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Aerospan (Flunisolide Hemihydrate Inhalation) - Description and Clinical Pharmacology

 
 



AEROSPAN™
(flunisolide HFA, 80 mcg)
Inhalation Aerosol

For Oral Inhalation Only

Rx Only

DESCRIPTION

Flunisolide hemihydrate, the active component of AEROSPANTM (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 content 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).

CLINICAL PHARMACOLOGY

Mechanism of Action: Flunisolide has demonstrated marked anti-inflammatory activity in classical test systems. It is a corticosteroid that is several hundred times more potent than cortisol in animal anti-inflammatory assays, and several hundred times more potent than dexamethasone in anti-inflammatory effect as determined by the McKenzie skin blanching test. The clinical significance of these findings is unknown.

Airway inflammation in both large and small airways is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators. It is presumed that these anti-inflammatory actions play an important role in the efficacy of flunisolide in controlling symptoms and improving lung function in asthma. Inhaled flunisolide probably acts topically at the site of deposition in the bronchial tree after inhalation.

Pharmacokinetics:

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

Absorption: Flunisolide is rapidly absorbed after oral inhalation. Mean values for the time to maximum concentration, Tmax, of flunisolide range from 0.09 to 0.17 hr after a single 320 mcg dose of AEROSPAN Inhalation Aerosol. The corresponding mean values for the maximum concentration, Cmax, of flunisolide vary from 1.9 to 3.3 ng/mL. Oral bioavailability is less than 7%. Over the dose range of 80 mcg to 320 mcg of AEROSPAN Inhalation Aerosol, values for Cmax increase proportionately with dose after single as well as multiple dose administration.

Distribution: Flunisolide is extensively distributed in the body, with mean values for apparent volume of distribution ranging from 170 to 350 L after a single 320 mcg dose of AEROSPAN Inhalation Aerosol.

Metabolism: Flunisolide is rapidly and extensively converted to 6ß-OH flunisolide and to water-soluble conjugates during the first pass through the liver. Conversion to 6ß-OH flunisolide, the only circulating metabolite detected in man, is thought to occur via the cytochrome P450 enzyme system, particularly the enzyme CYP3A4. 6ß-OH flunisolide has a low corticosteroid potency (ten times less potent than cortisol and more than 200 times less potent than flunisolide). Maximum levels of 6ß-OH flunisolide were 0.66 mcg/mL after a single 320 mcg dose of AEROSPAN Inhalation Aerosol, and 0.71 mcg/mL after multiple doses of AEROSPAN Inhalation Aerosol.

Excretion: Urinary excretion of flunisolide is low. Less than 1% of the administered dose of flunisolide is recovered in urine after inhalation. The half-life values for 6ß-OH flunisolide range from 3.1 to 5.1 hrs after administration of AEROSPAN Inhalation Aerosol in the dose range of 160 mcg to 320 mcg.

Disposition and Elimination: Twice daily inhalation administration of flunisolide hemihydrate for up to 14 days did not result in appreciable accumulation of flunisolide. Upon multiple dosing with 160 mcg and 320 mcg, the Cmax values were 1.0 ng/mL and 2.1 ng/mL, respectively. The corresponding AUC0-12hr values were 1.2 ng.hr/mL and 2.5 ng.hr/mL.

Flunisolide is rapidly cleared from the body, independent of route of administration or dose administered. Flunisolide is not detectable in plasma twelve hours post-dose. After administration of 320 mcg of AEROSPAN Inhalation Aerosol the elimination half-life ranges from 1.3 to 1.7 hours. After a single 320 mcg dose, mean oral clearance values, not adjusted for bioavailability, range from 83 to 167 L/hr.

Special Populations: There were no gender differences for flunisolide after single and multiple dose administration of the AEROSPAN Inhalation Aerosol. Formal pharmacokinetic studies using flunisolide were not carried out in any other special populations.

Pharmacodynamics: Dose finding for AEROSPAN Inhalation Aerosol was based on comparability of systemic exposure to flunisolide CFC inhalation aerosol. The effect of flunisolide CFC inhalation aerosol and AEROSPAN Inhalation Aerosol on pharmacokinetics and 12-hour plasma cortisol levels was investigated in two studies. In both studies, the Cmax and AUC of flunisolide, 6β-OH flunisolide, and 12-hour plasma cortisol measurements were comparable for 1000 mcg of flunisolide CFC inhalation aerosol and 320 mcg of AEROSPAN Inhalation Aerosol. The first was a parallel arm study in 31 subjects. Pharmacokinetics and plasma cortisol levels were determined after single and multiple doses of flunisolide CFC inhalation aerosol 1000 μg and AEROSPAN Inhalation Aerosol 160 μg or 320 μg administered twice daily for 13.5 days. At steady state, flunisolide mean peak plasma concentrations from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.6 ng/mL and 3.4 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 5.7 ng.hr/mL and 4.7 ng.hr/mL, respectively. At steady state, the mean peak plasma concentrations of 6β-OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 0.9 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 3.8 ng.hr/mL and 1.1 ng.hr/mL, respectively. The second was a crossover study in 11 subjects after single doses of flunisolide CFC inhalation aerosol 1000 mcg or AEROSPAN Inhalation Aerosol 320 mcg. The mean peak plasma concentrations of flunisolide from the flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.5 ng/mL and 3.3 ng/mL, respectively. The corresponding mean AUC values were 5.1 ng.hr/mL and 5.8 ng.hr/mL, respectively. The mean peak plasma concentrations of 6β-OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 μg were found to be 0.8 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values were 3.8 ng.hr/mL and 2.3 ng.hr/mL, respectively.

Controlled clinical studies with flunisolide CFC inhalation aerosol included over 500 treated asthma patients, among them 150 children aged 6 years and older. Open label studies of two years or more duration included more than 120 treated patients. No significant adrenal suppression attributed to flunisolide was seen in these studies.

The potential effects of AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 2 placebo- and active-controlled studies and 2 active-controlled, open label, long-term studies (see CLINICAL TRIALS). In the placebo-controlled studies, the ability to increase cortisol production in response to stress was assessed by the 60 minute cosyntropin (ACTH) stimulation test. For adult and adolescent patients treated with AEROSPAN Inhalation Aerosol 80 mcg, 160 mcg, 320 mcg, or placebo twice daily for 12 weeks, 92% (22/24), 93% (26/28), 93% (26/28), and 92% (22/24) of patients, normal at baseline, respectively, continued to have a normal stimulated cortisol response (peak cortisol ≥18 mcg/dL and an increase in plasma cortisol ≥7 mcg/dL within 60 minutes after cosyntropin injection) at trial's end. All patients had peak cortisol levels ≥ 18mcg/dL. There was no significant suppression of 24 hour urinary cortisol, and 100% (96/96) of patients treated with AEROSPAN Inhalation Aerosol had normal morning serum cortisol levels at the end of study. For pediatric patients treated with the AEROSPAN Inhalation Aerosol, 80 mcg and 160 mcg or placebo twice daily for 12 weeks, 91% (31/34), 97% (28/29), and 89% (24/27) of patients, respectively, continued to have a normal stimulated cortisol response (as defined above) at trial's end. No suppression of 24-hour urinary cortisol was noted. In these studies, comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol.

In the active-controlled, open label, long-term studies, 99.4% (161/162) of adult and adolescent patients and 98.4% (126/128) pediatric patients treated with AEROSPAN Inhalation Aerosol had normal morning serum cortisol levels (≥ 5 mcg/dL) after 12 or 52 weeks of treatment, respectively. For patients treated with AEROSPAN Inhalation Aerosol, 92.5% (99/107) continued to have a normal stimulated plasma cortisol response to cosyntropin at trial's end with all having peak cortisol levels ≥ 18mcg/dL. In these studies, no suppression of 24-hour urinary cortisol was noted, and comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol.

CLINICAL TRIALS

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.

Adult and Adolescent Patients with Asthma

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.

Pediatric Patients with Asthma

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.

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