1.1 Treatment of Allergic Rhinitis

ZETONNA® (ciclesonide) Nasal Aerosol is indicated for the treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older.

2.1 Administration Information

Administer ZETONNA by the intranasal route only. Prior to initial use, ZETONNA must be primed by actuating three times. If ZETONNA is not used for ten consecutive days, it must be primed by actuating three times. If ZETONNA is dropped, the canister and actuator may become separated. If this happens, reassemble ZETONNA and test spray once into the air before using. Illustrated patient’s instructions for proper use accompany each package of ZETONNA.

2.2 Allergic Rhinitis

Adults and Adolescents (12 Years of Age and Older): The recommended dose of ZETONNA is 1 actuation per nostril once daily (37 mcg per actuation). The maximum total daily dosage should not exceed 1 actuation in each nostril (74 mcg per day).

5.1 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 (6)]

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 (6)]

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 (6)]

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.

Candida Infection: 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.

5.2 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.

5.3 Hypersensitivity

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.

5.4 Immunosuppression

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.

5.5 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.

5.6 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 (8.4)]

6.1 Clinical Trials Experience

The safety data described below for adults and adolescents 12 years of age and older are based on 4 clinical trials evaluating doses of ciclesonide nasal aerosol from 74 to 282 mcg. Three of the clinical trials were 2 to 6 weeks in duration and one trial was 26 weeks in duration with an additional 26-week open-label extension. Data from the first 6 weeks of the 26-week trial were pooled with data from the three 2-week trials. Short-term data (2 to 6 weeks) included 3001 patients with seasonal and perennial allergic rhinitis, of these, 884 received ZETONNA  74 mcg once daily and 892 received placebo. The short-term data included 1098 (36.6%) males, 1903 (63.4%) females, 2587 (86.2%) Caucasians, 320 (10.7%) Blacks, 49 (1.6%) Asians, and 45 (1.5%) patients classified as Other. The 26-week trial was conducted in 1110 patients with perennial allergic rhinitis [394 (35.5%) males and 716 (64.5%) females, ages 12 to 78 years old] treated with ZETONNA 74 mcg, 148 mcg or placebo once daily. Of these patients, 298 were treated with 74 mcg ZETONNA, 505 with 148 mcg, and 307 with placebo. The racial distribution in this trial included 922 (83.1%) Caucasians, 146 (13.2%) Blacks, 18 (1.6%) Asians, and 24 (2.2%) patients classified as Other. The 26-week open-label extension included 824 patients [295 (35.8%) males and 529 (64.2%) females, ages 12 to 79 years old] given ZETONNA 148 mcg once daily. The racial distribution in the open-label extension included 690 (83.7%) Caucasians, 104 (12.6%) Blacks, 15 (1.8%) Asians, and 15 (1.8%) patients classified as Other.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Short-Term (2-6 weeks) Trials:

In three short-term trials and the first 6 weeks of one long-term trial, conducted in the US, 884 patients with a history of seasonal or perennial allergic rhinitis were treated with ZETONNA 74 mcg daily. Adverse reactions did not differ appreciably based on age, gender, or race. The table below displays reactions that occurred with an incidence of at least 2.0% and more frequently with ZETONNA 74 mcg than with placebo in seasonal or perennial allergic rhinitis clinical trials of 2 to 6 weeks duration.

When considering the data from higher doses evaluated in the short-term trials, epistaxis demonstrated a dose response. In addition, two patients treated with ZETONNA 74 mcg experienced nasal septal perforations in the short-term trials compared to no patients treated with placebo.

Approximately 1.2% of patients treated with ZETONNA 74 mcg in clinical trials discontinued because of adverse reactions; this rate was similar for patients treated with placebo. Discontinuations due to local adverse reactions were similar in ZETONNA 74 mcg treated patients (0.8%) compared to placebo treated patients (0.8%). Local adverse reactions leading to discontinuation that occurred only in ZETONNA treated patients included ear infection, nasal discomfort, nasal dryness, nasal mucosal/septum disorders, pharyngitis, streptococcal pharyngitis, sinus headache, and tonsillitis.

Long-Term (26-Week Double-Blind and 26-Week Open-Label) Safety Trial:

In one 26-week double-blind, placebo-controlled safety trial that included 1110 adult and adolescent patients with perennial allergic rhinitis, additional adverse reactions, with an incidence of at least 2%, that occurred more frequently with ZETONNA than with placebo were upper respiratory tract infection, urinary tract infection, oropharyngeal pain, nasal mucosal/septum disorders, viral upper respiratory tract infection, cough, influenza, bronchitis, streptococcal pharyngitis, muscle strain, and nausea. Nasal discomfort (5.7%) and epistaxis (11.4%) were also more frequent in the 26-week safety trial compared to clinical trials 2 to 6 weeks in duration. Nasal mucosal/septum disorders and cough demonstrated a dose response.

Discontinuations due to adverse reactions were higher in ZETONNA treated patients compared to placebo treated patients and demonstrated a dose response. Local adverse reactions leading to discontinuation were also higher in ZETONNA 74 mcg treated patients (1.7%) compared to placebo treated patients (0.7%). The only local adverse reaction leading to discontinuation that occurred in ZETONNA treated patients and was not observed in the 2- to 6-week trials was upper respiratory tract infection.

A total of 824 patients with perennial allergic rhinitis who completed the 26-week double-blind trial enrolled into an open-label extension and received ZETONNA 148 mcg for 26 weeks. Additional adverse reactions, observed with an incidence of at least 2% were sinusitis, nasopharyngitis, and back pain.

A total of 4 nasal septal ulcerations were also reported in the 26-week open-label extension.

There were no reports of nasal septal perforations in the long-term safety trial.

Long-Term (6-Month Open-Label) Nasal Safety Trial:

Nasal and ocular safety was evaluated in one 26-week, postmarketing, randomized, open-label, active-controlled trial, in adult and adolescent patients 12-74 years of age with a history of perennial allergic rhinitis. A total of 737 patients were treated with ZETONNA 74 mcg or ciclesonide nasal spray 200 mcg once daily. The combined incidence of nasal mucosal or septum disorders, including erosions and ulcerations, was 3 (0.8%) for ZETONNA 74 mcg and 4 (1.1%) for ciclesonide nasal spray 200 mcg treated patients. There were no nasal septal perforations reported with either treatment. Ocular findings, including the development or worsening of lens opacities, increase in intraocular pressure, and worsening visual acuity, were also evaluated over the 26-week treatment period. The occurrence of ocular safety events was similar for the ZETONNA 74 mcg and ciclesonide nasal spray 200 mcg treatment groups.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of other formulations of ciclesonide, ALVESCO® Inhalation Aerosol and OMNARIS® Nasal Spray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

ALVESCO® Inhalation Aerosol: immediate or delayed hypersensitivity reactions such as angioedema with swelling of the lips, tongue, and pharynx.

OMNARIS® Nasal Spray: nasal congestion, nasal ulcer, and dizziness. Localized infections of the nose or mouth with Candida albicans have also occurred with OMNARIS® Nasal Spray.

8.1 Pregnancy

Teratogenic Effects: 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 ¼ of the MRHDID in adults (on a mcg/m2 basis at a maternal dose of 1 mcg/kg/day).

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

8.3 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 radiolabeled ciclesonide were recovered in milk. Caution should be used when ZETONNA is administered to nursing women.

8.4 Pediatric Use

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 (6.1)].

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 (12.2)].

Studies in children under 6 years of age have not been conducted.

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 ruled out.

8.5 Geriatric Use

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.

12.1 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.

12.2 Pharmacodynamics

Adrenal Function: In a 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in adolescents and adults 12-73 years of age with perennial allergic rhinitis, daily doses of 148 mcg and 282 mcg of ZETONNA were compared to placebo nasal aerosol. Dexamethasone 6 mg was used as an active control during the last 4 days of the trial. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of 6 weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was ‑5.0 (4.6) mcg•hour/dL, -2.6 (4.6) mcg•hour/dL, and -4.6 (5.0) mcg•hour/dL for placebo (n=57), 148 mcg ZETONNA (n=60), and 282 mcg ZETONNA (n=50), respectively. The LS means difference from placebo for the change from baseline in serum cortisol AUC(0-24) was ‑2.4 mcg•hour/dL (95% CI: -15.1, 10.2) and -0.5 mcg•hour/dL (95% CI: ‑13.9, 13.0) for 148 mcg/day and 282 mcg/day treatments, respectively. 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 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in patients 6 to 11 years of age with perennial allergic rhinitis, a daily dose of 74 mcg of ZETONNA was compared to placebo nasal aerosol. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of 6 weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was 5.9 (5.6) mcg•hour/dL and 1.7 (5.2) mcg•hour/dL for placebo and ZETONNA, respectively. The LS means difference from placebo for the change from baseline in serum cortisol AUC(0-24) was 7.6 mcg•hour/dL (95% CI: -7.4, 22.6).

12.3 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 10 pg/mL, for both ciclesonide and des-ciclesonide, respectively.

The low systemic exposure of des-ciclesonide following ciclesonide nasal aerosol administration was confirmed in a crossover trial in 29 healthy adults. The median Cmax of des-ciclesonide was 59 pg/mL following a single dose of ciclesonide nasal aerosol (296 mcg) compared to 602 pg/mL following a single dose of orally inhaled ciclesonide (320 mcg) and 12 pg/mL following a single dose of ciclesonide aqueous nasal spray (300 mcg). The pharmacokinetics of intranasally administered ciclesonide have been assessed in perennial allergic rhinitis patients resulting in similar exposure compared to healthy subjects.

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/hr and 228 L/hr, respectively). 14C-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:

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

Drug-Drug Interactions: Ciclesonide inhibited human recombinant cytochrome P450 enzymes at high concentration (3 microM) in vitro, but clinically relevant metabolic interactions are not anticipated. Based on in vitro studies in human liver microsomes, ciclesonide and des-ciclesonide appear to have no inhibitory or induction potential on the metabolism of other drugs metabolized by cytochrome P450 enzymes. 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.

13.1 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).

14.1 Seasonal and Perennial Allergic Rhinitis

Adults and Adolescent Patients 12 Years of Age and Older:

The efficacy of ZETONNA was evaluated in one randomized, double-blind, parallel-group, multicenter, placebo-controlled dose-ranging trial (74 mcg, 148 mcg, and 282 mcg once daily) and 3 confirmatory trials (74 mcg and 148 mcg once daily) in adolescents and adults with allergic rhinitis. Efficacy endpoints were evaluated at 2 weeks for the two seasonal allergic rhinitis trials and at 6 weeks for the perennial allergic rhinitis trial. These trials were all conducted in the United States. A total of 3001 patients were included in these 4 trials. The dose-ranging trial included a total of 513 patients [193 males (37.6%) and 320 females (62.4%)], of whom 65 (12.7%) were adolescents. The three confirmatory trials included a total of 2488 patients (905 males and 1583 females) of whom 170 were adolescents, ages 12 to 18 years. Patients enrolled in the trials were 12 to 81 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 total nasal symptom scores (rTNSS and iTNSS respectively). Reflective scoring required the patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity over the previous 10 minutes.

Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) in the seasonal allergic rhinitis trials and the Rhinoconjunctivitis Quality of Life Questionnaire with Standardised Activities [RQLQ(S)] in both seasonal and perennial allergic rhinitis trials. TOSS is calculated as the sum of the patients’ scoring of the three individual ocular symptoms (itching, tearing, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous (iTOSS) scores. To assess efficacy, rTOSS and iTOSS were evaluated as described above for the TNSS. Patients perceptions of disease specific quality of life were evaluated through the use of the RQLQ(S), which assesses the impact of allergic rhinitis symptoms and treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = not troubled and 6 = extremely troubled. An overall RQLQ(S) score is calculated from the average of the domain scores. An absolute difference of ≥ 0.5 in mean change from baseline over placebo is considered the minimally clinically important difference (MCID) for the RQLQ(S).

Dose-Ranging Trial: There was a 2-week placebo-controlled, double-blind, dose-ranging trial that evaluated efficacy of three doses of ZETONNA (74 mcg, 148 mcg, and 282 mcg once daily) in patients with seasonal allergic rhinitis. 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 (rTNSS) averaged over the 2-week treatment period. The rTNSS showed a statistically significant estimated treatment difference from placebo of 0.81 (95% CI: 0.32, 1.29); 0.90 (95% CI: 0.40, 1.39); and 0.66 (95% CI: 0.16, 1.16) for 282 mcg, 148 mcg and 74 mcg, respectively.

Confirmatory Seasonal Allergic Rhinitis Trials: There were two 2-week placebo-controlled, double-blind confirmatory trials that evaluated efficacy of two doses of ZETONNA (74 mcg and 148 mcg once daily) in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the 2-week treatment period. Table 2 displays the efficacy results from one of these trials in patients with seasonal allergic rhinitis. The other trial showed similar results. In these trials, ZETONNA 74 mcg once daily was statistically significantly different from placebo. Statistically significant differences in the morning pre-dose iTNSS indicate that the effect was maintained over the full 24-hour dosing interval. ZETONNA 74 mcg demonstrated a statistically significant decrease from baseline in the rTOSS compared to placebo. Similarly, a clinically significant decrease (≥ 0.5) from baseline compared to placebo for the RQLQ(S) was also shown. ZETONNA 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Confirmatory Perennial Allergic Rhinitis Trial: There was one 26-week placebo-controlled, double-blind trial that evaluated efficacy of two doses of ZETONNA (74 mcg and 148 mcg once daily) in patients with perennial allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the average of morning and evening rTNSS averaged over the first 6 weeks of treatment. In this trial, ZETONNA 74 mcg once daily was statistically significantly different from placebo (Table 2) in decreasing nasal symptom scores. 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. ZETONNA 74 mcg did not demonstrate a clinically significant change from baseline in the overall RQLQ(S) compared to placebo. TOSS was not evaluated in this trial. ZETONNA 148 mcg once daily did not provide an efficacy benefit over the 74 mcg once daily dose.

Onset of Action: Onset of action was evaluated in both 2-week seasonal and one 6-week perennial allergic rhinitis trials by frequent recording of instantaneous symptom score. In these trials, 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.