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Ciclesonide (Oral Inhalation)

Pronunciation

(sye KLES oh nide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol Solution, Inhalation:

Alvesco: 80 mcg/actuation (6.1 g); 160 mcg/actuation (6.1 g)

Brand Names: U.S.

  • Alvesco

Pharmacologic Category

  • Corticosteroid, Inhalant (Oral)

Pharmacology

Ciclesonide is a nonhalogenated, glucocorticoid prodrug that is hydrolyzed to the pharmacologically active metabolite des-ciclesonide following administration. Des-ciclesonide has a high affinity for the glucocorticoid receptor and exhibits anti-inflammatory activity. The mechanism of action for corticosteroids is believed to be a combination of three important properties − anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions.

Absorption

52% (lung deposition)

Distribution

Vd: Ciclesonide: 2.9 L/kg; des-ciclesonide: 12.1 L/kg

Metabolism

Ciclesonide hydrolyzed to its active metabolite, des-ciclesonide via esterases in nasal mucosa and lungs; des-ciclesonide undergoes further hepatic metabolism primarily via CYP3A4 and to a lesser extent via CYP2D6

Excretion

Feces (66%); urine (≤20% as active metabolite)

Onset of Action

>4 weeks for maximum benefit

Time to Peak

~1 hour (des-ciclesonide)

Half-Life Elimination

Ciclesonide: 0.7 hours; des-ciclesonide: 6-7 hours

Protein Binding

≥99%

Special Populations: Hepatic Function Impairment

Cmax of des-ciclesonide in patients with moderate to severe liver impairment increased 1.4- to 2.7-fold after oral inhalation.

Use: Labeled Indications

Bronchial asthma: Prophylactic management of bronchial asthma

Guideline recommendations: A low-dose inhaled corticosteroid (in addition to an as-needed short acting beta2-agonist) is the initial preferred long term control medication for children, adolescents, and adult patients with persistent asthma who are candidates for treatment according to a step-wise treatment approach (GINA 2016; NAEPP 2007).

Contraindications

Hypersensitivity to ciclesonide or any component of the formulation; primary treatment of acute asthma or status asthmaticus

Canadian labeling: Additional contraindications (not in U.S. labeling): Untreated fungal, bacterial, or tuberculosis infections of the respiratory tract; moderate-to-severe bronchiectasis

Dosing: Adult

Asthma: Oral inhalation (Alvesco): Note: Titrate to the lowest effective dose once asthma stability is achieved:

US labeling:

Prior therapy with bronchodilators alone: Initial: 80 mcg twice daily (maximum dose: 320 mcg/day)

Prior therapy with inhaled corticosteroids: Initial: 80 mcg twice daily (maximum dose: 640 mcg/day)

Prior therapy with oral corticosteroids: Initial: 320 mcg twice daily (maximum dose: 640 mcg/day)

Canadian labeling: Initial: 400 mcg once daily; maintenance: 100-800 mcg/day (1-2 puffs once daily; more severe asthma may require 400 mcg twice daily). Note: Canadian Thoracic Society 2010 Asthma Management guidelines recommendation: Doses >200 mcg/day may provide minimal additional benefit while increasing risks for adverse events; add-on therapy should be considered prior to dose increases >200 mcg/day (Lougheed 2010).

Asthma guidelines: Global Initiative for Asthma guidelines (GINA 2016): HFA inhaler (refers to Alvesco 80 mcg and 160 mcg strengths available in the US):

“Low” dose: 80 to 160 mcg daily

“Medium” dose: >160 to 320 mcg daily

“High” dose: >320 mcg daily

Conversion: Conversion from oral to orally-inhaled steroid: Initiation of oral inhalation therapy should begin in patients who have previously been stabilized on oral corticosteroids (OCS). A gradual dose reduction of OCS should begin ~7-10 days after starting inhaled therapy. U.S. labeling recommends reducing prednisone dose no more rapidly than ≤2.5 mg/day on a weekly basis. The Canadian labeling recommends decreasing the daily dose of prednisone by 1 mg (or equivalent of other OCS) every 7 days in closely monitored patients, and every 10 days in patients whom close monitoring is not possible. In the presence of withdrawal symptoms, resume previous OCS dose for 1 week before attempting further dose reductions.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Asthma: Oral inhalation (Alvesco): Note: Titrate to the lowest effective dose once asthma stability is achieved:

US labeling: Children ≥12 years and Adolescents: Refer to adult dosing.

Canadian labeling:

Children 6 to 11 years: Initial: 100-200 mcg once daily; maintenance: 100-200 mcg/day (1-2 puffs once daily). Note: Canadian Thoracic Society 2010 Asthma Management guidelines recommend dose titration in children 6-11 years who fail to achieve an adequate response in spite of adherence to therapy and/or lack of alternative factors (eg, environmental triggers) which might impair response (Lougheed 2010).

Children ≥12 years and Adolescents: Refer to adult dosing.

Asthma guidelines: Global Initiative for Asthma guidelines (GINA 2016): HFA inhaler (refers to Alvesco 80 mcg and 160 mcg strengths available in the US):

Children ≤5 years: “Low” dose: 160 mcg daily

Children 6 to 11 years:

“Low” dose: 80 mcg daily

“Medium” dose: >80 to 160 mcg daily

“High” dose: >160 mcg daily

Children ≥12 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer labeling (has not been studied); however, dose adjustments may not be necessary as ≤20% of drug is eliminated renally.

Dosing: Hepatic Impairment

Dosage adjustments are not necessary.

Administration

Remove mouthpiece cover, place inhaler in mouth, close lips around mouthpiece, and inhale slowly and deeply. Press down on top of inhaler after slow inhalation has begun. Remove inhaler while holding breath for approximately 10 seconds. Breathe out slowly and replace mouthpiece on inhaler. Rinse mouth with water (and spit out) after inhalation. Do not wash or place inhaler in water. Clean mouthpiece using a dry cloth or tissue once weekly. Discard after the "discard by" date or after labeled number of doses has been used, even if container is not completely empty.

Shaking is not necessary since drug is formulated as a solution aerosol. Prime inhaler prior to initial use or if not in use for ≥7-10 days by releasing 3 puffs into the air.

Storage

Store at 25°C (77°F); excursions to 15°C to 30°C (59°F to 86°F) permitted. Do not puncture. Do not use or store near open flame or heat; canister may burst if exposed to temperatures >49°C (120°F); do not throw canister into fire or incinerator.

Drug Interactions

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination

Amphotericin B: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Ceritinib: Corticosteroids may enhance the hyperglycemic effect of Ceritinib. Monitor therapy

Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Monitor therapy

Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Loop Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Thiazide and Thiazide-Like Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (≤11%)

Respiratory: Nasopharyngitis (≤11%)

1% to 10%:

Cardiovascular: Facial edema (≥3%)

Central nervous system: Dizziness (≥3%), fatigue (≥3%), voice disorder (1%)

Dermatologic: Urticaria (≥3%)

Gastrointestinal: Gastroenteritis (≥3%), oral candidiasis (≥3%)

Infection: Influenza (≥3%)

Neuromuscular & skeletal: Arthralgia (≥3%), back pain (≥3%), limb pain (≥3%), musculoskeletal chest pain (≥3%)

Ophthalmic: Conjunctivitis (≥3%)

Otic: Otalgia (2%)

Respiratory: Upper respiratory tract infection (≤9%), nasal congestion (≤6%), pharyngolaryngeal pain (≤5%), hoarseness (≥3%), pneumonia (≥3%), sinusitis (≥3%), paradoxical bronchospasm (2%)

<1% (Limited to important or life-threatening): Angioedema (with swelling of lip/pharynx/tongue), cataract, chest discomfort, increased gamma-glutamyl transferase, increased intraocular pressure, increased serum ALT, nausea, palpitations, pharyngeal candidiasis, skin rash, weight gain, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: May cause hypercorticism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections. Select surgical patients on long-term, high-dose, inhaled corticosteroid (ICS), should be given stress doses of hydrocortisone intravenously during the surgical period and the dose reduced rapidly within 24 hours after surgery (NAEPP, 2007).

• Bronchospasm: May occur with wheezing after inhalation; if this occurs, stop steroid and treat with a fast-acting bronchodilator.

• Immunosuppression: Prolonged use of corticosteroids may also increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Exposure to chickenpox and measles should be avoided; use caution in patients with active or quiescent TB infections (contraindicated in Canada) or in patients with ocular herpes.

• Kaposi's sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi's sarcoma (case reports); if noted, discontinuation of therapy should be considered.

• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including depression, euphoria, insomnia, mood swings, and personality changes. Pre-existing psychiatric conditions may be exacerbated by corticosteroid use.

• Thrush: Candida albicans infections (mostly mild-to-moderate) of the mouth and pharynx may occur with orally inhaled corticosteroid use; interruption of therapy may be necessary at times while antifungal therapy is employed; advise patients to rinse mouth after use.

• Vasculitis: Rare cases of vasculitis (Churg-Strauss syndrome) or other eosinophilic conditions (eg, vasculitic rash, decreased pulmonary function, cardiac complications) can occur.

Disease-related concerns:

• Asthma: Supplemental steroids (oral or parenteral) may be needed during stress or severe asthma attacks. Not to be used in status asthmaticus or for the relief of acute bronchospasm.

• Cardiovascular disease: Use with caution following acute myocardial infarction (MI); corticosteroids have been associated with myocardial rupture. Use with caution in patients with HF; long-term use has been associated with fluid retention and hypertension.

• Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose production/regulation leading to hyperglycemia.

• Hepatic impairment: Systemic exposure to the active metabolite is increased in moderate-to-severe impairment; however, dosage adjustments are not recommended in hepatic impairment; monitor for increased systemic effects, particularly in patients with severe hepatic impairment, including cirrhosis.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms has occurred with corticosteroids especially during initial treatment.

• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use. Consider routine eye exams in chronic users.

• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.

• Renal impairment: Use in renally-impaired patients has not been studied; however, ≤20% of drug is eliminated renally.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.

• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.

Special populations:

• Elderly: Because of the risk of adverse effects, systemic corticosteroids should be used cautiously in the elderly in the smallest possible effective dose for the shortest duration.

• Pediatric: Orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 cm per year [range: 0.3-1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally inhaled corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.

Other warnings/precautions:

• Discontinuation of therapy: Withdraw systemic therapy with gradual tapering of dose. There have been reports of systemic corticosteroid withdrawal symptoms (eg, joint/muscle pain, lassitude, depression) when withdrawing oral inhalation therapy.

Monitoring Parameters

Growth (adolescents) and signs/symptoms of HPA axis suppression/adrenal insufficiency; ocular effects (eg, cataracts, increased intraocular pressure, glaucoma)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy. Based on available data, an overall increased risk of congenital malformations or a decrease in fetal growth has not been associated with maternal use of inhaled corticosteroids during pregnancy (Bakhireva, 2005; NAEPP, 2005; Namazy, 2004). Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, pre-eclampsia, preterm birth, low birth weight infants). Inhaled corticosteroids are recommended for the treatment of asthma during pregnancy (most information available using budesonide) (ACOG, 2008; NAEPP, 2005).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, rhinitis, pharyngitis, back pain, or painful extremities. Have patient report immediately to prescriber signs of infection, severe loss of strength and energy, irritability, tremors, tachycardia, confusion, dizziness, sweating, redness or white patches in mouth or throat, angina, bone pain, joint pain, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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