Alvesco

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Alvesco Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ciclesonide 80mcg/inh, 160mcg/inh; metered dose aerosol.

    Pharmacological Class

    Steroid.

    How Supplied

    Inhaler—6.1g (60 inh)

    How Supplied

    Alvesco is available in the following strengths and canister presentations:

    • Alvesco 80mcg/actuation: 60 actuations per canister
    • Alvesco 160mcg/actuation: 60 actuations per canister

    Alvesco canisters are for use with Alvesco Inhalation Aerosol actuators only. The actuators are fitted with a dose indicator and should not be used with other inhalation aerosol medications.

    Storage

    The canister should be at room temperature when used. Excursions between 15°C and 30°C (59°F and 86°F) are permitted.

    Exposure to temperatures above 49°C (120°F) may cause bursting.

     

    Manufacturer

    Covis Pharmaceuticals, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Ciclesonide is a prodrug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following oral inhalation. The precise mechanisms of corticosteroid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma.

    Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

    Alvesco Indications

    Indications

    Maintenance treatment of asthma as prophylactic therapy in patients ≥12 years of age.

    Limitations of Use

    Not indicated for the relief of acute bronchospasm or for children under 12 years of age.

     

    Alvesco Dosage and Administration

    Adult

    Previously on bronchodilators alone: initially 80mcg twice daily, max 160mcg twice daily. Previously on inhaled corticosteroids: initially 80mcg twice daily; max 320mcg twice daily. Previously on oral corticosteroids (see full labeling): 320mcg twice daily. Rinse mouth after use; avoid eyes.

    Adult

    For patients ≥12 years old:

    Previously on bronchodilators alone: initially 80mcg twice daily, max 160mcg twice daily.

    Previously on inhaled corticosteroids: initially 80mcg twice daily; max 320mcg twice daily.

    Previously on oral corticosteroids: 320mcg twice daily. Prednisone should be reduced gradually, no faster than 2.5mg/day on a weekly basis, beginning after at least 1 week of therapy with Alvesco. Monitor for signs of asthma instability, including monitoring of serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy.

    Maximum benefit may not be achieved for 4 weeks or longer after initiation. Higher doses may provide additional asthma control if patients do not respond adequately to the starting dose after 4 weeks of therapy. Do not exceed max recommended doses.

    Titrate to the lowest effective dosage to reduce the possibility of side effects once asthma stability has been achieved.

    Rinse mouth after inhalation of Alvesco.

    Children

    <12yrs: not established.

    Administration

    Alvesco should be administered by the orally inhaled route.

    Prime before the first use by actuating 3 times prior to using the first dose from a new canister or when the inhaler has not been used for >10 days.

    Nursing Considerations

    Patients should rinse the mouth after inhalation of Alvesco.

    Alvesco Contraindications

    Contraindications

    Primary treatment of status asthmaticus or other acute episodes of asthma requiring intensive measures.

    Alvesco Boxed Warnings

    Not Applicable

    Alvesco Warnings/Precautions

    Warnings/Precautions

    Do not exceed recommended dose. Risk of local infections (eg, mouth/pharynx candidiasis). Immunosuppression: active or quiescent tuberculosis, systemic infections, ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin or antiviral prophylactic therapies. Monitor for signs/symptoms of adrenal insufficiency when transferring from systemic corticosteroids. May need supplemental systemic corticosteroids during periods of stress or a severe asthma attack. May unmask previously suppressed allergic conditions. Monitor for hypercorticism and HPA axis suppression (if occurs, discontinue gradually), growth in children, change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts. Reevaluate periodically. Assess bone mineral density if risk factors exist (eg, prolonged immobilization, osteoporosis, or chronic use of drugs that can reduce bone mass [eg, anticonvulsants, oral steroids]). Discontinue if paradoxical bronchospasm occurs; use alternative therapy. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor. Eosinophilic conditions. Hepatic impairment. Pregnancy: monitor closely. Nursing mothers.

    Warnings/Precautions

    Localized Infections of the mouth and pharynx with Candida albicans have occurred in clinical trials. Infections should be treated with appropriate local or systemic therapy while remaining on Alvesco, though Alvesco may need to be interrupted in some cases. Patients should rinse the mouth after inhalation of Alvesco.

    Patients who are using drugs that suppress the immune system are more susceptible to infections. For patients who have not previously had chickenpox or measles or been vaccinated against these diseases, consider immunoglobulin prophylactic therapy if exposure occurs. Treatment with antivirals should be considered if chickenpox develops.

    Inhaled corticosteroids should be used with caution in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

    Transferring patients from systemic corticosteroids:

    • Particular care is needed for patients who are transferred from systemically active corticosteroids to Alvesco because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically-available inhaled corticosteroids.
    • Patients who have been previously maintained on 20mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.
    • During this period of HPA suppression, patients may exhibit signs/symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.
    • In recommended doses, Alvesco supplies less than normal physiological amounts of corticosteroid systemically and does not provide the mineralocorticoid activity that is necessary for coping with these emergencies.
    • Patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately during periods of stress or a severe asthma attack.
    • Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Alvesco.
    • Monitor lung function, beta-agonist use, and asthma symptoms during withdrawal.
    • Observe patients for signs/symptoms of adrenal insufficiency (eg, fatigue, lassitude, weakness, nausea, vomiting, hypotension).
    • Transfer from systemic corticosteroids may unmask allergic conditions.
    • Some patients may experience systemically active steroid withdrawal, despite maintenance of improvement of respiratory function.

    Monitor for hypercorticism and HPA axis suppression (if occur, reduce dose gradually).

    Decreases in bone mineral density have been observed with long-term administration of inhaled corticosteroids; patients with risk factors should be monitored and treated appropriately.

    Glaucoma, increased intraocular pressure and cataracts have been reported following administration of inhaled corticosteroids, including Alvesco. Close monitoring is warranted in patients with vision changes or in those with a history of increased intraocular pressure, glaucoma, and/or cataracts.

    Bronchospasm may occur after dosing; treat immediately with a fast-acting inhaled bronchodilator. Treatment with Alvesco should be discontinued and alternative treatment should be started.

    Pregnancy Considerations

    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 Mother Considerations

    It is not known whether ciclesonide is secreted in human milk; other corticosteroids are excreted in human milk. Caution should be used when Alvesco is administered to a nursing patient.

    Pediatric Considerations

    The safety and effectiveness of Alvesco in children under 12 years of age have not been established.

    Monitor for growth suppression in children. To minimize the systemic effects of orally inhaled corticosteroids, including Alvesco, each patient should be titrated to the lowest effective dose.

    Results from clinical studies evaluating Alvesco in patients 4 to 11 years old and in patients 2 to 6 years old were inconsistent and did not establish efficacy in these patient populations.

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients aged 65 years and older. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range.

    Renal Impairment Considerations

    Studies in renally-impaired patients were not conducted since renal excretion of des-ciclesonide is a minor route of elimination (≤20%).

    Hepatic Impairment Considerations

    Dose adjustment of Alvesco in patients with liver impairment is not necessary.

    Alvesco Pharmacokinetics

    Absorption

    The absolute bioavailability of ciclesonide was 22% and the relative systemic exposure of desciclesonide was 63%. The mean Cmax for des-ciclesonide was 1.02 ng/mL (range 0.6-1.5 ng/mL) in asthmatic patients following a single dose of 1280 mcg by oral inhalation.

    Distribution

    Following intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide was ~2.9 L/kg and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥99% each, with ≤ 1% of unbound drug detected in the systemic circulation.

    Metabolism

    Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. Des-ciclesonide undergoes further metabolism in the liver to additional metabolites mainly by the CYP3A4 isozyme and to a lesser extent by CYP2D6.

    Elimination

    14C-labeled ciclesonide was predominantly excreted via the feces after intravenous administration (66%) indicating that excretion through bile is the major route of elimination. Approximately 20% or less of des-ciclesonide was excreted in the urine. The mean half-life of ciclesonide and des-ciclesonide was 0.71 hours and 6 to 7 hours, respectively. Tmax of des-ciclesonide occurs at 1.04 hours following inhalation of ciclesonide.

     

    Alvesco Interactions

    Interactions

    Concurrent administration of ciclesonide and other drugs commonly used in the treatment of asthma (albuterol, formoterol) had no effect on pharmacokinetics of des-ciclesonide.

    Coadministration of orally inhaled ciclesonide and oral ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged.

    Alvesco Adverse Reactions

    Adverse Reactions

    Headache, nasopharyngitis, sinusitis, throat pain, upper respiratory infection, arthralgia, nasal congestion, back pain; hypersensitivity reactions, immunosuppression, glaucoma, cataracts, bronchospasm.

    Adverse Reactions

    Most common: Headache, nasopharyngitis, sinusitis, pharyngolaryngeal pain, upper respiratory infection, arthralgia, nasal congestion, pain in extremity and back pain.

    Adverse reactions that occurred in clinical trials with an incidence of <1% and at a greater incidence with Alvesco vs placebo included oral candidiasis, cough, dry mouth, nausea, chest discomfort, dysphonia, and dry throat.

    Corticosteroid use in general may result in Candida albicans infection, immunosuppression, hypercorticism and adrenal suppression, growth effects, glaucoma and cataracts.

    Alvesco Clinical Trials

    Clinical Trials

    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.

    Patients Previously Maintained on Bronchodilator Alone

    Two randomized, double-blind, placebo-controlled trials of 12-weeks duration.

    Trial 1:

    • Patients with mild to moderate persistent asthma (mean baseline percent predicted FEV1 of 79%), previously maintained on predominantly inhaled corticosteroids.
    • Randomly assigned to Alvesco 160mg once daily in the AM, Alvesco 80mcg twice daily, or placebo.
    • Statistically significantly more increases in AM pre-dose FEV1 compared with placebo were seen at 12 weeks for Alvesco 160mcg once daily (0.14L or 5.7%) and Alvesco 80mcg twice daily (0.19L or 7.5%). 
    • Asthma symptoms scores, AM PEF, and decreased need for rescue albuterol remained relatively stable in the Alvesco treatment groups compared with slight worsening in the placebo. 
    • Compared with placebo, fewer patients receiving Alvesco experienced worsening of asthma.

    Trial 2:

    • 257 patients with moderate to severe persistent asthma (mean baseline percent predicted FEV1 of 54%).
    • Randomly assigned to Alvesco 160mcg or 320mcg twice daily, or placebo for 12 weeks.
    • Both Alvesco doses showed statistically significantly more improvement in pre-dose FEV1 (0.11L or 8.6% and 0.18L or 11.8%), compared with placebo.
    • Other measures of asthma control, AM PEF, symptoms, and need for rescue albuterol also showed improvement compared with placebo. 
    • Fewer patients treated with Alvesco experienced worsening of asthma vs placebo.

    Patients Previously Maintained on Oral Corticosteroids

    • 12-week double-blind trial that included 140 patients with severe persistent asthma who had failed prior efforts to eliminate oral prednisone and had established the lowest effective prednisone dose (average prednisone dose at baseline: ~12mg/day)
    • Randomly assigned to Alvesco 320mcg or 640mcg twice daily or placebo.
    • Patients treated with Alvesco 320mcg and 640mcg twice daily significantly reduced their prednisone requirements by 47% and 62%, respectively, compared with a 4% increase in the placebo group.
    • Patients on Alvesco 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 by 50% or more as compared with placebo (64% and 77% of the patients treated with 320mcg and 640mcg, respectively twice daily vs 33% of patients on placebo). 
    • There was no statistically significant difference observed with Alvesco 640mcg twice daily compared with Alvesco 320mcg twice daily.

    Alvesco Note

    Not Applicable

    Alvesco Patient Counseling

    Patient Counseling

    Rinse mouth after inhalation to prevent oropharyngeal candidiasis.

    Acute asthma symptoms should be treated with an inhaled, short-acting beta2 agonist (eg, albuterol).

    Patients who have been withdrawn from systemic corticosteroids: Instruct them to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

    Alvesco use should not be stopped abruptly. Effectiveness depends on regular use. Maximum benefits may not be achieved for 4 weeks or longer after starting treatment.

    When the dose indicator display window shows a red zone, approximately 20 inhalations are left, and a refill is required. 

    Cost Savings Program

    Affordable access programs for Alvesco are available here.

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