Omnaris

1 INDICATIONS AND USAGE OMNARIS Nasal Spray is a corticosteroid indicated for treatment of nasal symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older and perennial allergic rhinitis in adults and adolescents 12 years of age and older. ( 1.1 , 1.2 ) 1.1 Treatment of Seasonal Allergic Rhinitis OMNARIS Nasal Spray is indicated for the treatment of nasal symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. 1.2 Treatment of Perennial Allergic Rhinitis OMNARIS Nasal Spray is indicated for the treatment of nasal symptoms associated with perennial allergic rhinitis in adults and adolescents 12 years of age and older.

2 DOSAGE AND ADMINISTRATION Administer OMNARIS Nasal Spray by the intranasal route only. Prior to initial use, OMNARIS Nasal Spray must be gently shaken and then the pump must be primed by actuating eight times. If the product is not used for four consecutive days, it should be gently shaken and reprimed with one spray or until a fine mist appears. Illustrated patient’s instructions for proper use accompany each package of OMNARIS Nasal Spray. For Intranasal Use Only • 2 sprays per nostril once daily. (200 mcg) ( 2.1 , 2.2 ) • Priming Information: Gently shake and prime OMNARIS Nasal Spray before using for the first time or when not used for four consecutive days. ( 2 ) 2.1 Seasonal Allergic Rhinitis Adults and Children (6 Years of Age and Older): The recommended dose of OMNARIS Nasal Spray is 2 sprays per nostril once daily (200 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). 2.2 Perennial Allergic Rhinitis Adults and Adolescents (12 Years of Age and Older): The recommended dose of OMNARIS Nasal Spray is 2 sprays per nostril once daily (200 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day).

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

5 WARNINGS AND PRECAUTIONS • Epistaxis, Candida albicans infection, nasal septal perforation, impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid spraying OMNARIS directly onto the nasal septum. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. ( 5.1 ) • Development of glaucoma or cataracts. Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. ( 5.2 ) • Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. ( 5.3 ) • Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue OMNARIS Nasal Spray slowly. ( 5.4 ) • Potential reduction in growth velocity in children. Monitor growth routinely in pediatric patients receiving OMNARIS Nasal Spray. ( 5.5 , 8.4 ) 5.1 Local Nasal Effects Epistaxis : In clinical studies of 2 to 52 weeks’ duration, epistaxis was observed more frequently in patients treated with OMNARIS Nasal Spray than those who received placebo [see Adverse Reactions ( 6 )] . Candida Infection : In clinical studies with OMNARIS Nasal Spray, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of OMNARIS Nasal Spray. Therefore, patients using OMNARIS Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Nasal Septal Perforation : Instances of nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. No cases of nasal septal perforation were identified in clinical studies with OMNARIS Nasal Spray. Avoid spraying OMNARIS Nasal Spray directly onto the nasal septum. Impaired Wound Healing : Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred. 5.2 Glaucoma and Cataracts Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. The risk of glaucoma was evaluated by assessments of intraocular pressure in 3 studies including 943 patients. Of these, 390 adolescents or adults were treated for up to 52 weeks and 186 children ages 2 to 11 received treatment with OMNARIS Nasal Spray 200 mcg daily for up to 12 weeks. In these studies, no significant differences in intraocular pressure changes were observed between OMNARIS Nasal Spray 200 mcg and placebo-treated patients. Additionally, no significant differences between OMNARIS Nasal Spray 200 mcg and placebo-treated patients were noted during the 52-week study of adults and adolescent patients in whom thorough ophthalmologic assessments were performed, including evaluation of cataract formation using slit lamp examinations. 5.3 Immunosuppression 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 contribution of the underlying disease and/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 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. 5.4 Hypothalamic-Pituitary-Adrenal Axis Effect Hypercorticism and Adrenal Suppression : When intranasal corticosteroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of OMNARIS Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroid therapy. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. 5.5 Effect on Growth Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely (e.g., via stadiometry) in pediatric patients receiving OMNARIS Nasal Spray.

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 a drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, a 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, a 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 )] .

6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following: • Epistaxis, nasal septal perforations, Candida albicans infection, impaired wound healing [see Warnings and Precautions ( 5.1 )] • Cataracts and glaucoma [see Warnings and Precautions ( 5.2 )] • Immunosuppression [see Warnings and Precautions ( 5.3 )] • Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions ( 5.4 , 5.5 ), Use in Specific Populations ( 8.4 )] The most common adverse reactions (>2% incidence) included headache, epistaxis, nasopharyngitis, ear pain, and pharyngolaryngeal pain. ( 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 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. The safety data described below for adults and adolescents 12 years of age and older are based on 3 clinical trials of 2 to 6 weeks duration and one 52-week trial. In the 3 trials of 2 to 6 weeks duration, 1524 patients (495 males and 1029 females, ages 12 to 86 years old) with seasonal or perennial allergic rhinitis were treated with OMNARIS Nasal Spray 200, 100, 50, or 25 mcg or placebo once daily. The racial distribution in these three trials included 1374 Caucasians, 69 Blacks, 31 Asians, and 50 patients classified as Other. The 52-week trial was conducted in 663 patients (227 males and 436 females, ages 12 to 73 years old) treated with OMNARIS Nasal Spray 200 mcg or placebo once daily. The racial distribution in this trial included 538 Caucasians, 69 Blacks, 16 Asians, and 40 patients classified as Other. The data from pediatric patients are based upon 4 clinical trials in which 1541 children (871 males and 670 females, ages 2 to 11 years old) with seasonal or perennial allergic rhinitis were treated with OMNARIS Nasal Spray 200, 100, or 25 mcg or placebo once daily for 2 to 12 weeks. The racial distribution in these four trials included 1136 Caucasians, 273 Blacks, 20 Asians, and 112 patients classified as Other. Adults and Adolescents 12 Years of Age and Older in Short-Term (2-6 weeks) Trials: In three short-term trials conducted in the US and Canada, 546 patients were treated with OMNARIS Nasal Spray 200 mcg daily. Adverse reactions did not differ appreciably based on age, gender, or race. Approximately 2% of patients treated with OMNARIS Nasal Spray 200 mcg in clinical trials discontinued because of adverse reactions; this rate was similar for patients treated with placebo. The table below displays reactions that occurred with an incidence of 2% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo in clinical trials of 2 to 6 weeks in duration. Table 1 Adverse Events from Controlled Clinical Trials 2 to 6 Weeks in Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis Adverse Event OMNARIS Nasal Spray 200 mcg Once Daily (N = 546) % Placebo (N = 544) % Headache 6.0 4.6 Epistaxis 4.9 2.9 Nasopharyngitis 3.7 3.3 Ear Pain 2.2 0.6 Pediatric Patients Aged 6 to 11 Years in Short-Term (2-12 weeks) Trials: In two short-term trials, conducted in the US and Canada, 913 patients were treated with OMNARIS Nasal Spray 200 mcg, 100 mcg or 25 mcg daily. Adverse events did not differ appreciably based on age, gender, or race. In clinical trials, 1.6% and 2.7% of patients treated with OMNARIS Nasal Spray 200 mcg or 100 mcg, respectively, discontinued because of adverse reactions; these rates were lower than the rate in patients treated with placebo (2.8%). Table 2 displays adverse events that occurred with an incidence of 3% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo. Table 2 Adverse Events from Controlled Clinical Trials 2 to 12 Weeks in Duration in Patients 6 to 11 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis Adverse Event OMNARIS Nasal Spray 200 mcg Once Daily (N = 380) % Placebo (N = 369) % Headache 6.6 5.7 Nasopharyngitis 6.6 5.4 Pharyngolaryngeal pain 3.4 3.3 Pediatric Patients Aged 2 to 5 Years in Short-Term (6-12 weeks) Trials: In two short-term trials conducted in the US, 183 patients were treated with OMNARIS Nasal Spray 200 mcg, 100 mcg or 25 mcg daily. The distribution of adverse events was similar to that seen in the 6 to 11 year old children. Long-Term (52-Week) Safety Trial: In a 52-week double-blind, placebo-controlled safety trial that included 663 adults and adolescent patients (441 treated with ciclesonide: 227 males and 436 females) with perennial allergic rhinitis, the adverse reaction profile over the treatment period was similar to the adverse event profile in trials of shorter duration. Adverse reactions, irrespective of drug relationship, that occurred with an incidence of 3% or greater and more frequently with OMNARIS Nasal Spray 200 mcg than with placebo were epistaxis, pharyngolaryngeal pain, sinusitis, headache, nasal discomfort, cough, bronchitis, influenza, back pain, and urinary tract infection. No patient experienced a nasal septal perforation or nasal ulcer during this long-term trial of OMNARIS Nasal Spray. 6.2 Post-Marketing Experience The following adverse reactions have been reported in association with post-marketing use of OMNARIS Nasal Spray and are not listed above: nasal congestion, nasal ulcer and dizziness. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

8.1 Pregnancy Risk Summary There are no data on ONMARIS nasal spray use in pregnant women to assess a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes . There is low systemic exposure following OMNARIS nasal spray 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 45 times the maximum recommended human daily intranasal dose (MRHDID) of 200 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 0.5 times the MRHDID and higher on a mcg/m 2 basis (see Data ). No evidence of fetal harm was observed in rabbits at doses 0.1 times the MRHDID. All pregnancies have a 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. Data Animal Data In an embryo-fetal development study in pregnant rats dosed by the oral route during the period of organogenesis from gestation days 6 to 15, ciclesonide did not cause any evidence of fetal harm at doses up to 45 times the MRHDID in adults (on a mcg/m 2 basis with maternal oral dose up to 900 mcg/kg/day). Maternal toxicity, as evidenced by decreased body weight gain, was observed at 45 times the MRHDID in adults (on a mcg/m 2 basis at a maternal dose of 900 mcg/kg/day); however, no adverse effects were observed at doses 15 times the MRHDID and lower (on a mcg/m 2 basis with maternal oral doses of 300 mcg/kg/day and lower). In two embryo-fetal development studies in pregnant rabbits dosed by the subcutaneous route during the period of organogenesis from gestation days 6 to 18, ciclesonide caused acampsia (flexures of legs) in fetuses at doses 0.5 times the MRHDID and higher (on a mcg/m 2 basis with maternal oral doses of 5 mcg/kg/day and higher), decreased body weight, cleft palate, enlarged fontanelle, parchment-like skin, and incomplete ossification of bones in fetuses at doses 2 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 25 µg/kg/day) and embryo-fetal death at doses 10 times the MRHDID and higher (on a mcg/m 2 basis at maternal subcutaneous doses of 100 mcg/kg/day and higher). No evidence of fetal harm was observed at a dose 0.1 times the MRHDID in adults (on a mcg/m 2 basis at a maternal subcutaneous dose of 1 mcg/kg/day). Maternal toxicity was observed at doses 10 times the MRHDID in adults (on a mcg/m 2 basis with maternal subcutaneous doses of 100 mcg/kg/day and lower); however, no evidence of toxicity was observed at doses 2 times the MRHDID and lower (on a mcg/m 2 basis with maternal subcutaneous doses of 25 mcg/kg/day and lower). In a prenatal and postnatal development study in pregnant rats dosed by the oral route from gestation day 6 to lactation day 20, ciclesonide produced no adverse developmental effects on offspring at doses up to approximately 45 times the MRHDID (on mcg/m 2 bases at maternal oral doses up to 900 mcg/kg/day).