Flovent HFA

Dosage Forms And Strengths

Inhalation Aerosol. Dark orange plastic inhaler with a peach strapcap containing a pressurized metereddose aerosol canister containing 120 metered inhalations and fitted with a counter. Each actuation delivers 44, 110, or 220 mcg of fluticasone propionate from the mouthpiece.

Storage And Handling

FLOVENT HFA 44 mcg Inhalation Aerosol is supplied in 10.6-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0718-20).

FLOVENT HFA 110 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0719-20).

FLOVENT HFA 220 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0720-20).

Each canister is fitted with a counter and supplied with a dark orange actuator with a peach strapcap. Each inhaler is packaged with a Patient Information leaflet.

The dark orange actuator supplied with FLOVENT HFA should not be used with any other product canisters, and actuators from other products should not be used with a FLOVENT HFA canister.

The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000.

Keep out of reach of children. Avoid spraying in eyes.

Contents under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator.

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C). Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use. Shake well before EACH SPRAY.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: Dec 2014

FLOVENT® HFA Inhalation Aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years 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.

Important Limitation Of Use

Flovent HFA is not indicated for the relief of acute bronchospasm.

FLOVENT HFA should be administered by the orally inhaled route only in patients aged 4 years and older. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

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 HFA when administered in excess of recommended dosages have not been established.

The recommended starting dosage and the highest recommended dosage of FLOVENT HFA, based on prior asthma therapy, are listed in Table 1.

Table 1: Recommended Dos ages of FLOVENT HFA Inhalation Aerosol
NOTE: In all patients, it is desirable to titrate to the lowest effective dos age once asthma stability is achieved.

Prime FLOVENT HFA before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 spray into the air away from the face.

The use of FLOVENT HFA is contraindicated in the following conditions:

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Local Effects Of Inhaled Corticosteroids

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT HFA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT HFA continues, but at times therapy with FLOVENT HFA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

Acute Asthma Episodes

FLOVENT HFA is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT HFA. During such episodes, patients may require therapy with oral corticosteroids.

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated  infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

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

Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although FLOVENT HFA may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT HFA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT HFA. Lung function (mean forced expiratory volume in 1 second [FEV₁] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, 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 HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

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

Hypercorticism And Adrenal Suppression

Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT HFA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT HFA.

Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with FLOVENT HFA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, FLOVENT HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

Immediate Hypersensitivity Reactions

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

Reduction In Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

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

Effect On Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving FLOVENT HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT HFA, titrate each patient's dosage to the lowest dosage that effectively controls his/her symptoms.

Glaucoma And Cataracts

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

Paradoxical Bronchospasm

As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT HFA, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT HFA should be discontinued immediately; and alternative therapy should be instituted.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT HFA is not recommended because increased systemic corticosteroid adverse effects may occur.

Eosinophilic Conditions And Churg-Strauss Syndrome

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.

Patient Counseling Information

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

Local Effects

Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT HFA, but at times therapy with FLOVENT HFA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus And Acute Asthma Symptoms

Inform patients that FLOVENT HFA is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism And Adrenal Suppression

Advise patients that FLOVENT HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT HFA.

Immediate Hypersensitivity Reactions

Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT HFA. Patients should discontinue FLOVENT HFA if such reactions occur.

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

Reduced Growth Velocity

Inform patients that orally inhaled corticosteroids, including FLOVENT HFA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Ocular Effects

Inform patients that long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily For Best Effect

Patients should use Flovent HFA at regular intervals as directed. Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Instruct patients not to stop use of FLOVENT HFA abruptly. Patients should contact their physicians immediately if they discontinue use of FLOVENT HFA.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

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

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

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with FLOVENT HFA in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, FLOVENT HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking FLOVENT HFA.

Mice and rats at fluticasone propionate doses approximately 0.1 and 0.5 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) for adults (on a mg/m² basis at maternal subcutaneous doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses up to 0.3 times the MRHDID (on a mcg/m² basis at maternal inhaled doses up to 68.7 mcg/kg/day).

In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose approximately 0.04 times the MRHDID for adults (on a mg/m² basis at a maternal subcutaneous dose of 4 mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 3 times the MRHDID for adults (on a mg/m² basis at a maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.

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

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.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Nursing Mothers

It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate at a dose approximately 0.05 times the MRHDID in adults on a mg/m² basis resulted in measurable radioactivity in milk.

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

Pediatric Use

The safety and effectiveness of FLOVENT HFA in children aged 4 years and older have been established.The safety and effectiveness of FLOVENT HFA in children younger than 4 years have not been established. Use of FLOVENT HFA in patients aged 4 to 11 years is supported by evidence from adequate and wellcontrolled trials in adults and adolescents aged 12 years and older, pharmacokinetic trials in patients aged 4 to 11 years, established efficacy of fluticasone propionate formulated as FLOVENT® DISKUS® (fluticasone propionate inhalation powder) and FLOVENT® ROTADISK® (fluticasone propionate inhalation powder) in patients aged 4 to 11 years, and supportive findings with FLOVENT HFA in a trial conducted in subjects aged 4 to 11 years.

Effects On Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticosteroids. The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that inhaled corticosteroids may cause a reduction in growth in pediatric patients. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown. The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT HFA, 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 HFA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

Since a cross trial comparison in adult and adolescent subjects (aged 12 years and older) indicated that systemic exposure of inhaled fluticasone propionate from FLOVENT HFA would be higher than exposure from FLOVENT ROTADISK, results from a trial to assess the potential growth effects of FLOVENT ROTADISK in pediatric subjects (aged 4 to 11 years) are provided.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the 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 trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50^th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50^th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

Children Younger Than 4 Years

Pharmacokinetics:.

Pharmacodynamics

A 12-week, double-blind, placebo-controlled, parallel-group trial was conducted in children with asthma aged 1 to younger than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week treatment period with 88 mcg of FLOVENT HFA twice daily (n = 73) and with placebo (n = 42) were calculated. The mean and median change from baseline in urine cortisol over 12 hours were -0.7 and 0.0 mcg for FLOVENT HFA and 0.3 and -0.2 mcg for placebo, respectively.

In a 1-way crossover trial in children aged 6 to younger than 12 months with reactive airways disease (N = 21), serum cortisol was measured over a 12-hour dosing period. Subjects received placebo treatment for a 2-week period followed by a 4-week treatment period with 88 mcg of FLOVENT HFA twice daily with an AeroChamber Plus® Valved Holding Chamber (VHC) with mask. The geometric mean ratio of serum cortisol over 12 hours (AUC0-12H ) following FLOVENT HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72, 1.27).

Safety: FLOVENT HFA administered as 88 mcg twice daily was evaluated for safety in 239 pediatric subjects aged 1 to younger than 4 years in a 12-week, double-blind, placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask. The following events occurred with a frequency greater than 3% and more frequently in subjects receiving FLOVENT HFA than in subjects receiving placebo, regardless of causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection, vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection.

FLOVENT HFA administered as 88 mcg twice daily was evaluated for safety in 23 pediatric subjects aged 6 to 12 months in an open-label placebo-controlled trial. Treatments were administered with an AeroChamber Plus VHC with mask for 2 weeks with placebo followed by 4 weeks with active drug. There was no discernable difference in the types of adverse events reported between subjects receiving placebo compared with the active drug.

In Vitro Testing of Dose Delivery with Holding Chambers: In vitro dose characterization studies were performed to evaluate the delivery of FLOVENT HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers (AeroChamber Plus VHC and AeroChamber Z-STAT Plus™ VHC) with masks (small and medium size) at inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively. The mean delivered dose of fluticasone propionate through the holding chambers with masks was lower than the 44 mcg of fluticasone propionate delivered directly from the actuator mouthpiece. The results were similar through both holding chambers (see Table 3 for data for the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5 μm) across the flow rates used in these studies was 70% to 84% of the delivered dose, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for FLOVENT HFA delivered without a holding chamber typically represents 42% to 55% of the delivered dose measured at the standard flow rate of 28.3 L/min. These data suggest that, on a per kilogram basis, young children receive a comparable dose of fluticasone propionate when delivered via a holding chamber and mask as adults do without their use.

Table 3: In Vitro Medication Delivery through AeroChamber Plus® Valved Holding Chamber with a Mask

Geriatric Use

Of the total number of subjects treated with FLOVENT HFA in US and non-US clinical trials, 173 were aged 65 years or older, 19 of which were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

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

Renal Impairment

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

Inhibitors of Cytochrome P450 3A4

Ritonavir: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction trial 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 (less than 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 AUC0-τ averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC0-τ increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/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 serum cortisol AUC.

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

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

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

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with FLOVENT HFA in pregnant women. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, FLOVENT HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking FLOVENT HFA.

Mice and rats at fluticasone propionate doses approximately 0.1 and 0.5 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) for adults (on a mg/m² basis at maternal subcutaneous doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses up to 0.3 times the MRHDID (on a mcg/m² basis at maternal inhaled doses up to 68.7 mcg/kg/day).

In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose approximately 0.04 times the MRHDID for adults (on a mg/m² basis at a maternal subcutaneous dose of 4 mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 3 times the MRHDID for adults (on a mg/m² basis at a maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration.

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

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.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection
• Immunosuppression
• Hypercorticism and adrenal suppression
• Reduction in bone mineral density
• Growth effects
• Glaucoma and cataracts

Clinical Trials Experience

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

The incidence of common adverse reactions in Table 2 is based upon 2 placebo-controlled US clinical trials in which 812 adult and adolescent subjects (457 females and 355 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with 2 inhalations of FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA 110 mcg Inhalation Aerosol, FLOVENT HFA 220 mcg Inhalation Aerosol (dosages of 88, 220, or 440 mcg twice daily), or placebo.

Table 2: Adverse Reactions with FLOVENT HFA with > 3% Incidence and More Common than Placebo in Subjects Aged 12 Years and Older with Asthma

Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of over 3% in any of the groups treated with FLOVENT HFA and were more common than in the placebo group. Less than 2% of subjects discontinued from the trials because of adverse reactions. The average duration of exposure was 73 to 76 days in the active treatment groups compared with 60 days in the placebo group.

Additional Adverse Reactions

Other adverse reactions not previously listed, whether considered drugrelated or not by the investigators, that were reported more frequently by subjects with asthma treated with FLOVENT HFA compared with subjects treated with placebo include the following: rhinitis, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis, diarrhea, viral gastrointestinal infections, dyspeptic symptoms, gastrointestinal discomfort and pain, hyposalivation, musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity, dizziness, migraines, fever, viral infections, pain, chest symptoms, viral skin infections, muscle injuries, soft tissue injuries, urinary infections.

Fluticasone propionate inhalation aerosol (440 or 880 mcg twice daily) was administered for 16 weeks to 168 subjects with asthma requiring oral corticosteroids (Trial 3). Adverse reactions not included above, but reported by more than 3 subjects in either group treated with FLOVENT HFA and more commonly than in the placebo group included nausea and vomiting, arthralgia and articular rheumatism, and malaise and fatigue.

In 2 long-term trials (26 and 52 weeks), the pattern of adverse reactions in subjects treated with FLOVENT HFA at dosages up to 440 mcg twice daily was similar to that observed in the 12-week trials. There were no new and/or unexpected adverse reactions with long-term treatment.

Pediatric Subjects Aged 4 To 11 Years

FLOVENT HFA has been evaluated for safety in 56 pediatric subjects who received 88 mcg twice daily for 4 weeks. Types of adverse reactions in these pediatric subjects were generally similar to those observed in adults and adolescents.

Postmarketing Experience

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

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

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

Eye: Cataracts.

Gastrointestinal Disorders: Dental caries and tooth discoloration.

Immune System Disorders: Immediate and delayed hypersensitivity reactions, including urticaria, anaphylaxis, rash, and angioedema and bronchospasm, have been reported.

Infections and Infestations: Esophageal candidiasis.

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

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

Skin: Contusions, cutaneous hypersensitivity reactions, ecchymoses, and pruritus.

Chronic overdosage may result in signs/symptoms of hypercorticism. Inhalation by healthy volunteers of a single dose of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

Serum cortisol concentrations, urinary excretion of cortisol, and urine 6-β-hydroxycortisol excretion collected over 24 hours in 24 healthy subjects following 8 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg decreased with increasing dose. However, in patients with asthma treated with 2 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg twice daily for at least 4 weeks, differences in serum cortisol AUC(0-12) (n = 65) and 24-hour urinary excretion of cortisol (n = 47) compared with placebo were not related to dose and generally not significant. In the trial with healthy volunteers, the effect of propellant was also evaluated by comparing results following the 220-mcg strength inhaler containing HFA 134a propellant with the same strength of inhaler containing CFC 11/12 propellant. A lesser effect on the HPA axis with the HFA formulation was observed for serum cortisol, but not urine cortisol and 6-betahydroxy cortisol excretion. In addition, in a crossover trial in children with asthma aged 4 to 11 years (N = 40), 24-hour urinary excretion of cortisol was not affected after a 4-week treatment period with 88 mcg of fluticasone propionate HFA twice daily compared with urinary excretion after the 2-week placebo period. The ratio (95% CI) of urinary excretion of cortisol over 24 hours following fluticasone propionate HFA versus placebo was 0.987 (0.796, 1.223).

The potential systemic effects of fluticasone propionate HFA on the HPA axis were also studied in subjects with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 440 or 880 mcg twice daily was compared with placebo in oral corticosteroid-dependent subjects with asthma (range of mean dose of prednisone at baseline: 13 to 14 mg/day) in a 16-week trial. Consistent with maintenance treatment with oral corticosteroids, abnormal plasma cortisol responses to short cosyntropin stimulation (peak plasma cortisol less than 18 mcg/dL) were present at baseline in the majority of subjects participating in this trial (69% of subjects later randomized to placebo and 72% to 78% of subjects later randomized to fluticasone propionate HFA). At week 16, 8 subjects (73%) on placebo compared with 14 (54%) and 13 (68%) subjects receiving fluticasone propionate HFA (440 and 880 mcg twice daily, respectively) had post-stimulation cortisol levels of less than 18 mcg/dL.

Absorption

Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 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.

Distribution

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

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

Metabolism

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the 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.

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.