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 antiinflammatory 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.

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, T_max, 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, C_max, 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 C_max 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 6b -OH flunisolide and to water-soluble conjugates during the first pass through the liver. Conversion to 6b -OH flunisolide, the only circulating metabolite detected in man, is thought to occur via the cytochrome P450 enzyme system, particularly the enzyme CYP3A4. 6b-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 6b -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 6b -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 C_max values were 1.0 ng/mL and 2.1 ng/mL, respectively. The corresponding AUC_0-12hr 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.

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