Included as part of the PRECAUTIONS section.
Local Nasal Effects
Epistaxis and Nasal Ulceration
In clinical trials of 2 to 26 weeks in duration,
epistaxis was observed more frequently in patients treated with ZETONNA than
those who received placebo. In the 26-week open-label extension of the
perennial allergic rhinitis trial, nasal ulceration was identified in 4 of 824
patients administered ZETONNA (148 mcg). [see ADVERSE REACTIONS]
The occurrence of local nasal adverse events was further
evaluated in a separate, postmarketing 26-week randomized, open-label,
active-controlled nasal and ocular safety trial conducted in patients with
perennial allergic rhinitis. In this study epistaxis was observed in 6% of
patients treated with ZETONNA and nasal ulceration was identified in 3 of 367
patients administered ZETONNA. [see ADVERSE REACTIONS]
Nasal Septal Perforation
Nasal septal perforation has been reported in patients
following the intranasal application of ZETONNA. Three short-term
placebo-controlled trials (2 weeks) and one long-term (26 weeks with placebo
control and 26 weeks open-label extension without placebo control) trial were
conducted in patients with seasonal and perennial allergic rhinitis. Nasal
septal perforations were reported in 2 patients out of 2335 treated with
ZETONNA compared with none of 892 treated with placebo. No nasal septal
perforations were reported in 367 patients treated with ZETONNA in a
postmarketing 26-week, open-label, active-controlled trial in patients with
perennial allergic rhinitis. [see ADVERSE REACTIONS]
Before starting ZETONNA conduct a nasal examination to
ensure that patients are free of nasal disease other than allergic rhinitis.
Periodically monitor patients with nasal examinations during treatment for
adverse effects in the nasal cavity. If an adverse reaction (e.g. erosion,
ulceration, perforation) is noted, discontinue ZETONNA. Avoid spraying ZETONNA
directly onto the nasal septum.
In clinical trials with another
formulation of ciclesonide, the development of localized infections of the nose
or pharynx with Candida albicans has occurred. If such an infection develops
with ZETONNA, it may require treatment with appropriate local therapy and
discontinuation of ZETONNA.
Impaired Wound Healing
Because of the inhibitory effect of corticosteroids on
wound healing, patients who have experienced recent nasal septal ulcers, nasal
surgery, or nasal trauma should not use ZETONNA until healing has occurred.
Glaucoma And Cataracts
Nasal and inhaled corticosteroids may result in the development
of glaucoma and cataracts. Therefore, close monitoring is warranted in patients
with a change in vision or with a history of increased intraocular pressure,
glaucoma, or cataracts.
ZETONNA is contraindicated in patients with a known
hypersensitivity to ciclesonide or any of the ingredients of ZETONNA. Cases of
hypersensitivity reactions following administration of ciclesonide with
manifestations such as angioedema, with swelling of the lips, tongue and
pharynx, have been reported.
Patients who are using drugs that suppress the immune
system are more susceptible to infections than healthy individuals. Chicken pox
and measles, for example, can have a more serious or even fatal course in
susceptible children or adults using corticosteroids. In 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 or prior corticosteroid
treatment to the risk is also not known. If a patient is exposed to chicken
pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.
If a patient is 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.
Corticosteroids should be used with caution, if at all,
in patients with active or quiescent tuberculosis infections of the respiratory
tract; or in patients with untreated local or systemic fungal or bacterial
infections; systemic viral or parasitic infections; or ocular herpes simplex
because of the potential for worsening of these infections.
Hypothalamic-Pituitary-Adrenal Axis Suppression
Hypercorticism and adrenal suppression may occur when
intranasal corticosteroids, such as ZETONNA, are used at higher than
recommended dosages or in susceptible individuals at recommended dosages. If
such changes occur, the dosage of ZETONNA should be discontinued slowly,
consistent with accepted procedures for discontinuing oral steroid therapy.
The replacement of a systemic corticosteroid with a
topical corticosteroid can be accompanied by signs of adrenal insufficiency. In
addition, some patients may experience symptoms of corticosteroid withdrawal,
e.g., joint and muscular pain, lassitude, and depression. Patients previously
treated for prolonged periods with systemic corticosteroids and transferred to
topical corticosteroids should be carefully monitored for acute adrenal
insufficiency in response to stress. In those patients who have asthma or other
clinical conditions requiring long-term systemic corticosteroid treatment,
rapid decreases in systemic corticosteroid dosages may cause a severe
exacerbation of their symptoms.
Effect On Growth
Corticosteroids may cause a reduction in growth velocity
when administered to pediatric patients. Monitor the growth routinely (e.g.,
via stadiometry) in pediatric patients receiving ZETONNA. [see Pediatric Use]
Patient Counseling Information
See FDA-Approved Patient Labeling accompanying the
Local Nasal Effects
Inform patients that treatment with ZETONNA may lead to
adverse reactions, which include nasal septal perforation, epistaxis, and nasal
ulceration. In addition, ciclesonide is associated with candidal infection, and
nasal corticosteroids are associated with impaired wound healing. Do not spray
ZETONNA directly onto the nasal septum. Patients who have experienced recent
nasal septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal
trauma should not use ZETONNA until healing has occurred [see WARNINGS AND
Glaucoma and Cataracts
Inform patients that glaucoma and cataracts are
associated with nasal and inhaled corticosteroid use. Instruct patients to
inform his/her health care provider if a change in vision is noted while using
ZETONNA [see WARNINGS AND PRECAUTIONS].
Warn patients who are on immunosuppressive doses of
corticosteroids to avoid exposure to chickenpox or measles, and if exposed, to
consult their physician without delay. Inform patients of potential worsening
of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or
ocular herpes simplex [see WARNINGS AND PRECAUTIONS].
Instruct patients to use ZETONNA on a regular, once daily
basis since its effectiveness depends on its regular use. In clinical trials,
the onset of effect was seen after 36 hours following the first dose. Maximum
benefit is usually achieved within 1 to 2 weeks after initiation of dosing.
Initial assessment of response should be made during this timeframe and
periodically until the patient's symptoms are stabilized. Instruct the patient
to take the medication as directed, not exceed the prescribed dosage, and
contact the physician if symptoms do not improve by a reasonable time or if the
Keep Spray Out of Eyes and Off Nasal Septum
Instruct patients to avoid spraying ZETONNA in their eyes
or directly on the nasal septum.
Storage And Handling
Instruct patients to use the ZETONNA canister only with
the ZETONNA actuator supplied with the product. The dose indicator display
window will show a red zone when it is about time to replace the ZETONNA.
Replace ZETONNA when the indicator shows zero.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Ciclesonide demonstrated no carcinogenic potential in
mice in a study of oral doses up to 900 mcg/kg (approximately 60 times the
maximum recommended human daily intranasal dose (MRHDID) in adults based on
mcg/m²/day) in mice for 104 weeks, nor in a study in rats of
inhalation doses up to 193 mcg/kg (approximately 25 times the maximum human
daily intranasal dose in adults and adolescents 12 years of age or older based
on mcg/m²/day) 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 120 times MRHDID in adults based on mcg/m²/day).
Use In Specific Populations
Pregnancy Category C.
There are no adequate and well-controlled trials in
pregnant women. ZETONNA 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.
Oral administration of ciclesonide in rats at
approximately 120 times the maximum recommended human daily intranasal dose (MRHDID)
in adults (on a mcg/m² basis at a maternal dose of 900 mcg/kg/day)
produced no teratogenicity or other fetal effects. However, subcutaneous
administration of ciclesonide in rabbits at similar to MRHDID (on a mcg/m² basis at a maternal dose of 5 mcg/kg/day) 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 Â¼ of the MRHDID in adults (on a mcg/m² basis at a maternal dose
of 1 mcg/kg/day).
Hypoadrenalism may occur in infants born of mothers
receiving corticosteroids during pregnancy. Such infants should be carefully
It is not known if ciclesonide is excreted in human milk.
However, other corticosteroids are excreted in human milk. In a study with
lactating rats, minimal but detectable levels of radiolabeled ciclesonide were
recovered in milk. Caution should be used when ZETONNA is administered to
The safety and effectiveness for seasonal and perennial
allergic rhinitis in children 12 years of age and older have been established.
The safety and efficacy of ZETONNA for treatment of the symptoms of seasonal
and perennial allergic rhinitis in patients 11 years of age and younger have
not been established.
The safety and efficacy of ZETONNA in pediatric patients
6-11 years of age were evaluated in two randomized, double blind, parallel
placebo-controlled clinical trials in 1693 pediatric patients with allergic
rhinitis. Of the two trials, one was 2 weeks in duration and evaluated the
efficacy of two doses of ZETONNA (37 mcg and 74 mcg once daily) in 847 patients
with seasonal allergic rhinitis. The second clinical trial was 12 weeks in
duration and evaluated the efficacy of two doses of ZETONNA (37 mcg and 74 mcg
once daily) in 846 patients with perennial allergic rhinitis. The trials were
similar in design to the trials conducted in adolescents and adults. The
primary efficacy endpoint was the difference from placebo in the change from
baseline of the average morning and evening reflective total nasal symptom
scores (rTNSS) averaged over 2 weeks of treatment in the seasonal allergic
rhinitis trial and over the first 6 weeks of treatment in the perennial
allergic rhinitis trial. In the 2-week trial in patients with seasonal allergic
rhinitis, treatment with ZETONNA at either dose failed to demonstrate efficacy.
In the 12-week trial in patients with perennial allergic rhinitis, ZETONNA 37
mcg and 74 mcg once daily both demonstrated significant improvement in rTNSS
compared to placebo with treatment differences of 0.59 (95% CI: 0.23, 0.95) and
0.47 (95% CI: 0.11, 0.83), respectively. The safety profile observed in
children 6 to 11 years of age with seasonal or perennial allergic rhinitis was
similar to the adverse reactions observed in the clinical trial population of
patients 12 year of age and older [see ADVERSE REACTIONS].
The effect of ZETONNA on the HPA axis was evaluated in
one placebo-controlled clinical study of 6 weeks in duration in children 6 to11
years of age with perennial allergic rhinitis [see CLINICAL PHARMACOLOGY].
Studies in children under 6 years of age have not been
Controlled clinical trials have shown that intranasal
corticosteroids may cause a reduction in growth velocity in pediatric patients.
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
intranasal corticosteroids, including the impact on final adult height, are
unknown. The potential for “catch-up” growth following discontinuation of
treatment with intranasal corticosteroids has not been adequately studied. The
growth of pediatric patients receiving intranasal corticosteroids, including
ZETONNA, should be monitored routinely (e.g., via stadiometry). A 52-week,
multi-center, double-blind, randomized, placebo-controlled parallel-group trial
was conducted to assess the effect of orally inhaled ciclesonide (ALVESCO® Inhalation Aerosol) 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 and 160 mcg and placebo groups. Conclusions cannot be drawn from
this trial because compliance could not be assured. Ciclesonide blood levels
were also not measured during the one-year treatment period. There was no
difference in efficacy measures between the placebo and the orally inhaled
ciclesonide (ALVESCO® Inhalation Aerosol) groups.
The potential growth effects of prolonged treatment
should be weighed against clinical benefits obtained and the availability of
safe and effective noncorticosteroid treatment alternatives. To minimize the
systemic effects of intranasal corticosteroids, each patient should be titrated
to the lowest dose that effectively controls his/her symptoms.
The potential for ZETONNA to cause growth suppression in
susceptible patients or when given at higher than recommended dosages cannot be
Clinical trials of ZETONNA did not include sufficient
numbers of patients age 65 and over to determine whether they responded
differently from 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 reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.