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Why Alvesco?

When considering an ICS to choose, here are some characteristics of Alvesco® (ciclesonide) Inhalation Aerosol to consider.

Alvesco Inhalation Aerosol is an ICS with a small particle size (1-2 μm)*

This enables Alvesco to reach areas of chronic inflammation in both the large and small airways

  • Aerosol particle size is a key factor in both the extent of lung deposition and the regional distribution within the lung.
  • ICS particle sizes <2 μm in diameter are more likely to reach the small airways – where they can have a targeted effect without as many local adverse effects in the throat and oral cavities as inhalers with larger particle sizes.

*Particle size does not necessarily correlate with clinical efficacy

Due to its small particle size, 52% of the delivered Alvesco Inhalation Aerosol dose was deposited in the lungs†,§

Based on 2-dimensional (2D) scintigraphy
§Scintigraphy is not a valid surrogate for clinical effect

Study Design: Single-dose, open-label, nonrandomized study performed in 12 patients with mild asthma. Patients received a single dose of 99mtechnetium (Tc)-ciclesonide HFA 320 mcg ex-actuator (400 mcg ex-valve). The primary study variable was the total and regional distribution of ciclesonide in the lungs, oropharynx, and exhaled air.

Within the lung, most of the Alvesco that was deposited was found in the small airways and alveoli.

The relationship of lung deposition to clinical efficacy is unknown.

Study Design: Single-dose, open-label, nonrandomized study performed in 12 patients with mild asthma. Patients received a single dose of 99mtechnetium (Tc)-ciclesonide HFA 320 mcg ex-actuator (400 mcg ex-valve). The primary study variable was the total and regional distribution of ciclesonide in the lungs, oropharynx, and exhaled air.

Alvesco Inhalation Aerosol offers a low systemic exposure and favorable pharmacokinetic profile

Systemic exposure is defined as the combination of:

  • the dose delivered to the lung (pulmonary availability)
  • the dose delivered to the GI tract (oral bioavailability)

One goal of ICS treatment is to have low oral bioavailability in order to reduce the risk of systemic side effects.

Ciclesonide is a prodrug that is metabolized to des-ciclesonide after oral inhalation.

  • Using a prodrug rather than one with full therapeutic effect may reduce the risk of adverse effects in the oral cavity and throat.
  • Des-ciclesonide has anti-inflammatory activity with an affinity for steroid receptors that is 120 times greater than that of the parent compound and 12 times greater than dexamethasone.
  • Ciclesonide and des-ciclesonide have negligible oral bioavailability (both <1%) due to low gastrointestinal absorption and high first-pass metabolism.
  • Most of the ciclesonide and des-ciclesonide remain bound to human plasma proteins (average ≥99% each), with ≤1% of unbound drug detected in the systemic circulation.

Ciclesonide demonstrates efficacy in all asthma severities with low systemic effects, in part due to its pharmacokinetic and pharmacodynamic properties.

The clinical significance of these findings is unknown.

References:

  1. Alvesco® Inhalation Aerosol Prescribing Information. Marlborough, United Kingdom: Sunovion Pharmaceuticals Inc.; January 2013.
  2. Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol. 2009;124:S88-S93.
  3. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol. 2002;109 (Suppl 2):S447-S460.
  4. Newman S, Salmon A, Nave R, Drollman A. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respiratory Medicine. 2006;100:375-384.
  5. Rohatagi S, Derendorf H, Zech K. Risk-Benefit Value of Inhaled Corticosteroids: A Pharmacokinetic/Pharmacodynamic Perspective. Chest. 2003;123:430S-431S.

Clinical Studies

The efficacy of Alvesco was evaluated in 6 randomized double-blind, placebo-controlled, parallel-group clinical trials in adult and adolescent patients 12 years of age and older with mild persistent to severe persistent asthma.

Primary Efficacy Endpoints:

  • In 4 of the 6 trials, the primary efficacy endpoint was the mean change from baseline in pre-dose FEV1 at endpoint (last observation)
  • In one trial, the primary endpoint was the change from baseline in the average of the pre-dose FEV1 at Weeks 12 and 16
  • In one trial, the primary efficacy endpoint was reduction of oral corticosteroid use

Secondary efficacy endpoints were asthma symptoms, use of albuterol for rescue, AM PEF, nighttime awakenings, and withdrawal due to asthma worsening.

Alvesco Inhalation Aerosol significantly improved pre-dose FEV1 at 16 weeks, compared to placebo, in patients new to ICS therapy

In that same study in patients new to ICS therapy, Alvesco Inhalation Aerosol reduced nighttime awakenings by 66% from baseline

Alvesco (ciclesonide) Inhalation Aerosol reduced nighttime awakenings by 66% from baseline in patients with mild-to-moderate asthma previously treated with a bronchodilator alone, vs a 48% reduction with placebo. LS mean reduction of 0.37 nighttime awakenings with Alvesco, baseline = 0.56 vs 0.22 with placebo, baseline = 0.46 (P=0.0036 vs placebo)

Study Design: Randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy of Alvesco, including 80 mcg twice daily, administered for 16 weeks in 708 patients ≥12 years of age with mild-to-moderate persistent asthma not currently taking ICS therapy. The primary endpoint was LS mean change from baseline in FEV1 to the average of week 12 and week 16, which was significantly improved vs placebo. Daily albuterol use and total asthma symptom score were key secondary endpoints, and nighttime awakenings was an additional secondary endpoint. (Alvesco 80 mcg bid, n=170; placebo, n=177).

In a trial of patients previously maintained on other ICSs, Alvesco Inhalation Aerosol maintained or improved pulmonary function (FEV1) in patients switched from other ICSs or low-dose ICS/LABA combination

References:

  1. Alvesco® Inhalation Aerosol Prescribing Information. Marlborough, United Kingdom: Sunovion Pharmaceuticals Inc.; January 2013.
  2. Berger WE, Kerwin E, Bernstein DI, Pedinoff A, Bensch G, Karafilidis J. Efficacy and safety evaluation of ciclesonide in subjects with mild-to-moderate asthma not currently using inhaled corticosteroids. Allergy Asthma Proc. 2009;30(3):304-314.
  3. Meltzer EO, Korenblat PE, Weinstein SF, Noonan M, Karafilidis J. Efficacy and safety evaluation of ciclesonide in mild-to-moderate persistent asthma previously treated with inhaled corticosteroids. Allergy Asthma Proc. 2009;30(3):293-303.

Safety Information

Alvesco Inhalation Aerosol was studied in 4 clinical trials with a total of 624 patients ages 12 years and older (359 females and 265 males) with asthma of varying severity.

  • Patients were treated with Alvesco 80 mcg, 160 mcg, or 320 mcg twice daily for 12 to 16 weeks
  • Patients had previously used either controller therapy (usually ICS) or reliever therapy (bronchodilator therapy alone).

In these trials, the most common adverse reactions (≥3% and more frequent than with placebo) were:

  • Headache
  • Nasopharyngitis
  • Sinusitis
  • Pharyngolaryngeal pain
  • Upper respiratory infection
  • Arthralgia
  • Nasal congestion
  • Pain in extremity
  • Back pain

Alvesco was studied in another 12-week trial in asthma patients 12 years of age and older who had previously required oral corticosteroids (average daily dose of oral prednisone of 12 mg/day)

  • Alvesco 320 mcg twice daily (n = 47) and 640 mcg twice daily (n = 49) were compared with placebo (n = 45) for the frequency of reported adverse reactions.

The following adverse reactions occurred at an incidence of ≥3% in the Alvesco-treated patients and were more frequent than with placebo:

  • Sinusitis
  • Hoarseness
  • Oral candidiasis
  • Influenza
  • Pneumonia
  • Nasopharyngitis
  • Arthralgia
  • Back pain
  • Musculoskeletal chest pain
  • Headache
  • Urticarial
  • Dizziness
  • Gastroenteritis
  • Face edema
  • Fatigue
  • Conjunctivitis

Use in Specific Populations

  • Pregnancy — There are no adequate and well-controlled studies in pregnant women. Alvesco should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
  • Nursing mothers — It is not known if ciclesonide is secreted in human milk. However, other corticosteroids are excreted in human milk. Caution should be used when Alvesco is administered to nursing women.
  • Pediatric use — The safety and effectiveness of Alvesco in children under 12 years of age have not been established.
  • Geriatric use — Clinical studies of Alvesco did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Reference:

Alvesco® Inhalation Aerosol Prescribing Information. Marlborough, United Kingdom: Sunovion Pharmaceuticals Inc.; January 2013.