Omnaris

Adults and Children (6 Years of Age and Older): The recommended dose of OMNARIS Nasal Spray is 2 sprays per nostril once daily (200 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day).

Adults and Adolescents (12 Years of Age and Older): The recommended dose of OMNARIS Nasal Spray is 2 sprays per nostril once daily (200 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day).

Epistaxis: In clinical studies of 2 to 52 weeks' duration, epistaxis was observed more frequently in patients treated with OMNARIS Nasal Spray than those who received placebo [see Adverse Reactions (6)].

Candida Infection: In clinical studies with OMNARIS Nasal Spray, the development of localized infections of the nose and pharynx with Candida albicans has 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.

Nasal Septal Perforation: Instances of nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. No cases of nasal septal perforation were identified in clinical studies with OMNARIS Nasal Spray. Avoid spraying OMNARIS Nasal Spray directly onto the nasal septum.

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 a nasal corticosteroid until healing has occurred.

Hypercorticism and Adrenal Suppression: When intranasal corticosteroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of OMNARIS Nasal Spray 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/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.

Adults and Adolescents 12 Years of Age and Older in Short-Term (2-6 weeks) Trials: In three short-term trials conducted in the US and Canada, 546 patients were treated with OMNARIS Nasal Spray 200 mcg daily. Adverse reactions did not differ appreciably based on age, gender, or race. Approximately 2% of patients treated with OMNARIS Nasal Spray 200 mcg in clinical trials discontinued because of adverse reactions; this rate was similar for patients treated with placebo. The table below displays reactions that occurred with an incidence of 2% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo in clinical trials of 2 to 6 weeks in duration.

Pediatric Patients Aged 6 to 11 Years in Short-Term (2-12 weeks) Trials: In two short-term trials, conducted in the US and Canada, 913 patients were treated with OMNARIS Nasal Spray 200 mcg, 100 mcg or 25 mcg daily. Adverse events did not differ appreciably based on age, gender, or race. In clinical trials, 1.6% and 2.7% of patients treated with OMNARIS Nasal Spray 200 mcg or 100 mcg, respectively, discontinued because of adverse reactions; these rates were lower than the rate in patients treated with placebo (2.8%). Table 2 displays adverse events that occurred with an incidence of 3% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo.

Pediatric Patients Aged 2 to 5 Years in Short-Term (6-12 weeks) Trials: In two short-term trials conducted in the US, 183 patients were treated with OMNARIS Nasal Spray 200 mcg, 100 mcg or 25 mcg daily. The distribution of adverse events was similar to that seen in the 6 to 11 year old children.

Long-Term (52-Week) Safety Trial: In a 52-week double-blind, placebo-controlled safety trial that included 663 adults and adolescent patients (441 treated with ciclesonide: 227 males and 436 females) with perennial allergic rhinitis, the adverse reaction profile over the treatment period was similar to the adverse event profile in trials of shorter duration. Adverse reactions, irrespective of drug relationship, that occurred with an incidence of 3% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo were epistaxis, pharyngolaryngeal pain, sinusitis, headache, nasal discomfort, cough, bronchitis, influenza, back pain, and urinary tract infection. No patient experienced a nasal septal perforation or nasal ulcer during this long-term trial of OMNARIS Nasal Spray.

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. OMNARIS Nasal Spray 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.

Oral administration of ciclesonide in rats at approximately 35 times the maximum human daily intranasal dose in adults based on mcg/m² produced no teratogenicity or other fetal effects. However, subcutaneous administration of ciclesonide in rabbits at less than the maximum human daily intranasal dose in adults based on mcg/m² produced fetal toxicity. This included fetal loss, reduced fetal weight, cleft palate, skeletal abnormalities including incomplete ossifications, and skin effects [see Nonclinical Toxicology (13.2)].

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Adrenal Function: In a 6-week trial in adolescents and adults 12-73 years of age with perennial allergic rhinitis, a daily dose of 200 mcg of OMNARIS Nasal Spray was compared to placebo nasal spray. Dexamethasone 6 mg was used as an active control during the last 4 days of the treatment period. Adrenal function was assessed by measurement of 24 hour serum cortisol levels before and after 6 consecutive weeks of treatment. The difference from placebo for the change from baseline in serum cortisol AUC_(0-24) was 10.4 mcg•hour/dL (95% CI: -4.7, 25.5) for 200 mcg of OMNARIS Nasal Spray. The effects observed with the active control (dexamethasone, n=18) validate the sensitivity of the study to assess the effect of ciclesonide on the HPA axis.

In a 12-week study in children 6 to 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 (12.3)].

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 (12.3)].

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. The low systemic exposure following ciclesonide nasal spray administration was confirmed in a crossover study in twenty-nine healthy adults. The median C_max was less than 10 pg/mL and 602 pg/mL following a single dose of ciclesonide nasal spray (300 mcg) and orally inhaled ciclesonide (320 mcg), 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: Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. 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 ¹⁴C-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). ¹⁴C-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.

Hepatic Impairment: 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 ex-actuator administration of 1280 mcg ciclesonide via oral inhalation. Dose adjustment in liver impairment is not necessary.

Renal Impairment: Studies in renally-impaired patients were not conducted since renal excretion of des-ciclesonide is a minor route of elimination (≤ 20%).

Pediatric: 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.

Drug-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 cytochrome P450 enzymes. The inhibitory potential of ciclesonide on cytochrome P450 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 ketoconazole, a strong inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of the active metabolite of ciclesonide, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged.

In another drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin.

Reproductive Toxicology Studies: Oral administration of ciclesonide in rats up to 900 mcg/kg (approximately 35 times the maximum human daily dose in adults based on mcg/m²) produced no teratogenicity or other fetal effects. However, subcutaneous administration of ciclesonide in rabbits at 5 mcg/kg (less than the maximum daily intranasal dose in adults based on mcg/m²) 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 in adults based on mcg/m²).

Adults and Adolescent Patients 12 Years of Age and Older: The efficacy of OMNARIS Nasal Spray was evaluated in 3 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 6 weeks duration conducted in the United States and Canada in adolescents and adults with allergic rhinitis. The three trials included a total of 1524 patients (495 males and 1029 females) of whom 79 were adolescents, ages 12 to 17 years. The racial distribution in these three trials included 1374 Caucasians, 69 Blacks, 31 Asians, and 50 patients classified as Other. 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.

Dose-Ranging Trial: One of the three trials 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 3. 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.

Seasonal Allergic Rhinitis Trial: The second trial was a 4-week single dose level trial conducted in patients with seasonal 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. In this trial, OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo (Table 4). 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.

Perennial Allergic Rhinitis Trial: The third trial was a 6-week single dose level trial conducted in patients with perennial allergic rhinitis. 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. In this trial, OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo (Table 4). 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.

Onset of action: Onset of action was evaluated in two environmental exposure unit studies in patients with seasonal allergic rhinitis receiving 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 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 5.

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 Pediatric Use (8.4)].