PrAlvesco(r) (ciclesonide inhalation aerosol) 50 mcg, 100 mcg and 200 mcg/ actuation (ex-valve) Corticosteroid for oral inhalation Date of Revision: August 24, 2007 Nycomed Canada Inc. Oakville, Ontario L6M 4X8 www.nycomed.ca Control #: 113078
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 13 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 16 DOSAGE FORMS, COMPOSITION AND PACKAGING 16
PHARMACEUTICAL INFORMATION 17 CLINICAL TRIALS 17 DETAILED PHARMACOLOGY 19 TOXICOLOGY 23 REFERENCES 26
PrAlvesco(r) (ciclesonide inhalation aerosol)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Non-medicinal Ingredients |
| Oral Inhalation | Metered Dose Inhaler 50 micrograms 100 micrograms 200 micrograms per actuation (ex-valve) | propellant HFA-134a (norflurane) and ethanol |
Note: All doses given in this monograph are ex-valve unless specified otherwise.
Alvesco(r)(ciclesonide) is indicated for: prophylactic management of steroid-responsive bronchial asthma in adults and adolescents 12 years of age and older.
Pediatrics:
Alvesco(r) is not presently recommended for patients younger than 12 years of age.
Geriatrics :
(>65 years of age)
Based on the pharmacokinetic characteristics obtained in patients older than 65 years of age, dose adjustment is not necessary in elderly patients.
Alvesco(r) is contraindicated in patients with known hypersensitivity to any of the ingredients Alvesco(r) is contraindicated in patients with untreated fungal, bacterial or tuberculosis infections of the respiratory tract Alvesco(r) is not to be used in the primary treatment of status asthmaticus or other acute episodes of asthma, or in patients with moderate to severe bronchiectasis.
General
It is essential that patients be instructed that Alvesco(r) is a preventative agent which must be taken daily at the intervals recommended by their doctors and is not to be used as acute treatment for an asthmatic attack. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. Treatment with Alvesco(r) should not be stopped abruptly, but tapered off gradually. Monitoring Asthma Control: Patients with severe asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests. Increasing use of short-acting bronchodilators to relieve asthma symptoms indicate deterioration of asthma control. If patients find that short-acting relief bronchodilator treatment becomes less effective, or they need more inhalations than usual, medical attention should be sought. In this situation, patients should be reassessed and consideration given to the need for increased anti- inflammatory treatment therapy (either higher doses of Alvesco(r) or a course of oral corticosteroids). Severe asthma exacerbations should be managed according to standard medical practice.
Carcinogenesis and Mutagenesis
See TOXICOLOGY.
Endocrine and Metabolism
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
Hematologic
In rare cases, patients on inhaled corticosteroid therapy may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic
corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids, and cases of serious eosinophilic conditions have been reported in the clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between ciclesonide and these underlying conditions has not been established.
Acetylsalicyclic acid should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Hepatic/Biliary/Pancreatic
There is an enhanced effect of corticosteroids on patients with cirrhosis.
Based on the pharmacokinetic characteristics obtained in patients with hepatic insufficiency, dose adjustment is not necessary in this population. There is limited data available in patients with severe hepatic impairment. An increased exposure in patients with severe hepatic impairment is expected and these patients should therefore be monitored for potential systemic effects.
Immune
Patients who are on drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localised infections has been observed during corticosteroid therapy. This may require treatment with appropriate therapy or stopping the administration of ciclesonide until the infection is eradicated.
Infection
Candidiasis and Oral Hygiene: Therapeutic dosages of inhaled corticosteroids may cause the appearance of Candida albicans (thrush) in the mouth and throat. The rate reported of candidiasis in clinical trials with Alvesco(r) was low (0.6%, see ADVERSE REACTIONS). The development of pharyngeal and laryngeal candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is unknown. Adequate oral hygiene is of primary importance in minimizing overgrowth of micro-organisms such as Candida albicans. Patients may find it helpful to rinse and gargle with water after using Alvesco(r). Symptomatic candidiasis can be treated with topical anti-fungal therapy while still continuing to use Alvesco(r).
Renal
: Due to the lack of renal excretion of the active metabolite, dose adjustment should not be necessary in renally impaired patients, however, specific studies in this patient group have not been performed.
Respiratory
Paradoxical Bronchospasm: As with other inhalation therapy, paradoxical bronchospasm may occur which is characterized by an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator to relieve acute asthmatic symptoms. Alvesco(r) should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.
Systemic Steroid Replacement by Inhaled Steroid
Particular care is needed in asthmatic patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred during and after transfer. For the transfer of patients being treated with oral corticosteroids, Alvesco(r) inhalation aerosol should first be added to the existing oral steroid therapy, which is then gradually withdrawn. Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced cautiously. Some patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled ciclesonide. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections, particularly gastroenteritis. Although Alvesco(r) inhalation aerosol may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. The physician may consider supplying oral steroids for use in times of stress (e.g. worsening asthma attacks, chest infections, surgery). During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level. Transfer of patients from systemic steroid therapy to Alvesco(r) inhalation aerosol may unmask allergic conditions outside the pulmonary tract that were previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema. These allergies should be symptomatically treated with anti-histamine and/or topical preparations, including topical steroids.
Systemic Effects
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and increased intraocular pressure, with or without glaucoma. Therefore, it is important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
The long-term effects of ciclesonide in human subjects are still unknown. In particular, the local effects of the drug on developmental or immunologic processes in the mouth, pharynx, trachea, and lungs are unknown. There is also no information about the possible long-term systemic effects of the agent (see Monitoring and Laboratory Tests).
Special Populations
There are no adequate and well controlled studies in pregnant women. However, serum concentrations of ciclesonide are generally very low following inhaled administration; thus, fetal exposure is expected to be negligible and the potential for reproductive toxicity low. As with other inhaled corticosteroids, ciclesonide should only be used during pregnancy when the potential benefit to the mother justifies the potential risk to the mother, fetus or infant. Infants born to mothers who received corticosteroids during pregnancy should be observed carefully for hypoadrenalism.
The extent of exposure in pregnancy during clinical trials: Very Limited: individual cases only Nursing Women: It is unknown if ciclesonide and/or its active metabolite is excreted in human milk. In rats, however, very low levels of ciclesonide and/or its metabolites (<0.05% of dose) were found to be excreted into the milk following intravenous or oral administration. As with other inhaled corticosteroids, Alvesco(r) should only be used in nursing women when the potential benefit to the mother justifies the potential risk to the mother and/or infant. Pediatrics (< 12 years of age): Alvesco(r) is not presently recommended for patients younger than 12 years of age.
(> 65 years of age)
Based on the pharmacokinetic characteristics obtained in patients older than 65 years of age, dose adjustment is not necessary in this population.
Monitoring and Laboratory Tests
As with all inhaled corticosteroids, during long-term therapy, HPA axis function (e.g. blood cortisol levels) and effects on the eye (examination for cataracts, increased intraocular pressure and glaucoma) should be assessed periodically by a specialist. See Systemic Effects.
Adverse Drug Reaction Overview
Inhaled corticosteroid therapy may be associated with dose dependent increases in incidence of ocular complications, reduced bone density, suppression of HPA axis responsiveness to stress, and inhibition of growth velocity in children. Although such events have been associated with inhaled corticosteroid therapy, no significant difference was detected between inhaled Alvesco(r) and placebo on HPA function and serum cortisol levels. See DETAILED PHARMACOLOGY. Glaucoma may be exacerbated by inhaled corticosteroid treatment for asthma or rhinitis. In patients with established glaucoma who require long-term inhaled corticosteroid treatment, it is prudent to measure intraocular pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients without established glaucoma, but with a potential for developing intraocular hypertension, intraocular pressure should be monitored at appropriate intervals. In all patients who are receiving long-term inhaled corticosteroid therapy, intraocular pressure should be monitored at appropriate intervals (see Monitoring and Laboratory Tests). In elderly patients treated with inhaled corticosteroids, the prevalence of posterior subcapsular and nuclear cataracts is probably low but increases in relation to the daily and cumulative lifetime dose. Cofactors such as smoking, ultraviolet B exposure, or diabetes may increase the risk. Osteoporosis and bone fracture are complications of long term asthma treatment with parenteral or oral steroids. Inhaled corticosteroid therapy has also been associated with dose dependent bone loss, although the risk is much less with inhaled therapy than with oral and parenteral therapy.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for
approximating rates. The clinical trial safety database for Alvesco(r) consists of a total of 9162 patients (740 adolescents and 8422 adults) treated with Alvesco(r), 100 to 1600 micrograms per day, in clinical studies ranging in duration from 2 weeks to 1 year. The majority of short-term trials had a randomized, blinded design. Three long-term studies were of open-label design. Approximately 6.6% of patients in placebo-controlled clinical trials experienced adverse events assessed as possibly related to treatment with Alvesco(r) by the investigator and/or sponsor (vs. 6.5% of patients treated with placebo). In the majority of cases (56.4%), these were mild and did not require discontinuation of treatment with Alvesco(r). Approximately 6.2% of patients treated with Alvesco(r) discontinued clinical trial participation due to an adverse event vs. 16.4% of patients in the placebo group. The primary adverse event leading to discontinuation was asthma in both treatment groups (Alvesco(r), 4.4% vs. placebo, 13.8%). The following adverse reactions were reported during placebo-controlled clinical trials in >= 1% of patients:
Table 1 - Common Adverse Reactions1 (>=1 - <10%) in Placebo-Controlled Clinical Trials
| Alvesco (r) n=1850 (%) | Placebo n= 934 (%) | |
| Respiratory Paradoxical bronchospasm 2 | 1.8 | 1.9 |
assessed as possibly related to the treatment by investigator and/or sponsor
Paradoxical bronchospasm refers to a known adverse drug reaction of all inhaled drugs, which may be related to the active drug substance, excipients, or in the case of metered dose inhalers, to the cooling caused by the propellant or evaporation. Suspected
paradoxical bronchospasm includes the preferred terms: chest discomfort, chest pain, asthma, bronchospasm, cough, dyspnea, obstructive airways disorder, wheezing.
Dose Response Information: The incidence of possibly treatment-related adverse events was generally comparable among the Alvesco(r) dose groups, with the exception of respiratory, thoracic and mediastinal disorders which showed a trend towards dose dependency. This could be due to the fact that the higher dose groups tended to include patients with more severe asthma.
Special Populations:
No safety signals specific for gender or for age were found in clinical trials.
The following adverse reactions (assessed as possibly related to treatment by the investigator and/or sponsor) were reported in clinical trials with Alvesco (placebo-controlled, active- controlled and open label studies):
Common Clinical Trial Adverse Drug Reactions (>=1% - <10%) Respiratory:
Paradoxical bronchospasm (1.6%), Dysphonia (1.0%)
Uncommon Clinical Trial Adverse Drug Reactions (>=0.1% to <1%) Cardiovascular:
Palpitations (0.1%)
Eye:
Cataract subcapsular (0.1%)
Gastrointestinal:
Nausea (0.2%), Dry mouth (0.1%), Dyspepsia (0.1%)
Infections:
Oral candidiasis (0.6%), Candidiasis (0.1%), Oral fungal infection (0.1%), Pharyngitis (0.1%)
Injury:
Contusion (0.1%)
Investigations:
ALT increased (0.1%), Gamma-glutamyltransferase increased (0.1%), Weight increased (0.1%)
Nervous System:
Headache (0.4%), Dysgeusia (0.3%), Dizziness (0.1%)
Respiratory, thoracic and mediastinal disorders:
Pharyngolaryngeal pain (0.4 %), Throat irritation (0.3%), Dry throat (0.1%)
Skin:
Rash (0.1%)
The incidence of local oropharyngeal adverse reactions in Alvesco(r)-treated patients was low and comparable to placebo, see Table 2.
Table 2 - Local Adverse Reactions1 in Placebo-Controlled Clinical Studies
| Alvesco (r) n=1850 (%) | Placebo n= 934 (%) | |
| Gastrointestinal | 0.2 | 0.1 |
| Dry Mouth | ||
| Local Infections | ||
| Oral candidiasis | 0.5 | 0.4 |
| Oral fungal infection NOS | 0.1 | 0.0 |
| Nervous System | ||
| Dysgeusia | 0.4 | 0.1 |
| Respiratory | ||
| Dysphonia/hoarseness | 0.9 | 0.4 |
| Dry Throat | 0.2 | 0.0 |
| Pharyngitis | 0.1 | 0.0 |
| Throat irritation | 0.1 | 0.0 |
Adverse events considered to be possibly related to treatment by investigator and/or sponsor
Abnormal Hematologic and Clinical Chemistry Findings:
Examination of the percentage of patients with normal values at baseline and values above or below the normal range at the end of treatment did not demonstrate any trends with respect to changes in hematology and biochemistry values. See Uncommon Clinical Trial Adverse Drug Reactions above.
Post-Market Adverse Drug Reactions
Very rare reports of immediate or delayed hypersensitivity reactions such as angioedema with swelling of lips, tongue and pharynx as well as increased intraocular pressure in susceptible patients.
Overview
In vitro
data indicate that CYP3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide (M1) in man.
The serum levels of ciclesonide and its active metabolite M1, are low. However, co- administration with a potent inhibitor of the cytochrome P 450 3A4 system (e.g. itraconazole, ritonavir or nelfinavir) should be considered with caution because there might be an increase in ciclesonide/active metabolite serum levels, as was observed when orally inhaled ciclesonide was concomitantly administered with ketoconazole (see Drug-Drug Interactions below). The risk of clinical adverse effect (e.g. cushingoid syndrome) cannot be excluded.
Drug-Drug Interactions
The drugs listed in the following table are based on drug-drug interaction clinical studies:
| Ciclesonide | Effect | Clinical Comment |
| Ketoconazole | The exposure of the ciclesonide active metabolite (M1) increased approximately 3.5 fold. | Co-administration should be considered with caution. The risk of clinical adverse effect cannot be excluded. |
| Erythromycin | No pharmacokinetic interaction was observed in this study. | No special precautions are necessary. |
Ciclesonide is not expected to influence the metabolism of other drugs.
Drug-Food Interactions
Interactions with food have not been established. Drug-food interactions are unlikely for inhaled corticosteroids.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established. Drug-laboratory interactions are unlikely for inhaled corticosteroids.
Recommended Dose and Dosage Adjustment
The recommended starting dose of Alvesco(r) therapy for most patients, whether previously maintained on either bronchodilators alone or inhaled corticosteroids, is 400 micrograms once daily. The recommended dose range is 100 to 800 micrograms per day. Alvesco(r) can be administered as 1 or 2 puffs once daily either in the morning or evening. Some patients with more severe asthma may be more adequately controlled on 800 micrograms daily (administered as 400 micrograms twice daily). As with all inhaled corticosteroids, the dose of Alvesco(r) should be adjusted according to individual response. Symptoms can start to improve with Alvesco(r) within 24 hours of treatment. Clinically, Alvesco(r) has been shown to improve lung function as measured by FEV1, peak expiratory flow, improved asthma symptom control, reduced exacerbations, and decreased need for inhaled beta- 2 agonists. It is important to gain control of asthma symptoms and optimize pulmonary function as soon as possible. If there has been no improvement within one to two weeks, the patient should consult with their physician. Due to its prophylactic nature, Alvesco(r) should be taken regularly even when patients are asymptomatic. The patient should be aware that the benefit of Alvesco(r) depends on regular use even when they are experiencing no symptoms. When patient symptoms remain under satisfactory control, the dose of Alvesco(r) should be titrated to the lowest dose at which effective control of asthma is maintained. Patients should be instructed to seek medical attention if their asthma symptoms worsen, or if their need for rescue medication increases. Dose adjustments are not necessary in elderly patients, patients with liver impairment and patients with renal impairment.
Missed Dose
It is very important that ciclesonide is used regularly. If a dose is missed, the next dose should be taken when it is due.
Administration
Alvesco(r) is for oral inhalation use only. To ensure the proper dosage and administration of the drug, the patient must be instructed by a physician or other health professional in the use of the inhalation aerosol (see CONSUMER INFORMATION). Inhaler technique of patients should be checked regularly to make sure that correct method is used and inhaler actuation is synchronized with inhalation to ensure optimum delivery to the lungs. In patients who find co-ordination of a pressurized metered dose inhaler difficult, a spacer device (AeroChamber Plus(r)) may be used with Alvesco(r). If the inhaler is new or has not been used for one week or more, three puffs should be released into the air. No shaking is necessary as Alvesco(r) is a solution aerosol. The mouthpiece should be cleaned with a dry tissue or cloth weekly. No part of the inhaler should be washed or put into water. Patients should be instructed to use the following technique to administer their medication: Instruct the patient to remove the mouthpiece cover, place the inhaler in their mouth, close their lips around the mouthpiece, and breathe in slowly and deeply. After starting to breathe in through the mouth, the top of the inhaler should be pressed down. Then, patients should move the inhaler away from their mouth, and hold their breath for about 10 seconds, or as long as is comfortable. The patient should not breathe out into the inhaler. Finally, patients should breathe out slowly, and replace the mouthpiece cover.
The patient should be in a relatively stable phase. A high dose of Alvesco(r) should be given in combination with the oral steroid for about 10 days. Then the oral steroid should be gradually reduced to the lowest possible level. The gradual withdrawal of the systemic steroid is started by reducing the daily dose by 1.0 mg of prednisone (or equivalent of another corticosteroid) at seven day intervals if the patient is under close observation. If close observation is not feasible, the withdrawal of the systemic steroid should be more gradual at approximately 1.0 mg of the daily dose of prednisone (or equivalent) every ten days. If withdrawal symptoms appear, the previous dose of the systemic drug should be resumed for a week before any further decrease is attempted.
Single doses of up to 3200 micrograms inhaled Alvesco(r) were administered to healthy volunteers and were well tolerated. The potential for acute toxic effects following overdose of inhaled ciclesonide is low. The only effect that follows inhalation of large amounts of the drug over a short period of time may be temporary suppression of adrenal function, symptoms of which may include: weakness, nausea, and hypotension. In such cases, treatment with Alvesco(r) should be continued at a dose sufficient to control asthma. Recovery of adrenal function can be verified by measuring plasma cortisol. If higher than recommended doses are administered continuously over prolonged periods, some degree of adrenal suppression may occur, therefore monitoring of adrenal reserve should be considered. Gradual reduction of the inhaled dose may be required. Treatment with Alvesco(r) should be continued at a dose sufficient to control asthma.
Mechanism of Action
Ciclesonide exhibits low binding affinity to the glucocorticoid receptor and is pharmacologically inactive. Once inhaled, ciclesonide is converted by esterases in the lungs to its active metabolite, 21 des-methylpropionyl-ciclesonide (M1), which is a potent glucocorticoid that binds to glucocorticoid receptors in the lung resulting in local pronounced anti-inflammatory activity.
Pharmacodynamics
The active metabolite of ciclesonide (M1) exhibits high receptor affinity. Ciclesonide possesses a unique combination of properties that limit systemic exposure to the active drug including: the conversion to the active metabolite predominantly in the lung, high lung deposition, reversible formation of fatty acid conjugates of M1 in lung tissue slices, high clearance, low oral bioavailability, high protein binding, and low receptor affinity of metabolites other than M1. The clinical effects of ciclesonide on the HPA function and serum cortisol levels were investigated and, at therapeutic doses, no significant difference was detected between inhaled ciclesonide and placebo. See DETAILED PHARMACOLOGY.
Pharmacokinetics
Ciclesonide is presented in HFA-134a propellant and ethanol as a solution aerosol, delivering 50 mcg, 100 mcg or 200 mcg ciclesonide ex-valve. The doses are proportionally formulated with respect to dose and puff strength and exhibit bioequivalent systemic exposure when the same dose is inhaled by the three different formulation strengths. Across the recommended dose range, ciclesonide demonstrates linear pharmacokinetics with increases in systemic exposure proportional to dose. When a single dose of 3200 mcg of ciclesonide was administered, a greater than proportional increase in systemic exposure was observed. The pharmacokinetic characterization of ciclesonide focused on the active metabolite (M1) of ciclesonide, as it is the active moiety. While systemic drug levels of M1 are relevant for the systemic effect profile, a close relationship between systemic exposure and efficacy response is not assumed for asthma treatment with inhaled corticosteroids due to their topical mode of action. Since ciclesonide is poorly absorbed via the gastrointestinal tract and shows an extensive first pass metabolism, systemic exposure will depend on the drug fraction that is absorbed via the lung. The following table describes the pharmacokinetic characteristics of the active metabolite M1 in healthy patients between 22 and 43 years of age following single and repeated inhalation of 400 mcg ciclesonide once daily. Pharmacokinetic data of healthy subjects and asthma patients were also shown to be similar. See DETAILED PHARMACOLOGY for further information.
| Active Metabolite (M1) | ||||
| C max ( u g/l) | AUC * ( u g *h/l) | t m ax (h) | t 1/2 (h) | |
| Single Dose | 0.30 (0.13) | 1.72 (0.73) | 1.08 (0.62) | 5.23 (1.28) |
| Steady State | 0.37 (0.06) | 2.18 (0.42) | 0.94 (0.44) | 6.72 (1.04) |
*Single Dose = AUC(0,inf); Steady State = AUC (0,24h) Absorption: Studies with oral and intravenous dosing of radiolabelled drug have shown low oral absorption (24.5%). When inhaled the oral bioavailability of both ciclesonide and the active metabolite is negligible (<0.5% for ciclesonide, <1% for the active metabolite). Based on a g- scintigraphy experiment, lung deposition in healthy subjects is 52%. The systemic bioavailability for the active metabolite is >50% by using the ciclesonide metered-dose inhaler. As the oral bioavailability for the active metabolite is <1%, the swallowed portion of the inhaled drug effectively does not contribute to the systemic absorption. Ciclesonide undergoes extensive first pass metabolism. See Table 4 for information regarding the pharmacokinetic characteristics (AUC, Tmax and Cmax) of ciclesonide following single and repeated dose administration.
Following intravenous administration to healthy subjects, the volume of distribution averaged 2.9 l/kg. The total serum clearance of ciclesonide is high (average 2.0 l/h/kg) indicating a high hepatic extraction. The percentage of ciclesonide bound to human plasma proteins is 99% and that of the active metabolite is greater than 98%. Only the unbound drug in the systemic circulation (approximately 1-2%) is available for further systemic pharmacodynamic effect. The active metabolite showed no accumulation in red blood cells, as could be concluded from high plasma/whole blood ratio of 1.5-1.6 at 0.5-6 hours post-dosing.
Metabolism: Ciclesonide is a prodrug and is hydrolysed to its pharmacologically active metabolite by esterase enzymes primarily in the lungs. Investigation of the enzymology of further metabolism by human liver microsomes showed that this compound is mainly metabolized to hydroxylated inactive metabolites by CYP3A4 catalysis. Lipophilic fatty acid ester conjugates of the active metabolite in the lung were detected using in vitro techniques.
After oral and intravenous administration, ciclesonide is predominantly excreted via the faeces (78 and 68%, respectively), indicating that excretion via the bile is the major route of elimination. After intravenous administration, the clearance of ciclesonide was 152 +- 37 L/h and that of the active metabolite, M1 (assuming full conversion from ciclesonide) was 228 +- 65 L/h. The half-life estimated from the terminal elimination phase after inhaled administration of ciclesonide was approximately 6 h.
Special Populations and Conditions
In a comparison between one study in elderly subjects and another study in young healthy subjects, there was an approximately 2-fold increase in the rate and extent of exposure to the active metabolite in elderly patients. However, in a population pharmacokinetic analysis of 9 studies, age did not impact the clearance or volume of distribution of the active metabolite.
Pediatrics: Alvesco(r) is currently not recommended in patients < 12 years of age.
Reduced liver function may affect the elimination of corticosteroids. In a study including patients with hepatic impairment suffering from liver cirrhosis, a higher systemic exposure (1.8 to 2.8 times) to the active metabolite was observed. See DETAILED PHARMACOLOGY.
Due to the low rate of renal excretion of ciclesonide metabolites, studies on renal impaired patients have not been performed.
The container contains a pressurized liquid and should not be pierced. It is recommended that Alvesco(r) be stored at room temperature between 15 - 30 oC. Do not freeze.
Alvesco(r) is a solution aerosol. Additional ingredients are propellant HFA-134a (Norflurane) and ethanol. The inhaler is comprised of an aluminum canister sealed with a metering valve, actuator and cap. Alvesco(r) is available in three strengths: 50 mcg per actuation (ex-valve), 100 mcg per actuation (ex-valve), and 200 mcg per actuation (ex-valve). Alvesco(r) is available in canisters containing 30, 60 or 120 actuations.