General Information

Alvesco is a non-halogenated glucocorticoid prodrug delivered via a metered dose inhaler.

Alvesco is specifically indicated for the maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients 12 years of age and older.

Alvesco is supplied as a 80 mcg or 160 mcg dose designed for oral inhalation. The recommended initial dose of the drug is as follows:

Patients over 12 years who previously received bronchodilators alone:
Recommended starting dose: 80 mcg twice daily.
Highest recommended dose: 160 mcg twice daily.

Patients over 12 years who previously received inhaled corticosteroids:
Recommended starting dose: 80 mcg twice daily.
Highest recommended dose: 320 mcg twice daily.

Patients over 12 years who received oral corticosteroids:
Recommended starting dose: 320 mcg twice daily.
Highest recommended dose: 320 mcg twice daily.

Clinical Results

FDA Approval
FDA approval of Alvesco was based on the results of six randomized double-blind, placebo controlled, parallel-group clinical trials in adult and adolescent subjects 12 years of age and older with mild persistent to severe persistent asthma. The primary efficacy endpoint in four of the six trials was the mean change from baseline in pre-dose FEV1 at endpoint (last observation). FEV1 was measured prior to the morning dose of study medication (at the end of the 24-hour dosing interval for once daily administration, and at the end of the 12-hour dosing interval for twice daily administration). In one of the six trials, the primary endpoint was the change from baseline in the average of the pre-dose FEV1 at Weeks 12 and 16, and in another trial, reduction of oral corticosteroid use was the primary efficacy endpoint. The results are as follows:

Patients Previously Maintained on Bronchodilators Alone
This randomized, double-blind, placebo controlled trial enrolled 691 subjects with a mean baseline percent predicted FEV1 of 72%. The subjects Alvesco 160 mcg once daily in the morning for 16 weeks, Alvesco 80 mcg twice daily for 16 weeks, or Alvesco 80 mcg twice daily for 4 weeks followed by Alvesco 160 mcg once daily in the morning for 12 weeks or placebo for 16 weeks. All Alvesco doses showed statistically significant improvement over placebo at week 16 in AM pre-dose FEV1. However, the increase in the Alvesco 80 mcg twice daily arm was significantly greater than that observed in the Alvesco 160 mcg administered once daily arm. Compared to placebo, increases in AM pre-dose FEV1 were 0.12 L or 5.0 % for Alvesco 160 mcg once daily, 0.24 L or 10.4 % for Alvesco 80 mcg twice daily, 0.13 L or 5.0 % for Alvesco 80 mcg twice daily for 4 weeks followed by Alvesco 160 mcg once daily. Other measures of asthma control, AM PEF and need for rescue albuterol also improved in all the Alvesco treatment groups compared to placebo but the improvement was greatest with the Alvesco 80 mcg twice daily treatment arm.

Patients Previously Maintained on Inhaled Corticosteroids
Nycomed conducted two randomized-double blind placebo controlled trials each of 12-weeks treatment duration. In the first trial subjects with mean baseline percent predicted FEV1 of 79% received Alvesco 160 mcg once daily in the morning, ALVESCO 80 mcg twice daily or placebo. Statistically significantly more increases in AM pre-dose FEV1 compared to placebo were seen at 12 weeks for Alvesco 160 mcg once daily (0.14 L or 5.7%) and Alvesco 80 mcg twice daily (0.19 L or 7.5%). Asthma symptoms scores, AM PEF, and decreased need for rescue albuterol remained relatively stable in the Alvesco treatment groups compared to slight worsening in the placebo group.

In the second trial, 257 subjects with mean baseline percent predicted FEV1 of 54% were treated with Alvesco 160 or 320 mcg twice daily for 12 weeks. Compared to placebo, both Alvesco doses showed statistically significantly more improvement in pre-dose FEV1 (0.11 L or 8.6% and 0.18 L or 11.8%). Other measures of asthma control, AM PEF, symptoms, and need for rescue albuterol also showed improvement compared to placebo.

Patients Previously Maintained on Oral Corticosteroids:
This 12-week, double-blind clinical trial enrolled 140 subjects with mean FEV1 at baseline 53% predicted. The subjects were randomized to Alvesco given by inhalation aerosol at doses of 320 or 640 mcg twice daily or placebo. The average corticosteroid (prednisone) dose at baseline was approximately 12 mg/day. Compared to patients on placebo whose prednisone requirements increased by 4%, those treated with Alvesco 320 mcg and 640 mcg twice daily significantly reduced their prednisone requirements by 47% and 62% respectively. Those on Alvesco also maintained asthma control as reflected by lung function, symptoms, and need for rescue albuterol. A significantly larger percentage of patients on Alvesco were able to reduce oral prednisone use by 50% or more as compared to placebo (64% and 77% of the patients treated with 320 mcg and 640 mcg respectively twice daily as compared with 33% of patients on placebo).

Side Effects

Adverse events associated with the use of Alvesco may include, but are not limited to, the following:

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

Mechanism of Action

Alvesco is a non-halogenated glucocorticoid prodrug delivered via a metered dose inhaler. It is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following oral inhalation. Des-ciclesonide has anti-inflammatory activity with affinity for glucocorticoid receptors that is 120 times greater than the parent compound and 12 times greater than dexamethasone.

Literature References

Bateman ED, Cheung D, Lapa E Silva J, Göhring UM, Schäfer M, Engelstätter R Randomized comparison of ciclesonide 160 and 640mug/day in severe asthma. Pulmonary Pharmacology & Therapeutics 2007 Nov 22

Adachi M, Ishihara K, Inoue H, Kudo K, Takahashi K, Morita Y, Masuda K, Takada Y, Kato R, Miyamoto T Efficacy and safety of once-daily inhaled ciclesonide in adults with mild to moderate asthma: a double-blind, placebo-controlled study. Respirology 2007 Jul;12(4):566-72

Derendorf H Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide. Journal of Clinical Pharmacology 2007 Jun;47(6):782-9

Wilson AM, Duong M, Pratt B, Dolovich M, O'Byrne PM Anti-inflammatory effects of once daily low dose inhaled ciclesonide in mild to moderate asthmatic patients. Allergy 2006 May;61(5):537-42

Belvisi MG, Bundschuh DS, Stoeck M, Wicks S, Underwood S, Battram CH, Haddad el-B, Webber SE, Foster ML Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma. The Journal of Pharmacology and Experimental Therapeutics Links 2005 Aug;314(2):568-74

Additional Information

For additional information regarding Alvesco or asthma, please visit the Alvesco web page.