Document
DailyMed Label: Omnaris
Title
DailyMed Label: Omnaris
Date
2010
Document type
DailyMed Prescription
Name
Omnaris
Generic name
ciclesonide
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-6020
Product information
NDC: 54868-6020
Description
The active component of OMNARIS Nasal Spray is ciclesonide, a non-halogenated
glucocorticoid having the chemical name pregna -1,4-diene-3,20-dione,
16,17-[[R-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-,(11β,16α)-.
Ciclesonide is delivered as the R-epimer. The empirical formula is C 32 H 44 O 7 and its
molecular weight is 540.7. Its structural formula is as follows:
Ciclesonide is a white to yellow-white powder, practically insoluble in water
and freely soluble in ethanol and acetone. OMNARIS Nasal Spray is a
metered-dose, manual-pump spray formulation containing a hypotonic aqueous
suspension of ciclesonide. OMNARIS Nasal Spray also contains microcrystalline
cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and
edetate sodium; and hydrochloric acid to adjust the pH to 4.5. The contents of
one 12.5 gram bottle provide 120 actuations, after initial priming. Prior to
initial use, OMNARIS Nasal Spray must be gently shaken and then the pump must be
primed by actuating eight times. Once primed, each actuation of the pump
delivers 50 mcg ciclesonide in a volume of 70 microliters from the nasal
actuator. If the product is not used for four consecutive days, it should be
gently shaken and reprimed with one spray or until a fine mist appears.
image of chemical structure
Indications
Seasonal Allergic Rhinitis OMNARIS Nasal Spray is indicated for the treatment of nasal
symptoms associated with seasonal allergic rhinitis in adults and children 6
years of age and older.
Perennial Allergic Rhinitis OMNARIS Nasal Spray is indicated for the treatment of nasal
symptoms associated with perennial allergic rhinitis in adults and adolescents
12 years of age and older.
Dosage
Seasonal Allergic Rhinitis
Adults and Children (6 Years of Age and Older): The
recommended dose of OMNARIS Nasal Spray is 200 mcg per day administered as 2
sprays (50 mcg/spray) in each nostril once daily.
Perennial Allergic Rhinitis
Adults and Adolescents (12 Years of Age and Older):
The recommended dose of OMNARIS Nasal Spray is 200 mcg per day administered as 2
sprays (50 mcg/spray) in each nostril once daily.
The maximum total daily dosage should not exceed 2 sprays in each nostril
(200 mcg/day).
Prior to initial use, OMNARIS Nasal Spray must be gently shaken and then the
pump must be primed by actuating eight times. If the product is not used for
four consecutive days, it should be gently shaken and reprimed with one spray or
until a fine mist appears.
Directions for Use
Illustrated patient's instructions for proper use accompany each package of
OMNARIS Nasal Spray.
Contraindications
OMNARIS Nasal Spray is contraindicated in patients with a hypersensitivity to
any of its ingredients.
Precautions
General Intranasal corticosteroids may cause a reduction in growth
velocity when administered to pediatric patients (see PRECAUTIONS: Pediatric Use ). Rarely, immediate
hypersensitivity reactions or contact dermatitis may occur after the
administration of intranasal corticosteroids. Patients with a known
hypersensitivity reaction to other corticosteroid preparations should use
caution when using ciclesonide nasal spray since cross reactivity to other
corticosteroids including ciclesonide may also occur.
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 a nasal corticosteroid until healing has occurred.
In clinical studies with OMNARIS Nasal Spray, the development of localized
infections of the nose and pharynx with Candida albicans
has rarely occurred. When such an infection develops, it may require
treatment with appropriate local therapy and discontinuation of OMNARIS Nasal
Spray. Therefore, patients using OMNARIS Nasal Spray over several months or
longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the
nasal mucosa. Intranasal 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.
If recommended doses of intranasal corticosteroids are exceeded or if
individuals are particularly sensitive or predisposed by virtue of recent
systemic steroid therapy, symptoms of hypercorticism may occur, including very
rare cases of menstrual irregularities, acneiform lesions, and cushingoid
features. If such changes occur, topical corticosteroids should be discontinued
slowly, consistent with accepted procedures for discontinuing oral steroid
therapy.
The risk of glaucoma was evaluated by assessments of intraocular pressure in
3 studies including 943 patients. Of these, 390 adolescents or adults were
treated for up to 52 weeks and 186 children ages 2 to 11 received treatment with
OMNARIS Nasal Spray 200 mcg daily for up to 12 weeks. In these trials, no
significant differences in intraocular pressure changes were observed between
OMNARIS Nasal Spray 200 mcg and placebo-treated patients. Additionally, no
significant differences between OMNARIS Nasal Spray 200 mcg and placebo-treated
patients were noted during the 52-week study of adults and adolescent patients
in whom thorough ophthalmologic assessments were performed including evaluation
of cataract formation using slit lamp examinations. Rare instances of wheezing,
nasal septum perforation, cataracts, glaucoma, and increased intraocular
pressure have been reported following the intranasal application of
corticosteroids. Close follow-up is warranted in patients with a change in
vision and with a history of glaucoma and/or cataracts.
Information for Patients Patients being treated with OMNARIS Nasal Spray should receive
the following information and instructions. This information is intended to aid
them in the safe and effective use of this medication. It is not a disclosure of
all possible adverse or intended effects.
Patients who are on immunosuppressive doses of corticosteroids should be
warned to avoid exposure to chickenpox or measles, and if exposed, to obtain
medical advice. Patients should use OMNARIS Nasal Spray at regular intervals
since its effectiveness depends on its regular use (See DOSAGE AND ADMINISTRATION ).
In clinical trials, the onset of effect was seen within 24 to 48 hours with
further symptomatic improvement observed over 1 to 2 weeks in seasonal allergic
rhinitis and 5 weeks in perennial allergic rhinitis. Initial assessment of
response should be made during this timeframe and periodically until the
patients symptoms are stabilized.
The patient should take the medication as directed and should not exceed the
prescribed dosage. The patient should contact the physician if symptoms do not
improve by a reasonable time or if the condition worsens. For the proper use of
this unit and to attain maximum improvement, the patients should read and follow
the accompanying patient instructions carefully. Spraying OMNARIS Nasal Spray
directly into the eyes or onto the nasal septum should be avoided. It is
important that the bottle is gently shaken prior to use to ensure that a
consistent amount is dispensed per actuation. The bottle should be discarded
after 120 actuations following initial priming or after 4 months after the
bottle is removed from the foil pouch, whichever occurs first.
Drug Interactions Based on in vitro studies in human liver microsomes,
des-ciclesonide appears to have no inhibitory or induction potential on the
metabolism of other drugs metabolized by CYP 450 enzymes. The inhibitory
potential of ciclesonide on CYP450 isoenzymes has not been studied. In vitro
studies demonstrated that the plasma protein binding of des-ciclesonide was not
affected by warfarin or salicylic acid, indicating no potential for protein
binding-based drug interactions.
In a drug interaction study, co-administration of orally inhaled ciclesonide
and oral erythromycin, an inhibitor of cytochrome P450 3A4, had no effect on the
pharmacokinetics of either des-ciclesonide or erythromycin. In another drug
interaction study, co-administration of orally inhaled ciclesonide and oral
ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure
(AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels
of ciclesonide remained unchanged. Therefore, ketoconazole should be
administered with caution with intranasal ciclesonide.
Carcinogenesis, Mutagenesis, Impairment of
Fertility Ciclesonide demonstrated no carcinogenic potential in a study of
oral doses up to 900 mcg/kg (approximately 20 and 10 times the maximum human
daily intranasal dose in adults and children, respectively, based on mcg/m 2 ) in mice for 104 weeks and in a study of inhalation doses up
to 193 mcg/kg (approximately 8 and 5 times the maximum human daily intranasal
dose in adults and children, respectively, based on mcg/m 2 ) 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 35 times the maximum human daily intranasal dose in adults based
on mcg/m 2 ).
Pregnancy: Teratogenic Effects
Pregnancy Category C
Oral administration of ciclesonide in rats up to 900 mcg/kg (approximately 35
times the maximum human daily intranasal dose in adults based on mcg/m 2 ) produced no teratogenicity or other fetal effects. However,
subcutaneous administration of ciclesonide in rabbits at 5 mcg/kg (less than the
maximum human daily intranasal dose in adults based on mcg/m 2 ) 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 intranasal dose based on mcg/m 2 ).
There are no adequate and well-controlled studies in pregnant women. OMNARIS
Nasal Spray, like other corticosteroids, 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.
Nonteratogenic effects Hypoadrenalism may occur in infants born of mothers receiving
corticosteroids during pregnancy. Such infants should be carefully
monitored.
Nursing Mothers 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 ciclesonide were recovered in
milk. Caution should be used when OMNARIS Nasal Spray is administered to nursing
women.
Pediatric Use The safety and effectiveness for seasonal and perennial allergic
rhinitis in children 12 years of age and older have been established. The
efficacy of OMNARIS Nasal Spray in patients 6 to 11 years of age for treatment
of the symptoms of seasonal allergic rhinitis is supported by evidence from four
adequate and well-controlled studies in adults and adolescents 12 years of age
and older with seasonal and perennial allergic rhinitis, and one study in
patients 6 to 11 years of age with seasonal allergic rhinitis. The efficacy of
OMNARIS Nasal Spray for the treatment of the symptoms of perennial allergic
rhinitis in patient 6 to 11 years of age has not been established (see CLINICAL TRIALS: Pediatric Patients Aged 6 to 11 Years ).
The efficacy of OMNARIS Nasal Spray in children 2 to 5 years of age has not been
established. The safety of OMNARIS Nasal Spray in children 2 to 11 years of age
was evaluated in 4 controlled clinical studies of 2 to 12 weeks duration (See CLINICAL PHARMACOLOGY: Pharmacodynamics , CLINICAL TRIALS , ADVERSE REACTIONS:
Pediatric Patients ).
Clinical studies in children less than two years of age have not been
conducted. Studies in children under 2 years of age are waived because of local
and systemic safety concerns.
Controlled clinical studies 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 OMNARIS Nasal Spray,
should be monitored routinely (e.g., via stadiometry). 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.
Geriatric Use Clinical studies of OMNARIS Nasal Spray did not include
sufficient numbers of subjects age 65 and over to determine whether they respond
differently from younger subjects. 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.
Adverse reactions
How supplied
OMNARIS is supplied in an amber glass bottle and provides for
nasal delivery with a manual metered pump. OMNARIS Nasal Spray is supplied with
an oxygen absorber sachet and enclosed in a foil pouch. OMNARIS Nasal Spray
provides 120 metered sprays after initial priming. Each spray delivers 50 mcg of
ciclesonide from the nasal actuator. The OMNARIS Nasal Spray bottle has been
filled with an excess to accommodate the priming activity. The bottle should be
discarded after removal from the foil pouch either after 120 sprays following
initial priming (since the amount of ciclesonide delivered per spray thereafter
may be substantially less than the labeled dose) or after 4 months. Patient
instructions are also provided.
OMNARIS Nasal Spray 50 mcg, 120 metered sprays; net fill weight 12.5 g. ( NDC 54868-6020-0 )
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP
Controlled Room Temp]. Do not freeze. Shake gently before use.
Do not spray in eyes. Keep out of reach of
children.
Manufactured for:
Sepracor Inc. Marlborough, MA 01752 USA
Made in Germany
For customer service, call 1-888-394-7377 To report adverse events, call
1-877-737-7226 For medical information, call 1-800-739-0565
November 2007
USA F.1/1207/3.5472.73
Relabeling of "Additional Barcode" by: Physicians Total Care, Inc. Tulsa, OK 74146
Clinical pharmacology
Mechanism of Action Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a
pharmacologically active metabolite, C21-desisobutyryl-ciclesonide
(des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has
anti-inflammatory activity with affinity for the glucocorticoid receptor that is
120 times higher than the parent compound.
The precise mechanism through which ciclesonide affects allergic rhinitis
symptoms is not known. Corticosteroids have been shown to have a wide range of
effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils,
macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids,
leukotrienes, and cytokines) involved in allergic inflammation.
Pharmacokinetics
Absorption
Ciclesonide and des-ciclesonide have negligible oral bioavailability (both
less than 1%) due to low gastrointestinal absorption and high first-pass
metabolism. The intranasal administration of ciclesonide at recommended doses
results in negligible serum concentrations of ciclesonide. However, the known
active metabolite (des-ciclesonide) is detected in the serum of some patients
after nasal inhalation of ciclesonide. The bioanalytical assay used has a lower
limit of quantification of 25 pg/mL and 10 pg/mL, for ciclesonide and
des-ciclesonide, respectively
In healthy adults treated for two weeks with 50 to 800 mcg of ciclesonide
nasal spray daily (n=6 in each treatment group), the peak serum concentrations
of des-ciclesonide in all subjects were found to be below 30 pg/mL. Of those
treated with 800 mcg and 400 mcg daily, 100% and 67% had detectable levels of
des-ciclesonide, respectively. With daily doses of 200 mcg or less, detectable
serum levels of des-ciclesonide were not observed.
In pediatric subjects treated with 25 to 200 mcg of ciclesonide nasal spray
daily, serum concentrations of des-ciclesonide were below 45 pg/mL, with the
exception of one value of 64.5 pg/mL. In a 12-week study in children 6 to 11
years of age with perennial allergic rhinitis, des-ciclesonide was detected in
50% of the subjects treated with 200 mcg and in 5% of those treated with 100 mcg
ciclesonide nasal spray daily. In a 6-week study in children 2 to 5 years of age
with perennial allergic rhinitis, des-ciclesonide was detected in 41%, 22%, and
13% of the subjects treated with 200 mcg, 100 mcg, and 25 mcg ciclesonide nasal
spray daily, respectively.
Distribution
Following intravenous administration of 800 mcg of ciclesonide, the volumes
of distribution of ciclesonide and des-ciclesonide were approximately 2.9 L/kg
and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide
bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug
detected in the systemic circulation. Des-ciclesonide is not significantly bound
to human transcortin.
Metabolism
Intranasal ciclesonide is hydrolyzed to a biologically active metabolite,
des-ciclesonide, by esterases in the nasal mucosa. Des-ciclesonide undergoes
further metabolism in the liver to additional metabolites mainly by the
cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. The full
range of potentially active metabolites of ciclesonide has not been
characterized. After intravenous administration of 14 C-ciclesonide, 19.3% of the resulting radioactivity in the
plasma is accounted for by ciclesonide or des-ciclesonide; the remainder may be
a result of other, as yet, unidentified multiple metabolites.
Elimination
Following intravenous administration of 800 mcg of ciclesonide, the clearance
values of ciclesonide and des-ciclesonide were high (approximately 152 L/h and
228 L/h, respectively). 14 C-labeled ciclesonide was
predominantly excreted via the feces after intravenous administration (66%)
indicating that excretion through bile is the major route of elimination.
Approximately 20% or less of drug related radioactivity was excreted in the
urine.
Special Populations
The pharmacokinetics of intranasally administered ciclesonide have not been
assessed in patient subpopulations because the resulting blood levels of
ciclesonide and des-ciclesonide are insufficient for pharmacokinetic
calculations. However, population pharmacokinetic analysis showed that
characteristics of des-ciclesonide after oral inhalation of ciclesonide were not
appreciably influenced by a variety of subject characteristics such as body
weight, age, race, and gender. Compared to healthy subjects, the systemic
exposure (Cmax and AUC) in patients with liver impairment increased in the range
of 1.4 to 2.7 fold after 1280 mcg ex-actuator ciclesonide by oral inhalation and
dose adjustment in liver impairment is not necessary. Studies in renal impaired
patients were not conducted.
Pharmacodynamics In a 12-week study in children 6-11 years of age with perennial
allergic rhinitis, daily doses of 200 mcg, 100 mcg, and 25 mcg of OMNARIS Nasal
Spray were compared to placebo nasal spray. Adrenal function was assessed by
measurement of 24-hour urinary free cortisol (in 32 to 44 patients per group)
and morning plasma cortisol levels (in 45 to 61 patients per group) before and
after 12 consecutive weeks of treatment. The ciclesonide-treated groups had a
numerically greater decline in 24-hour urinary free cortisol compared to the
placebo treated group. The differences (and 95% confidence intervals) from
placebo in the mean change from baseline to 12 weeks were -0.81 (-4.0, 2.4),
-0.08 (-3.1, 2.9), and -2.11 (-5.3, 1.1) mcg/day for 200 mcg, 100 mcg, and 25
mcg dose groups, respectively. The mean AM plasma cortisol value did not show
any consistent treatment effect with differences (and 95% confidence intervals)
from placebo in the mean change from baseline to 12 weeks of 0.35 (-1.4, 2.1),
0.12 (-1.5, 1.7), and -0.38 (-2.1, 1.3) mcg/dL for 200 mcg, 100 mcg, and 25 mcg
dose groups respectively. In this study, serum was assayed for ciclesonide and
des-ciclesonide (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Absorption ).
In a 6-week study in children 2 to 5 years of age with perennial allergic
rhinitis, daily doses of 200 mcg, 100 mcg, and 25 mcg of OMNARIS Nasal Spray
were compared to placebo nasal spray. Adrenal function was assessed by
measurement of 24-hour urinary free cortisol (in 15 to 22 patients per group)
and morning plasma cortisol levels (in 28 to 30 patients per group) before and
after 6 consecutive weeks of treatment. The ciclesonide-treated groups had a
numerically greater decline in 24-hour urinary free cortisol compared to the
placebo treated group. The differences (and 95% confidence intervals) from
placebo in the mean change from baseline to 6 weeks were -2.04 (-4.4, 0.3),
-1.96 (-4.5, 0.6), and -1.76 (-4.3, 0.8) mcg/day for the 200 mcg, 100 mcg, and
25 mcg dose groups, respectively. The plasma cortisol also decreased numerically
after treatment with ciclesonide. The differences (and 95% confidence intervals)
from placebo in the mean change in plasma cortisol from baseline to 6 weeks were
-1.04 (-2.7, 0.7), -0.36 (-2.1, 1.4), and -0.12 (-1.8, 1.6) mcg/dL for the 200
mcg, 100 mcg, and 25 mcg dose groups, respectively. In this study, serum was
assayed for ciclesonide and des-ciclesonide (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Absorption ).
There are no adequately conducted studies in adults and adolescents that
assess the effect of OMNARIS Nasal Spray on adrenal function.
Package label
OMNARIS (ciclesonide) Nasal Spray, 50 mcg
image of 50 mcg package label
2 organizations
1 product
Product
CiclesonideOrganization
Covis Pharma US, IncOrganization
Physicians Total Care, Inc.