5.1 Local Effects

In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicanshas occurred in patients 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. Patients should rinse the mouth after inhalation of FLOVENT DISKUS [see Adverse Reactions (6.1)].

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

Because of the potential for worsening infections, inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated 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 inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS. In a clinical trial of 111 patients, prednisone reduction was accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to FLOVENT DISKUS. Successive reduction of prednisone dose was allowed only when lung function; symptoms; and as-needed, short-acting beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Patients who have been previously maintained on 20 mg or more per day 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 inhaled corticosteroids may provide control of asthma symptoms during these episodes, in recommended doses they supply less than normal physiological amounts of glucocorticoid (cortisol) systemically and do 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 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.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions. Some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and 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. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of systemic absorption of inhaled corticosteroids, 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, particularly when FLOVENT DISKUS is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.

5.6 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and bronchospasm, may occur after administration of FLOVENT DISKUS. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take 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 inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes 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.

5.8 Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients [see Use in Specific Populations (8.4)]. 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 dose to the lowest dosage that effectively controls his/her symptoms.

5.9 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

5.10 Paradoxical Bronchospasm

As with other inhaled medications, 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 a fast-acting inhaled bronchodilator. Treatment with FLOVENT DISKUS should be discontinued immediately and alternative therapy 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 inhaled corticosteroids 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.

6.1 Clinical Trials Experience

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

The incidence of common adverse reactions in Table 2 is based upon 7 placebo-controlled US clinical trials in which 1,176 pediatric, adolescent, and adult patients (466 females and 710 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with FLOVENT DISKUS (doses of 50 to 500 mcg) or placebo.

Table 2. Adverse Reactions With >3% Incidence in US Controlled Clinical Trials With FLOVENT DISKUS in Patients With Asthma Previously Receiving Bronchodilators and/or Inhaled Corticosteroids

Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the groups treated with FLOVENT DISKUS and were more common than in the placebo group. Less than 2% of patients discontinued from the studies because of adverse reactions. The average duration of exposure was 73 to 79 days in the active treatment groups compared with 56 days in the placebo group.

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with FLOVENT DISKUS compared with patients treated with placebo include the following: palpitations; soft tissue injuries; contusions and hematomas; wounds and lacerations; burns; poisoning and toxicity; pressure-induced disorders; hoarseness/dysphonia; epistaxis; ear, nose, throat, and tonsil signs and symptoms; ear, nose, and throat polyps; allergic ear, nose, and throat disorders; throat constriction; fluid disturbances; weight gain; appetite disturbances; keratitis and conjunctivitis; blepharoconjunctivitis; gastrointestinal signs and symptoms; oral ulcerations; dental discomfort and pain; oral erythema and rashes; mouth and tongue disorders; oral discomfort and pain; tooth decay; cholecystitis; arthralgia and articular rheumatism; muscle cramps and spasms; musculoskeletal inflammation; dizziness; sleep disorders; migraines; paralysis of cranial nerves; edema and swelling; bacterial infections; fungal infections; mobility disorders; mood disorders; bacterial reproductive infections; photodermatitis; dermatitis and dermatosis; viral skin infections; eczema; pruritus; acne and folliculitis; urinary infections.

Three (3) of the 7 placebo-controlled US clinical trials were pediatric studies. A total of 592 patients 4 to 11 years were treated with FLOVENT DISKUS (dosages of 50 or 100 mcg twice daily) or placebo; an additional 174 patients 4 to 11 years received FLOVENT® ROTADISK® (fluticasone propionate inhalation powder) at the same doses. There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults.

In the first 16 weeks of a 52-week clinical trial in adult patients with asthma who previously required oral corticosteroids (daily doses of 5 to 40 mg oral prednisone), the effects of FLOVENT DISKUS 500 mcg twice daily (n = 41) and 1,000 mcg twice daily (n = 36) were compared with placebo (n = 34) for the frequency of reported adverse events. The average duration of exposure for patients taking FLOVENT DISKUS was 105 days compared with 75 days for placebo. Adverse events, whether or not considered drug related by the investigators, reported in more than 5 patients in the group taking FLOVENT DISKUS and that occurred more frequently with FLOVENT DISKUS than with placebo are shown below (percent FLOVENT DISKUS and percent placebo).

Ear, Nose, and Throat: Hoarseness/dysphonia (9% and 0%), nasal congestion/blockage (16% and 0%), oral candidiasis (31% and 21%), rhinitis (13% and 9%), sinusitis/sinus infection (33% and 12%), throat irritation (10% and 9%), and upper respiratory tract infection (31% and 24%).

Gastrointestinal: Nausea and vomiting (9% and 0%).

Lower Respiratory: Cough (9% and 3%) and viral respiratory infections (9% and 6%).

Musculoskeletal: Arthralgia and articular rheumatism (17% and 3%) and muscle pain (12% and 0%).

Non-Site Specific: Malaise and fatigue (16% and 9%) and pain (10% and 3%).

Skin: Pruritus (6% and 0%) and skin rashes (8% and 3%).

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors.

Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, and throat soreness.

Endocrine and Metabolic: Cushingoid features, growth velocity reduction in children/adolescents, hyperglycemia, and osteoporosis.

Eye: Cataracts.

Immune System Disorders: Immediate and delayed hypersensitivity reactions, including anaphylaxis, rash, angioedema, and bronchospasm, have been reported. Anaphylactic reactions in patients with severe milk protein allergy have been reported.

Psychiatry: Agitation, aggression, anxiety, depression, and restlessness. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Respiratory: Asthma exacerbation, bronchospasm, chest tightness, dyspnea, immediate bronchospasm, pneumonia, and wheeze.

Skin: Contusions and ecchymoses.

Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with 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 [see Warnings and Precautions (5.12)].

7.1 Strong Cytochrome P450 3A4 Inhibitors

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.

A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate concentration, 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 syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

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. Coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies with FLOVENT DISKUS in pregnant women. FLOVENT DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects: Subcutaneous studies in the mouse and rat at doses approximately 0.1 and 0.4, respectively, times the maximum recommended human daily inhalation dose (MRHD) in adults on a mg/m2 basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose approximately 0.03 times the MRHD in adults on a mg/m2 basis. However, no teratogenic effects were reported at oral doses up to approximately 2 times the MRHD in adults on a mg/m2 basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

8.3 Nursing Mothers

It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate at a dose approximately 0.04 times the MRHD in adults on a mg/m2 basis resulted in measurable radioactivity in milk.

Since there are no data from controlled trials on the use of FLOVENT DISKUS by nursing mothers, caution should be exercised when FLOVENT DISKUS is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of FLOVENT DISKUS in children 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 inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears 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 study to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the US 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 study 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 study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical significance of these growth data is not certain.

8.5 Geriatric Use

Safety data have been collected on 280 patients (FLOVENT DISKUS n = 83, FLOVENT ROTADISK n = 197) 65 years or older and 33 patients (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) 75 years or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using FLOVENT DISKUS have not been conducted in patients with hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.

8.7 Renal Impairment

Formal pharmacokinetic studies using FLOVENT DISKUS have not been conducted in patients with renal impairment.

12.1 Mechanism of Action

Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone­17­monopropionate (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 inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. 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.

Studies in patients 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.

12.2 Pharmacodynamics

In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL assessed by radioimmunoassay) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out with the DISKHALER® inhalation device in 64 patients with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol <18 mcg/dL). With a peak cortisol threshold <35 mcg/dL, 1 patient receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years.

In a placebo-controlled clinical study conducted in patients aged 4 to 11 years, a 30-minute cosyntropin stimulation test was performed in 41 patients after 12 weeks of dosing with 50 or 100 mcg twice daily of fluticasone propionate via the DISKUS device. One patient receiving fluticasone propionate via DISKUS had a prestimulation plasma cortisol concentration <5 mcg/dL, and 2 patients had a rise in cortisol of <7 mcg/dL. However, all poststimulation values were >18 mcg/dL.

The potential systemic effects of inhaled fluticasone propionate on the HPA axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing with placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared with 29% of patients treated with prednisone.

12.3 Pharmacokinetics

Absorption: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The absolute bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 7.8%.

Peak steady-state fluticasone propionate plasma concentrations in adult patients with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dosage of fluticasone propionate inhalation powder using the DISKUS device. The mean fluticasone propionate plasma concentration was 110 pg/mL.

Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Specific Populations:Gender: Full pharmacokinetic profiles were obtained from 9 female and 16 male patients given 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.

Pediatrics: In a clinical study conducted in patients aged 4 to 11 years with mild to moderate asthma, fluticasone propionate concentrations were obtained in 61 patients at 20 and 40 minutes after dosing with 50 and 100 mcg twice daily of fluticasone propionate inhalation powder using the DISKUS. Plasma concentrations were low and ranged from undetectable (about 80% of the plasma samples) to 88 pg/mL. Mean peak fluticasone propionate plasma concentrations at the 50- and 100-mcg dose levels were 5 and 8 pg/mL, respectively.

Hepatic and Renal Impairment: Formal pharmacokinetic studies using FLOVENT DISKUS have not been conducted in patients with hepatic or renal impairment. However, since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.

Drug Interactions:Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•hr/mL (range: 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range: 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate concentration resulted in a significant decrease (86%) in serum cortisol AUC.

Ketoconazole: In a placebo-controlled, crossover study in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Following orally inhaled fluticasone propionate alone, AUC(2-last) averaged 1.559 ng•hr/mL (range: 0.555 to 2.906 ng•hr/mL) and AUC(2-∞) averaged 2.269 ng•hr/mL (range: 0.836 to 3.707 ng•hr/mL). Fluticasone propionate AUC(2-last) and AUC(2-∞) increased to 2.781 ng•hr/mL (range: 2.489 to 8.486 ng•hr/mL) and 4.317 ng•hr/mL (range: 3.256 to 9.408 ng•hr/mL), respectively, after coadministration of ketoconazole with orally inhaled fluticasone propionate. This increase in plasma fluticasone propionate concentration resulted in a decrease (45%) in serum cortisol AUC.

Erythromycin: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 and 10 times the MRHD in adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 0.2 times and approximately equivalent to the MRHD in adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.2 times the MRHD in adults on a mg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology: Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg (approximately 0.1 and 0.4 times the MRHD in adults on a mg/m2 basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (approximately 0.03 times the MRHD in adults on a mg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 2 times the MRHD in adults on a mg/m2 basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

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

14.1 Adult and Adolescent Patients 12 Years and Older

Four randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,036 adult and adolescent patients (aged ≥12 years) 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. Patients in these studies included those inadequately controlled with bronchodilators alone and those already maintained on daily inhaled corticosteroids. 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 FEV1 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 FEV1 result, including most patients’ lung function data) are also displayed. Pulmonary function, as determined by percent change from baseline in FEV1 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 Adolescents and Adults Receiving Bronchodilators Alone

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

Figure 3. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone

Figure 4. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone

In all 4 efficacy trials, measures of pulmonary function (FEV1) were statistically significantly improved as compared with placebo at all twice-daily doses. Patients 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 patient-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 patients 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 patients to wean from oral prednisone as compared with placebo (75% of the patients on 500 mcg twice daily and 89% of the patients on 1,000 mcg twice daily as compared with 9% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

14.2 Pediatric Patients Aged 4 to 11 Years

A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric patients (177 received FLOVENT DISKUS), approximately half of whom were receiving inhaled corticosteroids at baseline. In this study, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV1 (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 study, patients 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 patient 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 patients with asthma, approximately half of whom were receiving inhaled corticosteroids at baseline. In these studies, 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 patients treated with FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration. One hundred ninety-two (192) patients 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.

17.1 Oral Candidiasis

Patients should be advised that localized infections with Candida albicans have occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated 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. Rinsing the mouth after inhalation is advised.

17.2 Status Asthmaticus and Acute Asthma Symptoms

Patients should be advised that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. Patients should be instructed to contact their physicians immediately if there is deterioration of their asthma.

17.3 Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and if they are exposed to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

17.4 Hypercorticism and Adrenal Suppression

Patients should be advised that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed 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.

17.5 Hypersensitivity Reactions, Including Anaphylaxis

Patients should be advised that hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and bronchospasm, 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; therefore, patients with severe milk protein allergy should not take FLOVENT DISKUS.

17.6 Reduction in Bone Mineral Density

Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

17.7 Reduced Growth Velocity

Patients should be informed 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.

17.8 Ocular Effects

Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

17.9 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. Patients should be instructed not to stop use of FLOVENT DISKUS abruptly. Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2011, GlaxoSmithKline. All rights reserved.

September 2011

FLD:6PI