Ciclesonide

Class: Adrenals
ATC Class: R03BA08
Chemical Name: 2 - [(1S,2S,4R,8S,9S,11S,12S,13R) - 6 - cyclohexyl - 11 - hydroxy - 9,13 - dimethyl - 16 - oxo - 5,7 - dioxapentacycloicosa - 14, 17-dien-8-yl]- 2-oxoethyl 2-methylpropanoate
Molecular Formula: C32H44O7
CAS Number: 141845-82-1
Brands: Alvesco

Introduction

Synthetic, non-halogenated glucocorticoid.1 3 4 7 9 10 12

Uses for Ciclesonide

Asthma

Long-term prevention of bronchospasm in patients with asthma.1

In corticosteroid-dependent patients, may permit a reduction in dosage or discontinuance of systemic corticosteroids.1 2

Slideshow: Top Prevention Tips: Springtime Allergies

Not indicated for management of acute bronchospasm.1 6

Ciclesonide Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response.1

  • Base initial and maximum dosages in adults and children ≥12 years of age on previous asthma therapy.1

  • After a satisfactory response is obtained, decrease dosage gradually to the lowest dosage that maintains an adequate clinical response.1 Achieve the lowest effective dosage, particularly in children, since inhaled corticosteroids have the potential to affect growth.1 (See Pediatric Use under Cautions.)

Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids

  • When switching from systemic corticosteroids to orally inhaled ciclesonide, asthma should be reasonably stable before initiating treatment with oral inhalation.1

  • Initially, administer oral inhalation concurrently with the maintenance dosage of the systemic corticosteroid.1 After at least 1 week, gradually withdraw the systemic corticosteroid.1

  • Decrements usually should not exceed 2.5 mg daily of prednisone (or its equivalent) each week in patients receiving the oral inhalation.1 Once oral corticosteroids are discontinued and symptoms of asthma have been controlled, titrate the dosage to the lowest effective level.1

  • Death has occurred in some individuals in whom systemic corticosteroids were withdrawn too rapidly.1 (See Withdrawal of Systemic Corticosteroid Therapy under Cautions.)

Administration

Oral Inhalation

Administer by oral inhalation using an oral aerosol inhaler.1 3 7

Test-spray aerosol (3 times) before first use or when the inhaler is unused for >10 days.1 6

Oral inhalation aerosol is formulated as a solution, which does not require shaking.1

Exhale completely and place the mouthpiece of the inhaler well into the mouth with the lips closed firmly around it; keep the tongue below the mouthpiece.1 Inhale slowly and deeply through the mouth while pressing the canister down with forefinger.1 Hold the breath for about 10 seconds, or as long as comfortable, then withdraw the mouthpiece and exhale gently.1

Patients receiving oral inhalation of ciclesonide should rinse their mouth with water after each dose to remove residual medication in the oropharyngeal area and to minimize the development of fungal overgrowth and/or infection.1 6 12

Dosage

Pediatric Patients

Asthma
Oral Inhalation

Children ≥12 years of age receiving bronchodilators alone previously: Initially 80 mcg twice daily.1 If control of asthma is inadequate after 4 weeks of therapy at the initial dosage, a higher dosage may provide additional asthma control.1 If required, may increase dosage to a maximum of 160 mcg twice daily.1

Children ≥12 years of age receiving inhaled corticosteroids previously: Initially 80 mcg twice daily.1 If control of asthma is inadequate after 4 weeks of therapy at the initial dosage, a higher dosage may provide additional asthma control.1 If required, may increase dosage to a maximum of 320 mcg twice daily.1

Children ≥12 years of age receiving oral corticosteroids previously: 320 mcg twice daily.1

Adults

Asthma
Oral Inhalation

Previously receiving bronchodilators alone: Initially 80 mcg twice daily.1 If control of asthma is inadequate after 4 weeks of therapy at the initial dosage, a higher dosage may provide additional asthma control.1 If required, may increase dosage to a maximum of 160 mcg twice daily.1

Previously receiving inhaled corticosteroids: Initially 80 mcg twice daily.1 If control of asthma is inadequate after 4 weeks of therapy at the initial dosage, a higher dosage may provide additional asthma control.1 If required, may increase dosage to a maximum of 320 mcg twice daily.1

Previously receiving oral corticosteroids: 320 mcg twice daily.1

Prescribing Limits

Pediatric Patients

Asthma
Oral Inhalation

Children ≥12 years of age receiving bronchodilators alone previously: Maximum 160 mcg twice daily.1

Children ≥12 years of age receiving inhaled corticosteroids previously: Maximum 320 mcg twice daily.1

Children ≥12 years of age receiving oral corticosteroids previously: Maximum 320 mcg twice daily.1

Adults

Asthma
Oral Inhalation

Previously receiving bronchodilators alone: Maximum 160 mcg twice daily.1

Previously receiving inhaled corticosteroids: Maximum 320 mcg twice daily.1

Previously receiving oral corticosteroids: Maximum 320 mcg twice daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Careful dosage selection, usually initiating therapy at the low end of the dosage range, recommended due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Cautions for Ciclesonide

Contraindications

  • Primary treatment of severe acute asthmatic attacks or status asthmaticus when intensive measures (e.g., oxygen, parenteral bronchodilators, IV corticosteroids)5 are required.1

  • Known hypersensitivity to ciclesonide or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including angioedema with swelling of the lips, tongue, and pharynx, reported.1

Infections

Localized candidal infections of the mouth and/or pharynx reported.1

If infection occurs, initiate appropriate local or systemic antifungal treatment while still continuing with inhaled ciclesonide therapy.1 May require interruption of ciclesonide therapy in some patients.1

Use with caution, if at all, in patients with clinical or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, parasitic, or viral infections; or ocular herpes simplex.1

Acute Exacerbations of Asthma

Treat acute asthma symptoms with a short-acting β2-agonist bronchodilator.1 5 6 If symptoms persist, promptly reevaluate asthma therapy and consider initiating systemic corticosteroids.1 5

Immunosuppressed Patients

Increased susceptibility to infections in patients who are taking immunosuppressive drugs compared with healthy individuals.1 12 Certain infections (e.g., varicella [chickenpox], measles) can have a more serious or even fatal outcome in such patients.1 12

Take particular care to avoid exposure in susceptible patients.1 If exposure to varicella or measles occurs in susceptible patients, consider administering varicella zoster immune globulin (VZIG) or pooled immune globulin (IG), respectively.1 Consider treatment with an antiviral agent if varicella develops.1

Withdrawal of Systemic Corticosteroid Therapy

Possible life-threatening adrenal insufficiency in patients being switched from systemic corticosteroids to orally inhaled ciclesonide.1

Withdraw systemic corticosteroid therapy gradually1 and monitor carefully for objective signs of adrenal insufficiency (e.g., fatigue, lassitude, weakness, nausea, vomiting, hypotension) during withdrawal of systemic therapy.1 Lung function (FEV1 or morning peak expiratory flow rate [PEFR]), adjunctive β2-adrenergic agonist use, and asthma symptoms also should be carefully monitored.1 In most patients, several months are required for total recovery of HPA function following withdrawal of systemic corticosteroid therapy.1 Patients who have been maintained on ≥20 mg of prednisone (or its equivalent) daily may be most susceptible to such adverse events, particularly during the later part of the transfer.1 (See Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids under Dosage and Administration.)

Corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression) may occur; carefully monitor during and for a number of months after withdrawal of systemic corticosteroids.1

Acute adrenal insufficiency may occur during exposure to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.1

Possible unmasking of allergic conditions previously controlled by systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).1 12

Systemic Corticosteroid Effects

Administration of higher than recommended dosages of inhaled ciclesonide over prolonged periods may result in manifestations of hypercorticism and suppression of HPA function.1 12 If such changes occur, reduce the dosage of ciclesonide slowly, consistent with accepted procedures for reducing systemic corticosteroid dosage and management of asthma symptoms.1

Take particular care in monitoring patients postoperatively or during periods of stress for evidence of inadequate adrenal response.1 Supplemental therapy with a systemic corticosteroid required during stress or severe asthma attacks.1 12

Musculoskeletal Effects

Long-term use of orally inhaled corticosteroids may affect normal bone metabolism, resulting in a loss of bone mineral density (BMD).1

Monitor patients with major risk factors for decreased BMD (e.g., family history of osteoporosis, prolonged immobilization, chronic use of drugs that can reduce bone mass [e.g., anticonvulsants, corticosteroids]) and treat with established standards of care.1 12

Ocular Effects

Glaucoma, increased IOP, and cataracts reported rarely in patients receiving orally inhaled corticosteroids.1 Carefully monitor patients who have a change in vision and those with a history of increased IOP, glaucoma, and/or cataracts.1

Respiratory Effects

Bronchospasm and wheezing may occur with oral inhalation therapy.1

If bronchospasm occurs, treat immediately with a short-acting bronchodilator, and discontinue treatment with ciclesonide and institute alternate therapy.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

With prolonged use, may slow growth rate in children and adolescents.1 Monitor routinely (e.g., via stadiometry) the growth and development of pediatric patients receiving corticosteroid therapy.1 12 Weigh benefits of corticosteroid therapy versus possibility of growth suppression and the risks associated with alternative therapies.1 Use the lowest possible dosage that effectively controls asthma.1

Geriatric Use

Insufficient experience with oral inhalation in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Increased systemic exposure in patients with moderate to severe hepatic impairment; however, dosage adjustments not necessary.1

Renal Impairment

Pharmacokinetics not evaluated but impact of renal impairment should be minimal.1

Common Adverse Effects

Headache,1 nasopharyngitis,1 sinusitis,1 pharyngolaryngeal pain,1 upper respiratory infection,1 arthralgia,1 nasal congestion,1 extremity pain,1 back pain,1 hoarseness,1 2 oral candidiasis,1 2 influenza,1 pneumonia,1 musculoskeletal chest pain,1 urticaria,1 dizziness,1 gastroenteritis,1 facial edema,1 fatigue,1 conjunctivitis.1

Interactions for Ciclesonide

Inhibitory potential of ciclesonide on CYP isoenzymes not evaluated; however des-ciclesonide (active metabolite) does not inhibit or induce the metabolism of other drugs metabolized by CYP isoenzymes in vitro.1

Ciclesonide and des-ciclesonide do not induce CYP isoenzymes in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma des-ciclesonide concentrations).1

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Albuterol

Pharmacokinetic interaction with des-ciclesonide not observed1

Erythromycin

Pharmacokinetic interaction not observed1

Formoterol

Pharmacokinetic interaction with des-ciclesonide not observed1

Ketoconazole

Increased plasma des-ciclesonide concentrations; however, plasma ciclesonide concentrations unchanged1 11

Use concomitantly with caution; no specific dosage recommendations at this time12

Salicylic acid

Pharmacokinetic interactions unlikely1

Plasma protein binding of des-ciclesonide not altered by salicylic acid in vitro 1 8

Warfarin

Pharmacokinetic interactions unlikely1

Plasma protein binding of des-ciclesonide not altered by warfarin in vitro1

Ciclesonide Pharmacokinetics

Absorption

Bioavailability

Negligible oral bioavailability (<1%) because of low GI absorption and high first-pass metabolism.1 4 7 9 11 Following oral inhalation, absolute bioavailability of ciclesonide is 22%; relative systemic exposure of des-ciclesonide is 63%.1

Special Populations

In patients with moderate to severe hepatic impairment, increased systemic exposure of des-ciclesonide (i.e., peak plasma concentrations, AUC).1

Distribution

Extent

Glucocorticoids cross the placenta.a Not known whether ciclesonide is distributed into milk;1 however, other corticosteroids are distributed into milk.1

Plasma Protein Binding

≥99%;1 3 7 8 9 11 12 des-ciclesonide is not appreciably bound to human transcortin.1 8 12

Elimination

Metabolism

Hydrolyzed by esterases to the active metabolite C21-desisobutyryl-ciclesonide (des-ciclesonide).1 3 4 7 8 9 11

Des-ciclesonide is metabolized in the liver principally by CYP3A4 and, to a lesser extent, by CYP2D6.1 4 11

Elimination Route

Excreted principally in feces (66%) as ciclesonide and to a lesser extent (≤20%) in urine as des-ciclesonide.1

Half-life

The mean elimination half-lives of ciclesonide and des-ciclesonide are 0.71 and 6–7 hours, respectively, following IV administration.1 12

Special Populations

In patients with renal impairment, pharmacokinetics not evaluated.1

Stability

Storage

Oral Inhalation

Inhalation Solution

25°C (may be exposed to 15–30°C).1 Contents of oral inhaler are under pressure; do not puncture, use or store aerosol container near heat or an open flame, expose to temperatures >49°C, or place into a fire or incinerator for disposal.1

Actions

  • Prodrug with little pharmacologic activity until hydrolyzed to active metabolite des-ciclesonide.1 3 4 7 8 9 11 Des-ciclesonide exhibits anti-inflammatory activity, with affinity for glucocorticoid receptors that is 120 times that of ciclesonide.1 4 7 11

  • Exact mechanism(s) of action not known; however, may reduce inflammatory asthmatic response by inhibiting multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes, basophils) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response.1

  • Improves lung function (e.g., FEV1, morning PEFR).1

Advice to Patients

  • Importance of providing the patient a copy of the manufacturer’s patient information and medication guide.1 6

  • Importance of adequate understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery system.1 6

  • Importance of pediatric patients receiving therapy under adult supervision.12

  • Risk of localized candidal infections of the mouth and pharynx.1 6 Importance of rinsing the mouth with water without swallowing after oral inhalation.1 6

  • Importance of advising patients that ciclesonide oral inhalation must be used at regular intervals to be therapeutically effective.1 6

  • Importance of advising patients that at least 4 weeks of continuous therapy may be required for optimum effects to be achieved.1 6

  • Importance of not exceeding the recommended dosage and of contacting a clinician immediately if symptoms of asthma worsen or fail to improve.1 6

  • Importance of not discontinuing therapy with ciclesonide abruptly and of contacting a clinician immediately if use of ciclesonide is discontinued as symptoms may recur.1 6

  • Importance of advising patients that orally inhaled ciclesonide should not be used as a bronchodilator and that the drug is not indicated for emergency use (e.g., relief of acute bronchospasm).1 6

  • Importance of availability and use of a short-acting β2-adrenergic agonist for relief of acute asthma symptoms.1 6

  • Importance of contacting a clinician immediately when asthmatic attacks are not controlled by current bronchodilator therapy.1 6

  • Importance of gradual withdrawal from systemic corticosteroids during transfer to orally inhaled ciclesonide and of monitoring by a clinician during such transfer of therapy.1 6

  • Importance of advising patients being transferred from systemic corticosteroid to ciclesonide oral inhalation therapy to carry special identification (e.g., card) indicating the need for supplementary systemic corticosteroids during periods of stress or severe exacerbation of asthma.1 Importance of advising patients to immediately resume therapy with large doses of systemic corticosteroids and to contact their clinician for further instructions during stressful periods (e.g., stress, severe asthmatic attack, surgery, trauma, infection).1 6

  • Risk of systemic corticosteroid effects (e.g., hypercorticism, potentially life-threatening adrenal suppression).1 6 Importance of informing a clinician of fatigue, weakness, nausea, vomiting, dizziness, or fainting.1 6

  • Importance of informing patients that corticosteroids may decrease BMD.1 6

  • Risk of reduction in growth velocity in children and adolescents with orally inhaled corticosteroids.1

  • Importance of immunosuppressed patients avoiding exposure to chickenpox and measles, and, if exposed, of immediately consulting their clinician.1

  • Importance of advising immunosuppressed patients of potential worsening of existing tuberculosis; fungal, bacterial, parasitic, or viral infections; or ocular herpes simplex.1 6 Importance of immunosuppressed patients informing clinician of a history of infections.6

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 6

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., infections).1 6

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ciclesonide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Aerosol

80 mcg/metered spray

Alvesco

Sepracor

160 mcg/metered spray

Alvesco

Sepracor

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Alvesco 160MCG/ACT Aerosol (SUNOVION PHARMACEUTICALS): 6/$175.99 or 18/$493.97

Alvesco 80MCG/ACT Aerosol (SUNOVION PHARMACEUTICALS): 6/$174.98 or 18/$480.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 12, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sepracor Inc. Alvesco (ciclesonide) inhalation aerosol prescribing information. Marlborough, MA; 2008 Jun.

2. Bateman E, Karpel J, Casale T et al. Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma. Chest. 2006; 129:1176-87. [PubMed 16685007]

3. . Ciclesonide (Alvesco)-a new inhaled corticosteroid for asthma. Med Lett Drugs Ther. 2008; 50:75-6. [PubMed 18800024]

4. Reynolds NA, Scott LJ. Ciclesonide. Drugs. 2004; 64:511-9; discussion 520-1. [PubMed 14977388]

5. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. Full report 2007. Bethesda, MD: National Institutes of Health, National Heart, Lung and Blood Institute. 2007 Aug 28. Available from website. Accessed 2008 Nov 7.

6. Sepracor Inc. Alvesco (ciclesonide) inhalation aerosol patient instructions for use. Marlborough, MA; 2008 Jun.

7. Deeks ED, Perry CM. Ciclesonide: a review of its use in the management of asthma. Drugs. 2008; 68:1741-70. [PubMed 18681495]

8. Rohatagi S, Luo Y, Shen L et al. Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther. 2005 May-Jun; 12:201-9.

9. Nave R, Drollmann A, Steinijans VW et al. Lack of pharmacokinetic drug-drug interaction between ciclesonide and erythromycin. Int J Clin Pharmacol Ther. 2005; 43:264-70. [PubMed 15968883]

10. Chu V, Zeng Z, Pan J et al. In vitro assessment of cytochrome P450 metabolic drug-drug interaction potential of ciclesonide [abstract no. 552]. Drug Metab Rev. 2004; 36 (Suppl 1):276.

11. Böhmer GM, Drollmann A, Gleiter CH et al. Effect of coadministered ketoconazole, a strong cytochrome P450 3A4 enzyme inhibitor, on the pharmacokinetics of ciclesonide and its active metabolite desisobutyryl-ciclesonide. Clin Pharmacokinet. 2008; 47:343-9. [PubMed 18399715]

12. Sepracor, Inc, Marlborough, MA: Personal communication.

a. AHFS Drug Information 2011. McEvoy GK, ed. Corticosteroids General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2011:3047-62.

Hide
(web3)