Aerospan

Name: Aerospan

Aerospan Overview

Aerospan is a prescription medication used to treat chronic asthma. Aerospan belongs to a group of drugs called corticosteroids, which help decrease inflammation in the nose.

Aerospan is available as an inhaler and is usually used twice a day.

Common side effects of flunisolide inhaler include headache and sore throat. 

Aerospan Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response.105

  • After a satisfactory response is obtained, decrease dosage gradually to the lowest possible dosage that maintains an adequate clinical response.105 Achieve the lowest effective dosage, particularly in children, since inhaled corticosteroids have the potential to affect growth.105 (See Pediatric Use under Cautions.)

Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids

  • When switching from systemic corticosteroids to orally inhaled flunisolide, initially administer oral inhalation concurrently with maintenance dosage of systemic corticosteroid.105 After at least 1 week, gradually withdraw the systemic corticosteroid.105

  • Decrements not to exceed 2.5 mg of prednisone (or its equivalent) every week in patients receiving the oral inhalation.105

  • During withdrawal of oral therapy, symptoms of systemic corticosteroid withdrawal may occur despite maintenance or even improvement in pulmonary function; continue oral inhalation therapy but monitor for objective signs of adrenal insufficiency.105

  • Death has occurred in some individuals in whom systemic corticosteroids were withdrawn too rapidly.105 (See Withdrawal of Systemic Corticosteroid Therapy under Cautions.)

  • If exacerbations of asthma occur after transfer to oral inhalation therapy, administer short courses of systemic corticosteroids, then taper dosage as symptoms subside.105 Supplemental systemic corticosteroid therapy may also be required during periods of stress.105

Administration

Oral Inhalation

Administer by oral inhalation using a metered-dose oral aerosol inhaler with internal spacer.105 Do not use this oral inhaler with external spacers or holding chambers.105

Administer twice daily.105

To prepare inhaler, pull purple actuator out from gray spacer; snap into place forming an “L” shape.105 Ensure that lines on the spacer match up with lines on the actuator.105

Before first use, and any time inhaler not used for >2 weeks, prime the inhaler with 2 test sprays by pressing down on the metal canister 2 times, holding for 1 second each time, with mouthpiece pointed away from face.105 Hold inhaler between thumb and index finger; shake immediately prior to use.105

Inhale and exhale normally through the mouth and place mouthpiece of inhaler into the mouth with lips closed firmly around it.105 Begin to inhale slowly through the mouth, then press canister down with index finger for at least 1 second.105 Continue to inhale through the mouth for 3 more seconds, then remove inhaler from the mouth, close the lips, and hold the breath for at least 10 seconds or as long as comfortable; then exhale and breathe normally.105

If additional inhalations are required, wait 20 seconds between inhalations, shake inhaler again, and repeat procedure.105

Following each treatment, rinse mouth thoroughly with water and expectorate to remove drug deposited in the oropharyngeal area.105 Brush teeth if desired.105

Appearance of white residue at mouthpiece opening and inside spacer is normal with use and does not affect inhaler performance.105 Cleaning inhaler is not necessary.105

Dosage

Available as flunisolide hemihydrate; dosage expressed in terms of flunisolide.105

Oral inhalation aerosol delivers 80 mcg of flunisolide from the actuator (mouthpiece) per metered spray.105 Commercially available aerosol inhaler delivers 60 metered sprays per 5.1-g canister or 120 metered sprays per 8.9-g canister.105

Carefully adjust dosage according to individual requirements and response; titrate to lowest effective dosage to minimize potential for adverse systemic effects.105

Pediatric Patients

Asthma Oral Inhalation

Children 6–11 years of age: Initially, 80 mcg (1 spray) twice daily.105 If required, dosage may be increased to 160 mcg (2 sprays) twice daily.105

Adolescents ≥12 years of age: Initially, 160 mcg (2 sprays) twice daily.105 If required, dosage may be increased to 320 mcg (4 sprays) twice daily.105

Adults

Asthma Oral Inhalation

Initially, 160 mcg (2 sprays) twice daily.105 If required, dosage may be increased to 320 mcg (4 sprays) twice daily.105

Prescribing Limits

Pediatric Patients

Oral Inhalation

Children 6–11 years of age: Maximum 160 mcg twice daily.105 Dosages >160 mcg (2 sprays) twice daily (320 mcg total daily dosage) not evaluated.105

Adolescents ≥12 years of age: Maximum 320 mcg twice daily.105 Dosages >320 mcg (4 sprays) twice daily (640 mcg total daily dosage) not evaluated.105

Adults

Oral Inhalation

Maximum 320 mcg twice daily.105 Dosages >320 mcg (4 sprays) twice daily (640 mcg total daily dosage) not evaluated.105

Special Populations

No special population dosage recommendations at this time.105

Aerospan Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral inhalation.105 Oral bioavailability <7%.105

Onset

2–4 weeks of continuous therapy may be required for optimum effectiveness.105

Distribution

Extent

Distribution into milk unknown, but other corticosteroids distributed into milk.105

Elimination

Metabolism

Rapidly and extensively metabolized in the liver to 6β-hydroxyflunisolide.105 Metabolite has >200 times less corticosteroid potency than flunisolide.105 Metabolism thought to occur via CYP isoenzymes (primarily CYP3A4).105

Elimination Route

Following oral inhalation, <1% of dose excreted in urine.105

Half-life

Approximately 1.3–1.7 hours.105

Commonly used brand name(s)

In the U.S.

  • Aerobid
  • Aerobid-M
  • Aerospan

Available Dosage Forms:

  • Aerosol Powder
  • Aerosol Liquid

Therapeutic Class: Anti-Inflammatory

Pharmacologic Class: Adrenal Glucocorticoid

What are some other side effects of Aerospan?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Throat irritation.
  • Nose stuffiness.
  • Runny nose.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Aerospan - 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.

The precise mechanism of corticosteroid action is unknown. Airway inflammation 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 (e.g. mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Pharmacodynamics

Dose finding for Aerospan was based on comparability of systemic exposure to flunisolide CFC inhalation aerosol. The effect of flunisolide CFC inhalation aerosol and Aerospan 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. 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 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 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 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 320 mcg. The mean peak plasma concentrations of flunisolide from the flunisolide CFC inhalation aerosol 1000 mcg and Aerospan 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 6 β -OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and Aerospan 320 mcg 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 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 Studies (14)]. 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 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 had normal morning serum cortisol levels at the end of study. For pediatric patients treated with the Aerospan, 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 had normal morning serum cortisol levels (≥ 5 mcg/dL) after 12 or 52 weeks of treatment, respectively. For patients treated with Aerospan, 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.

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. 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, 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.

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, and 0.71 mcg/mL after multiple doses of Aerospan.

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 in the dose range of 160 mcg to 320 mcg.

Disposition and Elimination

Twice daily inhalation administration of flunisolide 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 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. Formal pharmacokinetic studies using flunisolide were not carried out in any other special populations.

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