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In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans occurred in 32 of 3038 patients treated with ALVESCO. Of the 32 reported cases, 20 occurred in 1394 patients treated with a total daily dose of 320 mcg of ALVESCO or higher. Most cases of candida infection were mild to moderate. When such an infection develops, it should be treated with appropriate local or systemic (i.e. oral antifungal) therapy while remaining on treatment with ALVESCO, but at times therapy with ALVESCO may need to be interrupted. Patients should rinse the mouth after inhalation of ALVESCO.
Acute Asthma Episodes
ALVESCO is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with ALVESCO. During such episodes, patients may require therapy with oral corticosteroids.
Persons who are using 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 using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, 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 pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Inhaled corticosteroids should be used with caution, if at all, 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 Corticosteroid Therapy
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. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg 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 and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ALVESCO may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids 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. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during ALVESCO therapy [see DOSAGE AND ADMINISTRATION]. Lung function (FEV1 or AM PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic steroid therapy to ALVESCO may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.
During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.
Hypercorticism and Adrenal Suppression
ALVESCO will often help control asthma symptoms with less suppression of HPA function than therapeutically similar oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ALVESCO. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients particularly when ALVESCO is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ALVESCO should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma.
Reduction in Bone Mineral Density
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g. anticonvulsants and oral corticosteroids) should be monitored and treated with established standards of care.
Effect on Growth
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ALVESCO routinely (e.g. via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ALVESCO, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use In Specific Populations].
Glaucoma and Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported following the administration of inhaled corticosteroids including ALVESCO. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
In a comparator control study of one year treatment duration, 743 patients 18 years of age and older (mean age 43.1 years) with moderate persistent asthma were treated with ALVESCO 320 mcg twice daily and 742 were treated with a labeled dose of a comparator inhaled corticosteroid appropriate for the patient population. Patients had an ophthalmology examination that included visual acuity, intraocular pressure measurement, and a slit lamp examination at baseline, 4, 8 and 12 months. Lens opacities were graded using the Lens Opacification System III. After 52 weeks, CLASS I effects (minimally detected changes) were recorded in 36.1% of the ALVESCO-treated patients and in 38.4% of patients treated with the comparator inhaled corticosteroid. The more severe CLASS III effects were recorded in 8.1% of the ALVESCO-treated patients and 9.2% of patients treated with the comparator inhaled corticosteroid. Of those patients having a CLASS III effect, the incidence of posterior sub-capsular opacities was 0.9% and 0.5% in the ALVESCO- and comparator-treated patients respectively.
As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with ALVESCO, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with ALVESCO should be discontinued and alternative treatment should be instituted.
Patient Counseling Information
See FDA-Approved Patient Labeling accompanying the product.
Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with ALVESCO therapy, but at times therapy with the ALVESCO inhaler may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.
Status Asthmaticus and Acute Asthma Symptoms
Patients should be advised that ALVESCO is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. The patient should be instructed to contact their physician immediately if there is deterioration of their asthma.
Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.
Hypercorticism and Adrenal Suppression
Patients should be advised that ALVESCO may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ALVESCO.
Reduction in Bone Mineral Density
Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and where appropriate, be treated for this condition.
Reduced Growth Velocity
Patients should be informed that orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.
Use Daily for Best Effect
Patients should be advised to use ALVESCO at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for four weeks or longer after starting treatment. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop ALVESCO use abruptly. Patients should contact their physician immediately if use of ALVESCO is discontinued.
How to Use ALVESCO
Patients should use ALVESCO only with the actuator supplied with the product. When the dose indicator display window shows a red zone, approximately 20 inhalations are left, and a refill is required. Discard the inhaler when the indicator shows zero.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ciclesonide demonstrated no carcinogenic potential in a study of oral doses up to 900 mcg/kg/day (approximately 6 times the maximum human daily inhalation dose based on mcg/m²/day) in mice for 104 weeks and in a study of inhalation doses up to 193 mcg/kg/day (approximately 2 times the maximum human daily inhalation dose based on mcg/m²/day) in rats for 104 weeks.
Ciclesonide was not mutagenic in an Ames test or in a forward mutation assay and was not clastogenic in a human lymphocyte assay or in an in vitro micronucleus test. However, ciclesonide was clastogenic in the in vivo mouse micronucleus test. The concurrent reference corticosteroid (dexamethasone) in this study showed similar findings.
No evidence of impairment of fertility was observed in a reproductive study conducted in male and female rats both dosed orally up to 900 mcg/kg/day (approximately 10 times the maximum human daily inhalation dose based on mcg/m²/day).
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
Oral administration of ciclesonide in rats up to 900 mcg/kg/day (approximately 10 times the maximum human daily inhalation dose based on mcg/m²/day) produced no teratogenicity or other fetal effects. However, subcutaneous administration of ciclesonide in rabbits at 5 mcg/kg/day (less than the maximum human daily inhalation dose based on mcg/m²/day) or greater produced fetal toxicity. This included fetal loss, reduced fetal weight, cleft palate, skeletal abnormalities including incomplete ossifications, and skin effects. No toxicity was observed at 1 mcg/kg (less than the maximum human daily inhalation dose based on mcg/m²).
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. Experience with oral corticosteroids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
It is not known if ciclesonide is secreted in human milk. However, other corticosteroids are excreted in human milk. In a study with lactating rats, minimal, but detectable levels of ciclesonide were recovered in milk. Caution should be used when ALVESCO is administered to nursing women.
The safety and effectiveness of ALVESCO in children under 12 years of age have not been established.
Two randomized double-blind placebo-controlled studies were conducted to evaluate the efficacy of ALVESCO 40, 80, or 160 mcg administered once daily for 12 weeks in patients 4 to 11 years of age with asthma. These studies included 1018 patients previously using either controller therapy (predominately inhaled corticosteroids) or reliever therapy (bronchodilator therapy alone). The patients had a mean baseline percent predicated FEV1 of 68%. The primary efficacy endpoint was morning pre-dose FEV1. Other measures of efficacy included AM PEF, asthma symptoms, and rescue albuterol use. The studies showed inconsistent results and do not establish the efficacy of ALVESCO in patients 4 to 11 years of age.
One randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of ALVESCO 40, 80, and 160 mcg administered once daily for 24 weeks in 992 patients 2 to 6 years of age with persistent asthma. The primary efficacy endpoint was time to the first severe asthma exacerbation [defined as worsening of asthma which required treatment with systemic (including oral) steroids or any other asthma medication besides treatment medication and rescue medication] or lack of improvement, whichever occurred first. No statistically significant differences were observed for the individual comparisons of ALVESCO 40, 80, and 160 mcg to placebo. Results from this study did not establish efficacy of ALVESCO in patients 2 to 6 years of age.
The safety of ALVESCO was evaluated in 957 children between the ages of 4 and 11 and 747 children between the ages of 2 and 6 years of age who were treated with ALVESCO in the three controlled clinical studies, 2 open label one-year safety extensions of the controlled clinical studies, and one open label safety study. In the controlled studies, the distribution of adverse events in the ALVESCO and placebo groups was similar. The type of adverse events reported were similar to events reported in this patient population with other inhaled corticosteroids. The open label safety studies in children 4 to 11 years of age compared the safety of ALVESCO in doses up to 160 mcg once daily with an orally inhaled corticosteroid comparator. The types of adverse events seen were similar to those seen in the 12-week controlled studies.
Studies in children under 2 years of age have not been conducted given the lack of efficacy observed in patients 2 to 11 years of age.
Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids including ALVESCO should be monitored routinely (e.g., via stadiometry).
A 52-week, multi-center, double-blind, randomized, placebo-controlled parallel-group study was conducted to assess the effect of orally inhaled ciclesonide on growth rate in 609 pediatric patients with mild persistent asthma, aged 5 to 8.5 years. Treatment groups included orally inhaled ciclesonide 40 mcg or 160 mcg or placebo given once daily. Growth was measured by stadiometer height during the baseline, treatment and follow-up periods. The primary comparison was the difference in growth rates between ciclesonide 40 mcg and 160 mcg and placebo groups. Conclusions cannot be drawn from this study because compliance could not be assured. There was no difference in efficacy measures between the placebo and the ALVESCO groups. Ciclesonide blood levels were also not measured during the one-year treatment period.
The potential growth effects of prolonged treatment with orally inhaled corticosteroids should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, including ALVESCO, each patient should be titrated to his/her lowest effective dose.
Clinical studies of ALVESCO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/14/2013
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