Flovent

Generic Name: fluticasone propionate
Dosage Form: Inhalation powder

Flovent Description

The active component of Flovent DISKUS 50 mcg, Flovent DISKUS 100 mcg, and Flovent DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9 - difluoro - 11β,17 - dihydroxy - 16α - methyl - 3 - oxoandrosta - 1,4 - diene - 17β - carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white to off-white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

Flovent DISKUS 50 mcg, Flovent DISKUS 100 mcg, and Flovent DISKUS 250 mcg are specially designed plastic inhalation delivery systems containing a double-foil blister strip of a powder formulation of fluticasone propionate intended for oral inhalation only. The DISKUS® inhalation unit, which is the delivery component, is an integral part of the drug product. Each blister on the double-foil strip within the unit contains 50, 100, or 250 mcg of microfine fluticasone propionate in 12.5 mg of formulation containing lactose (which contains milk proteins). After a blister containing medication is opened by activating the DISKUS, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, Flovent DISKUS delivers 46, 94, or 235 mcg of fluticasone propionate from Flovent DISKUS 50 mcg, Flovent DISKUS 100 mcg, or Flovent DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV1] 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS® was 82.4 L/min (range, 46.1 to 115.3 L/min). In children with asthma 4 and 8 years old, mean PIF through Flovent DISKUS was 70 and 104 L/min, respectively (range, 48 to 123 L/min).

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

Flovent - Clinical Pharmacology

Mechanism of Action

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 systemic bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 18%.

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 dose 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 91%. 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 cytochrome P450 3A4 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.

Special Populations

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.

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 4 to 11 years of age 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.

Other

Formal pharmacokinetic studies using fluticasone propionate have not been conducted in other special populations.

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 (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). Fluticasonepropionate 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 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 concentration 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.

Pharmacodynamics

Clinical Trials

Adult and Adolescent Patients 12 Years of Age and Older

Four randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,036 adolescent and adult patients (≥12 years of age) with asthma to assess the efficacy and safety of fluticasone propionate inhalation powder 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 not adequately 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 the 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 fluticasone propionate inhalation powder (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 at recommended dosages of fluticasone propionate 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 successfully 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.

Pediatric Experience

A 12-week, placebo-controlled clinical trial was conducted in 437 patients (177 on fluticasone propionate via DISKUS) aged 4 to 11 years, 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 to placebo (7% change). Morning peak expiratory flow rate 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 to 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 PEFR, 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, fluticasone propionate inhalation powder was efficacious at doses of 50 and 100 mcg twice daily when compared to 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 fluticasone propionate were also less likely to discontinue study participation due to asthma deterioration. One hundred ninety-two (192) patients received fluticasone propionate 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.

Indications and Usage for Flovent

Flovent DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 4 years of age and older. 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 DISKUS is NOT indicated for the relief of acute bronchospasm.

Contraindications

Flovent DISKUS 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 and ADVERSE REACTIONS: Observed During Clinical Practice: Non-Site Specific).

Warnings

Particular care is needed for patients who are transferred from systemically active corticosteroids to Flovent DISKUS 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 fluticasone propionate inhalation powder may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid 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 concentration, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions and PRECAUTIONS: Drug Interactions: Inhibitors of Cytochrome P450). 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 fluticasone propionate inhalation powder. In a clinical trial of 111 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, short-acting 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 DISKUS may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

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.

Flovent DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of 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 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 DISKUS. During such episodes, patients may require therapy with oral corticosteroids.

Precautions

General

Eosinophilic Conditions

Information for Patients

Drug Interactions

Inhibitors of Cytochrome P450

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 concentration, resulting in significantly reduced serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: 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 plasma fluticasone propionate concentrations, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when Flovent DISKUS is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Teratogenic Effects

Pregnancy Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in the rat at inhalation doses up to 68.7 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/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: Pharmacokinetics: Absorption).

Fluticasone propionate crossed the placenta following administration of a subcutaneous dose of 100 mcg/kg to mice (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), a subcutaneous or an oral dose of 100 mcg/kg to rats (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis), and an oral dose of 300 mcg/kg to rabbits (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).

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

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.

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 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of Flovent DISKUS by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Flovent DISKUS, taking into account the importance of Flovent DISKUS to the mother.

Pediatric Use

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 8.5 years of age, 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. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. Patients should be maintained on the lowest dose of inhaled corticosteroid that effectively controls their asthma.

The safety and effectiveness of Flovent DISKUS in children below 4 years of age have not been established.

Geriatric Use

Safety data have been collected on 280 patients (Flovent DISKUS n = 83, Flovent ROTADISK n = 197) 65 years of age or older and 33 patients (Flovent DISKUS n = 14, Flovent ROTADISK n = 19) 75 years of age or older who have been treated with fluticasone propionate inhalation powder in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients. In addition, there were no apparent differences in efficacy between patients 65 years of age or older and younger patients. Fifteen patients 65 years of age or older and 1 patient 75 years of age or older were included in the efficacy evaluation of US clinical studies.

Adverse Reactions

The incidence of common adverse events in Table 1 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 with Flovent DISKUS (doses of 50 to 500 mcg twice daily for up to 12 weeks) or placebo.

Table 1. Overall Adverse Events With >3% Incidence in US Controlled Clinical Trials With Flovent DISKUS in Patients With Asthma Previously Receiving Bronchodilators and/or Inhaled Corticosteroids

		Flovent	Flovent	Flovent	Flovent
		DISKUS	DISKUS	DISKUS	DISKUS
		50 mcg	100 mcg	250 mcg	500 mcg
		Twice	Twice	Twice	Twice
	Placebo	Daily	Daily	Daily	Daily
	(n = 543)	(n = 178)	(n = 305)	(n = 86)	(n = 64)
Adverse Event	%	%	%	%	%
Ear, nose, and throat
Upper respiratory tract
infection	16	20	18	21	14
Throat irritation	8	13	13	3	22
Sinusitis/sinus infection	6	9	10	6	6
Upper respiratory
inflammation	3	5	5	0	5
Rhinitis	2	4	3	1	2
Oral candidiasis	7	<1	9	6	5
Gastrointestinal
Nausea and vomiting	4	8	4	1	2
Gastrointestinal discomfort
and pain	3	4	3	2	2
Viral gastrointestinal
infection	1	4	3	3	5
Non-site specific
Fever	4	7	7	1	2
Viral infection	2	2	2	0	5
Lower respiratory
Viral respiratory infection	4	4	5	1	2
Cough	4	3	5	1	5
Bronchitis	1	2	3	0	8
Neurological
Headache	7	12	12	2	14
Musculoskeletal and trauma
Muscle injury	1	2	0	1	5
Musculoskeletal pain	2	4	3	2	5
Injury	<1	2	<1	0	5
Average duration of exposure (days)	56	76	73	79	78

Table 1 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. In considering these data, differences in average duration of exposure should be taken into account.

These adverse events 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 rash and other rare events of angioedema and bronchospasm, have been reported.

Other adverse events that occurred in the groups receiving Flovent DISKUS in these studies with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo were:

Cardiovascular

Palpitations.

Drug Interaction, Overdose, and Trauma

Soft tissue injuries, contusions and hematomas, wounds and lacerations, postoperative complications, burns, poisoning and toxicity, pressure-induced disorders.

Ear, Nose, and Throat

Ear signs and symptoms; rhinorrhea/postnasal drip; hoarseness/dysphonia; epistaxis; tonsillitis; nasal signs and symptoms; laryngitis; unspecified oropharyngeal plaques; otitis; ear, nose, throat, and tonsil signs and symptoms; ear, nose, and throat polyps; allergic ear, nose, and throat disorders; throat constriction.

Endocrine and Metabolic

Fluid disturbances, weight gain, goiter, disorders of uric acid metabolism, appetite disturbances.

Eye

Keratitis and conjunctivitis, blepharoconjunctivitis.

Gastrointestinal

Diarrhea, gastrointestinal signs and symptoms, oral ulcerations, dental discomfort and pain, gastroenteritis, gastrointestinal infections, abdominal discomfort and pain, oral erythema and rashes, mouth and tongue disorders, oral discomfort and pain, tooth decay.

Hepatobiliary Tract and Pancreas

Cholecystitis.

Lower Respiratory

Lower respiratory infections.

Musculoskeletal

Muscle pain, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation.

Neurological

Dizziness, sleep disorders, migraines, paralysis of cranial nerves.

Non-Site Specific

Chest symptoms; malaise and fatigue; pain; edema and swelling; bacterial infections; fungal infections; mobility disorders; cysts, lumps, and masses.

Psychiatry

Mood disorders.

Reproduction

Bacterial reproductive infections.

Skin

Skin rashes, urticaria, photodermatitis, dermatitis and dermatosis, viral skin infections, eczema, fungal skin infections, pruritus, acne and folliculitis.

Urology

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 (doses of 50 or 100 mcg twice daily) or placebo; an additional 174 patients 4 to 11 years received Flovent ROTADISK 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. 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). In considering these data, the increased average duration of exposure for patients taking Flovent DISKUS (105 days for Flovent DISKUS versus 75 days for placebo) should be taken into account.

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%).

Observed During Clinical Practice

In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of fluticasone propionate in clinical practice. 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, and throat soreness.

Endocrine and Metabolic

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

Eye

Cataracts.

Psychiatry

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

Non-Site Specific

Very rare anaphylactic reaction, very rare anaphylactic reaction in patients with severe milk protein allergy.

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. 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).

Overdosage

Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS: General). Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate inhalation aerosol was well tolerated. Doses of 1,320 mcg administered to healthy human volunteers twice daily for 7 to 15 days were 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 mice and rats were >1,000 mg/kg (>2,000 and >4,100 times, respectively, the maximum recommended daily inhalation dose in adults and >9,600 and >20,000 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis).

Flovent Dosage and Administration

Flovent DISKUS should be administered by the orally inhaled route only in patients 4 years of age and older. 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.

After asthma stability has been achieved, 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 DISKUS when administered in excess of recommended dosages have not been established.

The recommended starting dosage and the highest recommended dosage of Flovent DISKUS, based on prior asthma therapy, are listed in Table 2.

Table 2. Recommended Dosages of Flovent DISKUS*

NOTE: In all patients, it is desirable to titrate to the lowest effective dosage once asthma stability is achieved.

Previous Therapy	Recommended Starting Dosage	Highest Recommended Dosage
Adults and Adolescents
Bronchodilators alone	100 mcg twice daily	500 mcg twice daily
Inhaled corticosteroids	100-250 mcg twice daily	500 mcg twice daily
Oral corticosteroids†	500-1,000 mcg twice daily‡	1,000 mcg twice daily
Children 4 to 11 Years
Bronchodilators alone	50 mcg twice daily	100 mcg twice daily
Inhaled corticosteroids	50 mcg twice daily	100 mcg twice daily

* Starting dosages above 100 mcg twice daily for adults and adolescents and 50 mcg twice daily for children 4 to 11 years of age may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for that specific agent.

†For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with Flovent DISKUS. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency (see WARNINGS). Once prednisone reduction is complete, the dosage of fluticasone propionate should be reduced to the lowest effective dosage.

‡ The choice of starting dosage should be made on the basis of individual patient assessment. A controlled clinical study of 111 oral corticosteroid-dependent patients with asthma showed few significant differences between the 2 doses of Flovent DISKUS on safety and efficacy endpoints. However, inability to decrease the dose of oral corticosteroids further during corticosteroid reduction may be indicative of the need to increase the dose of fluticasone propionate up to the maximum of 1,000 mcg twice daily.

Pediatric Use

Geriatric Use

Directions for Use

How is Flovent Supplied

Flovent DISKUS 50 mcg is supplied as a disposable orange inhalation unit containing 60 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02). Flovent DISKUS 50 mcg is also supplied in an institutional pack of 1 disposable orange inhalation unit containing 28 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0600-00).

Flovent DISKUS 100 mcg is supplied as a disposable orange inhalation unit containing 60 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02). Flovent DISKUS 100 mcg is also supplied in an institutional pack of 1 disposable orange inhalation unit containing 28 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0602-00).

Flovent DISKUS 250 mcg is supplied as a disposable orange inhalation unit containing 60 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02). Flovent DISKUS 250 mcg is also supplied in an institutional pack of 1 disposable orange inhalation unit containing 28 blisters. The drug product is packaged within an orange, plastic-coated, moisture-protective foil pouch (NDC 0173-0601-00).

Store at controlled room temperature (see USP), 20° to 25°C (68° to 77°F) in a dry place away from direct heat or sunlight. Keep out of reach of children. The DISKUS inhalation device is not reusable. The device should be discarded 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) after removal from the moisture-protective foil pouch or after all blisters have been used (when the dose indicator reads“0”), whichever comes first. Do not attempt to take the device apart.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2005, GlaxoSmithKline. All rights reserved.

Flovent (fluticasone propionate)

PRODUCT INFO Product Code 0173-0600 Dosage Form POWDER, METERED Route Of Administration RESPIRATORY (INHALATION) DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength fluticasone propionate (fluticasone) Active 50 MICROGRAM  In 1 BLISTER lactose Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color Score Shape Symbol Imprint Code Coating Size

PACKAGING # NDC Package Description Multilevel Packaging 1 0173-0600-00 28 BLISTER In 1 INHALER None 2 0173-0600-02 60 BLISTER In 1 INHALER None

Flovent (fluticasone propionate)

PRODUCT INFO Product Code 0173-0602 Dosage Form POWDER, METERED Route Of Administration RESPIRATORY (INHALATION) DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength fluticasone propionate (fluticasone) Active 100 MICROGRAM  In 1 BLISTER lactose Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color Score Shape Symbol Imprint Code Coating Size

PACKAGING # NDC Package Description Multilevel Packaging 1 0173-0602-00 28 BLISTER In 1 INHALER None 2 0173-0602-02 60 BLISTER In 1 INHALER None

Flovent (fluticasone propionate)

PRODUCT INFO Product Code 0173-0601 Dosage Form POWDER, METERED Route Of Administration RESPIRATORY (INHALATION) DEA Schedule

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