Alvesco

1 INDICATIONS AND USAGE ALVESCO is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 12 years of age and older. Limitations of Use : ALVESCO is not indicated for the relief of acute bronchospasm. ALVESCO is not indicated for children under 12 years of age. ALVESCO is an inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 12 years of age and older. ( 1 ) Limitations of Use : ALVESCO is not indicated for the relief of acute bronchospasm or in pediatric patients less than 12 years of age. ( 1 )

2 DOSAGE AND ADMINISTRATION For oral inhalation only. ( 2 ) Prime ALVESCO before first use or when inhaler not used for more than 10 days. ( 2 ) 1 Prednisone should be reduced gradually, no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with ALVESCO. Patients should be carefully monitored for signs of asthma instability, including monitoring of serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy [see Warnings and Precautions ( 5.1 )] . Previous Therapy Recommended Starting Dose Highest Recommended Dose Patients ≥ 12 years who received bronchodilators alone 80 mcg twice daily 160 mcg twice daily Patients ≥ 12 years who received inhaled corticosteroids 80 mcg twice daily 320 mcg twice daily Patients ≥ 12 years who received oral corticosteroids 1 320 mcg twice daily 320 mcg twice daily 2.1 Administration Information Administer ALVESCO by the orally inhaled route. After administration, rinse the mouth with water and spit out without swallowing to help reduce the risk of oropharyngeal candidiasis [see Warnings and Precautions ( 5.1 )] . Priming Prime ALVESCO before using for the first time by actuating 3 times prior to using the first dose from a new canister or when the inhaler has not been used for more than 10 days. 2.2 Recommended Dosage The recommended starting dosage and the highest recommended dosage of ALVESCO are listed in Table 1 Table 1: Recommended Dosages for Adults and Pediatric Patients 12 Years and Older 1 Prednisone should be reduced gradually, no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with ALVESCO. Patients should be carefully monitored for signs of asthma instability, including monitoring of serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy [see Warnings and Precautions ( 5.1 )] . Previous Therapy Recommended Starting Dosage Highest Recommended Dosage Patients ≥ 12 years who received bronchodilators alone 80 mcg twice daily 160 mcg twice daily Patients ≥ 12 years who received inhaled corticosteroids 80 mcg twice daily 320 mcg twice daily Patients ≥ 12 years who received oral corticosteroids 1 320 mcg twice daily 320 mcg twice daily General Dosing Recommendations Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for four weeks or longer after initiation. After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dose after 4 weeks of therapy, higher doses may provide additional asthma control. Patients should not exceed the highest recommended dosage per day.

5 WARNINGS AND PRECAUTIONS Candida albicans infection of the mouth and pharynx. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse mouth following inhalation. ( 5.1 ) Potential worsening of existing tuberculosis: fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with above because of the potential for worsening of these infections. ( 5.3 ) Risk of impaired adrenal function when transferring from oral steroids to inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to ALVESCO. ( 5.4 ) Hypercorticism, suppression of hypothalamic-pituitary-adrenal (HPA) function with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue ALVESCO slowly ( 5.5 ) Suppression of growth in children. Monitor growth routinely in pediatric patients receiving ALVESCO. ( 5.7 ) Development of glaucoma, increased intraocular pressure and posterior subcapsular cataracts. Monitor patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts closely. ( 5.8 ) 5.1 Oropharyngeal Candidiasis In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans occurred in 32 of 3038 patients treated with ALVESCO. Of the 32 reported cases, 20 occurred in 1394 patients treated with a total daily dose of 320 mcg of ALVESCO or higher. Most cases of Candida infection were mild to moderate. When such an infection occurs, treat it with appropriate local or systemic (i.e., oral antifungal) therapy and discontinue ALVESCO. Patients should rinse the mouth after inhalation of ALVESCO. 5.2 Acute Asthma Episodes ALVESCO is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with ALVESCO. During such episodes, patients may require therapy with oral corticosteroids. 5.3 Immunosuppression and Risk of Infections Persons 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 such 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 ALVESCO have not been established in pediatric patients less than 12 years of age and ALVESCO is not indicated for use in this population. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See Prescribing Information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.4 Transferring Patients from Systemic Corticosteroid Therapy HPA Suppression/Adrenal Insufficiency Particular care is needed for patients who are transferred from systemically active corticosteroids to ALVESCO because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from…

4 CONTRAINDICATIONS ALVESCO is contraindicated in: the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. patients with known hypersensitivity to ciclesonide or any of the ingredients of ALVESCO. Rare cases of hypersensitivity reactions with manifestations such as angioedema, with swelling of the lips, tongue and pharynx, have been reported. Patients with status asthmaticus or other acute episodes of asthma where intensive measures are required. ( 4 ) Patients with a known hypersensitivity to ciclesonide or any of the ingredients of ALVESCO. ( 4 )

7 DRUG INTERACTIONS In clinical studies, concurrent administration of ciclesonide and other drugs commonly used in the treatment of asthma (albuterol, formoterol) had no effect on pharmacokinetics of des-ciclesonide [see Clinical Pharmacology ( 12.3 )] . 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.

8.1 Pregnancy Risk Summary There are no available data on ALVESCO 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 ALVESCO oral inhalation 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 15 times the maximum recommended human daily oral inhalation dose (MRHDOID) of 640 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 0.15 times the MRHDOID and higher on a mcg/m 2 basis (see Data). No evidence of fetal harm was observed in rabbits at doses of 0.03 times the MRHDOID. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre‑eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. 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 approximately 15 times the MRHDOID 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 approximately 15 times the MRHDOID 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 5 times the MRHDOID 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 0.15 times the MRHDOID 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 0.76 times the MRHDOID (on a mcg/m 2 basis with a maternal subcutaneous dose of 25 mcg/kg/day), and embryo-fetal death at doses 3 times the MRHDOID and higher (on a mcg/m 2 basis with maternal subcutaneous doses of 100 mcg/kg/day and higher). No evidence of fetal harm was observed at a dose 0.03 times the MRHDOID in adults (on a mcg/m 2 basis at a maternal subcutaneous dose of 1 mcg/kg/day). Maternal toxicity was observed at doses 3 times the MRHDOID 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 0.76 times the MRHDOID 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 15 times the MRHDOID (on a mcg/m 2 basis at maternal oral doses…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.1 )] Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.3 )] Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.5 )] Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.6 )] Growth Effects [see Warnings and Precautions ( 5.7 )] Glaucoma and Cataracts [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥ 3%) are headache, nasopharyngitis, sinusitis, pharyngolaryngeal pain, upper respiratory infection, arthralgia, nasal congestion, pain in extremity and back pain. ( 6 ) Other adverse reactions have been reported. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience The safety data described below for adult and pediatric patients 12 years of age and older reflect exposure to ALVESCO in doses ranging from 80 mcg to 640 mcg twice daily in five double-blind placebo-controlled clinical trials. Studies with once daily dosing are omitted from the safety database because the doses studied once daily are lower than the highest recommended twice daily doses. The five studies were of 12 to 16 weeks treatment duration, one of which included a safety extension follow-up of one year. In the 12 to 16 week treatment studies, 720 patients (298 males and 422 females) aged 12 years and older were exposed to ALVESCO. In the long-term safety trial, 197 patients (82 males and 115 females) with severe persistent asthma from one of the 12-week trials were re-randomized and treated for up to one year with ALVESCO 320 mcg twice daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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. Adults and Pediatric Patients 12 Years of Age and Older Four of the five trials included a total of 624 patients ages 12 years and older (359 females and 265 males) with asthma of varying severity who were treated with ALVESCO 80 mcg, 160 mcg, or 320 mcg twice daily for 12 to 16 weeks. These studies included patients previously using either controller therapy (predominantly inhaled corticosteroids) or reliever therapy (bronchodilator therapy alone). In these trials, the mean age was 39.1 years, and the majority of the patients (79.0%) were Caucasian. In these trials, 52.3%, 59.8% and 54.1% of the patients in the ALVESCO 80 mcg, 160 mcg, and 320 mcg treatment groups, respectively, had at least one adverse event compared to 58.0% in the placebo group. Table 2 includes adverse reactions for the recommended doses of ALVESCO that occurred at an incidence of ≥ 3% in any of the ALVESCO groups and which were more frequent with ALVESCO compared to placebo. Table 2: Adverse Reactions with ≥ 3% Incidence Reported in Patients ≥ 12 Years of Age with ALVESCO in US Placebo-Controlled Clinical Trials in Patients Previously on Bronchodilators and/or Inhaled Corticosteroids Adverse Reaction Placebo (N=507) % ALVESCO 80 mcg BID (N=325) % 160 mcg BID (N=127) % 320 mcg BID (N=172) % Headache 7.3 4.9 11.0 8.7 Nasopharyngitis 7.5 10.5 8.7 7.0 Sinusitis 3.0 3.1 5.5 5.2 Pharyngolaryngeal pain 4.3 4.3 2.4 4.7 Upper respiratory Inf. 6.5 7.1 8.7 4.1 Arthralgia 1.0 0.9 2.4 3.5 Nasal congestion 1.6 1.8 5.5 2.9 Pain in extremity 1.0 0.3 3.1 2.3 Back pain 2.0 0.6 3.1 1.2 The following adverse reactions occurred in these clinical trials using ALVESCO with an incidence of less than 1% and occurred at a greater incidence with ALVESCO than with placebo. Infections and Infestations : Oral candidiasis Respiratory Disorders : Cough Gastrointestinal Disorders : Dry mouth, nausea General Disorders and Administrative Site Conditions : Chest disco…