anhydrous hydrogen fluoride. Stannous fluoride occurs as a white, crystalline powder with a bitter, salty taste and is freely soluble in water and practically insoluble in alcohol. Stannous fluoride is commercially available for topical administration in dentifrices and oral gels and rinsing solutions. A 0.4% aqueous solution of stannous fluoride has a pH of 2.8-3.5.

Sodium Monofluorophosphate

Sodium monofluorophosphate (Na3FPO4) occurs as a white to slightly gray powder and is freely soluble in water and practically insoluble in alcohol. Sodium monofluorophosphate is commercially available only in dentifrices for topical administration, which usually contain approximately 0.76% of the drug.100,103

Stability !!navigator!!

Sodium Fluoride

Aqueous solutions of sodium fluoride slowly decompose and become alkaline when stored in glass. Therefore, sodium fluoride solutions should be stored in tight, plastic containers, especially if the pH of the solution is less than 7.5. Sodium fluoride solutions should be stored at a temperature less than 40°C, preferably between 15-30°C; freezing of the solutions should be avoided.

Sodium fluoride chewable tablets should be stored at a temperature of 20-25°C.155

Sodium fluoride is incompatible with calcium and magnesium salts.

Acidulated Phosphate Fluoride

Acidulated phosphate fluoride oral topical gels and rinse solutions should be stored in tight, plastic containers.

Stannous Fluoride

Aqueous solutions of stannous fluoride decompose within a few hours to stannous hydroxides, forming a white precipitate; therefore, stannous fluoride solutions must be prepared just prior to use. Stannous fluoride is incompatible with alkaline substances and oxidizing agents.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sodium Fluoride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

1.1 mg/mL (0.5 mg of fluoride ion per mL)*

Sodium Fluoride Drops

Tablets, chewable

0.55 mg (0.25 mg of fluoride ion)*

Sodium Fluoride Chewable Tablets

1.1 mg (0.5 mg of fluoride ion)*

Sodium Fluoride Chewable Tablets

2.2 mg (1 mg of fluoride ion)*

Sodium Fluoride Chewable Tablets

Oral (Topical Use Only)

Foam

2% (0.9% fluoride ion)

Gelato® Neutral

Deepak

Kolorz® Neutral Fluoride

DMG America

PCxx® Neutral

Ross

Topex® Neutral

Sultan

Gel

1.1% (0.5% fluoride ion)

Gelato® Home-care Vivid

Keystone

NeutraMaxx® 5000

Massco

PCxx® Neutral

Ross

PreviDent®

Colgate Oral

SF®

Cypress

2% (0.9% fluoride ion)

DentiCare® Pro-Gel

AMD Medicom

Gelato® Neutral

Keystone

PCxx® Neutral

Ross

Topex® Neutral

Sultan

Zap®

Crosstex

Rinsing solution

0.02% (0.009% fluoride ion)

ACT®

Chattem

0.05% (0.02% fluoride ion)

ACT®

Chattem

PCxx®

Ross

0.2% (0.09% fluoride ion)

PreviDent®

Colgate Oral

2% (0.9% fluoride ion)

DentiCare® Pro-Rinse

AMD Medicom

PCxx® Neutral

Ross

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Acidulated Phosphate Fluoride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral (Topical Use Only)

Foam

Sodium Fluoride 2.72% (1.23% fluoride ion)

DentiCare® Pro-Foam

AMD Medicom

Kolorz® Sixty Second

DMG America

Zooby®

Denticator

Sodium Fluoride 2.73% (1.23% fluoride ion)

Nupro®

Dentsply

Topex® 60 Second

Sultan

Sodium Fluoride and Hydrogen Fluoride (1.23% fluoride ion)

DentiCare® Denti-Foam

AR Medicom

Minute-Foam®

Oral-B

PCxx® One Minute

Ross

Gel

Sodium Fluoride 1.1% (0.5% fluoride ion)

Phos-Flur®

Colgate Oral

Sodium Fluoride 2.59% (1.23% fluoride ion)

Topex® 60 Second

Sultan

Sodium Fluoride 2.72% (1.23% fluoride ion)

DentiCare® Pro-Gel

AMD Medicom

Kolorz® Sixty Second

DMG America

PCxx® One Minute

Ross

60 Second Taste®

Pascal

Sodium Fluoride and Hydrogen Fluoride (1.23% fluoride ion)

Gelato® APF

Keystone

Iris® 60-Second

Benco

Zap®

Crosstex

Rinsing solution

Sodium Fluoride 0.04% (0.02% fluoride ion)

Phos-Flur® Ortho Defense®

Colgate Oral

Acidulated Phosphate Fluoride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral (Topical Use Only)

Kit

Acidulated Phosphate Fluoride Solution (1.24% fluoride ion), Stannous Fluoride

Concentrate, 1.64%

Acclean® Dual Fluoride Rinse Kit

Henry Schein

Stannous Fluoride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral (Topical Use Only)

Gel

0.4% (0.12% fluoride ion)

Gelato® Home-care

Keystone

Gel-Kam®

Colgate Oral

Just for Kids®

3M ESPE

OMNI Gel®

3M ESPE

Rinsing solution, concentrate

0.63%

Fluoridex®

Den-Mat

Gelato® Perio Maintenance

Keystone

PerioMed®

3M ESPE

Stance®

Elevate Oral Care

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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102. American Academy of Pediatrics Committee on Nutrition. Pediatric nutrition handbook, 2nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1985:169-173.

103. Food and Drug Administration. Anticaries drug products for over-the-counter human use. [21 CFR Part 355 [4-1-2018 Ed.]]. [Web]

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114. Colgate Oral Pharmaceuticals. Colgate® Phos-Flur® Ortho Defense® (sodium fluoride 0.04%) rinse drug facts. New York, NY; Undated. From Dailymed website. Accessed 2018 Dec 7.

115. Colgate Oral Pharmaceuticals. Colgate® PreviDent® (neutral sodium fluoride 0.2%) rinse prescribing information. New York, NY; 2009 May.

116. Chattem. ACT® Anticavity Fluoride Rinse Mint (sodium fluoride 0.05% rinse) drug facts. Chattanooga, TN; Undated. From Dailymed website. Accessed 2018 Nov 16.

117. Den-Mat Holdings. Fluoridex® (stannous fluoride 0.63% concentrate) rinse drug facts. Lompoc, CA; Undated. From Dailymed website. Accessed 2018 Dec 6.

119. Colgate Oral Pharmaceuticals. Colgate® PreviDent® (sodium fluoride 1.1%) gel prescribing information. New York, NY; 2016 May.

120. Oral-B Laboratories. Neutra-Foam® (neutral sodium fluoride 2% foam) prescribing information. Cincinnati, OH; Undated. From Dailymed website. Accessed 2018 Dec 7.

121. Colgate Oral Pharmaceuticals. PreviDent® 5000 Plus® (sodium fluoride 1.1%) dental cream prescribing information. New York, NY; 2009 Mar.

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125. Proctor & Gamble. Crest® Pro-Health® (stannous fluoride 0.454%) gel drug facts. Cincinnati, OH; Undated. From Dailymed website. Accessed 2018 Dec 5.

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127. Fluorides. In: Ellenhorn MJ, Schonwald S, Ordog G et al, eds. Ellenhorn's medical toxicology: diagnosis and treatment of human poisoning. 2nd ed. Baltimore: Williams & Wilkins; 1997:1003-6.

128. Burrell KH, Chan JT. Systemic and topical fluorides. In: Cianco SG, ed. ADA guide to dental therapeutics. Chicago, ADA Publishing; 2000:230-41.

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154. H2-Pharma. Sodium fluoride drops prescribing information. Undated. From Dailymed website. Accessed 2021 Jun 16.

155. PureTek. Sodium fluoride chewable tablets prescribing information. San Fernando, CA; Undated. From Dailymed website. Accessed 2018 Dec 5.

156. GSK Consumer Healthcare. Sensodyne with Fluoride Daily Repair (stannous fluoride 0.454%) toothpaste drug facts. Warren, NJ; 2018.

158. Chattem. ACT® Total Care Anticavity Fluoride Rinse Dry Mouth (sodium fluoride 0.02% rinse) drug facts. Chattanooga, TN; Undated. From Dailymed website. Accessed 2018 Nov 16.

159. Colgate Oral Pharmaceuticals. Colgate® PreviDent® varnish (Rx only). From Colgate website. Accessed 2018 Dec 5.

160. AMD Medicom. DentiCare® Pro-Gel (neutral sodium fluoride 2%) gel prescribing information. Lockbourne, OH: Undated. From Dailymed website. Accessed 2018 Dec 11.

161. Crosstex International. Zap® (neutral sodium fluoride 2%) gel prescribing information. Hauppauge, NY; 2016 Aug.

162. AMD Medicom. Denti-Care® Pro-Rinse (neutral sodium fluoride 2% rinse) prescribing information. Pointe-Claire, Quebec, Canada; Undated. From Dailymed website. Accessed 2018 Nov 16.

163. DMG America. Kolorz Sixty Second Fluoride Foam Cherry Cheesecake (acidulated phosphate fluoride foam) prescribing information. Englewood, NJ; 2009 Dec.

164. Oral-B Laboratories. NeutraCare® (neutral sodium fluoride 1.1%) gel prescribing information. Cincinnati, OH; Undated. From Dailymed website. Accessed 2018 Dec 11.

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166. 3M. 3M® Vanish® (5% sodium fluoride) white varnish technical data sheet. From 3M website. Accessed 2018 Dec 12.

167. 3M. 3M® Vanish® (5% sodium fluoride) white varnish directions for care after treatment. From 3M website. Accessed 2018 Dec 12.

168. Colgate Oral Pharmaceuticals. Colgate® Prevident® 5000 ppm (1.1% sodium fluoride and 5% potassium nitrate) gel prescribing information. New York, NY; Undated. From Dailymed website. Accessed 2018 Dec 13.

169. 3M ESPE. PerioMed® (stannous fluoride 0.63% concentrate) rinse drug facts. St. Paul, MN; Undated. From Dailymed website. Accessed 2018 Dec 6.

170. Colgate Oral Pharmaceuticals. Colgate® Phos-Flur® rinse. From Colgate website. Accessed 2018 Nov 29.

171. Colgate Oral Pharmaceuticals. Phos-Flur® (1.1% sodium fluoride and accidulated phosphate) gel prescribing information. New York, NY; 2009 Apr.

172. Oral-B Laboratories. Minute-Foam® (acidulated phosphate fluoride) foaming solution prescribing information. Cincinnati, OH; Undated. From Dailymed website. Accessed 2018 Dec 6.

173. Pascal Company. 60 Second Taste (acidulated phosphate fluoride) gel prescribing information. Bellevue, WA; 2014 Aug.

174. Crosstex International. Zap® (sodium fluoride and hydrofluric acid) gel prescribing information. Hauppauge, NY; 2016 Aug.

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180. Method Pharmaceuticals. Sodium fluoride chewable tablets prescribing information. Fort Worth, TX. 2018 Jul. From Dailymed website. Accessed 2021 Jun 16.

181. 3M ESPE. Omni Gel® (stannous fluoride 0.4%) gel drug facts. St. Paul, MN; Undated. From Dailymed website. Accessed 2018 Dec 6.

182. Ross Healthcare. PCxx® Neutral (2% sodium fluoride) gel prescribing information. Point Roberts, WA; Undated. From Dailymed website. Accessed 2018 Dec 11.

183. Elevate Oral Care. Stance® (0.63% stannous fluoride) rinsing solution concentrate. West Palm Beach, FL; Undated. From Dailymed website. Accessed 2018 Dec 6.

184. Committee on Fluoride in Drinking Water, Board on Environmental Studies and Toxicology, Division on Earth and Life Sciences, National Research Council. Fluoride in drinking water: a scientific review of EPA's standards. Washington, DC: National Academies Press. 2006.

185. Ismail AI, Hasson H. Fluoride supplements, dental caries and fluorosis: a systematic review. J Am Dent Assoc . 2008; 139:1457-68. [PubMed 18978383]

186. Phocal Therapy Inc. phocal® (sodium fluoride and acidulated phosphate fuoride disk) instructions for use. Lewes, DE; Undated. From Dailymed website. Accessed 2019 Jan 11.