Fluorides

Class: Cariostatic Agents
ATC Class: A12CD
VA Class: TN470
Molecular Formula: NaFNa₃FPO₄SnF₂
CAS Number: 7681-49-4
Brands: APF , ACT, CaviRinse, CavityShield, ControlRX, DentinBloc, Duraphat, EtheDent, Fluorabon, Fluor-A-Day, Fluorinse, Fluoritab, FluoroFoam , Flura-Drops, Gel-Kam, Just for Kids, Minute-Foam, NeutraCare, Neutra-Foam, OMNI, OrthoWash, PerioMed, Phos-Flur, PreviDent, SF, Vanish

Introduction

Cariostatic agent; ionic form of fluorine.^{107 109 110 a d}

Uses for Fluorides

Dental Caries

Prevent or reduce the incidence of dental caries; slow or reverse the progression of existing dental lesions.^{107 109 b d e i j s t v}

Effect of fluoride is predominantly posteruptive; maintain consistent small amounts of fluoride in saliva and dental plaque.^{109 113} (See Actions.)

As a dietary supplement for the prevention of dental caries in children in areas where the concentration of fluoride ion in drinking water is less than optimal.¹⁰⁹

American Dental Association (ADA) recommends that all patients, including those without dental caries and with no apparent increased risk of dental caries, receive adequate water fluoridation or oral fluoride supplementation, combined with daily use of fluoridated dentifrice and twice-yearly topical application of fluoride.¹²⁸

In addition, ADA and others state that patients at low or slightly increased risk for dental caries (e.g., low socioeconomic status, low levels of parental education, no regular dental care, or without dental insurance or access to dental services) may require sodium fluoride 0.05% mouth rinse or 0.4% stannous fluoride gel.^{109 128}

ADA and others recommend that patients at moderate-to-high risk for dental caries (e.g., active dental caries, history of high incidence of caries in older siblings or caregivers, root surfaces exposed by gingival recession, impaired ability to maintain oral hygiene, malformed enamel or dentin, low salivary buffering capacity, wearing of orthodontic appliances, or reduced salivary flow from medications, radiation treatment, or disease) receive additional exposure to fluorides (e.g., home or professionally applied products).^{109 128}

CDC supports fluoridation of the public water supply as the most cost-effective means of providing optimal levels of fluoride to large segments of the population.¹⁰⁹

Optimal concentration of fluoride ion in drinking water is approximately 1 ppm (range 0.7–1.2 ppm), depending on the annual mean maximum daily temperature of the area.^{106 109 b w} In warm climates where more water is likely to be ingested, concentrations should be at the lower end of the range.^{106 109}

In communities where the concentration of fluoride in the water supply is >2 ppm, use an alternative source of drinking water for children ≤8 years of age.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 However, current recommendations in children continue to be based on the fluoride concentrations in local drinking water.^{106 107}

ADA and others recommend that in areas where oral fluoride supplements are necessary, children 6 months to 16 years of age receive daily fluoride supplements to provide maximum benefit to both deciduous and permanent teeth.^a

Efficacy of topically applied fluoride varies according to the concentration of fluoride ion in the preparation, method and frequency of application, and the duration of use.^a

Acidulated phosphate fluoride gels (alone or in combination with a saliva substitute) have been used to control dental decay after xerostomia-producing radiation therapy of tumors of the head and neck.^a

Stannous fluoride gels have been used to prevent decalcification in orthodontic patients.^a

Stannous fluoride gels have been used to protect against postirradiation caries.^a

Desensitizing Dentin

Topically to desensitize exposed root surfaces of teeth.^{f h}

Bone Diseases

Has been used to increase bone density and relieve bone pain in the treatment of various metabolic and neoplastic bone diseases†.^a

Has been used in conjunction with calcium and vitamin D or calcium and estrogen to reduce skeletal fracture rates in osteoporosis†; further study is needed.^a

Has been used alone or in conjunction with calcium carbonate as an adjunct in the management of bone lesions in multiple myeloma†.^a

Has been used to reduce bone pain in metastatic prostatic carcinoma†.^a

Has been reported to stabilize the progression of hearing loss in a limited number of patients with otosclerosis†.^a

Has been used to increase spinal (but not femoral neck) bone mineral density (BMD) in corticosteroid-induced osteoporosis†;¹⁰⁸ however, further studies are needed and other therapies are preferred.¹⁰⁸

Fluorides Dosage and Administration

Administration

Administer orally as a lozenge, solution, or chewable tablet or topically as a cream, dentifrice, foam, gel, rinsing solution, or solution.^{a e h l o p s v}

Oral Administration

Administer sodium fluoride orally as a lozenge, chewable tablet, or as a solution undiluted or mixed with juice or water.^b Dissolve chewable tablets in the mouth or chew before swallowing, preferably at bedtime after brushing the teeth.^{a b j}

Administer oral fluoride supplements 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).^a

Oral Topical Administration

Not for systemic treatment; do not swallow.^{119 121 a e f h i n o s t v}

Rinsing solution may be swallowed only if directed to do so by a clinician to provide systemic fluoride supplementation.¹⁰³

To minimize the amount of fluoride swallowed and absorbed systemically and the risk of fluorosis, instruct and/or supervise children <12 years of age regarding proper techniques for use of topical preparations.^{100 101 103 i} (See Dental Fluorosis under Cautions.)

For maximum benefit, do not eat or drink for ≥30 minutes after administration; adults, do not rinse mouth for 30 minutes after administration.^{119 121 a d e m n o s t v}

Oral Topical Administration (Sodium Fluoride)

1.1% cream: Apply a thin ribbon to toothbrush; brush thoroughly for 2 minutes.^{121 d e} Expectorate after use; children, expectorate and rinse mouth thoroughly.^{121 d e}

2% foam: Dental personnel may apply topically to teeth using trays or mouthpiece applicators.^{120 128}

1.1% gel: Rinse thoroughly after brushing teeth normally.^{119 s} Apply a ribbon of gel to teeth with toothbrush or mouth tray for ≥1 minute; expectorate.^{119 s} Children, rinse mouth thoroughly.^{119 s}

0.044, 0.05, and 0.2% rinsing solutions: After thoroughly brushing teeth, rinse solution vigorously around and between teeth for 1 minute.^{115 116 a m n} Expectorate.^{115 116 a m n}

5% solution: May be applied by dental personnel to moist teeth.^h Apply to teeth with cotton swabs, brush, or probe.^h Do not dry.^h Patient should not eat hard foods or brush for ≥2 hours after application.^h Avoid other fluoride preparations on the day of application.^h Suspend use of fluoride tablets for several days after treatment.^h

Oral Topical Administration (Sodium Fluoride Combinations)

Solution: Dental personnel may apply saturated foam applicator to the tooth surface with constant light pressure for 1 minute; have patient expectorate.^f

Oral Topical Administration (Acidulated Phosphate Fluoride)

Do not place in porcelain or glass containers.^{f o v} (See Teeth Surface and Restoration Staining under Cautions and also see Storage under Stability.)

1.1% gel: Rinse thoroughly after brushing teeth normally.^v Apply a thin ribbon of gel to teeth with toothbrush or mouth trays for ≥1 minute; expectorate.^v Children, rinse mouth thoroughly.^v

Foam or 1.23% gel: Dental personnel may apply after prophylaxis.^{o t} Prior to filling mouth trays, shake foam bottle vigorously for 3–4 seconds.^o Have patient bite down lightly on mouth tray(s) for 1–4 minutes.^{o t} Remove tray(s) and have patient expectorate excess.^{o t} Gel may also be applied by swab.^t

For desensitizing exposed root surfaces, use gel after brushing and flossing at bedtime.^a

Oral Topical Administration (Stannous Fluoride)

0.4% gel: After brushing teeth normally, shake toothbrush to remove excess water; apply the gel to cover the bristles.^l Brush teeth thoroughly; allow the gel to remain on the teeth for 1 minute, then expectorate.^{124 125 l} For sensitivity relief, use a toothbrush or cotton swab to ensure that all sensitive areas are covered with the gel.^{124 125 l}

0.1% rinsing solution: Dilute before use.ⁱ Use after regular brushing and flossing.^{117 118 i} Swish vigorously around and between teeth for 1 minute; expectorate.^{117 118 i} Repeat.^{117 118 i}

Reconstitution

Reconstitute fluoride powders as directed by the manufacturer.¹⁰³

Dilution

Prepare 0.1% rinsing solution from concentrate prior to use.^{117 118 i} Add 3.75 mL concentrated rinse to the mixing vial (or fill to 1/8 oz mark); add 26.25 mL water (or fill to 1 oz mark) and mix to provide a 0.1% rinsing solution.^{117 118 i} Use immediately;^{117 118 i} solutions may decompose within a few hours to stannous hydroxides, forming a white precipitate.^a

For home irrigators, pour 30 mL of the diluted 0.1% solution into the irrigator reservoir; add 120 mL of water and mix thoroughly to provide a 0.02% stannous fluoride rinse.ⁱ Consult the manufacturer’s prescribing information for additional information on preparation and use of the concentrated solution with home irrigators.^{117 118 i}

Dosage

Available as sodium fluoride, acidulated phosphate fluoride, sodium monofluorophosphate, or stannous fluoride; dosage expressed in terms of the fluoride ion.^{a c i j n o p}

Dosage of oral fluoride supplements varies according to the age of the child and the concentration of fluoride in the drinking water.^{109 110} Adjust dosage in proportion to the amount of fluoride provided from all possible sources (e.g., childcare settings, school, bottled water, dentifrice, multivitamins, mouth rinse).^{a 109 110} Do not exceed recommended dosages.^a (See Dental Fluorosis and also see Pediatric Use under Cautions.)

CDC recommends that patients at increased risk for dental caries receive fluoride applications by dental personnel twice a year.¹⁰⁹

Pediatric Patients

Dental Caries Prophylaxis

Fluoride-containing Dentifrices

Oral Topical

Children 2–6 years of age: Apply only a pea-sized amount (approximately 0.25 g) to the toothbrush no more often than twice daily.^{100 101 109}

Adequate Dietary Intake

Oral

For tolerable upper intake levels, see Prescribing Limits under Dosage and Administration.

Table 1. Adequate Daily Dietary Intake of Fluoride in Infants, Children, and Adolescents107

Age	Adequate Daily Dietary Intake of Fluoride
0– 6 months	0.01 mg
7–12 months	0.5 mg
1–3 years	0.7 mg
4–8 years	1.1 mg
9–13 years	2 mg
14–18 years	2.9–3.2 mg

Fluoride Supplementation in Areas with Insufficient Fluoride in Drinking Water

Oral

Table 2. Oral Daily Dosage of Supplemental Fluoride (as Lozenge, Chewable Tablet, or Solution) for Children Living in Areas with Insufficient Fluoride in Drinking Water (Expressed in Terms of Fluoride Ion)106107109jw

	Fluoride Ion Concentration in Drinking Water
Age	<0.3 ppm	0.3–0.6 ppm	>0.6 ppm
0 to <6 months	None	None	None
6 months to <3 years	0.25 mg	None	None
3 to <6 years	0.5 mg	0.25 mg	None
6–16 years	1 mg	0.5 mg	None

Sodium Fluoride

Oral Topical

1.1% cream in children ≥6 years of age: Brush for 2 minutes once daily, preferably at bedtime.^{121 d e}

1.1% gel in children ≥6 years of age: Once daily, preferably at bedtime.^{119 s}

0.044 or 0.05% rinsing solution in children ≥6 years of age: 10 mL once daily at bedtime.^{116 n p}

0.2% rinsing solution in children ≥6 years of age: 10 mL once weekly, preferably at bedtime.^{115 m}

Acidulated Phosphate Fluoride

Oral Topical

1.1% gel in children ≥6 years of age: Once daily, preferably at bedtime.^v

1.2 or 1.23% foam or 1.23% gel in children ≥6 years of age: Apply once every 6–12 months.^{a o} In patients with rampant or active caries, may repeat 1–2 times every 6 months.^{a o}

Stannous Fluoride

Oral Topical

0.4% gel in children ≥12 years of age: Once daily.^{124 125 l}

0.1% rinsing solution in children ≥12 years of age: Dilute before use to a 0.1% solution.ⁱ (See Dilution under Dosage and Administration.) Use 15 mL once daily.^{117 118 i} Repeat with an additional 15 mL.^{117 118 i} May use more frequently as directed by clinician.ⁱ

Desensitizing Dentin

Stannous Fluoride

Oral Topical

0.4% gel in children ≥12 years of age: Twice daily.^{124 125}

Adults

Dental Caries Prophylaxis

Adequate Daily Dietary Intake of Fluoride

Oral

Adults ≥19 years of age: 3.1–3.8 mg daily.^a

Sodium Fluoride

Oral Topical

1.1% cream: Brush for 2 minutes once daily, preferably at bedtime.^{121 d}

2% foam: Some clinicians recommend applying 5 mL to teeth by means of trays or mouthpiece applicators.^{120 128}

1.1% gel: Once daily, preferably at bedtime.^s

0.044 or 0.05% rinsing solution: 10 mL once daily, preferably at bedtime.^{n p}

0.2% rinsing solution: 10 mL once weekly, preferably at bedtime.^m

Acidulated Phosphate Fluoride

Oral Topical

1.1% gel: Once daily, preferably at bedtime.^v

1.2 or 1.23% foam or 1.23% gel: Apply once every 6–12 months.^{a o} May repeat 1–2 times every 6 months in patients with rampant or active caries.^{a o}

Stannous Fluoride

Oral Topical

0.4% gel: Once daily.^{124 125}

0.1% rinsing solution: Dilute before use to a 0.1% solution.ⁱ (See Dilution under Dosage and Administration.) Use 15 mL once daily.^{117 118 i} Repeat with an additional 15 mL.^{117 118 i} May use more frequently, as directed by clinician.ⁱ

Desensitizing Dentin

Sodium Fluoride

Oral Topical

0.2% rinsing solution: Once daily at bedtime.^a

Sodium Fluoride, Stannous Fluoride, and Hydrogen Fluoride

Oral Topical

Solution: Apply to the tooth surface for 1 minute.^f May require sequential 1-minute treatments.^f

Acidulated Phosphate Fluoride

Oral Topical

1.2% gel: Apply a few drops to a toothbrush and brush the affected area(s) each night at bedtime.^a Relief from sensitivity usually occurs within a few weeks.^a

Stannous Fluoride

Oral Topical

0.4% gel: Use twice daily (morning and evening).^{124 125 l}

Bone Diseases†

Hearing Loss in Otosclerosis: Sodium Fluoride†

Oral

25–60 mg daily has been used.^a

Prescribing Limits

Pediatric Patients

Fluoride Tolerable Daily Upper Intake Levels in Infants and Children¹⁰⁷

Table 3.

Age	Tolerable Daily Upper Intake Levels of Fluoride
Infants 0– 6 months of age	0.7 mg
Infants 7–12 months of age	0.9 mg
Children 1–3 years of age	1.3 mg
Children 4–8 years of age	2.2 mg
Children 9–18 years of age	10 mg

Adults

Prevention of Dental Caries

Oral Topical

Sodium fluoride 2% foam: Maximum 10 mL daily.¹²⁸

Stannous fluoride 0.4% gel (self-care): Maximum twice daily for 4 weeks for sensitive teeth.^l

Tolerable Daily Upper Intake Level

Oral

Maximum 10 mg daily.¹⁰⁷

Pregnant women: Maximum 10 mg daily.¹⁰⁷

Lactating women: Maximum 10 mg daily.¹⁰⁷

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^a

Renal Impairment

No specific dosage recommendations at this time; however, see Renal Impairment in Cautions.^{f m o}

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.^{f m o}

Cautions for Fluorides

Contraindications

• 
  

  Known hypersensitivity to fluoride or any ingredient in the formulation.^{a h}

  
  


• 
  

  Sodium fluoride 5% suspension: Known sensitivity to colophony (kolophonium).^h

  
  


• 
  

  Fluoride dietary supplements: Drinking water fluoride ion concentration ≥0.6 ppm (mg/L).^{a b j}

  
  


• 
  

  Sodium fluoride 1-mg chewable tablets: Drinking water fluoride ion concentration ≥0.3 ppm (mg/L).^j

  
  


• 
  

  Sodium fluoride 5% topical solution: Ulcerative gingivitis or stomatitis.^h

  
  


• 
  

  Sodium fluoride 0.2% rinsing solution: Dysphagia.^m

  
  


• 
  

  Stannous fluoride oral rinsing solutions and sodium fluoride 5% topical solution: Not for systemic treatment.^{h i} Do not ingest.^{h i}

  
  

Warnings/Precautions

Warnings

Dental Fluorosis

Excessive amounts may produce dose-related dental fluorosis (hypocalcification and hypoplasia) and osseous changes in children <8 years of age, especially where water fluoridation >0.6 ppm.^{107 a b d e f i j m o s v}

Follow proper techniques for applying topical preparations to minimize the amount ingested and systemically absorbed.^{100 101 103 e i}

Mild fluorosis has no effect on tooth function; may render the enamel more resistant to caries.¹⁰⁷ May cause white opaque patches on the incisal edges of anterior teeth or cusp tips of posterior teeth (“snow capping”).¹⁰⁷

Risk of stained and pitted teeth in moderate-to-severe fluorosis; effect primarily cosmetic.^{107 t}

Skeletal Fluorosis

Prolonged intake of high fluoride ion concentrations (i.e., 4–8 ppm [mg/L]) in drinking water may result in an increase in bone mineral density and apparent fluoride osteosclerosis.¹⁰⁷ Risk of developing fluorosis directly related to the extent and duration of fluoride exposure; crippling skeletal fluorosis is extremely rare in the US.¹⁰⁷

Teeth Surface and Restoration Staining

Staining or pigmentation (e.g., yellow, brown, brown-black) of the teeth may result from topical application of concentrated solutions or gels of stannous fluoride, particularly in patients with poor oral hygiene.^{a i} Good oral hygiene (e.g., adequate brushing) minimizes risk of staining; staining is not harmful or permanent and can be removed by dentist.^{103 i}

Acidulated phosphate fluoride preparations may cause dulling of porcelain and ceramic restorations unless protected from contact.^{a c f o t v}

Sodium-Free Diet

Some fluoride products (e.g., Fluor-A-Day) are not recommended by manufacturer for use in patients receiving a sodium-free diet.^b

Sensitivity Reactions

Allergic Reactions

Allergic rash and other idiosyncratic reactions rarely reported.^{a d f h i j m o s t v}

Urticaria, exfoliative dermatitis, atopic dermatitis, stomatitis, and GI and respiratory allergic reactions have occurred rarely following the use of dentifrices or multivitamin preparations containing fluoride.^{a h}

Patients with mucositis or with abraded or sensitive gingival tissue may be hypersensitive to alcohol or other ingredients contained in some oral or topical fluoride preparations.^{a f m o v}

Sodium fluoride 5% topical solution: Dyspnea has occurred rarely in asthmatic children.^h Edematous swelling reported rarely after application to extensive surfaces.^h If intolerance occurs, remove solution layer by brushing and rinsing.^h

General Precautions

Use of Fixed Combinations

When fluoride is used in fixed combination with other preparations, consider the cautions, precautions, and contraindications associated with the concomitant agent(s).^a (See Pediatric Use under Cautions.)

Specific Populations

Pregnancy

Category B.^{f i j m o v}

The ADA currently does not recommend fluoride supplements during pregnancy.^a

Lactation

Distributed into milk in small amounts.^a Use with caution in nursing women.^{f i j m o s v}

Pediatric Use

ADA, American Academy of Pediatric Dentistry (AAPD), and AAP currently do not recommend oral fluoride supplements in infants <6 months of age.^{106 107 j}

In children <2 years of age, consider other sources of fluoride when weighing the risks and benefits of using fluoridated dentifrice.¹⁰⁹

Instruct and/or supervise children 2–12 years of age carefully regarding the proper use of topical fluoride-containing products to minimize repeated swallowing and the risk of dental fluorosis.^{100 101 103 e i m s v}

Efficacy of oral fluoride supplements in controlling dental caries in children >16 years of age not established.¹⁰⁹

Sodium fluoride, stannous fluoride, and hydrogen fluoride fixed-combination solution: Safety and efficacy not established.^f

Sodium fluoride chewable tablets: Safety and efficacy not established in children <6 months of age.^j

Sodium fluoride 1.1% topical cream, gel, and rinsing solution: Safety and efficacy not established in children <6 years of age.^{d e m n s}

Acidulated phosphate fluoride topical foam and gel: Safety and efficacy not established in children <6 years of age.^{o v}

Stannous fluoride oral rinsing solutions and topical gels: Safety and efficacy not established in children <12 years of age.^{117 118 124 125 i}

May be difficult to appropriately adjust the amount of fluoride required from fixed-combination multivitamin or multivitamin/iron preparations used as oral fluoride supplements.^a (See Dosage in Dosage and Administration.)

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.^{f m o} Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.^{f m o}

Renal Impairment

Excreted by the kidney; therefore, risk of toxic reactions may be greater in patients with impaired renal function.^{f m o}

Interactions for Fluorides

Specific Drugs

Drug	Interaction	Comments
Aluminum hydroxide	Concomitant ingestion may decrease oral absorption of fluoridea
Calcium	May cause formation of calcium fluoride and may decrease fluoride absorption by 10–25%107 b j Simultaneous ingestion of dairy products containing calcium probably has little effect on absorption of the low concentrations of fluoride present in drinking watera	Avoid dairy products within 1 hour after oral fluoride systemic administrationj
Magnesium hydroxide	Concomitant ingestion may decrease oral absorption of fluoridea

Fluorides Pharmacokinetics

Absorption

Bioavailability

Sodium fluoride and other soluble fluoride salts: Readily and almost completely absorbed from the GI tract.^{107 a b}

≥80% of soluble fluoride probably absorbed from the GI tract in the absence of high dietary concentrations of calcium or certain other cations.¹⁰⁷ (See Interactions.)

Food

Milk, infant formula, or certain foods (e.g., with high concentrations of calcium or certain other divalent or trivalent cations that form insoluble fluoride salts) may decrease absorption of fluoride by 10–25%.¹⁰⁷

Distribution

Extent

Crosses the placenta and is distributed in small amounts into milk, sweat, tears, and hair.^a

Stored in bones, developing teeth, and skeletal tissue.^{a b}

Elimination

Elimination Route

Rapidly excreted principally in urine, and in small amounts in feces, sweat, and saliva.^{a b}

Special Populations

Hemodialysis may remove fluoride in patients with severe intoxication or with impaired renal function.^a

Stability

Storage

Oral

Solution

Sodium fluoride: Tight, plastic containers at <40°C (maintain between 15–30°C), especially if the pH of the solution is <7.5.^a May decompose and become alkaline when stored in ordinary pharmaceutical glass.^{a b} Store and dispense in plastic, paraffin-lined flasks or USP type 1 borosilicate glass containers.^b

Tablets

Sodium fluoride: 20–25°C.^j

Topical

Cream

Sodium fluoride 1.1%: 20–25°C.^e

Foam

Acidulated phosphate fluoride 1.2%: 20–25°C.^o Do not store at >48°C (120° F).^o Do not freeze.^o Do not puncture or incinerate.^o

Gel

Acidulated phosphate fluoride: Tight, plastic containers^a at 20–25°C.^{t v} Do not freeze.^t

Sodium fluoride 1.1%: 20–25°C.^s

Rinsing Solution

Sodium fluoride 0.2% 20–25°C.^m

Stannous fluoride: Tightly closed containers at 20–25°C.ⁱ Decomposes to stannous hydroxides within a few hours, forming a white precipitate; prepare just prior to use.^a

Solution

Sodium fluoride 5%: 20–25°C.^h

Sodium fluoride, stannous fluoride, and hydrogen fluoride: 20–25°C.^f

Drug Compatibility

Sodium fluoride is incompatible with calcium and magnesium salts.^a

Stannous fluoride is incompatible with alkaline substances and oxidizing agents.^a

ActionsActions

• 
  

  Mechanism of action in reducing tooth decay not fully understood;^a however, research now indicates predominant effect is posteruptive, not preeruptive as previously hypothesized.^{109 113}

  
  


• 
  

  Increases tooth resistance to acid dissolution, promotes remineralization, and inhibits the cariogenic microbial process.^{109 a b e i j m o s w v}

  
  


• 
  

  Prior to tooth eruption, fluoride is incorporated into tooth enamel during formation.^a

  
  


• 
  

  Cariostatic effects on teeth after eruption result from combined effects of bacterial metabolism in plaque and on the dynamics of enamel demineralization and remineralization during an acidogenic challenge.¹⁰⁷

  
  


• 
  

  Obturates dentin tubule orifices; reduces patency of the tooth pulp and decreases hypersensitivity.^{f h}

  
  


• 
  

  Increases skeletal density and bone mass; however, large doses can cause skeletal fluorosis and osteomalacia.^a

  
  

Advice to Patients

• 
  

  Advise patients receiving fluoride powders or concentrated rinsing solutions that the preparation must be reconstituted and/or diluted as directed prior to use.^{103 i}

  
  


• 
  

  Advise patients receiving fluoride treatment gels or rinsing solutions for self-administration that these preparations are to be used as directed and not as dentifrices or mouthwashes or gargles, respectively.^{103 i}

  
  


• 
  

  Advise individuals receiving stannous fluoride-containing preparations of the importance of good oral hygiene (e.g., adequate brushing) to minimize the risk of staining.^{103 i} Inform patients that such staining is not harmful or permanent and can be removed by a dentist or dental hygienist.^{103 i}

  
  


• 
  

  Instruct and/or supervise children <12 years of age during use of topical fluoride preparations (e.g., rinsing solutions, gels, dentifrices) to minimize the risk of fluorosis and the amount of fluoride swallowed and absorbed systemically.^{100 101 103 i} Instruct children, especially those 2–6 years of age, not to swallow topical fluoride products.^{100 101 109} Inform individuals with children that ingestion of higher than recommended levels of fluoride by children has been associated with an increase in mild dental fluorosis in developing, unerupted teeth.^w

  
  


• 
  

  Importance of long-term compliance on a daily basis in patients who require oral fluoride supplements.^w

  
  


• 
  

  Advise patients not to brush or eat hard foods for 2 hours after application of topical solution.^h

  
  


• 
  

  Advise patients to contact a poison control center or other qualified clinician immediately if they swallow more fluoride than the amount used for brushing or rinsing.^{l n}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{b c d e f i j l m n o p s t w v h}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{b c d e f i j l m n o p s t w v h}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{b c d e f i j l m n o p s t w v h} (See Cautions.)

  
  

Preparations

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

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

Sodium Fluoride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Lozenge	2.21 mg (1 mg of fluoride ion)	Fluor-A-Day	Pharmascience
	Solution	0.55 mg/mL (0.42 mg of fluoride ion per mL)	Fluorabon Drops	Kirkman
		5.56 mg/mL (2.5 mg of fluoride ion per mL	Fluor-A-Day	Pharmascience
		11 mg/mL (5 mg of fluoride ion per mL)	Fluoritab	Fluoritab
			Flura-Drops

Fluor-A-Day

Generic Name: fluoride (FLOR ide)

Brand Names: Altaflor, Ethedent Chewable, Fluor-A-Day, Fluoritab, Flura-Drops, Flura-Loz, Flura-Tab, Karidium, Lozi-Flur, Luride, Nafrinse, Pharmaflur, Pharmaflur 1.1

What is Fluor-A-Day (fluoride)?

Fluoride is a substance that strengthens tooth enamel. This helps to prevent dental cavities.

Fluoride is used as a medication to prevent tooth decay in people that have a low level of fluoride in their drinking water. Fluoride is also used to prevent tooth decay in people who undergo radiation of the head and/or neck, which may cause dryness of the mouth and an increased incidence of tooth decay.

Fluoride may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Fluor-A-Day (fluoride)?

You should not use fluoride if the level of fluoride in your drinking water is greater than 0.7 parts per million (ppm).

Before using fluoride, tell your dentist and doctor if you are on a low salt or a salt free diet. You may not be able to use fluoride, or you may need special tests while you are using it.

Do not take fluoride with milk, other dairy products, or calcium supplements. Calcium can make it harder for your body to absorb fluoride.

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Many antacids contain calcium, which can interfere with fluoride absorption.

What should I discuss with my healthcare provider before taking Fluor-A-Day (fluoride)?

You should not use fluoride if the level of fluoride in your drinking water is greater than 0.7 parts per million (ppm).

Before using fluoride, tell your dentist and doctor if you are on a low salt or a salt free diet. You may not be able to use fluoride, or you may need special tests while you are using it.

Talk to your doctor and dentist before taking fluoride if you are pregnant or could become pregnant during treatment. Talk to your doctor and dentist before taking fluoride if you are breast-feeding. The American Dental Association's Council on Dental Therapeutics recommends the use of fluoride by children up to 13 years of age; the American Academy of Pediatrics recommends fluoride supplementation by children until the age of 16 years of age. Do not give a 1-mg tablet to a child younger than 3 years old, or when your drinking water fluoride content is equal to or greater than 0.3 ppm.

How should I take Fluor-A-Day (fluoride)?

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

Take this medicine with a full glass of water. Do not take fluoride with milk or other dairy products. Calcium can make it harder for your body to absorb fluoride.

Suck on the fluoride lozenge until it dissolves completely in your mouth. Do not chew the lozenge or swallow it whole.

The chewable forms of fluoride can be chewed, swallowed, dissolved in the mouth, added to drinking water or fruit juice, or added to water for use in infant formula or other food.

The fluoride drops can be taken by mouth undiluted, or mixed with fluid or food.

If you mix fluoride with food or water, drink or eat this mixture right away. Do not save it for later use.

It is important to take fluoride regularly to get the most benefit.

Store fluoride at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include nausea, vomiting, stomach pain, diarrhea, drooling, numbness or tingling, loss of feeling anywhere in your body, muscle stiffness, or seizure (convulsions).

What should I avoid while taking Fluor-A-Day (fluoride)?

Do not take fluoride with milk, other dairy products, or calcium supplements. Calcium can make it harder for your body to absorb fluoride.

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends. Many antacids contain calcium, which can interfere with fluoride absorption.

Fluor-A-Day (fluoride) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor if you have any of the following side effects:

• 
  

  discolored teeth;

  
  


• 
  

  weakened tooth enamel; or

  
  


• 
  

  any changes in the appearance of your teeth.

  
  

Less serious side effects may include:

• 
  

  stomach upset;

  
  


• 
  

  headache; or

  
  


• 
  

  weakness.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Fluor-A-Day (fluoride)?

There may be other drugs that can interact with fluoride. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Fluor-A-Day resources

• Fluor-A-Day Side Effects (in more detail)
• Fluor-A-Day Use in Pregnancy & Breastfeeding
• Fluor-A-Day Support Group
• 0 Reviews for Fluor-A-Day - Add your own review/rating

• Fluor-A-Day Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Fluor-A-Day Advanced Consumer (Micromedex) - Includes Dosage Information


• Epiflur Prescribing Information (FDA)


• Fluor-a-Day Prescribing Information (FDA)


• Fluorides Monograph (AHFS DI)


• Fluoritab Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Lozi-Flur Lozenges MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Fluor-A-Day with other medications

• Prevention of Dental Caries

Where can I get more information?

• Your pharmacist can provide more information about fluoride.

See also: Fluor-A-Day side effects (in more detail)

Flavocoxid

Pronunciation: FLAV-voe-COX-ihd/SIT-rat-ed zink biz-GLIS-i-nate
Generic Name: Flavocoxid/Citrated Zinc Bisglycinate
Brand Name: Limbrel

Flavocoxid is used for:

Dietary management of osteoarthritis and associated swelling. It may also be used for other conditions as determined by your doctor.

Flavocoxid is a medical food. It works by reducing swelling and providing pain relief.

Do NOT use Flavocoxid if:

• you are allergic to any ingredient in Flavocoxid, to flavonoids, or foods rich in flavonoids (eg, colored fruits and vegetables, dark chocolate, tea [especially green tea], red wine, Brazil nuts)


• you are pregnant or breast-feeding


• you have a history of ulcers

Contact your doctor or health care provider right away if any of these apply to you.

Before using Flavocoxid:

Some medical conditions may interact with Flavocoxid. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of intestinal or stomach problems (eg, ulcers)


• if you are taking warfarin

Some MEDICINES MAY INTERACT with Flavocoxid. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, celecoxib) because the risk of ulcers or stomach bleeding or perforation may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Flavocoxid may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Flavocoxid:

Use Flavocoxid as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Flavocoxid by mouth on an empty stomach at least 1 hour before or after eating.


• If you miss a dose of Flavocoxid, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Flavocoxid.

Important safety information:

• Flavocoxid has zinc in it. Before you start any new medicine, check the label to see if it has zinc in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Flavocoxid is not recommended for use in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Flavocoxid while you are pregnant. It is not known if Flavocoxid is found in breast milk. Do not breast-feed while taking Flavocoxid.

Possible side effects of Flavocoxid:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; gas; nausea.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Flavocoxid:

Store Flavocoxid at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly sealed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Flavocoxid out of the reach of children and away from pets.

General information:

• If you have any questions about Flavocoxid, please talk with your doctor, pharmacist, or other health care provider.


• Flavocoxid is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Flavocoxid. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Flavocoxid resources

• Flavocoxid Use in Pregnancy & Breastfeeding
• Flavocoxid Drug Interactions
• Flavocoxid Support Group
• 3 Reviews for Flavocoxid - Add your own review/rating

Compare Flavocoxid with other medications

• Osteoarthritis

factor IX complex injectable

Generic Name: factor IX complex (injectable) (FAC tor NINE)

Brand names: Alphanine SD, Bebulin VH, Benefix, Konyne 80, Mononine, Profilnine SD, Proplex T, ...show all 14 brand names.Alphanine SD (obsolete), Mononine (obsolete), Proplex T (obsolete), Bebulin VH (obsolete), Konyne 80 (obsolete), Profilnine SD (obsolete), Benefix (obsolete)

What is factor IX complex?

Factor IX is a natural protein, normally present in the blood, that helps blood to clot. A lack of this protein causes hemophilia B (Christmas disease). Factor IX complex also contains small amounts of other blood clotting factors.

Factor IX complex is used to treat or prevent bleeding in people with hemophilia B. Some forms of factor IX complex may also be used to treat or prevent bleeding in people with factor VII deficiency or inhibitors to factor VIII.

Factor IX complex may also be used for purposes other than those listed here.

What is the most important information I should know about factor IX complex?

Factor IX complex is made from human plasma (part of the blood) and may contain infectious agents (e.g., viruses) that can cause disease. Although factor IX complex is screened, tested, and treated to reduce the possibility that it carries an infectious agent, it can still potentially transmit disease. Discuss with your doctor the risks and benefits of using factor IX complex.

Some viruses, such as parovovirus B19 and hepatitis A, may be more difficult to identify or remove from factor IX complex. Parovovirus B19 may more seriously affect pregnant women and those with poor immune systems. Symptoms of parovovirus B19 infection include fever, chills, runny nose, and drowsiness followed about 2 weeks later by a rash and joint pain. Symptoms of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark-colored urine and yellowing of the skin or whites of the eyes may also occur. Contact your doctor if you develop any of these symptoms after treatment with factor IX complex.

Carry or wear identification that will alert others that you have hemophilia or another blood clotting disorder in the case of an emergency.

Tell your doctor and dentist that you have hemophilia or another blood clotting disorder before having surgery or other invasive procedures.

What should I discuss with my healthcare provider before using factor IX complex?

Do not use factor IX complex without first talking to your doctor if you have

• had an unusual or allergic reaction to this medication, a similar medication, a human or animal (mouse or hamster) protein, dyes, additives, or preservatives;


• hardening of the arteries;


• 
  

  severe injury or infection;

  
  


• liver disease; or


• 
  

  other bleeding or blood clotting disorders.

  
  

You may not be able to use factor IX complex or you may require a dosage adjustment or special monitoring during treatment.

Factor IX complex is in the FDA pregnancy category C. This means that it is not known whether it will be harmful to an unborn baby. Do not use factor IX complex without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether factor IX complex could be harmful to a nursing baby. Do not use factor IX complex without first talking to your doctor if you are breast-feeding a baby.

How should I use factor IX complex?

Factor IX complex will be administered by intravenous (into a vein) injection by a healthcare provider.

Your doctor may want you to have blood tests or other medical evaluations during treatment with factor IX to monitor progress and side effects.

Carry or wear identification that will alert others that you have hemophilia or another blood clotting disorder in the case of an emergency.

Your healthcare provider will store factor IX complex as directed by the manufacturer.

If you are using factor IX complex at home, your doctor or healthcare provider will give you detailed instructions on how to administer and store the medication.

What happens if I miss a dose?

Contact your doctor if a dose of factor IX is missed.

What happens if I overdose?

Seek emergency medical attention if an overdose of factor IX complex is suspected.

What should I avoid while using factor IX complex?

Tell your doctor and dentist that you have hemophilia or another blood clotting disorder before having surgery or other invasive procedures.

Factor IX complex side effects

Factor IX complex is made from human plasma (part of the blood) and may contain infectious agents (e.g., viruses) that can cause disease. Although factor IX complex is screened, tested, and treated to reduce the possibility that it carries an infectious agent, it can still potentially transmit disease. Discuss with your doctor the risks and benefits of using factor IX complex.

Some viruses, such as parovovirus B19 and hepatitis A, may be more difficult to identify or remove from factor IX complex. Parovovirus B19 may more seriously affect pregnant women and those with poor immune systems. Symptoms of parovovirus B19 infection include fever, chills, runny nose, and drowsiness followed about 2 weeks later by a rash and joint pain. Symptoms of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark-colored urine and yellowing of the skin or whites of the eyes may also occur. Contact your doctor if you develop any of these symptoms after treatment with factor IX complex.

If you experience any of the following serious side effects, contact your healthcare provider immediately or seek emergency medical attention:

• 
  

  an allergic reaction (shortness of breath; wheezing; tightness of the chest; closing of the throat; hives; swelling of the lips, face, or tongue; hives or rash; dizziness or fainting); or

  
  


• 
  

  fever;

  
  


• 
  

  nausea or vomiting;

  
  


• 
  

  increased heart rate;

  
  


• 
  

  decreased blood pressure (may result in dizziness or fainting);

  
  


• 
  

  difficulty breathing, chest pain, or cough; or

  
  


• 
  

  pain, redness, or swelling at the injection site.

  
  

Other, less serious side effects may be more likely to occur. Continue to use factor IX complex and talk to your doctor if you experience

• 
  

  headache; or

  
  


• 
  

  flushing.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

Factor IX complex Dosing Information

Usual Adult Dose for Factor IX Deficiency:

Although the dose of factor IX should be individualized for each patient based on body weight, type of hemorrhage, and desired plasma factor IX concentration, the following formulas may be used as a guide in determining dosage.
Human-derived factor IX:
Dose factor IX (IU) = Body weight (kg) x Desired factor IX increase (% of normal) x 1.0 IU/kg.
Recombinant factor IX:
Dose factor IX (IU) = Body weight (kg) x Desired factor IX increase (% of normal) x 1.2 IU/kg.

The following are suggestions for approximate factor IX levels, typical initial doses, and the average duration of treatment:

Minor (uncomplicated hemarthrosis, superficial muscle, or soft tissue hemorrhage):
20% to 30% desired factor IX level for 1 to 2 days duration.

Moderate (intramuscle or soft tissue with disconnection, mucous membranes, dental extractions, or hematuria hemorrhage):
25% to 50% desired factor IX level until bleeding stops and healing begins (usually 2 to 7 days).

Major (pharynx, retropharynx, retroperitoneum, CNS, or surgery hemorrhage):
40% to 100% desired factor IX level for 7 to 10 days.

Relatively high levels may be maintained by daily or twice daily doses, while the lower effective levels may require injections only once every two to three days. A single dose may be sufficient to stop a minor bleeding episode.

The following are suggested administration rates for the various brands of factor IX complex: Bebulin VH 2 mL/min, Konyne 80 100 IU/min, Profiline SD 10 mL/min, and Proplex T 2 to 3 mL/min.

Usual Adult Dose for Factor VII Deficiency:

(For Proplex T brand only)
Units required to raise blood level percentages = 0.5 unit/kg x body weight (in kg) x desired increase (%of normal)
Repeat dose every 4 to 6 hours as needed.

In preparation for and following surgery, levels above 25%, maintained for at least a week after surgery, are suggested. To maintain levels above 25% for a reasonable time, each dose should be calculated to raise the level to 40% to 60% of normal.

What other drugs will affect factor IX complex?

Other drugs that affect bleeding or blood-clotting processes can interact with factor IX complex resulting in dangerous side effects and/or altered effectiveness. Do not take any other prescription or over-the-counter medicines, including herbal products, without first talking to your doctor during treatment with factor IX complex.

Where can I get more information?

• Your pharmacist has additional information about factor IX complex written for health professionals that you may read.

What does my medication look like?

Factor IX complex is available with a prescription under the several brand names. Generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

Fentora

Dosage Form: buccal tablet, oral tablet
FULL PRESCRIBING INFORMATION

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL

RESPIRATORY DEPRESSION

Fatal respiratory depression has occurred in patients treated with Fentora, including following use in opioid non-tolerant patients and improper dosing.The substitution of Fentora for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, Fentora is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see Contraindications (4)]

Fentora must be kept out of reach of children. [see Patient Counseling Information (17.3) and How Supplied/Storage and Handling (16.1)] 

The concomitant use of Fentora with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7)].

MEDICATION ERRORS

Substantial differences exist in the pharmacokinetic profile of Fentora compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.

- When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Fentora. [see Dosage and Administration (2.1)]

- When dispensing, do not substitute a Fentora prescription for other fentanyl products.

ABUSE POTENTIAL

Fentora contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentora can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Fentora in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, Fentora is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [see Warnings and Precautions (5.11)] Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Indications and Usage for Fentora

Fentora is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg/hr of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids while taking Fentora.

This product must not be  used in opioid non-tolerant patients  because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, Fentora is contraindicated in the management of acute or postoperative pain.

Fentora is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.

Limitations of Use:

As a part of the TIRF REMS Access program, Fentora may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions(5.11)]. For inpatient administration of Fentora (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

Fentora Dosage and Administration

Healthcare professionals who prescribe Fentora on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of Fentora [see Warnings and Precautions (5.11)].

As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.

Initial Dose

Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose.

Patients on Actiq

The initial dose of Fentora is always 100 mcg with the only exception being patients already using Actiq.

a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq table below (Table 1). The doses of Fentora in this table are starting doses and not intended to represent equianalgesic doses to Actiq. Patients must be instructed to stop the use of Actiq and dispose of any remaining units.

Table 1. Initial Dosing Recommendations for Patients on Actiq

Current Actiq Dose (mcg)	Initial Fentora Dose*
200	100 mcg tablet
400	100 mcg tablet
600	200 mcg tablet
800	200 mcg tablet
1200	2 x 200 mcg tablets
1600	2 x 200 mcg tablets

*From this initial dose, titrate patient to effective dose.

b. For patients converting from Actiq doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg Fentora tablet and should proceed using multiples of this tablet strength.

All Other Patients

The initial dose of Fentora is 100 mcg.

Repeat Dosing

a. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of Fentora for any episode of breakthrough pain.

b. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora.

Dose Titration

a. From an initial dose, patients should be closely followed by the prescriber and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of Fentora  over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted.

b. Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200 mcg Fentora tablet for doses  above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously.

c. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of Fentora for any breakthrough pain episode. During titration, one dose of Fentora  may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg).

d. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora. To reduce the risk of overdose during titration, patients should have only one strength of Fentora tablets available at any time.

e. Patients should be strongly encouraged to use all of their Fentora tablets of one strength prior to being prescribed the next strength. If this is not practical, unused Fentora should be disposed of safely [see How Supplied/Storage and Handling (16.2)]. Dispose of any unopened Fentora tablets remaining from a prescription as soon as they are no longer needed.

Maintenance Dosing

a. Once titrated to an effective dose, patients should generally use only ONE Fentora tablet of the appropriate strength per breakthrough pain episode.

b. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode.

c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora.

d. Dosage adjustment of Fentora may be required in some patients. Generally, the Fentora  dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes

e. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the around-the-clock opioid used for persistent pain should be re-evaluated.

Administration of Fentora

Opening the Blister Package

1. Instruct patients not to open the blister until ready to administer Fentora.


2. Separate a single blister unit from the blister card by bending and tearing apart at the perforations.


3. Bend the blister unit along the line where indicated.


4. Peel back the blister backing to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet.


5. Do not store the tablet once it has been removed from the blister package as the tablet integrity may be compromised and, more importantly, because this increases the risk of accidental exposure to the tablet.

 

Tablet Administration:

Once the tablet is removed from the blister unit, the patient should immediately place the entire Fentora tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not split the tablet.

The Fentora tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.

The Fentora tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately 14-25 minutes.

After 30 minutes, if remnants from the Fentora tablet remain, they may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when administering subsequent doses of Fentora.

Dosage Forms and Strengths

Fentora tablets are flat-faced, round, beveled-edge in shape; are white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg and 800 mcg strengths. Each tablet strength is marked with a unique identifier [see How Supplied/Storage and Handling (16.3)].

Contraindications

Fentora is contraindicated in opioid non-tolerant patients.

Fentora is contraindicated in the management of acute or postoperative pain including headache/migraine and dental pain. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.

Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.

Fentora is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.

Warnings and Precautions

See Boxed Warning - WARNING:RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL.

Respiratory Depression

Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in Fentora. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

Important Information Regarding Prescribing and Dispensing

Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) For patients being converted from Actiq, it is necessary to follow the instructions found in Table 1 in Section 2.1,.as Actiq and Fentora are not equivalent on a microgram per microgram basis. Fentora is NOT a generic version of Actiq. All patients should be titrated from the 100 mcg dose.

The initial dose of Fentora should be 100 mcg. Titrate each patient individually to provide adequate analgesia while minimizing side effects. [see Dosage and Administration (2.1)]

When dispensing, DO NOT substitute a Fentora prescription for an Actiq prescription under any circumstances. Fentora and Actiq are not equivalent. Substantial differences exist in the pharmacokinetic profile of Fentora compared to other fentanyl products including Actiq that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of Fentora for the same dose of Actiq or any other fentanyl product may result in a fatal overdose.

Patient/Caregiver Instructions

Patients and their caregivers must be instructed that Fentora contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children. [see How Supplied/Storage and Handling (16.1), and Medication Guide for specific patient instructions.]

Additive CNS Depressant Effects

The concomitant use of Fentora with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)].

Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of Fentora if warranted.

Effects on Ability to Drive and Use Machines

Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking Fentora of these dangers and counsel them accordingly.

Chronic Pulmonary Disease

Because potent opioids can cause respiratory depression, titrate Fentora with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of Fentora may further decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure

Administer Fentora with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

Application Site Reactions

In clinical trials, 10% of all patients exposed to Fentora reported application site reactions. These reactions ranged from paresthesia to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.

Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use Fentora with caution in patients with bradyarrhythmias.

MAO Inhibitors

Fentora is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9)], Fentora is available only through a restricted program called the TIRF REMS Access program.  Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of Fentora, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

• Healthcare professionals, who prescribe Fentora for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.


• To receive Fentora, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.


• Pharmacies that dispense Fentora must enroll in the program and agree to comply with the REMS requirements.


• Wholesalers and distributors that distribute Fentora must enroll in the program, and distribute only to authorized pharmacies.

 

Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Adverse Reactions

Clinical Studies Experience

The safety of Fentora has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.

The most commonly observed adverse events seen with Fentora are typical of opioid side effects. Opioid side effects should be expected and managed accordingly.

The clinical trials of Fentora were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received Fentora for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of Fentora therapy or cancer-related symptoms.

Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.

Table 2.

Adverse Events Which Occurred During Titration at a Frequency of ≥ 5%

System Organ Class MeDRA preferred term, n (%)	100 mcg (N=45)	200 mcg (N=34)	400 mcg (N=53)	600 mcg (N=56)	800 mcg (N=113)	Total (N=304)*
Gastrointestinal disorders
Nausea	4 (9)	5 (15)	10 (19)	13 (23)	18 (16)	50 (17)
Vomiting	0	2 (6)	2 (4)	7 (13)	3 (3)	14 (5)
General disorders and administration site conditions
Fatigue	3 (7)	1 (3)	9 (17)	1 (2)	5 (4)	19 (6)
Nervous system disorders
Dizziness	5 (11)	2 (6)	12 (23)	18 (32)	21 (19)	58 (19)
Somnolence	2 (4)	2 (6)	6 (12)	7 (13)	3 (3)	20 (7)
Headache	1 (2)	3 (9)	4 (8)	8 (14)	10 (9)	26 (9)

 * Three hundred and two (302) patients were included in the safety analysis.

Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.

Table 3.

Adverse Events Which Occurred During Long-Term Treatment at a Frequency of ≥ 5%

System Organ Class MeDRA preferred term, n (%)	100 mcg (N=19)	200 mcg (N=31)	400 mcg (N=44)	600 mcg (N=48)	800 mcg (N=58)	Total (N=200)
Blood and lymphatic system disorders
Anemia	6 (32)	4 (13)	4 (9)	5 (10)	7 (13)	26 (13)
Neutropenia	0	2 (6)	1 (2)	4 (8)	4 (7)	11 (6)
Gastrointestinal disorders
Nausea	8 (42)	5 (16)	14 (32)	13 (27)	17 (31)	57 (29)
Vomiting	7 (37)	5 (16)	9 (20)	8 (17)	11 (20)	40 (20)
Constipation	5 (26)	4 (13)	5 (11)	4 (8)	6 (11)	24 (12)
Diarrhea	3 (16)	0	4 (9)	3 (6)	5 (9)	15 (8)
Abdominal pain	2 (11)	1 (3)	4 (9)	7 (15)	4 (7)	18 (9)
General disorders and administration site conditions
Edema peripheral	6 (32)	5 (16)	4 (9)	5 (10)	3 (5)	23 (12)
Asthenia	3 (16)	5 (16)	2 (5)	3 (6)	8 (15)	21 (11)
Fatigue	3 (16)	3 (10)	9 (20)	9 (19)	8 (15)	32 (16)
Infections and infestations
Pneumonia	1 (5)	5 (16)	1 (2)	1 (2)	4 (7)	12 (6)
Investigations
Weight decreased	1 (5)	1 (3)	3 (7)	2 (4)	6 (11)	13 (7)
Metabolism and nutrition disorders
Dehydration	4 (21)	0	4 (9)	6 (13)	7 (13)	21 (11)
Anorexia	1 (5)	2 (6)	4 (9)	3 (6)	6 (11)	16 (8)
Hypokalemia	0	2 (6)	0	1 (2)	8 (15)	11 (6)
Musculoskeletal and connective tissue disorders
Back pain	2 (11)	0	2 (5)	3 (6)	2 (4)	9 (5)
Arthralgia	0	1 (3)	3 (7)	4 (8)	3 (5)	11 (6)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Cancer pain	3 (16)	1 (3)	3 (7)	2 (4)	1 (2)	10 (5)
Nervous system disorders
Dizziness	5 (26)	3 (10)	5 (11)	6 (13)	6 (11)	25 (13)
Headache	2 (11)	1 (3)	4 (9)	5 (10)	8 (15)	20 (10)
Somnolence	0	1 (3)	4 (9)	4 (8)	8 (15)	17 (9)
Psychiatric disorders
Confusional state	3 (16)	1 (3)	2 (5)	3 (6)	5 (9)	14 (7)
Depression	2 (11)	1 (3)	4 (9)	3 (6)	5 (9)	15 (8)
Insomnia	2 (11)	1 (3)	3 (7)	2 (4)	4 (7)	12 (6)
Respiratory, thoracic, and mediastinal disorders
Cough	1 (5)	1 (3)	2 (5)	4 (8)	5 (9)	13 (7)
Dyspnea	1 (5)	6 (19)	0	7 (15)	4 (7)	18 (9)

 

 In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of Fentora. There was no evidence of excess toxicity in this subset of patients.

The duration of exposure to Fentora  varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving Fentora.  Events are classified by system organ class.

Adverse Events (≥1%)

Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration

General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess

Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture

Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat

Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis

Drug Interactions

Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when Fentora is given concurrently with agents that affect CYP3A4 activity.

The concomitant use of Fentora with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving Fentora who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done cautiously [see Warnings and Precautions (5.4)]. The concomitant use of Fentora with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of Fentora. Patients receiving Fentora who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of increased Fentora activity and the dose of Fentora should be adjusted accordingly.

USE IN SPECIFIC POPULATIONS

Pregnancy

Category C

There are no adequate and well-controlled studies in pregnant women. Fentora should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Fentanyl is embryocidal as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Fentora.

Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not terat