fluticasone propionate 0.1 MG/ACTUAT Dry Powder Inhaler, 60 ACTUAT

Generic Name: FLUTICASONE PROPIONATE
Brand Name: FLOVENT DISKUS
  • Substance Name(s):
  • FLUTICASONE PROPIONATE

DRUG INTERACTIONS

7 Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended.

May increase risk of systemic corticosteroid effects ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4.

The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur.

Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] .

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

OVERDOSAGE

10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)] .

Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated.

Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated.

Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated.

Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

DESCRIPTION

11 FLOVENT DISKUS inhalation powder is a dry powder inhaler for oral inhalation.

The active component of FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S.

It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is an orange plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins).

After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, FLOVENT DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

In children with asthma aged 4 and 8 years, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Chemical structure

CLINICAL STUDIES

14 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Four randomized, double-blind, parallel-group, placebo-controlled, U.S.

clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma.

Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity.

Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily ICS.

All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV 1 prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults.

These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group.

Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most patients’ lung function data) are also displayed.

Pulmonary function, as determined by percent change from baseline in FEV 1 at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone In all 4 efficacy trials, measures of pulmonary function (FEV 1 ) were statistically significantly improved as compared with placebo at all twice-daily doses.

Subjects on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 subjects with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated.

Both doses enabled a statistically significantly larger percentage of subjects to wean from oral prednisone as compared with placebo (75% of the subjects on 500 mcg twice daily and 89% of the subjects on 1,000 mcg twice daily as compared with 9% of subjects on placebo).

Accompanying the reduction in oral corticosteroid use, subjects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS), approximately half of whom were receiving ICS at baseline.

In this trial, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV 1 (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change).

AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared with placebo (14% change).

In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approximately half of whom were receiving ICS at baseline.

In these trials, FLOVENT DISKUS was efficacious at doses of 50 and 100 mcg twice daily when compared with placebo on major endpoints including lung function and symptom scores.

Pulmonary function improved significantly compared with placebo by the first week of treatment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue trial participation due to asthma deterioration.

One hundred ninety-two (192) subjects received FLOVENT DISKUS for up to 1 year during an open-label extension.

Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOVENT DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02).

FLOVENT DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02).

FLOVENT DISKUS 100 mcg is also supplied in an institutional pack containing 28 blisters (NDC 0173-0602-00).

FLOVENT DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02).

FLOVENT DISKUS 250 mcg is also supplied in an institutional pack containing 28 blisters (NDC 0173-0601-00).

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature].

Store in a dry place away from direct heat or sunlight.

Keep out of reach of children.

FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard FLOVENT DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

GERIATRIC USE

8.5 Geriatric Use Safety data have been collected on 280 subjects (FLOVENT DISKUS n = 83, FLOVENT Rotadisk n = 197) aged 65 years and older and 33 subjects (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) aged 75 years and older who have been treated with fluticasone propionate inhalation powder in U.S.

and non-U.S.

clinical trials.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains fluticasone propionate 50, 100, or 250 mcg per blister.

Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity.

Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide.

Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate.

This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

INDICATIONS AND USAGE

1 Flovent DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

Important Limitation of Use FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

FLOVENT DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

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

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of FLOVENT DISKUS in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] .

The safety and effectiveness of FLOVENT DISKUS in children younger than 4 years have not been established.

Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.

A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS.

The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients.

In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.

This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The long‑term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown.

The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S.

in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years.

The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100‑mcg group (n = 89).

An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data.

A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100‑mcg group (n = 79).

In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3 rd percentile = 3.8 cm/year, 50 th percentile = 5.4 cm/year, and 97 th percentile = 7.0 cm/year; girls – 3 rd percentile = 4.2 cm/year, 50 th percentile = 5.7 cm/year, and 97 th percentile = 7.3 cm/year.

The clinical relevance of these growth data is not certain.

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient data on the use of FLOVENT DISKUS in pregnant women.

There are clinical considerations with the use of FLOVENT DISKUS in pregnant women.

(See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis.

(See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis.

(See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

The estimated risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.

Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed at approximately 0.15 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day).

The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.13 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).

Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • 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.

( 5.1 ) • 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.

( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue FLOVENT DISKUS slowly.

( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.7 ) • Monitor growth of pediatric patients.

( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS.

During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use FLOVENT DISKUS [see Contraindications (4)] .

5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

5.8 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients .

Monitor the growth of pediatric patients receiving FLOVENT DISKUS routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)] .

5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

5.10 Paradoxical Bronchospasm As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing.

If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate.

Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between fluticasone propionate and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus and Acute Asthma Symptoms Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations.

Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay.

Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

Patients should discontinue FLOVENT DISKUS if such reactions occur.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take FLOVENT DISKUS.

Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily for Best Effect Patients should use Flovent DISKUS at regular intervals as directed.

Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer.

Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens.

Instruct patients not to stop use of FLOVENT DISKUS abruptly.

Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

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DOSAGE AND ADMINISTRATION

2 For oral inhalation only.

( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity.

( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily.

( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily.

( 2.2 ) 2.1 Administration Information FLOVENT DISKUS should be administered by the orally inhaled route in patients aged 4 years and older.

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control.

The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily.

Pediatric Patients Aged 4 to 11 Years The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control.

The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily.

General Dosing Recommendations If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.

After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.