SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 8 OVERDOSAGE 9 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 11 SPECIAL HANDLING INSTRUCTIONS 11 DOSAGE FORMS, COMPOSITION AND PACKAGING 11
PHARMACEUTICAL INFORMATION 13 CLINICAL TRIALS 14 DETAILED PHARMACOLOGY 16 TOXICOLOGY 18 REFERENCES 22
(ciclesonide nasal spray)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Nasal | Spray 50 mcg/spray | For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. |
OMNARIS(tm) (ciclesonide nasal spray) is indicated for: the treatment of seasonal allergic rhinitis, including hayfever, and perennial allergic rhinitis in adults and adolescents 12 years of age and older.
Geriatrics (> 65 years of age)
A total of 31 patients 65 years of age and older (age range 65 to 75 years) have been treated with OMNARIS(tm) 200 mcg/day for up to 1 year. The adverse reactions reported in this population were similar in type and incidence to those reported by younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for OMNARIS(tm), no adjustment of dosage of OMNARIS(tm) in geriatric patients is warranted.
Pediatrics
OMNARIS(tm) is not presently approved for use in patients younger than 12 years of age. A total of 91 patients 12-17 years of age were treated with OMNARIS(tm) for up to one year. No differences in the rate or incidence of adverse events were observed.
OMNARIS(tm) is contraindicated in patients with a hypersensitivity to any of the ingredients. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. OMNARIS(tm) should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract.
Carcinogenesis and Mutagenesis
See TOXICOLOGY.
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 children or adults on corticosteroids. In 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 affects 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. If chickenpox develops, treatment with antiviral agents may be considered. 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.
Infection
In clinical studies with corticosteroids administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans have been reported only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with the intranasal steroid. Therefore, patients using intranasal corticosteroids over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. OMNARIS(tm) should be used with caution, if at all, in patients with untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex.
Systemic Effects
Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of intranasal corticosteroids. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids. The risk of glaucoma was evaluated by assessments of intraocular pressure in 390 adolescent or adult patients receiving treatment with OMNARIS(tm) 200 mcg daily for up to 52 weeks. In this trial, no significant differences in intraocular pressure changes were observed between OMNARIS(tm) and placebo-treated patients. Additionally, no significant differences between OMNARIS(tm) 200 mcg and placebo-treated patients were noted during the 52-week study of 577 patients in which thorough ophthalmologic assessments were performed including evaluation of cataract formation using slit lamp examinations. Although systemic effects have been minimal with recommended doses of OMNARIS(tm), any such effect is likely to be dose dependent. Therefore, larger than recommended doses of OMNARIS(tm) should be avoided. When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may occur. If such changes occur, the dosage of OMNARIS(tm) should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. To minimize the systemic effects of intranasal corticosteroids each patient should be titrated to his/her lowest effective dose.
Systemic Steroid Replacement by a Topical Steroid
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/or 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.
Special Populations
There are no adequate and well-controlled studies with OMNARIS(tm) in pregnant women. As with other 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
It is unknown if ciclesonide is excreted in human milk. As with other corticosteroids, OMNARIS(tm) should only be used in nursing women when the potential benefit to the mother justifies the potential risk to the mother and/or infant.
OMNARIS(tm) is not presently approved for use in patients younger than 12 years of age. A total of 91 patients 12-17 years of age were treated with OMNARIS(tm) for up to one year. No differences in the rate or incidence of adverse events were observed.
A total of 31 patients above 65 years of age (age range 65 to 75 years) have been treated with OMNARIS(tm) 200 mcg/day for up to 1 year. The adverse reactions reported in this population were similar in type and incidence to those reported by younger
patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for OMNARIS(tm), no adjustment of dosage of OMNARIS(tm) in geriatric patients is warranted.
Monitoring and Laboratory Tests
As with any long-term treatment, patients using OMNARIS(tm) over several months or longer should be examined periodically for possible changes in the nasal mucosa.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse 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. In controlled clinical studies, a total of 2013 patients ages 12 years and older received treatment with OMNARIS(tm). In studies of 2 to 6-weeks duration, 677 patients were treated with OMNARIS(tm) 200 mcg daily, and in a study of up to one year in duration, 441 patients were treated with OMNARIS(tm) 200 mcg daily. The overall incidence of adverse events for patients treated with OMNARIS(tm) was comparable to that in patients treated with the placebo. Approximately 2% of patients treated with OMNARIS(tm) 200 mcg in clinical trials discontinued because of adverse events; this rate was similar for patients treated with placebo. The table below displays adverse events, assessed as likely or definitely related to treatment by the investigator, that occurred with an incidence of 1% or greater in clinical trials of 2 to 6-weeks in duration.
Table 1: Common Adverse Reactions1 (1-10%) in Controlled Clinical Trials 2 to 6-weeks in Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis
| Adverse Reaction | OMNARIS(tm) 200 mcg n=677 (%) | Placebo n= 674 (%) |
| Epistaxis 2 | 2.7 | 2.1 |
| Nasal Passage Irritation 3 | 2.4 | 2.2 |
| Headache | 1.3 | 0.7 |
1assessed as likely or definitely related to the treatment by investigator 2epistaxis (e.g. frank bleeding, blood-tinged mucus and blood flecks) 3nasal passage irritation includes nasal discomfort In a 52-week long-term safety trial that included 663 adolescent and adult patients (227 males and 436 females) with perennial allergic rhinitis, the adverse event profile over the treatment period was similar to the adverse event profile in trials of shorter duration. Adverse events considered likely or definitely related to OMNARIS(tm) that were reported at an incidence of 1% or greater are presented in Table 2. No patient experienced a nasal septal perforation or nasal ulcer during long-term use of OMNARIS(tm) nor was there any evidence of HPA-axis suppression in this study.
Table 2: Common Adverse Reactions1 (1-10%) in a 52-week Study in Adult and Adolescent Patients with Perennial Allergic Rhinitis
| Adverse Reaction | OMNARIS(tm) 200 mcg n=441 (%) | Placebo n= 222 (%) |
| Epistaxis 2 | 8.4 | 6.3 |
| Nasal passage irritation 3 | 4.3 | 3.6 |
| Headache | 1.6 | 0.5 |
1assessed as likely or definitely related to the treatment by investigator 2epistaxis (e.g. frank bleeding, blood-tinged mucus and blood flecks) 3nasal passage irritation includes nasal discomfort The following less common adverse reactions (assessed as possibly related to treatment by the investigator) were reported in controlled clinical trials 2 to 52 weeks in duration in patients 12 years of age and older with Seasonal Allergic or Perennial Allergic Rhinitis treated with OMNARIS(tm) 200 mcg:
Less Common Clinical Trial Adverse Drug Reactions (>=0.1% to <1%)
Gastrointestinal:
dry mouth (0.2%), dyspepsia (0.2%)
Infections:
candidiasis (0.2%), rhinitis (0.2%),
Investigations:
laboratory test abnormal NOS (0.2%), white blood cell count increased (0.3%),
Nervous System:
dysgeusia (0.2%)
Respiratory, Thoracic and Mediastinal: nasal dryness (0.4%), pharyngolaryngeal pain (0.4%), rhinorrhoea * (0.3%), nasal septum disorder (0.2%), throat irritation * (0.2%)
*occurred at rates <= placebo
Special Populations
The incidence of adverse events did not differ appreciably based on age, gender or race.
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 Less Common Clinical Trial Adverse Drug Reactions above.
Overview
In vitro
data indicate that cytochrome P 450 3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide (M1) in man.
Based on in vitro studies in human liver microsomes, the active metabolite (M1) did not significantly inhibit or induce the metabolism of other drugs. Based on in vitro human hepatocyte studies, ciclesonide and M1 had no significant effect on the induction of major cytochrome P 450 isozymes. In vitro studies also demonstrated that the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating that protein binding- based drug interactions are unlikely. The serum levels of ciclesonide and its active metabolite M1, are negligible following administration of ciclesonide nasal spray. Therefore, the potential for clinically relevant drug- drug interactions is very low. However, co-administration with potent inhibitors of the cytochrome P 450 3A4 system (e.g. protease inhibitors for the treatment of HIV infections such as, ritonavir or nelfinavir) should be considered with caution because there might be an increase in systemic drug levels of the active metabolite M1.
Drug-Drug Interactions
A drug interaction study with orally inhaled ciclesonide and oral erythromycin, a substrate and weak inhibitor of cytochrome P 450 3A4, had no relevant effect on the pharmacokinetics of either M1 or erythromycin. In a drug interaction study at steady state with orally inhaled ciclesonide and oral ketoconazole, a potent cytochrome P 450 3A4 inhibitor, the exposure of the active metabolite M1 increased approximately 3.5-fold, while levels of ciclesonide remained unchanged. Due to the low systemic exposure of intranasal ciclesonide relative to orally inhaled ciclesonide, clinically relevant drug interactions with OMNARIS(tm), except with very potent inhibitors of the cytochrome P450 3A4 system, are not expected.
Drug-Food Interactions
Interactions with food have not been established. Drug-food interactions are unlikely for intranasal 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 intranasal corticosteroids.
Dosing Considerations
The therapeutic effects of corticosteroids, unlike those of decongestants, are not immediate. Since the effect of OMNARIS(tm) depends on its regular use, patients should be instructed to take the nasal inhalation at regular intervals and not, as with other nasal sprays, as they feel necessary.
Recommended Dose and Dosage Adjustment
The recommended dose of OMNARIS(tm) 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).
Missed Dose
It is very important that OMNARIS(tm) is used regularly. If a dose is missed, the next dose should be taken when it is due and patients should not exceed the prescribed daily dosage.
Administration
Prior to initial use, OMNARIS(tm) must be shaken gently and then the pump must be primed by actuating 8 times. If not used for 4 or more consecutive days, it should be shaken gently and reprimed with 1 spray or until a fine spray appears. It is recommended that the applicator tip be wiped with a clean tissue following daily use. It is also recommended that the applicator be cleaned weekly using warm water and reprimed with one spray or until a fine mist appears. OMNARIS(tm) delivers 50 mcg of ciclesonide per spray. Each bottle of OMNARIS(tm) contains 120 metered sprays after initial priming. The bottle should be discarded after 120 sprays following initial priming, since the amount of ciclesonide delivered per spray thereafter may be substantially less than the labeled dose. If more than 6 months have elapsed since the bottle was removed from the foil pouch, it should be discarded. Do not spray in eyes.
Acute overdosage with this dosage form is unlikely since one 120 spray bottle of OMNARIS(tm) only contains approximately 9.6 mg of ciclesonide. A single oral dose of up to 10 mg of ciclesonide in healthy volunteers was well tolerated and serum cortisol levels were virtually unchanged in comparison with placebo treatment. Considering the low systemic availability of ciclesonide administered intranasally or orally, systemic effects following an overdose are unlikely.
Mechanism of Action
Ciclesonide is a pro-drug with a low glucocorticoid receptor affinity and is pharmacologically inactive. Following intranasal application, ciclesonide is enzymatically converted by esterases in the nasal mucosa to the pharmacologically active metabolite, 21 des-methylpropionyl- ciclesonide (des-CIC, M1). M1 has potent anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound and 12 times higher than dexamethasone. The primary mechanism of corticosteroid action in allergic rhinitis is considered due to anti- inflammation. 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. The anti-inflammatory properties of ciclesonide and M1 were shown in several in vitro and in vivo investigations, including experiments using a guinea pig model of allergic rhinitis and several investigations in primary human nasal epithelial cells, bronchial epithelial and smooth muscle cells (see DETAILED PHARMACOLOGY).
Pharmacodynamics
Ciclesonide is a topical glucocorticosteroid delivered in a unique hypotonic solution that has local anti-inflammatory properties at doses that are minimally systemically active. The effects of ciclesonide nasal spray on the HPA (hypothalamic-pituitary-adrenal) axis were investigated in several Phase III clinical trials up to one-year in duration and no appreciable effects of intranasally administered ciclesonide on serum or urinary cortisol levels were detected (see DETAILED PHARMACOLOGY). This pharmacodynamic finding is consistent with the negligible systemic bioavailability of ciclesonide following intranasal administration.
Pharmacokinetics
Ciclesonide and des-ciclesonide (M1) 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 and its active metabolite (M1) in adult and pediatric subjects using a sensitive bioanalytical assay with a lower limit of quantification of 25 pg/mL and 10 pg/mL for ciclesonide and M1, respectively. Due to the negligible serum concentrations following intranasal administration of ciclesonide, pharmacokinetic calculations could not be performed.
Distribution: The volumes of distribution of ciclesonide and M1 following i.v. administration were approximately 2.9 L/kg and 12.1L/kg, respectively. The percentage of ciclesonide and the active metabolite M1 bound to human plasma proteins averaged >= 99% each. Only the unbound drug in the systemic circulation (approximately 1%) is available for further systemic pharmacodynamic effect. M1 is not significantly bound to human transcortin. Metabolism: Intranasal ciclesonide is primarily hydrolyzed to its biologically active metabolite, M1, by esterases in the nasal mucosa (primarily by carboxylesterases and cholinesterases). M1 is metabolized in the liver to inactive metabolites mainly by the CYP 3A4 isozyme. Furthermore, inactive fatty acid ester conjugates of M1 in human nasal epithelial cells were detected in vitro for up to 24 hours, providing a reversible depot of M1 due to gradual hydrolysis by lipases.
After oral and intravenous administration, ciclesonide is predominantly excreted via the faeces (66%), indicating that excretion via the bile is the major route of elimination.
Special Populations and Conditions
The pharmacokinetics of intranasally administered ciclesonide have not been assessed in patient subpopulations because the resulting blood levels are insufficient for pharmacokinetic calculations. However, the pharmacokinetic characteristics of M1 after oral inhalation of ciclesonide were not appreciably influenced by a variety of subject/patient characteristics such as body weight, advanced age, race, gender and liver impairment. Studies in renal impaired patients were not conducted since renal excretion of M1 is a minor route of elimination (<= 20%). Because the systemic exposure of intranasally administered ciclesonide is much lower than that of orally inhaled ciclesonide, it is not likely that these special populations will experience clinically relevant changes in the pharmacokinetics of intranasally administered ciclesonide.
Store at room temperature (15degC - 30degC) with the valve up. Do not freeze. Shake gently.
The ciclesonide nasal spray device is packaged within a tamper resistant foil pouch to protect the product from oxygen absorption. In addition, a sachet containing beads of iron powder/zeolites is contained within the overwrap to absorb atmospheric oxygen. OMNARIS(tm) should be stored in the foil pouch and only removed immediately before first use. OMNARIS(tm) should be discarded 6 months after removal from pouch.
OMNARIS(tm) is an unscented, metered-dose, manual-pump spray formulation containing a hypotonic aqueous suspension of ciclesonide. OMNARIS(tm) also contains disodium edetate, hydroxypropyl methylcellulose, microcrystalline cellulose and carboxymethylcellulose sodium, potassium sorbate and purified water; hydrochloric acid may be added to adjust the pH to a target 4.5. OMNARIS(tm) is contained within an amber glass bottle within a protective plastic sleeve and shrink wrap label and provides for nasal delivery with a manual metered pump. OMNARIS(tm) provides 120-metered sprays after initial priming; net fill weight 12.5 g. The OMNARIS(tm) bottle has been filled with an excess to accommodate the priming activity. The bottle should be discarded after 120 sprays following initial priming, since the amount of ciclesonide delivered per spray thereafter may be substantially less than the labeled dose. Each spray delivers 50 mcg of ciclesonide to the patient.