Included as part of the PRECAUTIONS section.
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
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
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
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
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
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
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,
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
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
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
Hypoadrenalism may occur in infants born of mothers
receiving corticosteroids during pregnancy. Such infants should be carefully
Â Nursing Mothers
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
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 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
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
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.