Omnaris

OMNARIS — ciclesonide spray
Physicians Total Care, Inc.

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 C32 H44 O7 and its molecular weight is 540.7. Its structural formula is as follows:

image of chemical structure
(click image for full-size original)

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.

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.

CLINICAL TRIALS

Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older:

The efficacy and safety of OMNARIS Nasal Spray were evaluated in 4 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 weeks to 1 year in duration conducted in the United States and Canada in adolescents and adults with allergic rhinitis. Three of these trials were 2 to 6 weeks in duration and primarily designed to assess efficacy. One of these trials was 1 year in duration and primarily designed to assess safety. The three trials of 2 to 6 weeks duration included a total of 1524 patients (495 males and 1029 females) of whom 79 were adolescents, ages 12 to 17 years. Of the 1524 patients, 546 patients received OMNARIS Nasal Spray 200 mcg once daily administered as 2 sprays in each nostril. Patients enrolled in the studies were 12 to 86 years of age with a history of seasonal or perennial allergic rhinitis, a positive skin test to at least one relevant allergen, and active symptoms of allergic rhinitis at study entry. Assessment of efficacy in these trials was based on patient recording of four nasal symptoms (runny nose, nasal itching, sneezing, and nasal congestion) on a 0-3 categorical severity scale (0=absent, 1=mild, 2=moderate, and 3=severe) as reflective or instantaneous scores. Reflective scoring required the patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity at the time of recording. The results of these trials showed that patients treated with OMNARIS Nasal Spray 200 mcg once daily exhibited statistically significantly greater decreases in total nasal symptom scores than placebo treated patients. Secondary measures of efficacy were also generally supportive.

Of the three trials primarily designed to assess efficacy, one was a 2-week dose-ranging trial that evaluated efficacy of four doses of OMNARIS Nasal Spray in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the sum of morning and evening reflective total nasal symptom score averaged over the 2-week treatment period. Results of the primary efficacy endpoint are shown in Table 1. In this trial OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo, but the lower doses were not statistically significantly different from placebo.

Table 1 Mean change in reflective total nasal symptom score over 2 weeks in patients with seasonal allergic rhinitis
Treatment N Baseline* Change fromBaseline Difference Estimate from Placebo 95% CI p-value
Seasonal Allergic Rhinits Trial — Reflective total nasal symptoms score
Ciclesonide 200 mcg14418.8-5.73-1.35(-2.43, -0.28)0.014
Ciclesonide 100 mcg14518.7-5.26-0.88(-1.96, 0.19)0.11
Ciclesonide 50 mcg14318.4-4.82-0.44(-1.52, 0.63)0.42
Ciclesonide 25 mcg14618.7-4.74-0.35(-1.42, 0.71)0.51
Placebo14817.8-4.38

Scores; Maximum score = 24Of the other trials primarily designed to assess efficacy, one was a 4-week single dose-level trial conducted in patients with seasonal allergic rhinitis and the other was a 6-week single dose-level trial conducted in patients with perennial allergic rhinitis. The primary efficacy endpoint in the seasonal allergic rhinitis trial was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score averaged over the first 2 weeks of treatment. The primary efficacy endpoint in the perennial allergic rhinitis trial was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score averaged over the 6 weeks of treatment. Efficacy results of these two trials are shown in Table 2. In these trials, OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo. Statistically significant differences in the morning pre-dose instantaneous total nasal symptom score indicate that the effect was maintained over the full 24-hour dosing interval.
Table 2 Mean changes in reflective total nasal symptom score and instantaneous total nasal symptom score in allergic rhinitis trials
Treatment n Baseline* Change fromBaseline Estimate Difference 95% CI from Placebo p-value
Seasonal Allergic Rhinitis Trial — Reflective total nasal symptom score
Ciclesonide 200 mcg1628.96-2.40-0.90(-1.36, -0.45)less than 0.001
Placebo1628.83-1.50
Seasonal Allergic Rhinitis Trial — Instantaneous total nasal symptom score
Ciclesonide 200 mcg1628.45-1.87-0.84(-1.30, -0.39)less than 0.001
Placebo1628.33-1.03
Perennial Allergic Rhinitis Trial — Reflective total nasal symptom score
Ciclesonide 200 mcg2327.59-2.51-0.62(-0.97, -0.28)less than 0.001
Placebo2297.72-1.89
Perennial Allergic Rhinitis Trial — Instantaneous total nasal symptom score
Ciclesonide 200 mcg2327.05-1.99-0.53(-0.90, -0.17)0.004
Placebo2297.05-1.46

Onset of action was evaluated in two environmental exposure unit studies with a single dose of OMNARIS Nasal Spray 200 mcg. Results from these two studies did not demonstrate a replicate onset of action within the assessment period. Onset of action was also evaluated in the 4-week seasonal allergic rhinitis and in the 6-week perennial allergic rhinitis trial by frequent recording of instantaneous symptom score after the first dose. In these trials, 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.

Pediatric Patients Aged 6 to 11 Years:

The efficacy of OMNARIS Nasal Spray was evaluated in two randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 and 12 weeks in duration in 1282 patients 6 to 11 years of age with allergic rhinitis. Of the two trials, one was 2 weeks in duration conducted in patients with seasonal allergic rhinitis that evaluated efficacy of 200 mcg and 100 mcg of OMNARIS nasal spray once daily. The other trial was 12 weeks in duration conducted in patients with perennial allergic rhinitis that evaluated efficacy of 200 mcg, 100 mcg, and 25 mcg of OMNARIS nasal spray once daily. Of the total number of patients enrolled in the 2 studies, 380 were treated with 200 mcg of OMNARIS nasal spray once daily. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score 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, the OMNARIS Nasal Spray 200 mcg once daily dose was statistically significantly different from placebo, but the 100 mcg once daily dose was not statistically significantly different from placebo. The efficacy results for the seasonal allergic rhinitis trial are shown in Table 3.

Table 3 Mean changes in reflective total nasal symptom score in 1 seasonal allergic rhinitis trial in children 6 to 11 years of age.
Treatment n Baseline* Change fromBaseline Estimate Difference 95% CI from Placebo p-value
Reflective total nasal symptom score
Ciclesonide 200 mcg2158.25-2.46-0.39(-0.76, -0.02)0.040
Ciclesonide 100 mcg1998.41-2.38-0.32(-0.69, 0.06)0.103
Placebo2048.41-2.07

In the 12-week trial in patients with perennial allergic rhinitis, none of the ciclesonide doses were statistically significantly different from placebo. The means and 95% confidence intervals for the differences (OMNARIS Nasal Spray minus placebo) between OMNARIS Nasal Spray 200 mcg, 100 mcg, and 25 mcg treatment groups and placebo were -0.31 (-0.75, 0.13), 0.02 (-0.41, 0.46), and 0.09 (-0.35, 0.53), respectively.

Pediatric Patients Aged 2 to 5 Years:

Efficacy of OMNARIS Nasal Spray in patients 2 to 5 years of age has not been established (See PRECAUTIONS: Pediatric Use).

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