The active component of FLOVENT 44 mcg Inhalation Aerosol, FLOVENT 110 mcg Inhalation Aerosol, and FLOVENT 220 mcg Inhalation Aerosol is fluticasone propionate, a glucocorticoid having the chemical name S-(fluoromethyl)6a,9-difluoro-11b,17-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17b-carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT 44 mcg Inhalation Aerosol, FLOVENT 110 mcg Inhalation Aerosol, and FLOVENT 220 mcg Inhalation Aerosol are pressurized, metered-dose aerosol units intended for oral inhalation only. Each unit contains a microcrystalline suspension of fluticasone propionate (micronized) in a mixture of 2 chlorofluorocarbon propellants (trichlorofluoromethane and dichlorodifluoromethane) with soya lecithin. Each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate from the valve and 44, 110, or 220 mcg, respectively, of fluticasone propionate from the actuator.

FLOVENT Inhalation Aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.

FLOVENT Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.

FLOVENT Inhalation Aerosol should be administered by the orally inhaled route in patients 12 years of age and older. Individual patients will experience a variable time to onset and degree of symptom relief. Generally, FLOVENT Inhalation Aerosol has a relatively rapid onset of action for an inhaled glucocorticoid. Improvement in asthma control following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

After asthma stability has been achieved (see Table 2), it is always desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of FLOVENT Inhalation Aerosol when administered in excess of recommended dosages have not been established.

The recommended starting dosage and the highest recommended dosage of FLOVENT Inhalation Aerosol, based on prior antiasthma therapy, are listed in Table 2.

In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with FLOVENT Inhalation Aerosol, efficacy and safety did not differ from that in younger patients. Consequently, no dosage adjustment is recommended. Directions for Use

Illustrated Patient’s Instructions for Use accompany each package of FLOVENT Inhalation Aerosol.

FLOVENT 44 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered inhalations in institutional pack boxes of 1 (NDC 0173-0497-00) and in 13-g canisters containing 120 metered inhalations in boxes of 1 (NDC 0173-0491-00). Each canister is supplied with a dark orange oral actuator with a peach strapcap and patient s instructions. Each actuation of the inhaler delivers 44 mcg of fluticasone propionate from the actuator.

FLOVENT 110 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered inhalations in institutional pack boxes of 1 (NDC 0173-0498-00) and in 13-g canisters containing 120 metered inhalations in boxes of 1 (NDC 0173-0494-00). Each canister is supplied with a dark orange oral actuator with a peach strapcap and patient s instructions. Each actuation of the inhaler delivers 110 mcg of fluticasone propionate from the actuator.

FLOVENT 220 mcg Inhalation Aerosol is supplied in 7.9-g canisters containing 60 metered inhalations in institutional pack boxes of 1 (NDC 0173-0499-00) and in 13-g canisters containing 120 metered inhalations in boxes of 1 (NDC 0173-0495-00). Each canister is supplied with a dark orange oral actuator with a peach strapcap and patient s instructions. Each actuation of the inhaler delivers 220 mcg of fluticasone propionate from the actuator.

FLOVENT canisters are for use with FLOVENT Inhalation Aerosol actuators only. The actuators should not be used with other aerosol medications.

The correct amount of medication in each inhalation cannot be assured after 60 inhalations from the 7.9-g canister or 120 inhalations from the 13-g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.

Store between 2° and 30°C (36° and 86°F). Store canister with mouthpiece down. Protect from freezing temperatures and direct sunlight.

Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperatures above 120°F. Keep out of reach of children. For best results, the canister should be at room temperature before use. Shake well before using.

The indented statement below is required by the Federal Government s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).

Warning

Contains trichlorofluoromethane and dichlorodifluoromethane, substances that harm public health and environment by destroying ozone in the upper atmosphere.

A notice similar to the above WARNING has been placed in the patient information leaflet of this product pursuant to EPA regulations.

GlaxoSmithKline, Research Triangle Park, NC 27709, ©2004, GlaxoSmithKline. All rights reserved. March 2004 RL-2067

The incidence of common adverse events in Table 1 is based upon 7 placebo-controlled US clinical trials in which 1,243 patients (509 female and 734 male adolescents and adults previously treated with as-needed bronchodilators and/or inhaled corticosteroids) were treated with FLOVENT Inhalation Aerosol (doses of 88 to 440 mcg twice daily for up to 12 weeks) or placebo.

Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in groups treated with FLOVENT Inhalation Aerosol and were more common than in the placebo group. In considering these data, differences in average duration of exposure should be taken into account.

These adverse reactions were mostly mild to moderate in severity, with £2% of patients discontinuing the studies because of adverse events. Rare cases of immediate and delayed hypersensitivity reactions, including urticaria and rash and other rare events of angioedema and bronchospasm, have been reported.

Systemic glucocorticoid side effects were not reported during controlled clinical trials with FLOVENT Inhalation Aerosol. If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptoms of hypercorticism, e.g., Cushing syndrome, could occur.

Other adverse events that occurred in these clinical trials using FLOVENT Inhalation Aerosol with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Ear, Nose, and Throat: Pain in nasal sinus(es), rhinitis.

Eye: Irritation of the eye(s).

Gastrointestinal: Nausea and vomiting, diarrhea, dyspepsia and stomach disorder.

Miscellaneous: Fever.

Mouth and Teeth: Dental problem.

Musculoskeletal: Pain in joint, sprain/strain, aches and pains, pain in limb.

Neurological: Dizziness/giddiness.

Respiratory: Bronchitis, chest congestion.

Skin: Dermatitis, rash/skin eruption.

Urogenital: Dysmenorrhea.

In a 16-week study in patients with asthma requiring oral corticosteroids, the effects of FLOVENT Inhalation Aerosol, 660 mcg twice daily (N = 32) and 880 mcg twice daily (N = 32), were compared with placebo. Adverse events (whether considered drug-related or nondrug-related by the investigator) reported by more than 3 patients in either group treated with FLOVENT Inhalation Aerosol and that were more common with FLOVENT than placebo are shown below:

Ear, Nose, and Throat: Pharyngitis (9% and 25%), nasal congestion (19% and 22%), sinusitis (19% and 22%), nasal discharge (16% and 16%), dysphonia (19% and 9%), pain in nasal sinus(es) (13% and 0%), Candida-like oral lesions (16% and 9%), oropharyngeal candidiasis (25% and 19%).

Respiratory: Upper respiratory infection (31% and 19%), influenza (0% and 13%). Other: Headache (28% and 34%), pain in joint (19% and 13%), nausea and vomiting (22% and 16%), muscular soreness (22% and 13%), malaise/fatigue (22% and 28%), insomnia (3% and 13%).

In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of fluticasone propionate. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. 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, hoarseness, laryngitis, and throat soreness and irritation.

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

Eye: Cataracts.

Non-Site Specific: Very rare anaphylactic reaction.

Psychiatry: Agitation, aggression, depression, and restlessness.

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

Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus. 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. 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 (see PRECAUTIONS: Eosinophilic Conditions).

Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions). 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.

In a placebo-controlled, crossover study in 8 healthy 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 mean plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLOVENT Inhalation Aerosol is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

Particular care is needed for patients who are transferred from systemically active corticosteroids to FLOVENT Inhalation Aerosol 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 HPA function.

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 FLOVENT Inhalation Aerosol may provide control of 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.

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). 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.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT Inhalation Aerosol. In a trial of 96 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV₁ or 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.

Transfer of patients from systemic corticosteroid therapy to FLOVENT Inhalation Aerosol may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.

Persons who are on 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 on corticosteroids. In such children or adults who have not had these diseases, 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.

FLOVENT Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT Inhalation Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with FLOVENT Inhalation Aerosol should be discontinued and alternative therapy instituted.

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

During withdrawal from oral corticosteroids, 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.

Fluticasone propionate will often permit control of 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 Inhalation Aerosol 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 FLOVENT Inhalation Aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT Inhalation Aerosol.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs 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 Inhalation Aerosol is administered at higher than recommended doses over prolonged periods of time. If such effects occur, fluticasone propionate inhalation aerosol should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if an adolescent s growth appears slowed.

The long-term effects of fluticasone propionate in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients have received fluticasone propionate inhalation aerosol on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for nearly 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including fluticasone propionate.

In clinical studies with inhaled fluticasone propionate, the development of localized infections of the pharynx with Candida albicans has occurred. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on treatment with FLOVENT Inhalation Aerosol, but at times therapy with FLOVENT Inhalation Aerosol may need to be interrupted.

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.

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. 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 (see ADVERSE REACTIONS).

Information for Patients

Patients being treated with FLOVENT Inhalation Aerosol should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Patients should use FLOVENT Inhalation Aerosol at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or two of treatment; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.

After inhalation, rinse the mouth with water without swallowing.

Patients should be warned to avoid exposure to chickenpox or measles and, if they are exposed, to consult the physician without delay.

For the proper use of FLOVENT Inhalation Aerosol and to attain maximum improvement, the patient should read and follow carefully the Patient s Instructions for Use accompanying the product.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone propionate demonstrated no tumorigenic potential in studies of oral doses up to 1,000 mcg/kg (approximately 2 times the maximum human daily inhalation dose based on mcg/m²) for 78 weeks in the mouse or inhalation of up to 57 mcg/kg (approximately 1/4 the maximum human daily inhalation dose based on mcg/m²) for 104 weeks in the rat.

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 mouse micronucleus test when administered at high doses by the oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.

No evidence of impairment of fertility was observed in reproductive studies conducted in rats dosed subcutaneously with doses up to 50 mcg/kg (approximately 1/4 the maximum human daily inhalation dose based on mcg/m²) in males and females. However, prostate weight was significantly reduced in rats.

Pregnancy

Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (approximately 1/10 and 1/2 the maximum human daily inhalation dose based on mcg/m², respectively), revealed fetal toxicity characteristic of potent glucocorticoid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed following subcutaneous doses of 4 mcg/kg (approximately 1/25 the maximum human daily inhalation dose based on mcg/m²). However, following oral administration of up to 300 mcg/kg (approximately 3 times the maximum human daily inhalation dose based on mcg/m²) of fluticasone propionate to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY).

Less than 0.008% of the administered dose crossed the placenta following oral administration of 100 mcg/kg to rats or 300 mcg/kg to rabbits (approximately 1/2 and 3 times the maximum human daily inhalation dose based on mcg/m², respectively).

There are no adequate and well-controlled studies in pregnant women. FLOVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Nursing Mothers

It is not known whether fluticasone propionate is excreted in human breast milk. Subcutaneous administration of 10 mcg/kg tritiated drug to lactating rats (approximately 1/20 the maximum human daily inhalation dose based on mcg/m²) resulted in measurable radioactivity in both plasma and milk. Because glucocorticoids are excreted in human milk, caution should be exercised when fluticasone propionate inhalation aerosol is administered to a nursing woman.

Pediatric Use

One hundred thirty-seven (137) patients between the ages of 12 and 16 years were treated with FLOVENT Inhalation Aerosol in the US pivotal clinical trials. The safety and effectiveness of FLOVENT Inhalation Aerosol in children below 12 years of age have not been established. Oral corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS).

Geriatric Use

Five hundred seventy-four (574) patients 65 years of age or older have been treated with FLOVENT Inhalation Aerosol in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients.

Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone propionate inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at doses 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 patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. The oral and subcutaneous median lethal doses in rats and mice were >1,000 mg/kg (>2,000 times the maximum human daily inhalation dose based on mg/m²).

FLOVENT Inhalation Aerosol is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity to any of the ingredients of these preparations contraindicates their use (see DESCRIPTION).

Fluticasone propionate is a synthetic, trifluorinated glucocorticoid 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 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 precise mechanisms of glucocorticoid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Glucocorticoids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of glucocorticoids may contribute to their efficacy in asthma.

Though highly effective for the treatment of asthma, glucocorticoids do not affect asthma symptoms immediately. However, improvement following inhaled administration of fluticasone propionate can occur within 24 hours of beginning treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer.

Absorption: The activity of FLOVENT Inhalation Aerosol is due to the parent drug, fluticasone propionate. 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 systemic bioavailability of fluticasone propionate inhalation aerosol in healthy volunteers averaged about 30% of the dose delivered from the actuator.

Peak plasma concentrations after an 880-mcg inhaled dose ranged from 0.1 to 1.0 ng/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 averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate 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 17b-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had approximately 2,000 times less affinity than the parent drug for the glucocorticoid 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.

Excretion: 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.

Special Populations: Formal pharmacokinetic studies using fluticasone propionate were not carried out in any special populations. In a clinical study using fluticasone propionate inhalation powder, trough fluticasone propionate plasma concentrations were collected in 76 males and 74 females after inhaled administration of 100 and 500 mcg twice daily. Full pharmacokinetic profiles were obtained from 7 female patients and 13 male patients at these doses, and no overall differences in pharmacokinetic behavior were found.

Drug Interactions

Fluticasone propionate is a substrate of cytochrome P450 3A4.

Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 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 (C_max averaged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUC_(0-t) averaged 8.43 pg· hr/mL [range, 4.2 to 18.8 pg· hr/mL]). Fluticasone propionate C_max and AUC_(0-t) 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 exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).

Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.

In another 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.

To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled and oral fluticasone propionate was conducted. Doses of 100 and 500 mcg twice daily of fluticasone propionate inhalation powder were compared to oral fluticasone propionate, 20,000 mcg given once daily, and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption.

The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in patients with asthma.

Fluticasone propionate given by inhalation aerosol at doses 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 less than 18 mcg/dL) after dosing with placebo or 220 mcg twice daily. Ten percent (10%) to 16% of patients treated with fluticasone propionate at doses of 440 mcg or more twice daily had an abnormal response as compared to 29% of patients treated with prednisone.

Double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,818 adolescent and adult patients with asthma to assess the efficacy and/or safety of FLOVENT Inhalation Aerosol in the treatment of asthma. Fixed doses ranging from 22 to 880 mcg twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients with asthma included in these studies were those not adequately controlled with beta-agonists alone, those already maintained on daily inhaled corticosteroids, and those requiring oral corticosteroid therapy. In all efficacy trials, at all doses, measures of pulmonary function (forced expiratory volume in 1 second [FEV₁] and morning peak expiratory flow [AM PEF]) were statistically significantly improved as compared with placebo.

In 2 clinical trials of 660 patients with asthma inadequately controlled on bronchodilators alone, FLOVENT Inhalation Aerosol was evaluated at doses of 44 and 88 mcg twice daily. Both doses of FLOVENT Inhalation Aerosol improved asthma control significantly as compared with placebo.

Figure 1 displays results of pulmonary function tests for the recommended starting dosage of FLOVENT Inhalation Aerosol (88 mcg twice daily) and placebo from a 12-week trial in patients with asthma inadequately controlled on bronchodilators alone. Because this trial used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint, which is the last evaluable FEV₁ result and includes most patients lung function data, are also provided. Pulmonary function improved significantly with FLOVENT Inhalation Aerosol compared with placebo by the second week of treatment, and this improvement was maintained over the duration of the trial.

In clinical trials of 924 patients with asthma already receiving daily inhaled corticosteroid therapy (doses of at least 336 mcg/day of beclomethasone dipropionate) in addition to as-needed albuterol and theophylline (46% of all patients), 22- to 440-mcg twice-daily doses of FLOVENT Inhalation Aerosol were also evaluated. All doses of FLOVENT Inhalation Aerosol were efficacious when compared to placebo on major endpoints including lung function and symptom scores. Patients treated with FLOVENT Inhalation Aerosol 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).

Figure 2 displays results of pulmonary function from a 12-week clinical trial in patients with asthma already receiving daily inhaled corticosteroid therapy (beclomethasone dipropionate 336 to 672 mcg/day). The mean percent change from baseline in lung function results for FLOVENT Inhalation Aerosol dosages of 88, 220, and 440 mcg twice daily and placebo are shown over the 12-week trial. Because this trial also used predetermined criteria for lack of efficacy, which caused more patients in the placebo group to be withdrawn, pulmonary function results at Endpoint are included. Pulmonary function improved significantly with FLOVENT Inhalation Aerosol compared with placebo by the first week of treatment, and the improvement was maintained over the duration of the trial. Analysis of the endpoint results that adjusted for differential withdrawal rates indicated that pulmonary function significantly improved with FLOVENT Inhalation Aerosol compared with placebo treatment. Similar improvements in lung function were seen in the other 2 trials in patients treated with inhaled corticosteroids at baseline.

In a clinical trial of 96 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 10 mg), twice-daily doses of 660 and 880 mcg of FLOVENT Inhalation Aerosol were evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (69% of the patients on 660 mcg twice daily and 88% of the patients on 880 mcg twice daily as compared with 3% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with FLOVENT Inhalation Aerosol had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Patients being treated with FLOVENT Inhalation Aerosol should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Patients should use FLOVENT Inhalation Aerosol at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or two of treatment; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.

After inhalation, rinse the mouth with water without swallowing.

Patients should be warned to avoid exposure to chickenpox or measles and, if they are exposed, to consult the physician without delay.

For the proper use of FLOVENT Inhalation Aerosol and to attain maximum improvement, the patient should read and follow carefully the Patient s Instructions for Use accompanying the product.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FLUTICASONE HFA INHALER - ORAL

(flew-TICK-uh-sown)

USES: Fluticasone is a corticosteroid that works directly in the lungs to make breathing easier by reducing the swelling and inflammation of the airways. This medication must be used regularly to prevent the wheezing and shortness of breath caused by asthma, bronchitis, or some types of emphysema.

This medication does not work immediately. Therefore, it is not used to relieve an asthma attack. If an asthma attack occurs, use your quick-relief inhaler (e.g., albuterol, salbutamol) as prescribed.

HOW TO USE: Read the Patient Information Leaflet which contains instructions for proper use of this medication. Consult your doctor or pharmacist if you have any questions.

Shake the canister well before using. Follow the instructions for test sprays in the air if you are using a canister for the first time or if you have not used it for a week or more. Avoid spraying the medication in your eyes. A fine mist is a sign that the inhaler is properly working.

Inhale this medication by mouth usually twice a day or as directed by your doctor. Dosage is based on your medical condition and response to therapy. It is recommended that you use a spacer device with this medication. Ask your doctor or pharmacist for more information. Follow the detailed instructions for proper use of the inhaler and cleaning of the mouthpiece.

If two inhalations/puffs are prescribed, wait at least one minute between them. If you are using other inhalers at the same time, wait several minutes between the use of each medication, and use this drug (the corticosteroid) last.

To prevent dry mouth, hoarseness and oral yeast infections from developing, gargle and rinse your mouth after each use. Do not swallow the rinse solution.

Use this medication regularly in order to get the most benefit from it. This medication works best if used consistently at even intervals. Remember to use it at the same times each day. Do not increase your dose, use this more frequently or stop using this medication without first consulting your doctor.

Keep track of the number of inhalations used from each canister. Discard the canister after you have used the number of inhalations specified on the manufacturer's package.

It may take up to 2 weeks or longer before the full benefit of this drug takes effect. Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Dry or irritated throat, stuffy nose, hoarseness, or coughing may occur as your body adjusts to this drug. A bad taste in the mouth or flu-like symptoms may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these serious side effects occur: white patches in your mouth or on your tongue, persistent coughing, increased wheezing/trouble breathing.

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: vision changes, increased thirst or urination, unusual or persistent headaches, chest pain or discomfort, numbness/tingling of the hands/feet, mental/mood changes (e.g., depression, agitation).

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking fluticasone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: tuberculosis, untreated or active infections, herpes infection of the eye, eye disease (glaucoma), decreased adrenal gland function.

If you have switched from an oral corticosteroid (e.g., prednisone tablets) to this inhaler within the past 12 months, or if you have been using this product in higher-than-usual doses and suddenly stop using it, your body may not produce enough natural steroids. You may need to start taking additional corticosteroids, especially if your body is stressed due to a major infection, surgery or injury. Tell your doctor immediately if you experience unusual weakness, weight loss, or dizziness. Consult your doctor or pharmacist for more details, and inform them that you use (or have used) any type of corticosteroid.

This medication may mask signs of infection or put you at greater risk of developing them. Report any signs of infection (e.g., persistent sore throat/fever/cough) that occur during treatment.

Avoid exposure to chickenpox or measles infection while taking this medication. If you are exposed to these infections, seek immediate medical attention.

Caution is advised when using this drug in children. Though it is unlikely to occur with inhaled steroids (fluticasone), this medication may temporarily slow down a child's rate of growth, but it will probably not affect final adult height. Monitor your child's height periodically.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: natalizumab.

If you are currently using this medication, tell your doctor or pharmacist before starting fluticasone.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: aldesleukin, oral corticosteroids (e.g., prednisone, dexamethasone), mifepristone, drugs affecting the removal of fluticasone from your system (potent CYP 3A4 inhibitors such as ketoconazole, ritonavir).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Learn to use a peak flow meter, use it daily, and tell your doctor promptly if you have signs of worsening asthma (such as readings in the yellow/red range, increased use of quick-relief inhalers). Also tell your doctor immediately if you notice that you need to use your quick-relief inhaler more often (4 or more puffs daily for 2 days in a row, or more than 1 canister every 8 weeks).

Make sure all of your doctors know that you are using this medication or have used it in the past.

Laboratory and/or medical tests (e.g., cortisol levels, lung function, eye exam) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C).

Store the medication away from light and moisture. Avoid freezing. Do not puncture or expose this medication to high heat or open flame. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.