FDA label 59ab31b1-00ec-4716-95e6-4e360755989f

5 WARNINGS AND PRECAUTIONS • Local nasal adverse reactions, 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 ) • Development of glaucoma or cataracts: Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, or cataracts. ( 5.2 ) • Hypersensitivity reactions have been reported following administration of ciclesonide with manifestations such as angioedema, with swelling of the lips, tongue and pharynx. ( 5.3 ) • Potential 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 ) • Hypercorticism 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 ) • Potential reduction in growth velocity in children: Monitor growth routinely in pediatric patients receiving ZETONNA. ( 5.6 , 8.4 ) 5.1 Local Nasal Adverse Reactions 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 nasal 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 patients treated with ZETONNA compared with none of 892 patients 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 : Localized infections of the nose or pharynx with Candida albicans has occurred from the use of ciclesonide. If such an infection occurs with ZETONNA, treat it with appropriate local therapy and discontinue 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, including ZETONNA, can 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 Reactions ZETONNA is contraindicated in patients with a known hypersensitivity to ciclesonide or any of the ingredients of ZETONNA. Hypersensitivity reactions including angioedema, with swelling of the lips, tongue and pharynx, have occurred after nasal administration of ZETONNA. Discontinue ZETONNA if such reactions occur. 5.4 Immunosuppression and Risk of Infections Patients who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in 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 safety and effectiveness of ZETONNA have not been established in pediatric patients less than 12 years of age and ZETONNA is not indicated for use in this population. The contribution of the underlying disease or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, 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 Prescribing Information for VZIG and IG). 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 Hypercorticism and Adrenal Suppression Hypercorticism and adrenal suppression may occur when nasal corticosteroids, including ZETONNA, are used at higher-than-recommended dosages [see Dosage and Administration ( 2 )] or patients at risk for such effects. 5.6 Effect on Growth Corticosteroids, including ZETONNA, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of ZETONNA have not been established in pediatric patients less than 12 years of age and ZETONNA is not indicated for use in this population. Monitor the growth routinely (e.g., via stadiometry) in pediatric patients receiving ZETONNA [see Pediatric Use ( 8.4 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Epistaxis, Ulcerations, Nasal Septal Perforations, Candida albicans Infection, Impaired Wound Healing [see Warnings and Precautions ( 5.1 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.2 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.4 )] • Hypercorticism and Adrenal Suppression, 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 adult and pediatric patients 12 years of age and older are based on 4 clinical trials evaluating doses of ciclesonide 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. Table 1 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. Table 1: Adverse Reactions Occurring with a Frequency of at least 2.0% and Greater than Placebo from Controlled Clinical Trials 2 to 6 Weeks in Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis a Nasal discomfort includes both nasal discomfort and instillation site discomfort Adverse Reaction ZETONNA 74 mcg Once Daily N = 884 Placebo N = 892 Nasal discomfort a 28 (3.2%) 16 (1.8%) Headache 27 (3.1%) 11 (1.2%) Epistaxis 26 (2.9%) 24 (2.7%) When considering the data from higher doses evaluated in the short-term trials, epistaxis demonstrated a dose response. In addition, 2 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 pediatric patients (12 to 17 years of age) 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 pediatric 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.

<table ID="_Ref128315153" cellpadding="3.6pt" width="75%"><caption>Table 1: Adverse Reactions Occurring with a Frequency of at least 2.0% and Greater than Placebo from Controlled Clinical Trials 2 to 6 Weeks in Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis</caption><col width="28%"/><col width="32%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a Nasal discomfort includes both nasal discomfort and instillation site discomfort</td></tr></tfoot><tbody><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">ZETONNA 74 mcg Once Daily N = 884</content></paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Placebo N = 892</content></paragraph></td></tr><tr><td styleCode="Toprule " valign="top"><paragraph>Nasal discomfort^a</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>28 (3.2%)</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>16 (1.8%)</paragraph></td></tr><tr><td valign="top"><paragraph>Headache</paragraph></td><td align="center" valign="top"><paragraph>27 (3.1%)</paragraph></td><td align="center" valign="top"><paragraph>11 (1.2%)</paragraph></td></tr><tr><td valign="top"><paragraph>Epistaxis</paragraph></td><td align="center" valign="top"><paragraph>26 (2.9%)</paragraph></td><td align="center" valign="top"><paragraph>24 (2.7%)</paragraph></td></tr></tbody></table>