AEROSPAN™
(flunisolide HFA, 80 mcg)
Inhalation Aerosol

For Oral Inhalation Only

Rx Only

Flunisolide hemihydrate, the active component of AEROSPAN^TM (flunisolide HFA, 80 mcg) Inhalation Aerosol, is a corticosteroid having the chemical name 6α-Fluoro-11β, 16α, 17, 21 –tetrahydroxylpregna-1, 4-diene-3, 20-dione cyclic-16, 17-acetal with acetone, hemihydrate and the following chemical structure:

Flunisolide hemihydrate is a white to creamy white crystalline powder with a molecular weight of 443.51 and an empirical formula of C₂₄H₃₁O₆F •½ H₂O. It is soluble in acetone, ethyl alcohol and HFA-134a and practically insoluble in water.

AEROSPAN Inhalation Aerosol is a pressurized, metered-dose inhaler unit intended for oral inhalation only. The inhaler unit consists of a metal canister, a purple actuator, and a gray spacer. Each unit contains a 0.24 % w/w solution of flunisolide hemihydrate in 10:90 w/w ethanol:1,1,1,2-tetrafluoroethane (HFA 134a). After priming, each actuation delivers 139 mcg of flunisolide hemihydrate in 58 mg of solution from the canister valve and 80 mcg of flunisolide hemihydrate (equivalent to 78 mcg flunisolide) from the spacer at a flow rate of 30 L/min for 4 seconds.

Using an in-vitro method at a fixed volume of 2 L, each actuation at the beginning of canister span delivers from the spacer 76 mcg (95% of the label claim) at a flow rate of 30 L/min, 61 mcg (76% of the label claim) at a flow rate of 20 L/min, 85 mcg (106% of the label claim) at a flow rate of 40 L/min, and 96 mcg (120% of the label claim) at a flow rate of 60 L/min. The actual amount of drug delivered to the lung may depend upon patient factors, such as timing and coordination between the actuation and inspiration and the strength and duration of the inspiration. Data show that both the one- and two-actuation doses are depleted by 75% or more after waiting one second between actuation and inhalation.

The 5.1-g net weight canister provides 60 metered actuations and the 8.9-g net weight canister provides 120 metered actuations.

AEROSPAN Inhalation Aerosol should be primed before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler has not been used for more than 2 weeks, the inhaler should be primed again by releasing 2 test sprays into the air away from the face.

This product does not contain chlorofluorocarbon (CFC).

All the data described below is based on studies conducted in subjects 18 to 51 years of age.

The efficacy of AEROSPAN Inhalation Aerosol has been studied in two double-blind, parallel, placebo-and active-controlled clinical studies of 12 weeks duration involving more than 1250 patients. In patients 12 to 78 years of age, efficacy was evaluated in patients previously treated with inhaled corticosteroids. In patients 6 to 11 years of age, efficacy was evaluated in patients previously treated with bronchodilators alone or inhaled corticosteroids. Both studies had a 2-week run-in period followed by a 12-week randomized treatment period. During the run-in period all patients received flunisolide CFC inhalation aerosol 500 mcg twice daily. Patients were then randomized to double-blind treatment with different doses of AEROSPAN Inhalation Aerosol or flunisolide CFC inhalation aerosol and monitored for lung function changes to see if they maintained, improved, or lost stability. Baseline was assessed at the end of the run-in period. The primary endpoint was the change from baseline in percent predicted FEV₁ after 12 weeks treatment.

Efficacy was evaluated in 669 asthma patients, age 12 to 78 years of age, including 88 patients 12-17 years of age and 581 patients 18 years and older. Mean FEV₁ at screening was 2.44 L and mean FEV₁ at baseline was 2.72 L following the 2-week run-in period. Patients were randomized to AEROSPAN Inhalation Aerosol 80 mcg, 160 mcg or 320 mcg twice daily, flunisolide CFC inhalation aerosol 250 mcg, 500 mcg, or 1000 mcg twice daily, or placebo. Change from baseline in percent predicted FEV₁ over 12 weeks treatment demonstrated that placebo patients deteriorated 4.3% from baseline after 12 weeks of treatment, whereas patients treated with AEROSPAN Inhalation Aerosol 160 mcg or 320 mcg twice daily maintained FEV₁ over the course of the study. Results for the comparison to placebo were statistically significant for the 160 and 320 mcg twice daily AEROSPAN Inhalation Aerosol doses (see Figure below), but not for the 80 mcg dose. Secondary endpoints of AM peak expiratory flow rate, AM and PM asthma symptoms, nocturnal awakenings requiring a β₂ agonist, and as needed use of inhaled β₂ agonists showed differences from baseline favoring AEROSPAN Inhalation Aerosol over placebo. AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol gave comparable results.

The study enrolled 583 asthma patients, 4 to 11 years of age, although the primary efficacy parameter was evaluated only in the population of 513 patients 6 to 11 years of age. In these patients, the mean FEV₁ at screening was 81.2% predicted, and the mean FEV₁ at baseline following a two week run-in period was 87.5% predicted. Patients were randomized to AEROSPAN Inhalation Aerosol 80 mcg or 160 mcg twice daily, flunisolide CFC inhalation aerosol 250 mcg or 500 mcg twice daily, or placebo. Change from baseline in percent predicted FEV₁ over 12 weeks in patients 6 years of age and older demonstrated that placebo patients deteriorated 4.0% from baseline after 12 weeks of treatment, whereas patients treated with AEROSPAN Inhalation Aerosol 80 mcg or 160 mcg twice daily maintained FEV₁ over the course of the study. Results for the comparison to placebo were statistically significant for the 80 mcg and 160 mcg doses doses of AEROSPAN Inhalation Aerosol, but there was no added benefit for the 160 mcg BID dose over the 80 mcg BID dose (see Figure below). AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol gave comparable results in patients 6 years of age and older.

AEROSPAN Inhalation Aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 6 years of age and older. AEROSPAN Inhalation Aerosol is also indicated for asthma patients requiring oral corticosteroid therapy, where adding AEROSPAN Inhalation Aerosol may reduce or eliminate the need for oral corticosteroids.

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

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

Hypersensitivity to flunisolide or any of the ingredients of this preparation contraindicates the use of AEROSPAN Inhalation Aerosol.

Particular care is needed in patients who are transferred from systemically active corticosteroids to AEROSPAN Inhalation Aerosol because deaths due to adrenal insufficiency have occurred in asthmatic patients 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 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 infections (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although AEROSPAN Inhalation Aerosol may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than the physiologic 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 asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to AEROSPAN Inhalation Aerosol. 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 AEROSPAN Inhalation Aerosol may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g. rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on 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 affects 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.

AEROSPAN Inhalation Aerosol is not a bronchodilator and is not indicated for rapid relief of bronchospasm.

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

Patients should be instructed to contact their physician immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with AEROSPAN Inhalation Aerosol. During such episodes, patients may require therapy with systemic corticosteroids.

Patients being treated with AEROSPAN Inhalation Aerosol should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or beneficial effects. See Patient Information and illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol for supplemental information.

• Patients should be advised that the effectiveness of AEROSPAN Inhalation Aerosol depends on its regular use and on the proper inhalation-administering technique (see Patient Information and illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol).
• It is important that patients are instructed to begin inhalation immediately prior to actuation. A delay between actuation and inhalation will lead to inadequate drug delivery from the spacer to the patient. Data show that doses are depleted by 75% or more after waiting one second between actuation and inhalation.
• Two to 4 weeks may pass before maximum benefit is obtained after starting AEROSPAN Inhalation Aerosol. If symptoms do not improve, or if the condition worsens, patients should not increase dosage, but should contact the physician immediately.
• Patients should be advised that AEROSPAN Inhalation Aerosol is not a bronchodilator and is not intended for relief of acute asthma symptoms. Patients should be made aware the AEROSPAN Inhalation Aerosol is a controller therapy for asthma, and that it should be taken regularly even if they are asymptomatic.
• Patients should be instructed to prime the inhaler by releasing two test sprays into the air away from the face before first use of AEROSPAN Inhalation Aerosol, and when the inhaler has not been used for more than 2 weeks.
• Patients should be instructed that they will receive a new AEROSPAN Inhalation Aerosol unit each time they refill their prescription. Patients should be advised to discard the whole unit including the metal canister, purple actuator, and gray spacer after the labeled number of actuations have been used. The appearance of a white ring on the orifice of the actuator is normal. The performance of AEROSPAN Inhalation Aerosol is not affected by this residue. No cleaning is required. The gray spacer should not be removed from the purple actuator.
• The gray spacer should not be bitten or chewed.
• Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that they may need supplemental systemic corticosteroids during periods of stress or a severe asthma attack that is not responsive to bronchodilators.
• Patients who are on immunosuppressant doses of corticosteroids or other immunosuppressant drugs should be warned to avoid exposure to chickenpox or measles. If they are exposed, patients should seek medical advice without delay.
• Patients should be advised that the use of AEROSPAN Inhalation Aerosol should not be stopped abruptly.
• Women should consult with their doctor if they are pregnant or intend on becoming pregnant, or if they are breast-feeding a baby.
• Patients should consult with their doctor if they are allergic to any orally-inhaled corticosteroid.
• Patients should inform their doctor of other medications they are taking as this medication may not be suitable in some circumstances, and the doctor may wish to use a different medicine.

The following table shows the adverse reactions that were reported in patients previously receiving bronchodilators and/or orally inhaled corticosteroids in two double-blind, placebo-controlled US clinical studies, in which 519 adult and pediatric patients age 4-78 years (279 males and 240 females) were treated with the AEROSPAN Inhalation Aerosol (80 mcg to 320 mcg twice daily for 12 weeks) or placebo. The mean duration of exposure was 76.7, 78.2, 80.5, and 69.4 days for AEROSPAN Inhalation Aerosol 80 mcg, 160 mcg, 320 mcg, and placebo, all dosed twice daily, respectively. The table includes all events (whether considered drug-related or non-drug-related by the investigators) that occurred at a rate of >3% in any AEROSPAN Inhalation Aerosol group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for AEROSPAN Inhalation Aerosol patients should be taken into account, compared with placebo-treated patients.

The following other adverse events occurred in patients in these clinical studies using AEROSPAN Inhalation Aerosol with an incidence of 1 to 3% and were more common in AEROSPAN Inhalation Aerosol than in the placebo group.

•  Body As A Whole: abdominal pain, chest pain, infection, neck pain
•  Digestive System: diarrhea, gastroenteritis, nausea, oral moniliasis
•  Metabolic And Nutritional Disorders: edema
•  Musculoskeletal System: myalgia
•  Nervous System: dizziness, insomnia, migraine
•  Respiratory System: bronchitis, laryngitis, voice alteration
•  Skin And Appendages: erythema multiforme
•  Special Senses: conjunctivitis, ear pain, taste perversion
•  Urogenital System: dysmenorrhea, vaginitis

Cases of growth suppression have been reported for orally inhaled corticosteroids (see PRECAUTIONS, Pediatric Use section.)

Two 52-week open label safety studies of AEROSPAN Inhalation Aerosol were conducted in 162 asthma patients 12 to 60 years of age and in 152 asthma patients 4 to 11 years of age. The adverse event profile exhibited in these studies was similar to that seen in the two 12-week studies.

The following additional adverse events were derived from clinical studies conducted with flunisolide CFC inhalation aerosol with a frequency of ≥1% and not described above:

•  Body as a Whole: flu, decreased appetite, chills, increased appetite, weight gain, malaise, peripheral edema, sweating, weakness
•  Gastrointestinal System: upset stomach, heartburn, constipation, gas, abdominal fullness
•  Cardiovascular System: palpitations, hypertension, tachycardia
•  Nervous System: headache, irritability, shakiness, anxiety, depression, faintness, fatigue, hyperactivity, hypoactivity, moodiness, numbness, vertigo,
•  Respiratory System: cold symptoms, nasal congestion, upper respiratory tract infection, chest congestion, hoarseness, runny nose, sinus congestion, sinus drainage, sinus infection, sneezing, sputum, wheezing, chest tightness, bronchospasm, dyspnea, head stuffiness, nasal irritation, pleurisy, pneumonia, sinus discomfort
•  Skin and Appendages: eczema, pruritus, acne, urticaria
•  Special Senses: loss of smell, loss of taste, ear infection, blurred vision, eye discomfort, eye infection
•  Hemic and Lymph: capillary fragility, enlarged lymph nodes
•  Mouth and Throat: sore throat, dry throat, glossitis, mouth irritation, phlegm, throat irritation

Flunisolide hemihydrate infused intravenously at doses up to 4000 mcg/kg in mice, rats and dogs (approximately 25, 50 and 170 times, respectively, the maximum recommended daily inhalation dose in adults and approximately 30, 60 and 200 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m² basis) produced no mortality.

In a double-blind, placebo-controlled study, 18 mg of flunisolide hemihydrate was administered via the CFC formulation over a three-hour period (nine times the maximum labeled daily dose) in 94 patients with acute asthma, and no clinically deleterious effects were observed.

AEROSPAN Inhalation Aerosol should be administered by the orally inhaled route in asthmatic patients aged 6 years and older. The onset and degree of symptom relief with orally inhaled corticosteroids is usually apparent within 2-4 weeks after the start of treatment, and varies with individual patients. The time to improvement in asthma control was not evaluated in clinical studies with AEROSPAN Inhalation Aerosol. For patients who do not respond adequately to the starting dose after 3-4 weeks of therapy, higher doses may provide additional asthma control. The safety and efficacy of AEROSPAN Inhalation Aerosol when administered in excess of recommended doses have not been established.

Note: In all patients it is desirable to titrate to the lowest effective dose once asthma stability is achieved.

AEROSPAN Inhalation Aerosol is supplied as a pressurized lined aluminum canister in boxes of one. Each canister is supplied with a two-piece plastic purple actuator and gray spacer assembly, and tear-off patient's instructions, including a Patient Information and an illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol.

The following canister sizes are available: 8.9 g net weight, providing 120 metered actuations (trade size, NDC 0456-5550-12); 5.1 g net weight providing 60 metered actuations (hospital size, NDC 0456-5550-63); 5.1 g net weight providing 60 metered actuations (professional sample, NDC 0456-5550-06).

When not in use, keep AEROSPAN Inhalation Aerosol out of reach of children. Pediatric patients should only administer AEROSPAN Inhalation Aerosol under adult supervision.

The plastic purple actuator and gray spacer assembly supplied as part of AEROSPAN Inhalation Aerosol should not be used with any other product canisters; and the actuator from other products should not be used with an AEROSPAN Inhalation Aerosol canister. Do not separate the purple actuator from the gray spacer. Do not use this product with any external spacer devices.

The labeled amount of medication in each actuation cannot be assured after 120 metered actuations (or 60 metered actuations in the hospital and sample size canisters), even though the canister is not completely empty and will continue to operate. The inhaler (canister plus actuator) should be discarded when the labeled number of actuations have been used. Never immerse the canister into water to determine the amount of formulation remaining in the canister (“float test”).

Store at 25 °C (77 °F); excursions permitted to 15 – 30 °C (59 – 86 °F) [see USP Controlled Room Temperature]. For best results, the canister should be at room temperature before use.