INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE ZETONNA Nasal Aerosol is corticosteroid indicated for treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older. (1.1). 1.1 Treatment of Allergic Rhinitis ZETONNA(R) (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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following:oEpistaxis, ulcerations, nasal septal perforations, Candida albicans infection, impaired wound healing [see Warnings and Precautions (5.1)]oGlaucoma and cataracts [see Warnings and Precautions (5.2)]oImmunosuppression [see Warnings and Precautions (5.4)]oHypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.4)]. oEpistaxis, ulcerations, nasal septal perforations, Candida albicans infection, impaired wound healing [see Warnings and Precautions (5.1)]. oGlaucoma and cataracts [see Warnings and Precautions (5.2)]. oImmunosuppression [see Warnings and Precautions (5.4)]. oHypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.4)]. The most common adverse reactions (>=2% incidence) included nasal discomfort, headache and epistaxis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-866-488-4423 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The safety data described below for adults and adolescents 12 years of age and older are based on clinical trials evaluating doses of ciclesonide nasal aerosol from 74 to 282 mcg. Three of the clinical trials were to weeks in duration and one trial was 26 weeks in duration with an additional 26-week open-label extension. Data from the first weeks of the 26-week trial were pooled with data from the three 2-week trials. Short-term data (2 to 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 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 weeks of one long-term trial, conducted in the US, 884 patients with 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 to weeks duration.Table 1: Adverse Reactions Occurring with Frequency of at least 2.0% and Greater than Placebo from Controlled Clinical Trials to Weeks in Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitisa Nasal discomfort includes both nasal discomfort and instillation site discomfortAdverse ReactionZETONNA Nasal Aerosol74 mcg Once DailyN 884Placebo = 892Nasal discomforta 28 (3.2%)16 (1.8%)Headache27 (3.1%)11 (1.2%)Epistaxis26 (2.9%)24 (2.7%)When considering the data from higher doses evaluated in the short-term trials, epistaxis demonstrated 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 to weeks in duration. Nasal mucosal/septum disorders and cough demonstrated dose response. Discontinuations due to adverse reactions were higher in ZETONNA treated patients compared to placebo treated patients and demonstrated 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 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 history of perennial allergic rhinitis. 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 (0.8%) for ZETONNA 74 mcg and (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(R) Inhalation Aerosol and OMNARIS(R) Nasal Spray. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.ALVESCO(R) Inhalation Aerosol: immediate or delayed hypersensitivity reactions such as angioedema with swelling of the lips, tongue, and pharynx.OMNARIS(R) Nasal Spray: nasal congestion, nasal ulcer, and dizziness. Localized infections of the nose or mouth with Candida albicans have also occurred with OMNARIS(R) Nasal Spray.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ciclesonide demonstrated no carcinogenic potential in mice in 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 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 forward mutation assay and was not clastogenic in 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 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ciclesonide is pro-drug that is enzymatically hydrolyzed to 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 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 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 mg was used as an active control during the last days of the trial. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was -5.0 (4.6) mcgohour/dL, -2.6 (4.6) mcgohour/dL, and -4.6 (5.0) mcgohour/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 mcgohour/dL (95% CI: -15.1, 10.2) and -0.5 mcgohour/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 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in patients to 11 years of age with perennial allergic rhinitis, 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 weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was 5.9 (5.6) mcgohour/dL and 1.7 (5.2) mcgohour/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 mcgohour/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 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 crossover trial in 29 healthy adults. The median Cmax of des-ciclesonide was 59 pg/mL following single dose of ciclesonide nasal aerosol (296 mcg) compared to 602 pg/mL following single dose of orally inhaled ciclesonide (320 mcg) and 12 pg/mL following 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 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 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 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 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 drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, 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, moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 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 confirmatory trials (74 mcg and 148 mcg once daily) in adolescents and adults with allergic rhinitis. Efficacy endpoints were evaluated at weeks for the two seasonal allergic rhinitis trials and at weeks for the perennial allergic rhinitis trial. These trials were all conducted in the United States. total of 3001 patients were included in these trials. The dose-ranging trial included 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 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 history of seasonal or perennial allergic rhinitis, 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 0-3 categorical severity scale (0 absent, = mild, = moderate, and = 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 0 to categorical severity scale (0 absent, = mild, = moderate, = 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 texts in domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on 7-point scale where = not troubled and = 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 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 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 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 statistically significant decrease from baseline in the rTOSS compared to placebo. Similarly, 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 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 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.Table 2: Mean Changes in Efficacy Variables in Adult and Adolescent Patients With Seasonal or Perennial Allergic RhinitisTreatmentNMeanBaselinea LS MeanChange from BaselineDifference from Placebob Estimate(LS Mean)95% CIp-valueca Baseline for rTNSS, iTNSS, and rTOSS are averages of the AM and PM responses obtained during the Run-in Period up to days prior to randomization and includes AM score prior to randomization. Baseline for morning iTNSS is the average of the AM responses obtained during the Run-in Period up to days prior to randomization and includes the AM score prior to randomization. Baseline RQLQ(S) is from the randomization visit assessment. Estimates (LS Mean), 95% Confidence Intervals, and p-values were obtained from ANCOVA analyses with treatment and center as fixed effects and baseline as covariate in the model. P-values are significant at the 0.025 level based on Bonferroni correction.Seasonal Allergic Rhinitis Reflective Total Nasal Symptom Score Ciclesonide 74 mcg2379.3-1.50.90.6, 1.3<0.001Placebo2359.1-0.5Instantaneous Total Nasal Symptom ScoreCiclesonide 74 mcg2378.7-1.30.90.5, 1.3<0.001Placebo2358.6-0.5Reflective Total Ocular Symptom ScoreCiclesonide 74 mcg2375.8-0.80.50.3, 0.80.001Placebo2355.7-0.2Rhinoconjunctivitis Quality of Life Questionnaire with Standardized ActivitiesCiclesonide 74 mcg2374.0-0.80.60.4, 0.8<0.001Placebo2344.0-0.2Perennial Allergic Rhinitis Reflective Total Nasal Symptom ScoreCiclesonide 74 mcg2988.5-2.00.70.4, 1.0<0.001Placebo3078.6-1.3Instantaneous Total Nasal Symptom ScoreCiclesonide 74 mcg2987.7-1.80.60.3, 0.9<0.001Placebo3077.7-1.2Onset 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 to weeks after initiation of dosing.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS ZETONNA is contraindicated in patients with known hypersensitivity to ciclesonide or any of the ingredients of ZETONNA [see Warnings and Precautions (5.3)].. Patients with known hypersensitivity to ciclesonide or any of the ingredients of ZETONNA. (4).

DESCRIPTION SECTION.

11 DESCRIPTION The active component of ZETONNA is ciclesonide, 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)-,(11ss,16)-. Ciclesonide is delivered as the R-epimer. The empirical formula is C32H44O7 and its molecular weight is 540.7. Its structural formula is as follows:Ciclesonide is white to yellow-white powder. It is soluble in dehydrated alcohol, acetone, dichloromethane, and chloroform. ZETONNA is comprised of pressurized, metered-dose aerosol canister and actuator, which is fitted with dose indicator. ZETONNA is intended for intranasal use only. Each canister contains solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. After priming, ZETONNA delivers 50 mcg of ciclesonide from the valve and 37 mcg of ciclesonide from the actuator. This product delivers 50 microliters (59.3 milligrams) of solution as fine particle mist from the valve with each actuation.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION For Intranasal use onlyo1 actuation per nostril once daily. (74 mcg per day) (2.1). o1 actuation per nostril once daily. (74 mcg per day) (2.1). 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 patients 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 actuation per nostril once daily (37 mcg per actuation). The maximum total daily dosage should not exceed actuation in each nostril (74 mcg per day).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS ZETONNA Nasal Aerosol is provided at strength of 37 mcg per actuation strength containing 60 actuations per canister.. oNasal Aerosol: 37 mcg of ciclesonide per actuation. (3)oSupplied in 6.1 canister containing 60 actuations. (16). oNasal Aerosol: 37 mcg of ciclesonide per actuation. (3). oSupplied in 6.1 canister containing 60 actuations. (16).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS In vitro studies and clinical pharmacology studies suggested that des-ciclesonide has no potential for metabolic drug interactions or protein binding-based drug interactions [see Clinical Pharmacology (12.3)]. In drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of des-ciclesonide by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. Erythromycin, moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin following oral inhalation of ciclesonide [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING ZETONNA is supplied as pressurized aluminum canister with purple and white plastic actuator integrated with dose indicator and cap. The contents of one 6.1 gram canister provide 60 actuations, after initial priming. Each actuation delivers 37 mcg of ciclesonide from the nasal actuator. Prior to initial use, or when not used for ten consecutive days, ZETONNA must be primed by actuating three times. If ZETONNA is dropped, the canister and actuator may become separated. If this happens, ZETONNA should be reassembled and actuated once into the air to test before using. The actuator and canister should be discarded after reaching zero in the indicator window since the amount of ciclesonide delivered per spray thereafter may be substantially less than the labeled dose. The ZETONNA canister should only be used with the ZETONNA actuator. The actuator is fitted with dose indicator and should not be used with other inhalation aerosol medications. The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. Illustrated patients instructions for proper use accompany each package of ZETONNA.Store at 25C (77F); excursions permitted to 15-30C (59-86F) [See USP Controlled Room Temp]. For optimal results, canister should be at room temperature when used.Contents under PressureDo not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49C (120F) may cause bursting. Never throw canister into fire or incinerator.Keep out of reach of children. Avoid spraying in eyes or directly onto the nasal septum.ZETONNA 37 mcg, 60 metered actuations; net fill weight 6.1 g.NDC Number 70515-737-60.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling accompanying the product.Local Nasal EffectsInform patients that treatment with ZETONNA may lead to adverse reactions, which include nasal septal perforation, epistaxis, and nasal ulceration. In addition, ciclesonide is associated with candidal infection, and nasal corticosteroids are associated with impaired wound healing. Do not spray ZETONNA directly onto the nasal septum. Patients who have experienced recent nasal septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal trauma should not use ZETONNA until healing has occurred [see Warnings and Precautions (5.1)].Glaucoma and CataractsInform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Instruct patients to inform his/her health care provider if change in vision is noted while using ZETONNA [see Warnings and Precautions (5.2)].ImmunosuppressionWarn patients who are on immunosuppressive doses of corticosteroids to avoid exposure to chickenpox or measles, and if exposed, to consult their physician without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4)].Use DailyInstruct patients to use ZETONNA on regular, once daily basis since its effectiveness depends on its regular use. In clinical trials, the onset of effect was seen after 36 hours following the first dose. Maximum benefit is usually achieved within to weeks after initiation of dosing. Initial assessment of response should be made during this timeframe and periodically until the patients symptoms are stabilized. Instruct the patient to take the medication as directed, not exceed the prescribed dosage, and contact the physician if symptoms do not improve by reasonable time or if the condition worsens.Keep Spray Out of Eyes and Off Nasal SeptumInstruct patients to avoid spraying ZETONNA in their eyes or directly on the nasal septum.Storage and HandlingInstruct patients to use the ZETONNA canister only with the ZETONNA actuator supplied with the product. The dose indicator display window will show red zone when it is about time to replace the ZETONNA. Replace ZETONNA when the indicator shows zero.Manufactured for: Covis Pharma Zug, 6300 SwitzerlandMade the United Kingdom(C) 2018 Covis Pharma and AstraZeneca Group of companies. All rights reserved.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Ciclesonide is pro-drug that is enzymatically hydrolyzed to 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ciclesonide demonstrated no carcinogenic potential in mice in 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 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 forward mutation assay and was not clastogenic in 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 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).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers It is not known if ciclesonide is excreted in human milk. However, other corticosteroids are excreted in human milk. In 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE Chronic overdosage may result in signs or symptoms of hypercorticism [see Warnings and Precautions (5.5)]. There are no data on the effects of acute or chronic overdosage with ZETONNA.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL Carton Label Carton LabelNDC 70515-737-60Net Contents: 6.1 gZetonna(TM) (ciclesonide) Nasal Aerosol37 mcg per actuationFor Intranasal Use Only.Zetonna(TM) Nasal Aerosol CanisterShould Be Used with Zetonna(TM)Nasal Aerosol Actuator Only.60 Metered ActuationsRx OnlyCOVISEach 6.1 canister of Zetonna(TM)Nasal Aerosol contains solution ofciclesonide in propellant HFA-134a(1,1,1,2 tetrafluoroethane) andethanol. The 37 mcg strength ofZetonna(TM) Nasal Aerosol delivers37 mcg of ciclesonide from theactuator.Usual Dosage: See Prescribing Information.Avoid spraying in eyes.CONTENTS UNDER PRESSURE. Do not puncture. Do not use or storenear heat or open flame. Exposureto temperatures above 49C (120F)may cause bursting. Never throwcanister into fire or incinerator.Store at 25C (77F); excursionsbetween 15-30C (59-86F)are permitted [see USP]. For optimalresults, canister should be at roomtemperature when used.Pharmacist: Dispense with PatientsInstructions for Use from packageinsert.Keep out of reach of children.Manufactured forCovis PharmaZug, 6300 SwitzerlandMade in the United Kingdom(C) 2020 Covis Pharma All rights reserved.Zetonna(TM) (ciclesonide) Nasal Aerosol37 mcg per actuation60 Metered ActuationsGTIN: XXXXXXXXXXXXXXSN: XXXXXXXXXXXXXXEXP: MM-YYYYLOT: XXXXXXX. Principal Display Panel Carton Label.

PEDIATRIC USE SECTION.

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 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 weeks of treatment in the seasonal allergic rhinitis trial and over the first 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 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 weeks in duration in children to11 years of age with perennial allergic rhinitis [see Clinical Pharmacology (12.2)].Studies in children under years of age have not been conducted.Controlled clinical trials have shown that intranasal corticosteroids may cause 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 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). 52-week, multi-center, double-blind, randomized, placebo-controlled parallel-group trial was conducted to assess the effect of orally inhaled ciclesonide (ALVESCO(R) Inhalation Aerosol) on growth rate in 609 pediatric patients with mild persistent asthma, aged 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(R) 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Adrenal Function: In 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 mg was used as an active control during the last days of the trial. Adrenal function was assessed by 24-hr serum cortisol AUC before and after the treatment. At the end of weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was -5.0 (4.6) mcgohour/dL, -2.6 (4.6) mcgohour/dL, and -4.6 (5.0) mcgohour/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 mcgohour/dL (95% CI: -15.1, 10.2) and -0.5 mcgohour/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 6-week, randomized, double-blind, placebo-controlled, parallel-group trial in patients to 11 years of age with perennial allergic rhinitis, 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 weeks of treatment, the LS means (SE) change from baseline in serum cortisol AUC(0-24) was 5.9 (5.6) mcgohour/dL and 1.7 (5.2) mcgohour/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 mcgohour/dL (95% CI: -7.4, 22.6).

PHARMACOKINETICS SECTION.

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 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 crossover trial in 29 healthy adults. The median Cmax of des-ciclesonide was 59 pg/mL following single dose of ciclesonide nasal aerosol (296 mcg) compared to 602 pg/mL following single dose of orally inhaled ciclesonide (320 mcg) and 12 pg/mL following 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 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 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 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 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 drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, 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, moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin.

PREGNANCY SECTION.

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 mcg/m2 basis at 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 mcg/m2 basis at maternal dose of 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 1/4 of the MRHDID in adults (on mcg/m2 basis at maternal dose of mcg/kg/day).Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information ZETONNA(R)<<Ze toe nah>>(ciclesonide) Nasal AerosolNote: For Use in the Nose Only.oDo not spray ZETONNA Nasal Aerosol in your eyes or directly onto your nasal septum (the wall between the nostrils).oDo not use your ZETONNA Nasal Aerosol near heat or an open flame.Read this Patient Information leaflet before you start using ZETONNA Nasal Aerosol and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ZETONNA Nasal Aerosol, ask your healthcare provider or pharmacist.What is ZETONNA Nasal AerosolZETONNA Nasal Aerosol is prescription medicine that treats seasonal and year-round allergy symptoms in adults and children 12 years of age and older.ZETONNA Nasal Aerosol contains ciclesonide, which is man-made (synthetic) corticosteroid. Corticosteroids are natural substances found in the body and reduce inflammation. When you spray ZETONNA Nasal Aerosol into your nose, it may help reduce nasal symptoms of allergic rhinitis (inflammation of the lining of the nose) such as stuffy nose, runny nose, itching and sneezing. ZETONNA Nasal Aerosol may also help you if you have red, itchy, and watery eyes.It is not known if ZETONNA Nasal Aerosol is safe and effective in children 11 years of age and younger.Who should not use ZETONNA Nasal AerosolDo not use ZETONNA Nasal Aerosol if you are allergic to ciclesonide or any of the ingredients in ZETONNA Nasal Aerosol. See the end of this Patient Information leaflet for complete list of ingredients in ZETONNA Nasal Aerosol.What should tell my healthcare provider before using ZETONNA Nasal AerosolBefore you use ZETONNA Nasal Aerosol tell your healthcare provider if you:ohave had recent nose problems such as hole in the cartilage of your nose, nasal ulcers, nasal surgery, or nasal injury.ohave or have had eye problems such as increased intraocular pressure, glaucoma, or cataracts.ohave any infections including tuberculosis or ocular herpes simplex.ohave not had or been vaccinated for chicken pox or measles.oare pregnant or plan to become pregnant. It is not known if ZETONNA Nasal Aerosol will harm your unborn baby. Talk to your healthcare provider about the best way to feed your baby if you are using ZETONNA Nasal Aerosol.oare breastfeeding or plan to breastfeed. It is not known if ZETONNA Nasal Aerosol passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you are using ZETONNA Nasal Aerosol.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them to show your doctors and pharmacist when you get new medicine.How should use ZETONNA Nasal AerosoloRead the Instructions for Use at the end of this leaflet for specific information about the right way to use ZETONNA Nasal Aerosol. oUse ZETONNA Nasal Aerosol exactly as your healthcare provider tells you to use it. Do not take more of your medicine or take it more often than your healthcare provider tells you.oZETONNA Nasal Aerosol is used time each day, spray in each nostril. Do not use more than total of spray in each nostril per day.oZETONNA Nasal Aerosol may begin to work within 36 hours after you take your first dose. Maximum benefit is usually achieved within to weeks after initiation of dosing.oIf your symptoms do not improve or get worse, call your healthcare provider.What are the possible side effects of ZETONNA Nasal AerosolZETONNA Nasal Aerosol may cause serious side effects, including:onose bleeds and nasal ulcers. Call your healthcare provider right away if you start to have more nose bleeds or nasal ulcers.ohole in the cartilage in the nose (nasal septal perforation). Stop using ZETONNA Nasal Aerosol and call your doctor right away if you have symptoms of nasal perforation. Symptoms of nasal perforation may include:ocrusting in the noseonosebleedsorunny noseowhistling sound when you breathe othrush (Candida), fungal infection in your nose, mouth, or throat. Tell your healthcare provider if you have any redness or white colored patches in your mouth or throat.oslow wound healing. You should not use ZETONNA Nasal Aerosol until your nose has healed, if you have sore in your nose, if you have had surgery in your nose, or if your nose has been injured.oeye problems such as glaucoma and cataracts. If you have history of glaucoma or cataracts or have family history of eye problems, you should have regular eye exams while you use ZETONNA Nasal Aerosol.oimmune system problems that may increase your risk of infections. You are more likely to get infections if you take medicines that may weaken your bodys ability to fight infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while you use ZETONNA Nasal Aerosol. Symptoms of an infection may include:ofeveropainoachesochillsofeeling tiredonauseaovomiting oadrenal insufficiency. Adrenal insufficiency is condition in which the adrenal glands do not make enough steroid hormones. Call your healthcare provider right away if you experience the following symptoms of adrenal insufficiency:otirednessoweaknessodizzinessonauseaovomiting oslowed or delayed growth in children. childs growth should be checked regularly while using ZETONNA Nasal Aerosol.oallergic reactions. Call your healthcare provider right away if you experience swelling of the lips, tongue, or throat.The most common side effects with ZETONNA Nasal Aerosol include:oNasal discomfortoHeadacheoNose bleedsTell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of ZETONNA Nasal Aerosol. For more information, ask your doctor or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ZETONNA Nasal AerosoloStore ZETONNA Nasal Aerosol at room temperature between 59F and 86F (15C to 30C). oDo not puncture the ZETONNA Nasal Aerosol canister.oDo not store the ZETONNA Nasal Aerosol canister near heat or flame. Temperatures above 120F (49C) may cause the canister to burst.oDo not throw the ZETONNA Nasal Aerosol canister into fire or an incinerator.oSafely throw away medicine that is out of date or no longer needed.oKeep ZETONNA Nasal Aerosol clean and dry at all times.Keep ZETONNA Nasal Aerosol and all medicines out of the reach of children.General Information About the Safe and Effective Use of ZETONNA Nasal Aerosol Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ZETONNA Nasal Aerosol for condition for which it was not prescribed. Do not give ZETONNA Nasal Aerosol to other people, even if they have the same symptoms that you have. It may harm them.This Patient Information summarizes the most important information about ZETONNA Nasal Aerosol. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ZETONNA Nasal Aerosol that is written for health professionals. You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine.What are the ingredients in ZETONNA Nasal AerosolActive ingredient: ciclesonideInactive ingredients: HFA propellant and ethanol Instructions for UseZETONNA(R) <<Ze toe nah>>(ciclesonide)Nasal AerosolRead these Instructions for Use for ZETONNA Nasal Aerosol before you start using it and each time you get refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment.Note: For Use in the Nose Only.oDo not spray ZETONNA Nasal Aerosol in your eyes or directly onto your nasal septum (the wall between your nostrils).oDo not use your ZETONNA Nasal Aerosol near heat or an open flame.The Parts of Your ZETONNA Nasal AerosolZETONNA Nasal Aerosol comes as canister fitted into nasal actuator with dose indicator. Do not use the actuator with canister of medicine from any other inhaler. Do not use the ZETONNA Nasal Aerosol canister with an actuator from any other inhaler. (See Figure A)Figure APriming Your ZETONNA Nasal Aerosol For UseoRemove ZETONNA Nasal Aerosol from its package.oBefore you use ZETONNA Nasal Aerosol for the first time or if you have not used your medicine for 10 days in row, you will need to prime your ZETONNA Nasal Aerosol. oOpen the purple plastic dust cap by gently squeezing both sides and pulling the cap away from the nasal actuator. Hold the nasal actuator upright. (See Figure B)Figure BoSpray times into the air away from the face, by pressing down fully on the top of the canister three times (See Figure C). Make sure the canister returns to its original position after each spray.Figure CUsing Your ZETONNANasal Aerosol Step 1.Open the purple plastic dust cap. Step 2.Hold the nasal actuator upright, with the nose piece pointing upwards, between your thumb and forefinger (and middle finger) (See Figure D).Figure Step 3.Tilt your head back slightly and insert the end of the nose piece into nostril, pointing it slightly toward the outside nostril wall away from the nasal septum (the wall between the nostrils), while holding your other nostril closed with finger (See Figure E). Do not get any spray in your eyes or directly on your nasal septum. Figure Step 4.Press down on the canister to release spray and at the same time breathe in gently through the nostril. Hold your breath for few seconds then breathe out slowly through your mouth. Step 5.Remove the nose piece from your nostril. Make sure the canister has returned to its original position and repeat steps 2-4 for the second spray in your other nostril. Step 6.Replace the protective purple dust cap on the nasal actuator. Step 7.Avoid blowing your nose for the next 15 minutes.Cleaning Your Nasal Actuator The outside of the nose piece should be cleaned weekly, by wiping with clean, dry tissue or cloth (see Figure F). Do not wash or put any part of the ZETONNA Nasal Aerosol canister or actuator in water.Figure FHow to Tell if Your ZETONNA Nasal Aerosol Is EmptyoEach canister of ZETONNA Nasal Aerosol contains enough medicine for you to spray medicine 60 times (or 30 times for sample size product). This does not count the first priming sprays. oThe actuator of your ZETONNA Nasal Aerosol is fitted with dose indicator which shows you how much medicine is left after each use. The dose indicator will display the number of sprays remaining in groups of or 10 actuations. oThe display window will begin showing green color. As you continue to use the medicine, the window will show yellow color. yellow color in the window means that you need to replace your medicine soon. When the medicine is almost empty, the window will show red color. oWhen the window shows red and you see the dose indicator read zero, 0 (see Figure G), you should throw away the canister and nasal actuator. Figure GoDo not throw your ZETONNA Nasal Aerosol canister in the fire or an incinerator.oDo not use your ZETONNA Nasal Aerosol after zero is shown in the window of the dose indicator even though it may look like there is medicine left in the canister. You may not get the right amount of medicine. oTalk with your healthcare provider before your supply of ZETONNA Nasal Aerosol runs out to see if you should get refill of your medicine.What to Do if You Drop Your ZETONNA Nasal AerosoloIf you drop your ZETONNA Nasal Aerosol, the canister may become separated from the actuator. If this happens, insert the canister into the actuator as shown in Figure H, test spray once into the air away from your face, then use as described above.Figure HoIf the ZETONNA Nasal Aerosol is dropped, the dose counter may not work. It is recommended to keep track of the number of sprays taken from your ZETONNA Nasal Aerosol based on your records.This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.Manufactured for: Covis Pharma Zug, 6300 SwitzerlandMade in the United Kingdom(C) 2018 Covis Pharma and AstraZeneca Group of companies. All rights reserved.. oDo not spray ZETONNA Nasal Aerosol in your eyes or directly onto your nasal septum (the wall between the nostrils).. oDo not use your ZETONNA Nasal Aerosol near heat or an open flame.. ohave had recent nose problems such as hole in the cartilage of your nose, nasal ulcers, nasal surgery, or nasal injury.. ohave or have had eye problems such as increased intraocular pressure, glaucoma, or cataracts.. ohave any infections including tuberculosis or ocular herpes simplex.. ohave not had or been vaccinated for chicken pox or measles.. oare pregnant or plan to become pregnant. It is not known if ZETONNA Nasal Aerosol will harm your unborn baby. Talk to your healthcare provider about the best way to feed your baby if you are using ZETONNA Nasal Aerosol.. oare breastfeeding or plan to breastfeed. It is not known if ZETONNA Nasal Aerosol passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you are using ZETONNA Nasal Aerosol.. oRead the Instructions for Use at the end of this leaflet for specific information about the right way to use ZETONNA Nasal Aerosol. oUse ZETONNA Nasal Aerosol exactly as your healthcare provider tells you to use it. Do not take more of your medicine or take it more often than your healthcare provider tells you.. oZETONNA Nasal Aerosol is used time each day, spray in each nostril. Do not use more than total of spray in each nostril per day.. oZETONNA Nasal Aerosol may begin to work within 36 hours after you take your first dose. Maximum benefit is usually achieved within to weeks after initiation of dosing.. oIf your symptoms do not improve or get worse, call your healthcare provider.. onose bleeds and nasal ulcers. Call your healthcare provider right away if you start to have more nose bleeds or nasal ulcers.. ohole in the cartilage in the nose (nasal septal perforation). Stop using ZETONNA Nasal Aerosol and call your doctor right away if you have symptoms of nasal perforation. Symptoms of nasal perforation may include:ocrusting in the noseonosebleedsorunny noseowhistling sound when you breathe ocrusting in the nose. onosebleeds. orunny nose. owhistling sound when you breathe. othrush (Candida), fungal infection in your nose, mouth, or throat. Tell your healthcare provider if you have any redness or white colored patches in your mouth or throat.. oslow wound healing. You should not use ZETONNA Nasal Aerosol until your nose has healed, if you have sore in your nose, if you have had surgery in your nose, or if your nose has been injured.. oeye problems such as glaucoma and cataracts. If you have history of glaucoma or cataracts or have family history of eye problems, you should have regular eye exams while you use ZETONNA Nasal Aerosol.. oimmune system problems that may increase your risk of infections. You are more likely to get infections if you take medicines that may weaken your bodys ability to fight infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while you use ZETONNA Nasal Aerosol. Symptoms of an infection may include:ofeveropainoachesochillsofeeling tiredonauseaovomiting ofever. opain. oaches. ochills. ofeeling tired. onausea. ovomiting. oadrenal insufficiency. Adrenal insufficiency is condition in which the adrenal glands do not make enough steroid hormones. Call your healthcare provider right away if you experience the following symptoms of adrenal insufficiency:otirednessoweaknessodizzinessonauseaovomiting otiredness. oweakness. odizziness. onausea. ovomiting. oslowed or delayed growth in children. childs growth should be checked regularly while using ZETONNA Nasal Aerosol.. oallergic reactions. Call your healthcare provider right away if you experience swelling of the lips, tongue, or throat.. oNasal discomfort. oHeadache. oNose bleeds. oStore ZETONNA Nasal Aerosol at room temperature between 59F and 86F (15C to 30C). oDo not puncture the ZETONNA Nasal Aerosol canister.. oDo not store the ZETONNA Nasal Aerosol canister near heat or flame. Temperatures above 120F (49C) may cause the canister to burst.. oDo not throw the ZETONNA Nasal Aerosol canister into fire or an incinerator.. oSafely throw away medicine that is out of date or no longer needed.. oKeep ZETONNA Nasal Aerosol clean and dry at all times.. oDo not spray ZETONNA Nasal Aerosol in your eyes or directly onto your nasal septum (the wall between your nostrils).. oDo not use your ZETONNA Nasal Aerosol near heat or an open flame.. oRemove ZETONNA Nasal Aerosol from its package.. oBefore you use ZETONNA Nasal Aerosol for the first time or if you have not used your medicine for 10 days in row, you will need to prime your ZETONNA Nasal Aerosol. oOpen the purple plastic dust cap by gently squeezing both sides and pulling the cap away from the nasal actuator. Hold the nasal actuator upright. (See Figure B). oSpray times into the air away from the face, by pressing down fully on the top of the canister three times (See Figure C). Make sure the canister returns to its original position after each spray.. Step 1.Open the purple plastic dust cap.. Step 2.Hold the nasal actuator upright, with the nose piece pointing upwards, between your thumb and forefinger (and middle finger) (See Figure D).. Step 3.Tilt your head back slightly and insert the end of the nose piece into nostril, pointing it slightly toward the outside nostril wall away from the nasal septum (the wall between the nostrils), while holding your other nostril closed with finger (See Figure E). Do not get any spray in your eyes or directly on your nasal septum. Step 4.Press down on the canister to release spray and at the same time breathe in gently through the nostril. Hold your breath for few seconds then breathe out slowly through your mouth.. Step 5.Remove the nose piece from your nostril. Make sure the canister has returned to its original position and repeat steps 2-4 for the second spray in your other nostril.. Step 6.Replace the protective purple dust cap on the nasal actuator.. Step 7.Avoid blowing your nose for the next 15 minutes.. oEach canister of ZETONNA Nasal Aerosol contains enough medicine for you to spray medicine 60 times (or 30 times for sample size product). This does not count the first priming sprays. oThe actuator of your ZETONNA Nasal Aerosol is fitted with dose indicator which shows you how much medicine is left after each use. The dose indicator will display the number of sprays remaining in groups of or 10 actuations. oThe display window will begin showing green color. As you continue to use the medicine, the window will show yellow color. yellow color in the window means that you need to replace your medicine soon. When the medicine is almost empty, the window will show red color. oWhen the window shows red and you see the dose indicator read zero, 0 (see Figure G), you should throw away the canister and nasal actuator. oDo not throw your ZETONNA Nasal Aerosol canister in the fire or an incinerator.. oDo not use your ZETONNA Nasal Aerosol after zero is shown in the window of the dose indicator even though it may look like there is medicine left in the canister. You may not get the right amount of medicine. oTalk with your healthcare provider before your supply of ZETONNA Nasal Aerosol runs out to see if you should get refill of your medicine.. oIf you drop your ZETONNA Nasal Aerosol, the canister may become separated from the actuator. If this happens, insert the canister into the actuator as shown in Figure H, test spray once into the air away from your face, then use as described above.. oIf the ZETONNA Nasal Aerosol is dropped, the dose counter may not work. It is recommended to keep track of the number of sprays taken from your ZETONNA Nasal Aerosol based on your records.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Allergic Rhinitis ZETONNA(R) (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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 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 mcg/m2 basis at 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 mcg/m2 basis at maternal dose of 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 1/4 of the MRHDID in adults (on mcg/m2 basis at maternal dose of 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 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 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 weeks of treatment in the seasonal allergic rhinitis trial and over the first 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 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 weeks in duration in children to11 years of age with perennial allergic rhinitis [see Clinical Pharmacology (12.2)].Studies in children under years of age have not been conducted.Controlled clinical trials have shown that intranasal corticosteroids may cause 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 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). 52-week, multi-center, double-blind, randomized, placebo-controlled parallel-group trial was conducted to assess the effect of orally inhaled ciclesonide (ALVESCO(R) Inhalation Aerosol) on growth rate in 609 pediatric patients with mild persistent asthma, aged 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(R) 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oLocal Nasal Effects, including epistaxis, ulceration, nasal septal perforations, Candida albicans infection, impaired wound healing: Prior to initiating therapy, examine patients for evidence of septal perforation, erosions, ulceration, nasal surgery, and trauma. Avoid spraying ZETONNA directly onto the nasal septum. Avoid use in patients with recent septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal trauma. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue ZETONNA if erosions, ulcerations or perforations occur. (5.1)oDevelopment of glaucoma or cataracts: Monitor patients closely with change in vision or with history of increased intraocular pressure, glaucoma, or cataracts. (5.2)oHypersensitivity reactions have been reported following administration of ciclesonide with manifestations such as angioedema, with swelling of the lips, tongue and pharynx. (5.3) oPotential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chicken pox or measles in susceptible individuals. Use caution in patients with the above because of the potential for worsening of these infections. (5.4)oHypercorticism and adrenal suppression: May occur with higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, discontinue ZETONNA slowly. (5.5)oPotential reduction in growth velocity in children: Monitor growth routinely in pediatric patients receiving ZETONNA. (5.6, 8.4). oLocal Nasal Effects, including epistaxis, ulceration, nasal septal perforations, Candida albicans infection, impaired wound healing: Prior to initiating therapy, examine patients for evidence of septal perforation, erosions, ulceration, nasal surgery, and trauma. Avoid spraying ZETONNA directly onto the nasal septum. Avoid use in patients with recent septal perforation, nasal erosion, nasal ulcers, nasal surgery, or nasal trauma. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue ZETONNA if erosions, ulcerations or perforations occur. (5.1). oDevelopment of glaucoma or cataracts: Monitor patients closely with change in vision or with history of increased intraocular pressure, glaucoma, or cataracts. (5.2). oHypersensitivity reactions have been reported following administration of ciclesonide with manifestations such as angioedema, with swelling of the lips, tongue and pharynx. (5.3) oPotential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chicken pox or measles in susceptible individuals. Use caution in patients with the above because of the potential for worsening of these infections. (5.4). oHypercorticism and adrenal suppression: May occur with higher than recommended dosages or in susceptible individuals at recommended dosages. If such changes occur, discontinue ZETONNA slowly. (5.5). oPotential reduction in growth velocity in children: Monitor growth routinely in pediatric patients receiving ZETONNA. (5.6, 8.4). 5.1 Local Nasal Effects Epistaxis and Nasal Ulceration: In clinical trials of 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 of 824 patients administered ZETONNA (148 mcg). [see Adverse Reactions (6)]The occurrence of local nasal adverse events was further evaluated in 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 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 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 postmarketing 26-week, open-label, active-controlled trial in patients with perennial allergic rhinitis. [see Adverse Reactions (6)]Before starting ZETONNA conduct 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 change in vision or with history of increased intraocular pressure, glaucoma, or cataracts.. 5.3 Hypersensitivity ZETONNA is contraindicated in patients with 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 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 disseminated infection is not known. The contribution of the underlying disease or prior corticosteroid treatment to the risk is also not known. If patient is exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If 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 systemic corticosteroid with 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 severe exacerbation of their symptoms.. 5.6 Effect on Growth Corticosteroids may cause 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)].

LACTATION SECTION.

8.2 Lactation Risk Summary. There are no data on the presence of ciclesonide or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether administration of ciclesonide at the recommended dose could result in sufficient systemic absorption to produce detectable quantities in human milk [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ZETONNA, and any potential adverse effects on the breastfed infant from ZETONNA, or from the underlying maternal condition.. Clinical Considerations. The molecular weight of the prodrug ciclesonide (approximately 541 g/mol) is small enough to be excreted into breast milk; however, its high plasma protein binding affinity and very short half-life suggest that minimal amounts will be present within the milk. Conversely, the half-life of the active metabolite des-ciclesonide (approximately 471 g/mol) suggests that exposure to the nursing infant will be greater than that of the prodrug ciclesonide. Although ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1% for each) due to low gastrointestinal absorption and high first-pass metabolism, the relative anti-inflammatory activity of des-ciclesonide is 12-times greater than that of dexamethasone. The effects of this exposure on nursing infant are unknown; however, like all corticosteroids, suppression of the HPA function is potential complication.. Data. Human DataAt recommended doses, the nasal administration of ciclesonide 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 lower limit of quantification of 25 pg/mL and 10 pg/mL, for ciclesonide and des-ciclesonide, respectively.Animal DataA study with 14C-ciclesonide showed milk exposure of rat pups to 0.006% of the dose secreted in milk.

RISKS.

Risk Summary. There are no available data on ZETONNA use in pregnant women to assess drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is low systemic exposure following ZETONNA administration at the recommended dose [see Clinical Pharmacology (12.3)].In animal reproduction studies, ciclesonide, administered by the oral route to pregnant rats, during the period of organogenesis, did not cause any evidence of fetal harm at doses up to 120 times the maximum recommended human daily intranasal dose [MRHDID] of 74 mcg/day. Teratogenicity, characteristic of corticosteroids, decreased body weight and/or skeletal variations were observed in rabbit fetuses following administration of ciclesonide to pregnant rabbits by the subcutaneous route during the period of organogenesis at doses times the MRHDID and higher on mcg/m2 basis (see Data). No evidence of fetal harm was observed in rabbits at doses 0.3 times the MRHDID.All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.