Armonair Respiclick

Fluticasone belongs to the family of medicines known as corticosteroids (cortisone-like medicines). It is used to help prevent the symptoms of asthma. When used regularly every day, inhaled fluticasone decreases the number and severity of asthma attacks. However, it will not relieve an asthma attack that has already started.

This medicine must be used with a short-acting medicine (eg, albuterol) for an asthma attack or asthma symptoms that need attention right away.

This medicine is available only with your doctor's prescription.

ARMONAIR™ RESPICLICK® is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older.

Important Limitation of Use: ArmonAir Respiclick is NOT indicated for the relief of acute bronchospasm.

Status Asthmaticus

ArmonAir Respiclick is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)].

Hypersensitivity

ArmonAir Respiclick is contraindicated in patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see Warnings and Precautions (5.6), Description (11)].

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 ArmonAir Respiclick. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with ArmonAir Respiclick continues, but at times therapy with ArmonAir Respiclick 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

ArmonAir Respiclick is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ArmonAir Respiclick, should be used to relieve acute symptoms such as shortness of breath. When prescribing ArmonAir Respiclick, the physician must provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily use of ArmonAir Respiclick. Instruct patients to contact their physicians immediately if episodes of asthma not responsive to bronchodilators occur during the course of treatment with ArmonAir Respiclick. 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 patients who have not had these diseases or who have not 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) or pooled intravenous immunoglobulin (IVIG) 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; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who are 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 ArmonAir Respiclick may improve 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 that is necessary for coping with these emergencies.

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

Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ArmonAir Respiclick. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ArmonAir Respiclick. 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 systemic 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 ArmonAir Respiclick 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

ArmonAir Respiclick will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since ArmonAir Respiclick is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ArmonAir Respiclick 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 ArmonAir Respiclick.

Because of the possibility of significant systemic absorption of inhaled corticosteroids, patients treated with ArmonAir Respiclick 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, the dosage of ArmonAir Respiclick should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and for management of asthma symptoms.

Hypersensitivity Reactions, Including Anaphylaxis

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ArmonAir Respiclick. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use ArmonAir Respiclick [see Contraindications (4.2)].

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, 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.

Effect on Growth

Orally inhaled corticosteroids, including ArmonAir Respiclick, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ArmonAir Respiclick routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ArmonAir Respiclick, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2), Use in Specific Populations (8.4)].

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 ArmonAir Respiclick, it should be treated immediately with an inhaled, short-acting bronchodilator; ArmonAir Respiclick 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 ArmonAir Respiclick is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Eosinophilic Conditions and ChurgStrauss 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.

Mechanism of Action

Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time of onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic availability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

Pharmacodynamics

ArmonAir Respiclick: Hypothalamic Pituitary Adrenal Axis Effects.

The potential systemic effects of ArmonAir Respiclick on the HPA axis were not fully studied, but other clinical trials evaluated the systemic effects of fluticasone propionate inhalation powder on the HPA axis in healthy subjects and in subjects with asthma.

ArmonAir Respiclick: Subjects with Asthma: Adults and Adolescents: Hypothalamic Pituitary Adrenal Axis Effects.

There are no data regarding serum cortisol from controlled trials using ArmonAir Respiclick in healthy subjects or subjects with asthma.

Pharmacokinetics

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 was 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 was systemically absorbed.

Following ArmonAir Respiclick administration, the peak plasma concentration of fluticasone propionate occurs at approximately 1 hour after inhalation.

The mean peak concentration following a 232 mcg single oral inhalation of ArmonAir Respiclick to patients 12 years and older with persistent asthma was 73 pg/mL.

Distribution

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

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

Elimination

Terminal half-life estimate of fluticasone propionate following oral inhalation administration of ArmonAir Respiclick was approximately 11.2 hours.

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 has 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.

Less than 5% of a radiolabeled oral dose of fluticasone propionate was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Special Populations

Age: No pharmacokinetic studies have been performed with ArmonAir Respiclick in children or geriatric patients. A subgroup analysis was conducted to compare patients aged 12-17 (n=16) and ≥18 (n=23) years following administration of 232 mcg ArmonAir Respiclick. No overall differences in fluticasone propionate pharmacokinetics were observed.

Sex: A subgroup analysis was conducted to compare male (n=22) and female (n=17) patients following administration of 232 mcg ArmonAir Respiclick. No overall differences in fluticasone propionate pharmacokinetics were observed.

Renal Impairment: The effect of renal impairment on the pharmacokinetics of ArmonAir Respiclick has not been evaluated.

Hepatic Impairment: Formal pharmacokinetic studies using ArmonAir Respiclick have not been conducted in patients with hepatic impairment. However, since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma.

Drug Interaction Studies: In vitro and in vivo drug interaction studies have not been conducted with ArmonAir Respiclick. Known clinically significant drug interactions are outlined in Drug Interactions (7).

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 (<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, AUC2-last averaged 1.559 ng•h/mL (range: 0.555 to 2.906 ng•h/mL) and AUC2-∞ averaged 2.269 ng•h/mL (range: 0.836 to 3.707 ng•h/mL). Fluticasone propionate AUC2-last and AUC2-∞ 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.

The safety and efficacy of ArmonAir Respiclick were evaluated in 2130 patients with asthma. The development program included 2 confirmatory trials of 12 weeks duration, a 26 week safety trial and two dose-ranging trials of 12 weeks duration. The efficacy of ArmonAir Respiclick is based primarily on the dose-ranging trials and the confirmatory trials described below.

Dose-Ranging Trials

Six doses of fluticasone propionate ranging from 16 mcg to 434 mcg (expressed as metered doses) administered twice daily via a multidose dry powder inhaler were evaluated in 2 randomized, double-blind, placebo-controlled 12 week trials. Trial 201 was conducted in patients who were uncontrolled at baseline and had been treated by SABA alone or in combination with non-corticosteroid asthma medication. Low dose ICS patients may have been included after a minimum of 2 weeks washout. This trial contained an open-label active comparator fluticasone propionate inhalation powder 100 mcg administered twice daily. Trial 202 was conducted in patients who were uncontrolled at baseline and had been treated with high dose ICS with or without a LABA. This study contained an open-label active comparator fluticasone propionate inhalation powder 250 mcg twice daily. The trials were dose-ranging trials of ArmonAir Respiclick and not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate inhalation powder. The metered doses for fluticasone multidose dry powder inhaler (16, 28, 59, 118, 225, 434 mcg) used in Trial 201 and Trial 202 (see Figure 1) are slightly different from the metered doses for the comparator products (fluticasone inhalation powder) and the Phase 3 investigational products which are the basis of the proposed commercial labeled claim (55, 113, 232 mcg for fluticasone). The changes in doses between Phase 2 and 3 resulted from optimization of the manufacturing process.

FAS = full analysis set; aTrials were not designed to provide comparative effectiveness data and should not be interpreted as superiority/inferiority to fluticasone propionate inhalation powder.

Trials in the Maintenance Treatment of Asthma

Adult and Adolescent Patients Aged 12 Years and Older:

Two Phase 3 clinical trials were conducted comparing ArmonAir Respiclick with placebo (Trial 1 and Trial 2).

Trials Comparing ArmonAir Respiclick with Placebo

Two double-blind, parallel-group clinical trials, Trial 1 and Trial 2, were conducted with ArmonAir Respiclick in 1375 adult and adolescent patients (aged 12 years and older, with baseline FEV1 40% to 85% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were given as 1 inhalation twice a day from the RESPICLICK inhaler, and other maintenance therapies were discontinued.

Trial 1: This randomized, double-blind, placebo-controlled, 12-week, global efficacy and safety trial compared Fluticasone Propionate Multidose Dry Powder Inhaler (ArmonAir Respiclick) 55 mcg and 113 mcg (1 inhalation twice a day), Fluticasone/Salmeterol Multidose Dry Powder Inhaler (AIRDUO RESPICLICK) 55/14 mcg and 113/14 mcg (1 inhalation twice a day), and placebo in adolescents and adult patients with persistent symptomatic asthma despite low-dose or mid-dose inhaled corticosteroid or inhaled corticosteroid/LABA therapy. Patients received single-blinded placebo MDPI and were switched from their baseline ICS therapy to QVAR 40 mcg twice daily during the run-in period. Patients who met all randomization criteria were randomly assigned to receive treatment as follows: 130 received placebo, 129 received ArmonAir Respiclick 55 mcg, 130 received ArmonAir Respiclick 113 mcg, 129 received AIRDUO RESPICLICK 55/14 mcg, and 129 received AIRDUO RESPICLICK 113/14 mcg. Baseline FEV1 measurements were similar across treatments: ArmonAir Respiclick 55 mcg 2.134 L, ArmonAir Respiclick 113 mcg 2.166 L, and placebo 2.188 L. The primary endpoints for this trial were the change from baseline in trough FEV1 at week 12 for all patients and standardized baseline-adjusted FEV1 AUEC0-12h at week 12 analyzed for a subset of 312 patients who performed postdose serial spirometry.

Patients receiving ArmonAir Respiclick  55 mcg and ArmonAir Respiclick 113 mcg had significantly greater improvements in trough FEV1 (ArmonAir Respiclick 55 mcg, LS mean change of 0.172 L at 12 weeks and ArmonAir Respiclick 113 mcg, LS mean change of 0.204 L at 12 weeks) compared with placebo (LS mean change of 0.053 L at 12 weeks). Estimated mean differences between ArmonAir Respiclick 55 mcg and ArmonAir Respiclick 113 mcg compared to placebo are 0.119 L (95% CI: 0.025, 0.212) and 0.151 L (95% CI: 0.057, 0.244), respectively. In addition, the mean FEV1 results at each visit are displayed in Figure 2.

FAS = full analysis set; FEV1 = forced expiratory volume in 1 second

There was supportive evidence of efficacy for ArmonAir Respiclick compared with placebo for secondary endpoints such as the weekly average of daily trough morning peak expiratory flow and the total daily use of rescue medication. The Asthma Quality of Life Questionnaire (AQLQ) for patients’ age ≥ 18 years or the pediatric AQLQ (PAQLQ) for patients aged 12-17 were assessed in Trial 1. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold. In Trial 1, the responder rate for patients receiving ArmonAir Respiclick 55 mcg and ArmonAir Respiclick 113 mcg was 46% and 45%, respectively, compared to 40% for patients receiving placebo with odds ratios of 1.23 (95% CI: 0.74, 2.06) and 1.25 (95% CI: 0.75, 2.08), respectively.

Improvements in FEV1 for both ArmonAir Respiclick dose groups were sustained over the 12 hours of testing at week 12 (Figure 3). No diminution in the 12 hour bronchodilator effect was observed with ArmonAir Respiclick as assessed by FEV1 following 12 weeks of therapy.

FAS = full analysis set; FEV1 = forced expiratory volume in 1 second

Trial 2: This randomized, double-blind, placebo-controlled, 12-week, global efficacy and safety trial compared Fluticasone Propionate Multidose Dry Powder Inhaler (ArmonAir Respiclick) 113 mcg and 232 mcg (1 inhalation twice a day), Fluticasone/Salmeterol Multidose Dry Powder Inhaler (AIRDUO RESPICLICK) 113/14 mcg and 232/14 mcg (1 inhalation twice a day), and placebo in adolescents and adult patients with persistent symptomatic asthma despite inhaled corticosteroid or inhaled corticosteroid/LABA therapy. Patients received single-blinded placebo MDPI and were switched from their baseline ICS therapy to ArmonAir Respiclick 55 mcg twice daily during the run-in period. Patients who met all randomization criteria were randomly assigned to receive treatment as follows: 145 patients received placebo, 146 patients received ArmonAir Respiclick 113 mcg, 146 patients received ArmonAir Respiclick 232 mcg, 145 patients received AIRDUO RESPICLICK 113/14 mcg, and 146 patients received AIRDUO RESPICLICK 232/14 mcg. Baseline FEV1 measurements were similar across treatments, as follows: ArmonAir Respiclick 113 mcg 2.069 L, ArmonAir Respiclick 232 mcg 2.075 L, and placebo 2.141 L. The primary endpoints for this trial were the change from baseline in trough FEV1 at week 12 for all patients and standardized baseline-adjusted FEV1 AUEC0-12h at week 12 analyzed for a subset of 312 patients who performed postdose serial spirometry.

Efficacy results in this trial were similar to those observed in Trial 1. Patients receiving ArmonAir Respiclick 113 mcg and ArmonAir Respiclick 232 mcg had significantly greater improvements in trough FEV1 (ArmonAir Respiclick 113 mcg, LS mean change of 0.119 L at 12 weeks and ArmonAir Respiclick 232 mcg, LS mean change of 0.179 L at 12 weeks) compared with placebo (LS mean change of ‑0.004 L at 12 weeks). Estimated mean differences between ArmonAir Respiclick 113 mcg and ArmonAir Respiclick 232 mcg compared to placebo are 0.123 L (95% CI: 0.038, 0.208) and 0.183 L (95% CI: 0.098, 0.268), respectively. In addition, the mean FEV1 results at each visit are displayed in Figure 4.

FAS = full analysis set; FEV1 = forced expiratory volume in 1 second

There was supportive evidence of efficacy for ArmonAir Respiclick compared with placebo for secondary endpoints such as the weekly average of daily trough morning peak expiratory flow and total daily use of rescue medication. There were fewer withdrawals due to worsening asthma in patients treated with ArmonAir Respiclick than with placebo. The AQLQ (patients age ≥ 18 years) or the PAQLQ (patients aged 12-17) were assessed in Trial 2. The responder rate for patients receiving ArmonAir Respiclick 113 mcg and ArmonAir Respiclick 232 mcg was 38% and 44%, respectively, compared to 27% for patients receiving placebo, with an odds ratio of 1.75 (95% CI:1.05, 2.93) and 2.12 (95% CI: 1.27, 3.53), respectively.

Improvements in FEV1 for both ArmonAir Respiclick dose groups were sustained over the 12 hours of testing at week 12 (Figure 5). No diminution in the 12 hour bronchodilator effect was observed with ArmonAir Respiclick as assessed by FEV1 following 12 weeks of therapy.

FAS = full analysis set; FEV1 = forced expiratory volume in 1 second

ArmonAir™ RespiClick® (fluticasone propionate 55 mcg) Inhalation Powder, 60 Metered Inhalations Carton Text

TEVA

NDC 59310-705-06

Rx Only

ArmonAir™

RespiClick® 55

(fluticasone propionate 55 mcg)

Inhalation Powder

55 mcg

With Dose Counter

FOR ORAL INHALATION ONLY

60 METERED INHALATIONS

0.9 g NET CONTENTS

Refer to enclosed Patient Leaflet and

Instructions for Use for detailed

information on product use and handling.

Applies to fluticasone: inhalation aerosol powder, inhalation disk, inhalation powder

Along with its needed effects, fluticasone (the active ingredient contained in ArmonAir RespiClick) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fluticasone:

• White patches in the mouth and throat

• Diarrhea
• ear ache
• fever
• lower abdominal or stomach pain
• nausea
• pain on passing urine
• redness or discharge of the eye, eyelid, or lining of the eye
• shortness of breath
• sore throat
• trouble swallowing
• vaginal discharge (creamy white) and itching
• vomiting

• Blindness, blurred vision, eye pain
• bone fractures
• excess facial hair in women
• fullness or roundness of the face, neck, and trunk
• growth reduction in children or adolescents
• heart problems
• high blood pressure
• hives and skin rash
• impotence in males
• increased hunger, thirst, or urination
• lack of menstrual periods
• muscle wasting
• numbness and weakness of hands and feet
• swelling of the face, lips, or eyelids
• tightness in the chest, troubled breathing
• weakness

• Dizziness
• fast heartbeat

Get emergency help immediately if any of the following symptoms of overdose occur while taking fluticasone:

• Darkening of skin
• fainting
• loss of appetite
• mental depression
• unusual tiredness or weakness

Some side effects of fluticasone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Cough
• general aches and pains or general feeling of illness
• greenish-yellow mucus in the nose
• headache
• hoarseness or other voice changes
• runny, sore, or stuffy nose

• Bloody mucus or unexplained nosebleeds
• eye irritation
• fainting
• headache, severe and throbbing
• irregular or painful menstrual periods
• joint pain
• mouth irritation
• muscle soreness, sprain, or strain
• sneezing
• stomach pain

• Aggression
• agitation
• bruising
• itching
• restlessness
• weight gain

• Blurred vision
• decrease in height
• dry mouth
• flushed, dry skin
• fruit-like breath odor
• loss of voice
• pain in the back, ribs, arms or legs
• sweating
• trouble sitting still
• unexplained weight loss

Applies to fluticasone: compounding powder, inhalation aerosol, inhalation aerosol with adapter, inhalation powder, inhalation suspension

General

The most commonly reported adverse events have included headache, upper respiratory tract infection or inflammation, throat irritation, oral candidiasis, nausea and vomiting.[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 21%), nasal congestion/blockage
Common (1% to 10%): Cough, lower respiratory infection, sinusitis/sinus infection, hoarseness/dysphonia, bronchitis, pneumonia (in COPD patients), rhinitis
Rare (0.01% to 0.1%): Paradoxical bronchospasm
Very rare (less than 0.01%):
Frequency not reported: Epistaxis; ear, nose, throat, and tonsil signs and symptoms; ear, nose, and throat polyps
Postmarketing reports: Asthma exacerbation, wheeze[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Cutaneous hypersensitivity reactions
Rare (0.01% to 0.1%): Angioedema (mainly facial and oropharyngeal), respiratory symptoms (dyspnea and/or bronchospasm)
Very rare (less than 0.01%): Anaphylactic reactions[Ref]

Gastrointestinal

Very common (10% or more): Oropharyngeal candidiasis (up to 13.7%), throat irritation (up to 22%)
Common (1% to 10%): Nausea, vomiting, throat irritation, gastrointestinal discomfort and pain, viral gastrointestinal infection, toothache
Very rare (less than 0.01%): Dyspepsia
Frequency not reported: Abdominal discomfort, oral ulcerations, dental discomfort, oral erythema and rashes, month and tongue disorders
Postmarketing reports: Sore throat[Ref]

Endocrine

Rare (0.01% to 0.1%): Adrenal suppression
Frequency not reported: Cushing's syndrome, cushingoid features[Ref]

Ocular

Rare (0.01% to 0.1%): Cataract, glaucoma
Frequency not reported: Keratitis, conjunctivitis, blepharoconjunctivitis[Ref]

Psychiatric

Very rare (less than 0.01%): Anxiety, sleep disorders, behavioral changes including hyperactivity and irritability (predominantly in children), depression[Ref]

Musculoskeletal

Common (1% to 10%): Muscle injury, musculoskeletal pain, back pain
Rare (0.01% to 0.1%): Growth retardation (pediatrics), decrease in bone mineral density
Very rare (less than 0.01%): Arthralgia
Postmarketing reports: Osteoporosis[Ref]

Nervous system

Very common (10% or more): Headache (up to 14%)
Common (1% to 10%): Malaise and fatigue
Frequency not reported: Dizziness
Postmarketing reports: Aphonia[Ref]

Other

Common (1% to 10%): Malaise, fever
Frequency not reported: Allergic ear, nose, and throat disorders[Ref]

Dermatologic

Common (1% to 10%): Contusions, pruritus, skin rash
Frequency not reported: Photodermatitis, acne and folliculitis
Postmarketing reports: Ecchymosis[Ref]

Hematologic

Rare (0.01% to 0.1%): Systemic eosinophilic conditions[Ref]

Metabolic

Very rare (less than 0.01%): Hyperglycemia
Frequency not reported: Fluid disturbances, weight gain, appetite disturbances[Ref]

Cardiovascular

Frequency not reported: Palpitations
Postmarketing reports: Chest tightness[Ref]

Some side effects of ArmonAir RespiClick may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use is not recommended unless the benefit outweighs the risk to the fetus AU TGA pregnancy category: B3 US FDA pregnancy category: Not assigned Comments: -Pregnant women with asthma should be closely monitored to maintain optimal asthma control. -Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in utero; carefully observe neonates for signs and symptoms of hypoadrenalism.

Animal studies have shown teratogenicity typical of corticosteroids (decreased fetal body weight and/or skeletal variations) with subcutaneously administered doses of this drug. Rats dosed via inhalation have shown decreased fetal body weight, but teratogenicity was not observed. Epidemiologic data of other inhaled corticosteroids have not demonstrated these effects in animals to occur in humans. Women with poorly or moderately controlled asthma have shown an increased risk of pre-eclampsia, and there has been an increased incidence of prematurity, low birth weight, and small for gestational age events observed in their babies. There are no adequate and well controlled studies in pregnant women. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.