Fluticare-C

Ciclopirox:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage and handling
• References
• Patient package insert
• Fluticare-C (Ciclopirox) reviews

INDICATIONS AND USAGE

(To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.)

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), as a component of a comprehensive management program, is indicated as topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum. The comprehensive management program includes removal of the unattached, infected nails as frequently as monthly, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures.

- No studies have been conducted to determine whether Fluticare-C (Ciclopirox) might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% Fluticare-C (Ciclopirox) topical solution and systemic antifungal agents for onychomycosis, is not recommended.

- Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be used only under medical supervision as described above.

- The effectiveness and safety of Fluticare-C (Ciclopirox) Topical Solution, 8%,(Nail Lacquer), in the following populations has not been studied. The clinical trials with use of Fluticare-C (Ciclopirox) Topical Solution, 8%,(Nail Lacquer), excluded patients who: were pregnant or nursing, planned to become pregnant, had a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of dermatomycoses, extensive seborrheic dermatitis, recent or recurring herpes zoster, or persistent herpes simplex), were HIV seropositive, received organ transplant, required medication to control epilepsy,were insulin dependent diabetics or had diabetic neuropathy. Patients with severe plantar (moccasin) tinea pedis were also excluded.

- The safety and efficacy of using Fluticare-C (Ciclopirox) Topical Solution, 8%,(Nail Lacquer), daily for greater than 48 weeks have not been established.

Clinical Trials Data:

The results of use of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), in treatment of onychomycosis of the toenail without lunula involvement were obtained from two double-blind, placebo-controlled studies conducted in the US. In these studies, patients with onychomycosis of the great toenails without lunula involvement were treated with Fluticare-C (Ciclopirox) topical solution, 8% in conjunction with monthly removal of the unattached, infected toenail by the investigator. Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), was applied for 48 weeks. At baseline, patients had 20-65% involvement of the target great toenail plate. Statistical significance was demonstrated in one of two studies for the endpoint "complete cure" (clear nail and negative mycology), and in two studies for the endpoint "almost clear" (†10% nail involvement and negative mycology) at the end of study. These results are presented below.

The summary of reported patient outcomes for the ITT population at 12 weeks following the end of treatment are presented below. Note that post-treatment efficacy assessments were scheduled only for patients who achieved a complete cure.

*Four patients (from studies 312 and 313) who were completely cured did not have post-treatment Week 12 planimetry data.

CONTRAINDICATIONS

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is contraindicated in individuals who have shown hypersensitivity to any of its components.

WARNINGS

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is not for ophthalmic, oral, or intravaginal use. For use on nails and immediately adjacent skin only.

PRECAUTIONS

If a reaction suggesting sensitivity or chemical irritation should occur with the use of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), treatment should be discontinued and appropriate therapy instituted.

So far there is no relevant clinical experience with patients with insulin dependent diabetes or who have diabetic neuropathy. The risk of removal of the unattached, infected nail, by the health care professional and trimming by the patient should be carefully considered before prescribing to patients with a history of insulin dependent diabetes mellitus or diabetic neuropathy.

Information for Patients

Patients should have detailed instructions regarding the use of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product.

The patient should be told to:

1. Use Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), as directed by a health care professional. Avoid contact with the eyes and mucous membranes. Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided. Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is for external use only.

2. Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer),should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g.,onycholysis). Contact with the surrounding skin may produce mild, transient irritation (redness).

3. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional is needed with use of this medication. Inform a health care professional if they have diabetes or problems with numbness in your toes or fingers for consideration of the appropriate nail management program.

4. Inform a health care professional if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing).

5. Up to 48 weeks of daily applications with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), and professional removal of the unattached, infected nail, as frequently as monthly, are considered the full treatment needed to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement).

6. Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.

7. A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a completely clear or almost clear toenail.

8. Do not use the medication for any disorder other than that for which it is prescribed.

9. Do not use nail polish or other nail cosmetic products on the treated nails.

10. Avoid use near heat or open flame, because product is flammable.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No carcinogenicity study was conducted with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), formulation. A carcinogenicity study of Fluticare-C (Ciclopirox) (1% and 5% solutions in polyethylene glycol 400) in female mice dosed topically twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application sites.

In human systemic tolerability studies following daily application (~340 mg of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer)) in subjects with distal subungual onychomycosis, the average maximal serum level of Fluticare-C (Ciclopirox) was 31±28 ng/mL after two months of once daily applications. This level was 159 times lower than the lowest toxic dose and 115 times lower than the highest nontoxic dose in rats and dogs fed 7.7 and 23.1 mg Fluticare-C (Ciclopirox) (as Fluticare-C (Ciclopirox) olamine)/kg/day.

The following in vitro genotoxicity tests have been conducted with Fluticare-C (Ciclopirox): evaluation of gene mutation in Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Chinese hamster lung fibroblasts, with and without metabolic activation (positive); gene mutation assay in the HGPRT-test with V79 Chinese hamster lung fibroblasts (negative); unscheduled DNA synthesis in human A549 cells (negative); and BALB/c3T3 cell transformation assay (negative). In an in vivo Chinese hamster bone marrow cytogenetic assay, Fluticare-C (Ciclopirox) was negative for chromosome aberrations at 5,000 mg/kg.

The following in vitro genotoxicity tests were conducted with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer): Ames Salmonella test (negative); unscheduled DNA synthesis in the rat hepatocytes (negative); cell transformation assay in BALB/c3T3 cell assay (positive). The positive response of the lacquer formulation in the BALB/c3T3 test was attributed to its butyl monoester of poly [methylvinyl ether/maleic acid] resin component (Gantrez® ES-435), which also tested positive in this test. The cell transformation assay may have been confounded because of the film-forming nature of the resin. Gantrez® ES-435 tested nonmutagenic in both the in vitro mouse lymphoma forward mutation assay with or without activation and unscheduled DNA synthesis assay in rat hepatocytes.

Oral reproduction studies in rats at doses up to 3.85 mg Fluticare-C (Ciclopirox) (as Fluticare-C (Ciclopirox) olamine)/kg/day [equivalent to approximately 1.4 times the potential exposure at the maximum recommended human topical dose (MRHTD)] did not reveal any specific effects on fertility or other reproductive parameters. MRHTD (mg/m2) is based on the assumption of 100% systemic absorption of 27.12 mg Fluticare-C (Ciclopirox) (~340 mg Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer)) that will cover all the fingernails and toenails including 5 mm proximal and lateral fold area plus onycholysis to a maximal extent of 50%.

Pregnancy:

Teratogenic effects: Pregnancy Category B

Teratology studies in mice, rats, rabbits, and monkeys at oral doses of up to 77, 23, 23, or 38.5 mg, respectively, of Fluticare-C (Ciclopirox) as Fluticare-C (Ciclopirox) olamine/kg/day (14, 8, 17, and 28 times MRHTD), or in rats and rabbits receiving topical doses of up to 92.4 and 77 mg/kg/day, respectively (33 and 55 times MRHTD), did not indicate any significant fetal malformations.

There are no adequate or well-controlled studies of topically applied Fluticare-C (Ciclopirox) in pregnant women. Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is administered to a nursing woman.

Pediatric Use:

Based on the safety profile in adults, Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is considered safe for use in children twelve years and older. No clinical trials have been conducted in the pediatric population.

Geriatric Use:

Clinical studies of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

ADVERSE REACTIONS

In the vehicle-controlled clinical trials conducted in the US, 9% (30/327) of patients treated with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), and 7% (23/328) of patients treated with vehicle reported treatment-emergent adverse events (TEAE) considered by the investigator to be causally related to the test material. The incidence of these adverse events, within each body system, was similar between the treatment groups except for Skin and Appendages: 8%(27/327) and 4% (14/328) of subjects in the Fluticare-C (Ciclopirox) and vehicle groups reported at least one adverse event, respectively.

The most common were rash-related adverse events: periungual erythema and erythema of the proximal nail fold were reported more frequently in patients treated with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), (5% [16/327]) than in patients treated with vehicle (1% [3/328]). Other TEAEs thought to be causally related included nail disorders such as shape change, irritation, ingrown toenail, and discoloration.

The incidence of nail disorders was similar between the treatment groups (2% [6/327] in the Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), group and 2% [7/328] in the vehicle group). Moreover, application site reactions and/or burning of the skin occurred in 1% of patients treated with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), (3/327) and vehicle (4/328).

A 21-Day Cumulative Irritancy study was conducted under conditions of semi-occlusion. Mild reactions were seen in 46% of patients with the Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), 32% with the vehicle and 2% with the negative control, but all were reactions of mild transient erythema. There was no evidence of allergic contact sensitization for either the Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), or the vehicle base. In a separate study of the photosensitization potential of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), in a maximized test design that included the occluded application of sodium lauryl sulfate, no photoallergic reactions were noted. In four subjects localized allergic contact reactions were observed. In the vehicle-controlled studies, one patient treated with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), discontinued treatment due to a rash, localized to the palm (causal relation to test material undetermined).

Use of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), for 48 additional weeks was evaluated in an open-label extension study conducted in patients previously treated in the vehicle-controlled studies. Three percent (9/281) of subjects treated with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), experienced at least one TEAE that the investigator thought was causally related to the test material. Mild rash in the form of periungual erythema (1% [2/281]) and nail disorders (1% [4/281]) were the most frequently reported. Four patients discontinued because of TEAEs. Two of the four had events considered to be related to test material: one patient’s great toenail “broke away” and another had an elevated creatine phosphokinase level on Day 1 (after 48 weeks of treatment with vehicle in the previous vehicle-controlled study).

To report SUSPECTED ADVERSE REACTIONS, contact G&W Laboratories, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DOSAGE AND ADMINISTRATION

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be used as a component of a comprehensive management program for onychomycosis. Removal of the unattached, infected nail, as frequently as monthly, by a health care professional, weekly trimming by the patient, and daily application of the medication are all integral parts of this therapy. Careful consideration of the appropriate nail management program should be given to patients with diabetes (see PRECAUTIONS).

Nail Care By Health Care Professionals:

Removal of the unattached, infected nail, as frequently as monthly, trimming of onycholytic nail, and filing of excess horny material should be performed by professionals trained in treatment of nail disorders.

Nail Care By Patient:

Patients should file away (with emery board) loose nail material and trim nails, as required, or as directed by the health care professional, every seven days after Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is removed with alcohol.

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be applied once daily (preferably at bedtime or eight hours before washing) to all affected nails with the applicator brush provided. The Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be applied evenly over the entire nail plate.

If possible, Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be applied to the nail bed, hyponychium, and the under surface of the nail plate when it is free of the nail bed (e.g., onycholysis).

The Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should not be removed on a daily basis. Daily applications should be made over the previous coat and removed with alcohol every seven days. This cycle should be repeated throughout the duration of therapy.

HOW SUPPLIED

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is supplied in 3.3 mL (NDC 0713-0317-87) and 6.6 mL (NDC 0713-0317-88) glass bottles with screw caps which are fitted with brushes.

Protect from light (e.g., store the bottle in the carton after every use.)

STORAGE AND HANDLING

Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), should be stored at room temperature between 59° and 86° F (15° and 30° C).

CAUTION: Flammable. Keep away from heat and flame.

REFERENCES

1. Dittmar W., Lohaus G. 1973. HOE296, A new antimycotic compound with a broad antimicrobial spectrum. Arzneim-Forsch./Drug Res.23:670-674.

2. Niewerth et. al., 1998. Antimicrobial susceptibility testing of dermatophytes: Comparison of the agar macrodilution and broth micro dilution tests. Chemotherapy. 44:31-35.

3. Yang et. al. 1997. A new simulation model for studying in vitro topical penetration of antifungal drugs into hard keratin. J. Mycol. Med. 7:195-98.

Gantrez is a registered trademark of GAF Corporation

G&W Laboratories, Inc.

South Plainfield, NJ 07080

8-0317GW3

Rev. 03/2015

PATIENT PACKAGE INSERT

Fluticare-C (Ciclopirox)

Topical Solution, 8%,

(Nail Lacquer)

Patient Information and Instructions

Patients should have detailed instructions regarding the use of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), as a component of a comprehensive management program for onychomycosis in order to achieve maximum benefit with the use of this product. Discuss your treatment plan with your health care professional for regular removal of the unattached, infected nail. Before using this medication, tell your doctor if you:

- Are pregnant or nursing

- Are an insulin dependent diabetic or have diabetic neuropathy

- Have a history of immunosuppression

- Are immunocompromised (e.g., received an organ transplant, etc.)

- Require medication to control epilepsy- Use or require topical corticosteroids on a repeated monthly basis

- Use steroid inhalers on a regular basis

Patient Information:

- Use Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), as directed by your health care professional.

- Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), is for external use only.

- Contact with skin other than skin immediately surrounding the treated nail(s) should be avoided.

- Avoid contact with the eyes and mucous membranes.

- Removal of the unattached, infected nail, as frequently as monthly, by your health care professional is needed with use of this medication to obtain maximal benefit with use of this product. If you have diabetes or problems with numbness in your toes or fingers, talk to your health care provider before trimming your nails or removing any nail material.

- Inform your health care professional if the area of application shows signs of increased irritation (redness, itching, burning,blistering, swelling, oozing).

- Up to 48 weeks of daily applications with Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), and professional removal, as frequently as monthly, of the unattached, infected nail are considered the full treatment time to achieve a clear or almost clear nail (defined as 10% or less residual nail involvement). Six months of therapy with professional removal of the unattached, infected nail may be required before initial improvement of symptoms is noticed.

- A completely clear nail may not be achieved with use of this medication. In clinical studies less than 12% of patients were able to achieve either a clear or almost clear toenail.

- Do not use nail polish or other nail cosmetic products on the treated nails.

- Avoid use near heat or open flame, because product is flammable.

Patient Instructions

1. Before starting treatment, remove any loose nail or nail material using nail clippers or nail files. If you have diabetes or problems with numbness in your toes or fingers, talk to your health care provider before trimming your nails or removing any nail material.

2. Apply Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), once daily (preferably at bedtime) to all affected nails with the applicator brush provided. Apply the lacquer evenly over the entire nail. Where possible, nail lacquer should also be applied to the underside of the nail and to the skin beneath it. Allow lacquer to dry (approximately 30 seconds) before putting on socks or stockings. After applying medication, wait 8 hours before taking a bath or shower.

3. Apply Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), daily over the previous coat.

4. Once a week, remove the Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), with alcohol. Remove as much as possible of the damaged nail using scissors, nail clippers, or nail files.

5. Repeat process (steps 2 through 4).

Please Note:

1. To prevent screw cap from sticking to the bottle, do not allow solution to get into the bottle threads.

2. To prevent the solution from drying out, bottle should be closed tightly after every use.

3. To protect from light, replace bottle into carton after each use.

G&W Laboratories, Inc.

South Plainfield, NJ 07080

8-0317GW3

Rev. 03/2015

NDC 0713-0317-88

Fluticare-C (Ciclopirox) Topical Solution, 8% (Nail Lacquer)

FOR DERMATOLOGIC USE ONLY

NOT FOR USE IN EYES

Rx Only

One 6.6 mL Bottle

Each gram of Fluticare-C (Ciclopirox) Topical Solution, 8%, (Nail Lacquer), contains 80 mg Fluticare-C (Ciclopirox) in a solution base consisting of ethylacetate, NF; isopropyl alcohol,USP; and butyl monoester of poly[methylvinyl ether/maleic acid] in isopropyl alcohol.

Usual

Dosage: Apply to the affected nails once daily. See package insert for full prescribing information.

WARNING: Keep out of reach of children.

Important: This package is not child resistant.

Store at room temperature between 59-86°F (15-30°c). Protect bottle from light.

CAUTION: Flammable. Keep away from heat and flame.

Store bottle in carton after every use.

Fluticasone Propionate:

• Warning: asthma-related death
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Fluticare-C (Fluticasone Propionate) reviews

WARNING: ASTHMA-RELATED DEATH

Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR^® HFA Inhalation Aerosol, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Therefore, when treating patients with asthma, physicians should only prescribe Fluticare-C (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Fluticare-C (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Fluticare-C (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids .

WARNING: ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning

• Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in Fluticare-C (Fluticasone Propionate) Inhalation Aerosol, increase the risk of asthma-related death. A U.S. trial showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1)
• When treating patients with asthma, only prescribe Fluticare-C (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Fluticare-C (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Fluticare-C (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. (1, 5.1)

1 INDICATIONS AND USAGE

Fluticare-C (Fluticasone Propionate) is indicated for the treatment of asthma in patients aged 12 years and older.

LABA, such as salmeterol, one of the active ingredients in Fluticare-C (Fluticasone Propionate), increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients . Therefore, when treating patients with asthma, physicians should only prescribe Fluticare-C (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Fluticare-C (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Fluticare-C (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use

Fluticare-C (Fluticasone Propionate) is NOT indicated for the relief of acute bronchospasm.

Fluticare-C (Fluticasone Propionate) is a combination product containing a corticosteroid and a LABA indicated for treatment of asthma in patients aged 12 years and older.

Important limitation:

• Not indicated for relief of acute bronchospasm. (1)

2 DOSAGE AND ADMINISTRATION

Fluticare-C (Fluticasone Propionate) should be administered as 2 inhalations twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of Fluticare-C (Fluticasone Propionate) is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using Fluticare-C (Fluticasone Propionate) should not use additional LABA for any reason.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta₂-agonist should be taken for immediate relief.

For patients aged 12 years and older, the dosage is 2 inhalations twice daily, approximately 12 hours apart.

The recommended starting dosages for Fluticare-C (Fluticasone Propionate) for patients aged 12 years and older are based upon patients’ asthma severity.

The maximum recommended dosage is 2 inhalations of Fluticare-C (Fluticasone Propionate) 230/21 twice daily.

Improvement in asthma control following inhaled administration of Fluticare-C (Fluticasone Propionate) can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Fluticare-C (Fluticasone Propionate) with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Fluticare-C (Fluticasone Propionate) with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.

Prime Fluticare-C (Fluticasone Propionate) before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

• For oral inhalation only. (2)
• Treatment of asthma in patients aged 12 years and older: 2 inhalations of Fluticare-C (Fluticasone Propionate) 45/21, 115/21, or 230/21 twice daily. Starting dosage is based on asthma severity. (2)

3 DOSAGE FORMS AND STRENGTHS

Inhalation Aerosol. Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of Fluticare-C (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece.

Inhalation Aerosol. Inhaler containing a combination of Fluticare-C (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) as an aerosol formulation for oral inhalation. (3)

4 CONTRAINDICATIONS

The use of Fluticare-C (Fluticasone Propionate) is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required .
• Hypersensitivity to any of the ingredients .

• Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4)
• Hypersensitivity to any ingredient. (4)

5 WARNINGS AND PRECAUTIONS

• LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations.
• Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2)
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3)
• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4)
• Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (5.5)
• Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.6)
• Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Fluticare-C (Fluticasone Propionate). (5.7)
• Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Fluticare-C (Fluticasone Propionate) slowly. (5.8)
• If paradoxical bronchospasm occurs, discontinue Fluticare-C (Fluticasone Propionate) and institute alternative therapy. (5.10)
• Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. (5.12)
• Assess for decrease in bone mineral density initially and periodically thereafter. (5.13)
• Monitor growth of pediatric patients. (5.14)
• Close monitoring for glaucoma and cataracts is warranted. (5.15)
• Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18)
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17)

5.1 Asthma-Related Death

LABA, such as salmeterol, one of the active ingredients in Fluticare-C (Fluticasone Propionate), increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Fluticare-C (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Fluticare-C (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Fluticare-C (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol. The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naive subjects with asthma to assess the safety of salmeterol 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%; relative risk: 4.37 [95% CI: 1.25, 15.34]).

Post hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%; relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%; relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (Table 1). Given the similar basic mechanisms of action of beta₂-agonists, the findings seen in the SMART trial are considered a class effect.

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as Fluticare-C (Fluticasone Propionate) propionate, the other active ingredient in Fluticare-C (Fluticasone Propionate), or other long-term asthma control therapy mitigates the risk of asthma-related death.

Table 1. Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART)

^a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial.

^b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

^c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

^d The total population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the total population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment

• The counter starts at either 124 or 064, depending on which size inhaler you have. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000.
• Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister.
• The purple plastic actuator sprays the medicine from the canister. The actuator has a protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the canister is not in use. The strap keeps the cap attached to the actuator.
• Do not use the actuator with a canister of medicine from any other inhaler.
• Do not use an Fluticare-C (Fluticasone Propionate) canister with an actuator from any other inhaler.

Before using your Fluticare-C (Fluticasone Propionate) inhaler

• Take Fluticare-C (Fluticasone Propionate) out of the foil pouch just before you use it for the first time. Safely throw away the pouch and the drying packet that comes inside the pouch.
• The inhaler should be at room temperature before you use it.

Priming your Fluticare-C (Fluticasone Propionate) inhaler

• Before you use Fluticare-C (Fluticasone Propionate) for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it.
• To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes.

• Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120 or 060, depending on which size inhaler you have. See Figure D.

• You must prime your inhaler again if you have not used it in more than 4 weeks or if you drop it. Take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 1 more time to finish priming it.

How to use your Fluticare-C (Fluticasone Propionate) inhaler

Follow these steps every time you use Fluticare-C (Fluticasone Propionate).

• Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the window in the actuator.
  • Shake the inhaler well for 5 seconds before each spray.
• Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, and take out any you see.
• Step 2. Hold the inhaler with the mouthpiece down. See Figure E.

• Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it. See Figure F.
• Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. See Figure F.

• Step 5. After the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.
  • Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can.
    • Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat steps 2 through 6.
• Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure G.

• Step 8. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it snaps firmly into place.

Cleaning your Fluticare-C (Fluticasone Propionate) inhaler

Clean your inhaler at least 1 time each week after your evening dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H.

Figure H

• Step 9. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator.
• Step 10. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine. See Figure I.

Figure I

• Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight.

Step 12. Put the cap back on the mouthpiece after the actuator has dried.

Replacing your Fluticare-C (Fluticasone Propionate) inhaler

• When the counter reads 020, you should refill your prescription or ask your healthcare provider if you need another prescription for Fluticare-C (Fluticasone Propionate).
• When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of medicine.
• Do not use the inhaler after the expiration date, which is on the packaging it comes in.

For correct use of your Fluticare-C (Fluticasone Propionate) inhaler, remember:

• The canister should always fit firmly in the actuator.
• Breathe in deeply and slowly to make sure you get all the medicine.
• Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully.
• After each dose, rinse your mouth with water and spit it out. Do not swallow the water.
• Do not take the inhaler apart.
• Always keep the protective cap on the mouthpiece when your inhaler is not in use.
• Always store your inhaler with the mouthpiece pointing down.
• Clean your inhaler at least 1 time each week.

If you have questions about Fluticare-C (Fluticasone Propionate) or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit www.advair.com.

ADVAIR is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 the GSK group of companies. All rights reserved.

ADH:1IFU

• This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: February 2017