ALVESCO is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 12 years of age and older.

{ "type": "p", "children": [], "text": "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:

{ "type": "p", "children": [], "text": "\nLimitations of Use: " }

ALVESCO is not indicated for the relief of acute bronchospasm.

{ "type": "p", "children": [], "text": "ALVESCO is not indicated for the relief of acute bronchospasm." }

ALVESCO is not indicated for children under 12 years of age.

{ "type": "p", "children": [], "text": "ALVESCO is not indicated for children under 12 years of age." }

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.

The recommended starting dosage and the highest recommended dosage of ALVESCO are listed in Table 1

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <caption> <span>Table 1: Recommended Dosages for Adults and Pediatric Patients 12 Years and Older</span> </caption> <col width="48%"/> <col width="25%"/> <col width="27%"/> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="3" valign="top"><span class="Sup">1</span> 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 <span class="Italics">[see Warnings and Precautions (<a href="#ID_28ae3eda-6ea2-486f-b0da-697ab6b4081a">5.1</a>)]</span>.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule" valign="middle"> <p class="First"> <span class="Bold">Previous Therapy</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First"> <span class="Bold">Recommended Starting Dosage</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First"> <span class="Bold">Highest Recommended Dosage</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Patients ≥ 12 years who received bronchodilators alone</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">80 mcg twice daily</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">160 mcg twice daily</p> </td> </tr> <tr> <td valign="middle"> <p class="First">Patients ≥ 12 years who received inhaled corticosteroids </p> </td><td align="center" valign="middle"> <p class="First">80 mcg twice daily</p> </td><td align="center" valign="middle"> <p class="First">320 mcg twice daily</p> </td> </tr> <tr class="Last"> <td valign="middle"> <p class="First">Patients ≥ 12 years who received oral corticosteroids<span class="Sup">1</span> </p> </td><td align="center" valign="middle"> <p class="First">320 mcg twice daily </p> </td><td align="center" valign="middle"> <p class="First">320 mcg twice daily</p> </td> </tr> </tbody> </table></div>

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.

Inhalation aerosol:

{ "type": "p", "children": [], "text": "Inhalation aerosol:" }

{ "type": "", "children": [], "text": "" }

ALVESCO is contraindicated in:

{ "type": "p", "children": [], "text": "ALVESCO is contraindicated in:" }

{ "type": "", "children": [], "text": "" }

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.

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.

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.

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 systemic corticosteroids to less systemically-available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ALVESCO may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ALVESCO. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during ALVESCO therapy [see Dosage and Administration (2)]. Lung function (FEV1 or AM PEFR), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids

Transfer of patients from systemic steroid therapy to ALVESCO may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

Corticosteroid Withdrawal Symptoms

During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

ALVESCO will often help control asthma symptoms with less suppression of HPA function than therapeutically similar oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ALVESCO. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

Hypercorticism and adrenal suppression may occur when corticosteroids, including ALVESCO, are used at higher-than-recommended dosages [see Dosage and Administration (2)] or patients at risk for such effects.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and oral corticosteroids) should be monitored and treated with established standards of care.

Orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. 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. Monitor the growth of pediatric patients receiving ALVESCO routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ALVESCO, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].

Glaucoma, increased intraocular pressure, and cataracts have been reported following the administration of inhaled corticosteroids including ALVESCO. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

In a comparator control study of one-year treatment duration, 743 patients 18 years of age and older (mean age 43.1 years) with moderate persistent asthma were treated with ALVESCO 320 mcg twice daily and 742 were treated with a labeled dose of a comparator-inhaled corticosteroid appropriate for the patient population. Patients had an ophthalmology examination that included visual acuity, intraocular pressure measurement, and a slit lamp examination at baseline, 4, 8 and 12 months. Lens opacities were graded using the Lens Opacification System III. After 52 weeks, CLASS I effects (minimally detected changes) were recorded in 36.1% of the ALVESCO-treated patients and in 38.4% of patients treated with the comparator-inhaled corticosteroid. The more severe CLASS III effects were recorded in 8.1% of the ALVESCO-treated patients and 9.2% of patients treated with the comparator-inhaled corticosteroid. Of those patients having a CLASS III effect, the incidence of posterior sub-capsular opacities was 0.9% and 0.5% in the ALVESCO- and comparator-treated patients, respectively.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with ALVESCO, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with ALVESCO should be discontinued and alternative treatment should be instituted.

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.

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <caption> <span>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</span> </caption> <col width="30%"/> <col width="14%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <tbody class="Headless"> <tr class="First Toprule"> <td rowspan="2" valign="top"> <p class="First">Adverse Reaction</p> </td><td align="center" rowspan="2" valign="bottom"> <p class="First">Placebo<br/>(N=507)<br/>%</p> </td><td align="center" class="Botrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">ALVESCO</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">80 mcg BID<br/>(N=325)<br/>%</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">160 mcg BID<br/>(N=127)<br/>%</p> </td><td align="center" class="Botrule Toprule" valign="bottom"> <p class="First">320 mcg BID<br/>(N=172)<br/>%</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">7.3</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">4.9</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">11.0</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">8.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nasopharyngitis</p> </td><td align="center" valign="middle"> <p class="First">7.5</p> </td><td align="center" valign="middle"> <p class="First">10.5</p> </td><td align="center" valign="middle"> <p class="First">8.7</p> </td><td align="center" valign="middle"> <p class="First">7.0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Sinusitis</p> </td><td align="center" valign="middle"> <p class="First">3.0</p> </td><td align="center" valign="middle"> <p class="First">3.1</p> </td><td align="center" valign="middle"> <p class="First">5.5</p> </td><td align="center" valign="middle"> <p class="First">5.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pharyngolaryngeal pain</p> </td><td align="center" valign="middle"> <p class="First">4.3</p> </td><td align="center" valign="middle"> <p class="First">4.3</p> </td><td align="center" valign="middle"> <p class="First">2.4</p> </td><td align="center" valign="middle"> <p class="First">4.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">Upper respiratory Inf.</p> </td><td align="center" valign="middle"> <p class="First">6.5</p> </td><td align="center" valign="middle"> <p class="First">7.1</p> </td><td align="center" valign="middle"> <p class="First">8.7</p> </td><td align="center" valign="middle"> <p class="First">4.1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Arthralgia</p> </td><td align="center" valign="middle"> <p class="First">1.0</p> </td><td align="center" valign="middle"> <p class="First">0.9</p> </td><td align="center" valign="middle"> <p class="First">2.4</p> </td><td align="center" valign="middle"> <p class="First">3.5</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nasal congestion</p> </td><td align="center" valign="middle"> <p class="First">1.6</p> </td><td align="center" valign="middle"> <p class="First">1.8</p> </td><td align="center" valign="middle"> <p class="First">5.5</p> </td><td align="center" valign="middle"> <p class="First">2.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pain in extremity</p> </td><td align="center" valign="middle"> <p class="First">1.0</p> </td><td align="center" valign="middle"> <p class="First">0.3</p> </td><td align="center" valign="middle"> <p class="First">3.1</p> </td><td align="center" valign="middle"> <p class="First">2.3</p> </td> </tr> <tr class="Botrule Last"> <td valign="top"> <p class="First">Back pain</p> </td><td align="center" valign="middle"> <p class="First">2.0</p> </td><td align="center" valign="middle"> <p class="First">0.6</p> </td><td align="center" valign="middle"> <p class="First">3.1</p> </td><td align="center" valign="middle"> <p class="First">1.2</p> </td> </tr> </tbody> </table></div>

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 discomfort

Respiratory, Thoracic, and Mediastinal Disorders: Dysphonia, dry throat

The fifth study was a 12-week clinical trial in asthma patients 12 years of age and older who previously required oral corticosteroids (average daily dose of oral prednisone of 12 mg/day), in which the effects of ALVESCO 320 mcg twice daily (n = 47) and 640 mcg twice daily (n = 49) were compared with placebo (n = 45) for the frequency of reported adverse reactions. The following adverse reactions occurred at an incidence of ≥ 3% in the ALVESCO-treated patients and were more frequent compared to placebo: sinusitis, hoarseness, oral candidiasis, influenza, pneumonia, nasopharyngitis, arthralgia, back pain, musculoskeletal chest pain, headache, urticaria, dizziness, gastroenteritis, face edema, fatigue, and conjunctivitis.

Long-Term Clinical Trials Experience

A total of 197 patients 12 years of age and older (82 males and 115 females) from one of the 12-week treatment placebo-controlled studies were re-randomized to ciclesonide 320 mcg twice daily and followed for one year. The safety profile from the one-year follow-up was similar to that seen in the 12- and 16-week treatment studies.

In addition to adverse reactions identified from clinical trials, the following adverse reactions have been identified during worldwide post-marketing use of ciclesonide oral inhalation. 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.

Immune System Disorders: Immediate or delayed hypersensitivity reactions such as angioedema with swelling of the lips, tongue and pharynx.

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)].

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "\nIn 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.

{ "type": "p", "children": [], "text": "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." }

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/m2 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.

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.

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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis at maternal oral doses up to 900 mcg/kg/day).

There are no data on the presence of ciclesonide or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether oral inhalation administration of ciclesonide at the recommended dose could result in sufficient systemic absorption to produce detectable quantities in human milk [seeClinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALVESCO, and any potential adverse effects on the breastfed infant from ALVESCO, or from the underlying maternal condition.

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 suggests 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 120 times greater than that of the ciclesonide and 12 times greater than that of dexamethasone [seeClinical Pharmacology (12.1)]. The effects of this exposure on a nursing infant are unknown, however, like all corticosteroids, suppression of the HPA function is a potential complication.

Animal Data

A study with 14C-ciclesonide showed milk exposure of rat pups to 0.006% of the dose secreted in milk.

The safety and effectiveness of ALVESCO for the maintenance treatment of asthma as prophylactic therapy have been established in pediatric patients aged 12 years and older. Use of ALVESCO for this indication is supported by evidence from randomized, double-blind, placebo-controlled, parallel-group clinical trials in adult and pediatric patients 12 years of age and older with mild persistent to severe persistent asthma [see Clinical Studies (14)].

The safety and effectiveness of ALVESCO have not been established in pediatric patients younger than 12 years of age.

Pediatric Patients 4 to 11 years of age

Effectiveness was not demonstrated in two randomized, double-blind, placebo-controlled studies that were conducted to evaluate the efficacy of ALVESCO 40, 80, or 160 mcg administered once daily for 12 weeks in patients 4 to 11 years of age with asthma. These studies included 1018 patients previously using either controller therapy (predominately inhaled corticosteroids) or reliever therapy (bronchodilator therapy alone). The patients had a mean baseline percent predicted FEV1 of 68%. The primary efficacy endpoint was morning pre-dose FEV1. Other measures of efficacy included AM PEF, asthma symptoms, and rescue albuterol use. The studies showed inconsistent results and did not establish the efficacy of ALVESCO in patients 4 to 11 years of age.

Pediatric Patients 2 to 6 years of age

Effectiveness was not demonstrated in one randomized, double-blind, placebo-controlled study that was conducted to evaluate the efficacy of ALVESCO 40, 80, and 160 mcg administered once daily for 24 weeks in 992 patients 2 to 6 years of age with persistent asthma. The primary efficacy endpoint was time to the first severe asthma exacerbation [defined as worsening of asthma which required treatment with systemic (including oral) steroids or any other asthma medication besides treatment medication and rescue medication] or lack of improvement, whichever occurred first. No statistically significant differences were observed for the individual comparisons of ALVESCO 40, 80, and 160 mcg to placebo. Results from this study did not establish efficacy of ALVESCO in patients 2 to 6 years of age.

Studies in children under 2 years of age have not been conducted given the lack of efficacy observed in patients 2 to 11 years of age.

Effect on Growth

Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including ALVESCO, should be monitored routinely (e.g., via stadiometry).

A 52-week, multi-center, double-blind, randomized, placebo-controlled, parallel-group study was conducted to assess the effect of orally inhaled ciclesonide on growth rate in 609 pediatric patients with mild persistent asthma, aged 5 to 8.5 years. Treatment groups included orally inhaled ciclesonide 40 mcg or 160 mcg or placebo given once daily. Growth was measured by stadiometer height during the baseline, treatment and follow-up periods. The primary comparison was the difference in growth rates between ciclesonide 40 mcg and 160 mcg and placebo groups. Conclusions cannot be drawn from this study because compliance could not be assured. There was no difference in efficacy measures between the placebo and the ALVESCO groups. Ciclesonide blood levels were also not measured during the one-year treatment period.

The potential growth effects of prolonged treatment with orally inhaled corticosteroids should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, including ALVESCO, each patient should be titrated to his/her lowest effective dose.

Clinical studies of ALVESCO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than 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, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. " }

The active component of ALVESCO 80 mcg, and ALVESCO 160 mcg is ciclesonide, a 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)-,(11β,16α). The empirical formula is C32H44O7 and its molecular weight is 540.7. Its structural formula is as follows:

{ "type": "p", "children": [], "text": "The active component of ALVESCO 80 mcg, and ALVESCO 160 mcg is ciclesonide, a 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)-,(11β,16α). The empirical formula is C32H44O7 and its molecular weight is 540.7. Its structural formula is as follows:" }

Ciclesonide is a white to yellow-white powder. It is soluble in dehydrated alcohol, acetone, dichloromethane, and chloroform.

{ "type": "p", "children": [], "text": "Ciclesonide is a white to yellow-white powder. It is soluble in dehydrated alcohol, acetone, dichloromethane, and chloroform." }

ALVESCO 80 mcg and ALVESCO 160 mcg are pressurized, metered-dose aerosol units fitted with a dose indicator. ALVESCO is intended for oral inhalation only. Each unit contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. After priming, ALVESCO 80 mcg delivers 100 mcg from the valve and 80 mcg of ciclesonide from the actuator. ALVESCO 160 mcg delivers 200 mcg from the valve and 160 mcg of ciclesonide from the actuator. This product delivers 50 microliters (59.3 milligrams) of solution as a fine particle mist from the valve with each actuation. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. ALVESCO should be “primed” 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. Avoid spraying in the eyes or face while priming ALVESCO.

{ "type": "p", "children": [], "text": "ALVESCO 80 mcg and ALVESCO 160 mcg are pressurized, metered-dose aerosol units fitted with a dose indicator. ALVESCO is intended for oral inhalation only. Each unit contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. After priming, ALVESCO 80 mcg delivers 100 mcg from the valve and 80 mcg of ciclesonide from the actuator. ALVESCO 160 mcg delivers 200 mcg from the valve and 160 mcg of ciclesonide from the actuator. This product delivers 50 microliters (59.3 milligrams) of solution as a fine particle mist from the valve with each actuation. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system. ALVESCO should be “primed” 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. Avoid spraying in the eyes or face while priming ALVESCO." }

Ciclesonide is a prodrug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following oral inhalation. Des-ciclesonide has anti-inflammatory activity with affinity for glucocorticoid receptors that is 120 times greater than the parent compound and 12 times greater than dexamethasone. The clinical significance of these findings is unknown.

The precise mechanisms of corticosteroid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. 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 starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

The effect of ciclesonide by oral inhalation on the HPA axis was assessed in adults with mild asthma in a 29-day placebo-controlled study. Twenty-four-hour urinary-free cortisol was assessed in a total of 59 adults who were randomized to 320 mcg or 640 mcg ALVESCO, a comparator corticosteroid, or placebo twice daily. At the end of 29 days of treatment, the mean (SE) change from baseline in 24-hr urinary-free cortisol was -8.69 (5.6) mcg/day, -4.01 (5.03) mcg/day, and -8.84 (5.02) mcg/day for the placebo, ALVESCO 640 mcg/day, and ALVESCO 1280 mcg/day, respectively. The difference from placebo for the change from baseline in 24-hr urinary-free cortisol was +4.7 mcg/day [95% CI: -10.58; 19.93] and -0.16 mcg/day [95% CI: -15.20; 14.89] for the 640 mcg/day or 1280 mcg/day treatments, respectively. The effects observed with the comparator corticosteroid validate the sensitivity of the study to assess the effect of ciclesonide on the HPA axis.

Absorption: Ciclesonide and des-ciclesonide have negligible oral bioavailability (both are less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. Serum concentrations of ciclesonide and des-ciclesonide were measured and compared following oral inhalation of 1280 mcg ALVESCO and intravenous administration of 800 mcg ciclesonide. The absolute bioavailability of ciclesonide was 22% and the relative systemic exposure of des-ciclesonide was 63%. The mean Cmax for des-ciclesonide was 1.02 ng/mL (range 0.6-1.5 ng/mL) in asthmatic patients following a single dose of 1280 mcg by oral inhalation. The mean Cmax (0.369 ng/mL) and AUC0-∞ (2.18 ng·hr/mL) of des‑ciclesonide following multiple dose administration of ciclesonide 320 mcg once daily increased up to 26% compared to single dose administration.

Distribution: Following intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide was 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.

Elimination: Following intravenous administration of 800 mcg of ciclesonide, the clearances of ciclesonide and des-ciclesonide were high (approximately 152 L/L/hr and 228 L/L/hr, respectively). 14C-labeled 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 des-ciclesonide was excreted in the urine. The mean half-life of ciclesonide and des-ciclesonide was 0.71 hours and 6 to 7 hours, respectively. Tmax of des-ciclesonide occurs at 1.04 hours following inhalation of ciclesonide.

Metabolism: Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. Des-ciclesonide undergoes further metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. The full range of potentially active metabolites of ciclesonide has not been characterized. After intravenous administration of 14C-ciclesonide, 19.3% of the resulting radioactivity in the plasma is accounted for by ciclesonide or des-ciclesonide; the remainder may be a result of other, as yet, unidentified multiple metabolites.

Specific Populations: Population pharmacokinetic analysis showed that characteristics of des-ciclesonide after oral inhalation of ciclesonide were not appreciably influenced by a variety of subject characteristics such as body weight, age, race, and gender.

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

Patients with Hepatic Impairment: Compared to healthy subjects, the systemic exposure of des-ciclesonide (Cmax and AUC) in patients with moderate to severe liver impairment increased in the range of 1.4 to 2.7 fold after 1280 mcg ex-actuator ciclesonide by oral inhalation. Dose adjustment in patients with liver impairment is not necessary.

Drug Interaction Studies: 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 ciclesonide active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged [see Drug Interactions (7)].

In another single-dose drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, an inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either ciclesonide and the active metabolite, des-ciclesonide, or erythromycin.

Based on in vitro studies in human liver microsomes, des-ciclesonide had no significant potential to inhibit or induce the metabolism of other drugs metabolized by CYP450 enzymes. The inhibitory potential of ciclesonide on CYP450 isoenzymes has not been studied. Based on in vitro human hepatocyte studies, ciclesonide and des-ciclesonide had no potential to induce major CYP450 isozymes.

In vitro studies demonstrated that the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating no potential for protein binding-based drug interactions.

In a population pharmacokinetic analysis including 98 subjects, co-administration of ALVESCO and albuterol had no effect on the pharmacokinetics of des-ciclesonide.

Concomitant administration of ALVESCO (640 mcg) and formoterol (24 mcg) did not change the pharmacokinetics of either des-ciclesonide or formoterol.

Two-year carcinogenicity studies in B6C3F1 mice and Wistar rats were conducted to assess the carcinogenic potential of ciclesonide. Ciclesonide demonstrated no tumorigenic potential in a study with mice that received oral doses up to 900 mcg/kg/day (approximately 7 times the MRHDOID in adults and pediatric patients ≥ 12 years of age on a mcg/m2 basis) and a study with rats that received inhalation doses up to 193 mcg/kg/day (approximately 3 times the MRHDOID in adults and pediatric patients ≥ 12 years of age on a mcg/m2 basis).

Ciclesonide was not mutagenic in an Ames test or in the Chinese hamster lung V79 cell/hypoxanthine-guanine phosphoribosyl transferase (HGPRT) forward mutation assay and was not clastogenic in a human lymphocyte chromosomal aberration assay or in an in vitro micronucleus test. However, ciclesonide was clastogenic in an in vivo mouse micronucleus test. The concurrent reference corticosteroid (dexamethasone) in this study showed similar findings.

Fertility and reproductive performance were unaffected in male and female rats dosed by the oral route up to 900 mcg/kg/day (approximately 15 times the MRHDOID in adults based on mcg/m2).

Adults and Pediatric Patients 12 Years of Age and Older

The efficacy of ALVESCO was evaluated in six randomized, double-blind, placebo-controlled, parallel-group clinical trials in adult and pediatric patients 12 years of age and older with mild persistent to severe persistent asthma. The six trials included two trials in which patients were treated with ALVESCO administered once daily for 12 weeks, two trials in which patients were treated with ALVESCO twice daily for 12 weeks, and two trials in which patients were treated with ALVESCO using once daily and twice daily dosing regimens for 12 or 16 weeks. These trials included a total of 2843 patients (1167 males and 1676 females) of whom 296 were pediatric patients 12 to 17 years of age. The primary efficacy endpoint in four of the six trials was the mean change from baseline in pre-dose FEV1 at endpoint (last observation). FEV1 was measured prior to the morning dose of study medication (at the end of the 24-hour dosing interval for once daily administration, and at the end of the 12-hour dosing interval for twice daily administration). In one of the six trials, the primary endpoint was the change from baseline in the average of the pre-dose FEV1 at Weeks 12 and 16, and in another trial, reduction of oral corticosteroid use was the primary efficacy endpoint. Additional efficacy variables were asthma symptoms, use of albuterol for rescue, AM PEF, nighttime awakenings, and withdrawal due to asthma worsening.

The two once daily dosing trials were identically designed and were conducted to evaluate the efficacy of ALVESCO 80, 160, and 320 mcg given once daily in the morning for 12 weeks in patients with mild to moderate asthma maintained on inhaled bronchodilators and/or corticosteroids. The results of these trials, along with other trials that explored twice daily dosing, indicate that once daily dosing is not the optimum dosing regimen for ALVESCO.

Four trials were designed to evaluate the efficacy of ALVESCO administered twice daily in patients with asthma who were previously maintained on bronchodilators alone, patients who were previously maintained on inhaled corticosteroids, and patients who were previously maintained on oral corticosteroids.

Patients Previously Maintained on Bronchodilators Alone

The efficacy of ALVESCO was studied in a randomized, double-blind, placebo-controlled trial in 691 patients with mild-to-moderate persistent asthma (mean baseline percent predicted FEV1 of 72%) previously using reliever therapy (bronchodilator therapy alone). In this trial, patients were treated with ALVESCO 160 mcg once daily in the morning for 16 weeks, ALVESCO 80 mcg twice daily for 16 weeks, or ALVESCO 80 mcg twice daily for 4 weeks followed by ALVESCO 160 mcg once daily in the morning for 12 weeks or placebo for 16 weeks. Compared to placebo, all ALVESCO doses showed statistically significant improvement at Week 16 in AM pre-dose FEV1. However, the increase in AM pre-dose FEV1 in the patients treated with ALVESCO 80 mcg twice daily was significantly greater than that observed in patients treated with ALVESCO 160 mcg administered once daily. Compared to placebo, increases in AM pre-dose FEV1 were 0.12 L or 5.0% for ALVESCO 160 mcg once daily, 0.24 L or 10.4% for ALVESCO 80 mcg twice daily, 0.13 L or 5.0% for ALVESCO 80 mcg twice daily for 4 weeks followed by ALVESCO 160 mcg once daily. Other measures of asthma control, AM PEF, and need for rescue albuterol also improved in all the ALVESCO treatment groups compared to placebo but the improvement was greatest with the ALVESCO 80 mcg twice daily treatment arm. Discontinuations from the study for lack of efficacy were lower in the ALVESCO treatment groups compared to placebo. Fewer patients receiving ALVESCO experienced asthma worsening than did patients receiving placebo. The AM pre-dose FEV1 results are shown in Figure 1 below.

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy of ALVESCO in asthma patients previously maintained on inhaled corticosteroids was evaluated in two randomized, double-blind, placebo-controlled trials of 12-weeks treatment duration. In one trial, asthmatic patients with mild to moderate persistent asthma (mean baseline percent predicted FEV1 of 79%), previously maintained on controller therapy (predominantly inhaled corticosteroids) were treated with ALVESCO 160 mcg once daily in the morning, ALVESCO 80 mcg twice daily or placebo.

The AM pre-dose FEV1 results are shown in Figure 2 below.

Statistically significantly more increases in AM pre-dose FEV1 compared to placebo were seen at 12 weeks for ALVESCO 160 mcg once daily (0.14 L or 5.7%) and ALVESCO 80 mcg twice daily (0.19 L or 7.5%). Asthma symptoms scores, AM PEF, and decreased need for rescue albuterol remained relatively stable in the ALVESCO treatment groups compared to slight worsening in the placebo. Compared to placebo, fewer patients receiving ALVESCO experienced worsening of asthma.

In the other trial, 257 patients with moderate to severe persistent asthma (mean baseline percent predicted FEV1 of 54%) were treated with ALVESCO 160 or 320 mcg twice daily for 12 weeks. The AM pre-dose FEV1 results are shown in Figure 3 below.

Compared to placebo, both ALVESCO doses showed statistically significantly more improvement in pre-dose FEV1 (0.11 L or 8.6% and 0.18 L or 11.8%). Other measures of asthma control, AM PEF, symptoms, and need for rescue albuterol also showed improvement compared to placebo. Compared to placebo, fewer patients treated with ALVESCO experienced worsening of asthma.

Patients treated with ALVESCO were also less likely to discontinue study participation due to asthma deterioration.

Patients Previously Maintained on Oral Corticosteroids

In a 12-week double-blind clinical trial, 140 patients with severe persistent asthma (mean FEV1 at baseline 53% predicted) who had failed prior efforts to eliminate oral prednisone use and had established their lowest effective prednisone dose were randomized to ALVESCO given by oral inhalation at doses of 320 or 640 mcg twice daily or placebo. The average prednisone dose at baseline was approximately 12 mg/day. Compared to patients on placebo whose prednisone requirements increased by 4%, those treated with ALVESCO 320 mcg and 640 mcg twice daily significantly reduced their prednisone requirements by 47% and 62%, respectively. At the same time, patients on ALVESCO maintained asthma control as reflected by lung function, symptoms, and need for rescue albuterol. A significantly larger percentage of patients on ALVESCO were able to reduce oral prednisone use by 50% or more as compared to placebo (64% and 77% of the patients treated with 320 mcg and 640 mcg, respectively twice daily as compared with 33% of patients on placebo). There was no statistically significant difference observed with ALVESCO 640 mcg twice daily compared to ALVESCO 320 mcg twice daily.

ALVESCO is available in the following strengths and canister presentations.

{ "type": "p", "children": [], "text": "ALVESCO is available in the following strengths and canister presentations." }

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <col width="17%"/> <col width="26%"/> <col width="22%"/> <col width="17%"/> <col width="18%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Micrograms per Actuation</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Number of Actuations per Canister</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Canister Weight</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Canister per Box</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">NDC Number</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">ALVESCO<br/>80 mcg</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">60</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">6.1 g</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">1</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">70515-711-01</p> </td> </tr> <tr> <td valign="top"> <p class="First">ALVESCO<br/>160 mcg</p> </td><td align="center" valign="top"> <p class="First">60</p> </td><td align="center" valign="top"> <p class="First">6.1 g</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">70515-712-01</p> </td> </tr> <tr> <td valign="top"> <p class="First">ALVESCO<br/>80 mcg</p> </td><td align="center" valign="top"> <p class="First">30</p> </td><td align="center" valign="top"> <p class="First">4.7 g</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">70515-711-04</p> </td> </tr> <tr> <td valign="top"> <p class="First">ALVESCO<br/>160 mcg</p> </td><td align="center" valign="top"> <p class="First">30</p> </td><td align="center" valign="top"> <p class="First">4.7 g</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">70515-712-04</p> </td> </tr> <tr> <td valign="top"> <p class="First">ALVESCO<br/>80 mcg</p> </td><td align="center" valign="top"> <p class="First">60</p> </td><td align="center" valign="top"> <p class="First">6.1 g</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">70515-711-05</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">ALVESCO<br/>160 mcg</p> </td><td align="center" valign="top"> <p class="First">60</p> </td><td align="center" valign="top"> <p class="First">6.1 g</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">70515-712-05</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"3.6pt\" width=\"100%\">\n<col width=\"17%\"/>\n<col width=\"26%\"/>\n<col width=\"22%\"/>\n<col width=\"17%\"/>\n<col width=\"18%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Micrograms per Actuation</span>\n</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Number of Actuations per Canister</span>\n</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Canister Weight</span>\n</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Canister per Box</span>\n</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NDC Number</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Toprule\" valign=\"top\">\n<p class=\"First\">ALVESCO<br/>80 mcg</p>\n</td><td align=\"center\" class=\"Toprule\" valign=\"top\">\n<p class=\"First\">60</p>\n</td><td align=\"center\" class=\"Toprule\" valign=\"top\">\n<p class=\"First\">6.1 g</p>\n</td><td align=\"center\" class=\"Toprule\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" class=\"Toprule\" valign=\"top\">\n<p class=\"First\">70515-711-01</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">ALVESCO<br/>160 mcg</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">60</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">6.1 g</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">70515-712-01</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">ALVESCO<br/>80 mcg</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">30</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">4.7 g</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">70515-711-04</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">ALVESCO<br/>160 mcg</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">30</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">4.7 g</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">70515-712-04</p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">ALVESCO<br/>80 mcg</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">60</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">6.1 g</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">70515-711-05</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td valign=\"top\">\n<p class=\"First\">ALVESCO<br/>160 mcg</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">60</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">6.1 g</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">1</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">70515-712-05</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

ALVESCO (ciclesonide) 80 mcg inhalation aerosol is supplied with a brown plastic actuator with a red dust cap. Each actuation of the inhaler delivers 80 mcg of ciclesonide from the actuator and contains 60 actuations fill/canister.

{ "type": "p", "children": [], "text": "ALVESCO (ciclesonide) 80 mcg inhalation aerosol is supplied with a brown plastic actuator with a red dust cap. Each actuation of the inhaler delivers 80 mcg of ciclesonide from the actuator and contains 60 actuations fill/canister." }

ALVESCO 160 (ciclesonide) mcg inhalation aerosol is supplied with a red plastic actuator with a red dust cap. Each actuation of the inhaler delivers 160 mcg of ciclesonide from the actuator and contains 60 actuations fill/canister.

{ "type": "p", "children": [], "text": "ALVESCO 160 (ciclesonide) mcg inhalation aerosol is supplied with a red plastic actuator with a red dust cap. Each actuation of the inhaler delivers 160 mcg of ciclesonide from the actuator and contains 60 actuations fill/canister." }

ALVESCO canisters are for use with ALVESCO actuators only. The actuators are fitted with a dose indicator and should not be used with other medications. The correct amount of medication in each actuation cannot be assured from the canister labeled to contain 60 actuations when the dose indicator display window shows zero even though the canister is not completely empty. The canister should be discarded when the dose indicator display window shows zero.

{ "type": "p", "children": [], "text": "ALVESCO canisters are for use with ALVESCO actuators only. The actuators are fitted with a dose indicator and should not be used with other medications. The correct amount of medication in each actuation cannot be assured from the canister labeled to contain 60 actuations when the dose indicator display window shows zero even though the canister is not completely empty. The canister should be discarded when the dose indicator display window shows zero. " }

Store at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted (see USP). For optimal results, the canister should be at room temperature when used.

{ "type": "p", "children": [], "text": "Store at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted (see USP). For optimal results, the canister should be at room temperature when used. " }

Contents under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator.

{ "type": "p", "children": [], "text": "Contents under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator." }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)" }

Oropharyngeal Candidiasis

{ "type": "p", "children": [], "text": "\nOropharyngeal Candidiasis\n" }

Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with ALVESCO therapy, but at times therapy with the ALVESCO inhaler may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with ALVESCO therapy, but at times therapy with the ALVESCO inhaler may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)]." }

Acute Asthma Episodes

{ "type": "p", "children": [], "text": "\nAcute Asthma Episodes\n" }

Patients should be advised that ALVESCO is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. The patient should be instructed to contact their physician immediately if there is deterioration of their asthma [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Patients should be advised that ALVESCO is not a bronchodilator and is not intended for use as rescue medication for acute asthma exacerbations. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. The patient should be instructed to contact their physician immediately if there is deterioration of their asthma [see Warnings and Precautions (5.2)]." }

Immunosuppression and Risk of Infections

{ "type": "p", "children": [], "text": "\nImmunosuppression and Risk of Infections\n" }

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.3)]." }

Hypercorticism and Adrenal Suppression

{ "type": "p", "children": [], "text": "\nHypercorticism and Adrenal Suppression\n" }

Patients should be advised that ALVESCO may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ALVESCO [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Patients should be advised that ALVESCO may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ALVESCO [see Warnings and Precautions (5.5)]." }

Reduction in Bone Mineral Density

{ "type": "p", "children": [], "text": "\nReduction in Bone Mineral Density\n" }

Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and where appropriate, be treated for this condition [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and where appropriate, be treated for this condition [see Warnings and Precautions (5.6)]." }

Effect on Growth

{ "type": "p", "children": [], "text": "\nEffect on Growth\n" }

Patients should be informed that orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Patients should be informed that orally inhaled corticosteroids, including ALVESCO, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.7)]." }

Use Daily for Best Effect

{ "type": "p", "children": [], "text": "\nUse Daily for Best Effect\n" }

Patients should be advised to use ALVESCO at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for four weeks or longer after starting treatment. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop ALVESCO use abruptly. Patients should contact their physician immediately if use of ALVESCO is discontinued.

{ "type": "p", "children": [], "text": "Patients should be advised to use ALVESCO at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for four weeks or longer after starting treatment. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens. Patients should be instructed not to stop ALVESCO use abruptly. Patients should contact their physician immediately if use of ALVESCO is discontinued." }

How to Use ALVESCO

{ "type": "p", "children": [], "text": "\nHow to Use ALVESCO\n" }

Patients should use ALVESCO only with the actuator supplied with the product. When the dose indicator display window shows a red zone, approximately 20 inhalations are left, and a refill is required. Discard the inhaler when the indicator shows zero.

{ "type": "p", "children": [], "text": "Patients should use ALVESCO only with the actuator supplied with the product. When the dose indicator display window shows a red zone, approximately 20 inhalations are left, and a refill is required. Discard the inhaler when the indicator shows zero." }

Manufactured for: Covis Pharma Zug, 6300 SwitzerlandMade in United Kingdom

{ "type": "p", "children": [], "text": "Manufactured for: \nCovis Pharma\nZug, 6300 SwitzerlandMade in United Kingdom" }

ALVESCO® [ael-‘ves-ko℧](ciclesonide)

{ "type": "p", "children": [], "text": "\nALVESCO® [ael-‘ves-ko℧](ciclesonide)\n" }

Note: For Oral Inhalation Only

{ "type": "p", "children": [], "text": "\nNote: For Oral Inhalation Only\n" }

Do not use your ALVESCO near heat or an open flame.

{ "type": "p", "children": [], "text": "\nDo not use your ALVESCO near heat or an open flame." }

Read this Patient Information leaflet before you start using ALVESCO and each time you get a 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 ALVESCO, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Read this Patient Information leaflet before you start using ALVESCO and each time you get a 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 ALVESCO, ask your healthcare provider or pharmacist." }

What is ALVESCO?

{ "type": "p", "children": [], "text": "\nWhat is ALVESCO?\n" }

ALVESCO is a prescription medicine used for the control and prevention of asthma in adults and children 12 years of age and older.

{ "type": "p", "children": [], "text": "ALVESCO is a prescription medicine used for the control and prevention of asthma in adults and children 12 years of age and older." }

ALVESCO contains ciclesonide, which is a man-made (synthetic) corticosteroid. Corticosteroids are natural substances found in the body and reduce inflammation. When you inhale ALVESCO it may help to control and prevent your symptoms of asthma by reducing your airway inflammation.

{ "type": "p", "children": [], "text": "ALVESCO contains ciclesonide, which is a man-made (synthetic) corticosteroid. Corticosteroids are natural substances found in the body and reduce inflammation. When you inhale ALVESCO it may help to control and prevent your symptoms of asthma by reducing your airway inflammation." }

ALVESCO is not for the relief of acute bronchospasm. ALVESCO is not a bronchodilator and does not treat sudden symptoms of an asthma attack such as wheezing, cough, shortness of breath, and chest pain or tightness. Always have a fast-acting bronchodilator medicine (rescue inhaler) with you to treat sudden symptoms.

{ "type": "p", "children": [], "text": "ALVESCO is not for the relief of acute bronchospasm. ALVESCO is not a bronchodilator and does not treat sudden symptoms of an asthma attack such as wheezing, cough, shortness of breath, and chest pain or tightness. Always have a fast-acting bronchodilator medicine (rescue inhaler) with you to treat sudden symptoms.\n" }

It is not known if ALVESCO is safe and effective in children 11 years of age and younger.

{ "type": "p", "children": [], "text": "It is not known if ALVESCO is safe and effective in children 11 years of age and younger." }

Who should not use ALVESCO?

{ "type": "p", "children": [], "text": "\nWho should not use ALVESCO?\n" }

Do not use ALVESCO:

{ "type": "p", "children": [], "text": "\nDo not use ALVESCO:\n" }

{ "type": "", "children": [], "text": "" }

What should I tell my healthcare provider before using ALVESCO?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before using ALVESCO?\n" }

Before you use ALVESCO tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "\nBefore you use ALVESCO tell your healthcare provider if you:\n" }

{ "type": "", "children": [], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

{ "type": "p", "children": [], "text": "\nTell 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 a list of them to show your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. " }

How should I use ALVESCO?

{ "type": "p", "children": [], "text": "\nHow should I use ALVESCO?\n" }

{ "type": "", "children": [], "text": "" }

What are the possible side effects of ALVESCO?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of ALVESCO?\n" }

ALVESCO may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nALVESCO may cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects with ALVESCO. For more information, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects with ALVESCO. For more information, ask your healthcare provider or pharmacist." }

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "\nCall your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n" }

How should I store ALVESCO?

{ "type": "p", "children": [], "text": "\nHow should I store ALVESCO?\n" }

{ "type": "", "children": [], "text": "" }

Keep ALVESCO and all medicines out of reach of children.

{ "type": "p", "children": [], "text": "\nKeep ALVESCO and all medicines out of reach of children.\n" }

General Information About the Safe and Effective use of ALVESCO

{ "type": "p", "children": [], "text": "\nGeneral Information About the Safe and Effective use of ALVESCO \n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ALVESCO for a condition for which it is not prescribed. Do not give ALVESCO to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ALVESCO for a condition for which it is not prescribed. Do not give ALVESCO 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 ALVESCO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ALVESCO that is written for health professionals.

{ "type": "p", "children": [], "text": "This Patient Information summarizes the most important information about ALVESCO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ALVESCO that is written for health professionals." }

For more information, go to www.alvesco.us/.

{ "type": "p", "children": [], "text": "For more information, go to www.alvesco.us/." }

What are the ingredients in ALVESCO?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in ALVESCO?\n" }

Active ingredient: ciclesonide

{ "type": "p", "children": [], "text": "\nActive ingredient: ciclesonide" }

Inactive ingredients: propellant HFA-134a and ethanol

{ "type": "p", "children": [], "text": "\nInactive ingredients: propellant HFA-134a and ethanol\n\n" }

Instructions for UseALVESCO® [ael-‘ves- ko℧](ciclesonide)

{ "type": "p", "children": [], "text": "\nInstructions for UseALVESCO® [ael-‘ves- ko℧](ciclesonide)\n" }

Read this Instructions for Use for ALVESCO before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use for ALVESCO before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment." }

Note: For Oral Inhalation Only

{ "type": "p", "children": [], "text": "\nNote: For Oral Inhalation Only\n" }

Do not use your ALVESCO near heat or an open flame.

{ "type": "p", "children": [], "text": "\nDo not use your ALVESCO near heat or an open flame." }

The parts of your ALVESCO

{ "type": "p", "children": [], "text": "\nThe parts of your ALVESCO \n" }

ALVESCO comes as a canister that fits into an actuator with a dose indicator. Do not use the actuator with a canister of medicine from any other inhaler. Do not use ALVESCO canister with an actuator from any other inhaler. (See Figure A)

{ "type": "p", "children": [], "text": "ALVESCO comes as a canister that fits into an actuator with a dose indicator. Do not use the actuator with a canister of medicine from any other inhaler. Do not use ALVESCO canister with an actuator from any other inhaler. (See Figure A)" }

Priming your ALVESCO for use

{ "type": "p", "children": [], "text": "\nPriming your ALVESCO for use\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

Using Your ALVESCO

{ "type": "p", "children": [], "text": "\nUsing Your ALVESCO \n" }

Step 1. Remove the cap from the mouthpiece. (See Figure C)

{ "type": "p", "children": [], "text": "\nStep 1. Remove the cap from the mouthpiece. (See Figure C)" }

Step 2. Hold the actuator upright, between your thumb, forefinger, and middle finger with the mouthpiece pointing towards you. (See Figure D)

{ "type": "p", "children": [], "text": "\nStep 2. Hold the actuator upright, between your thumb, forefinger, and middle finger with the mouthpiece pointing towards you. (See Figure D)" }

Step 3. Breathe out as fully as you comfortably can. Close your lips around the mouthpiece, keeping your tongue below it. (See Figure E)

{ "type": "p", "children": [], "text": "\nStep 3. Breathe out as fully as you comfortably can. Close your lips around the mouthpiece, keeping your tongue below it. (See Figure E)" }

Step 4.

{ "type": "p", "children": [], "text": "\nStep 4. \n" }

{ "type": "", "children": [], "text": "" }

Step 5.

{ "type": "p", "children": [], "text": "\nStep 5.\n" }

Take your finger completely off the center of the dose indicator and remove the inhaler from your mouth. Breathe out gently. (See Figure F)

{ "type": "p", "children": [], "text": "Take your finger completely off the center of the dose indicator and remove the inhaler from your mouth. Breathe out gently. (See Figure F)" }

Step 6. Replace the cap to keep the mouthpiece clean.

{ "type": "p", "children": [], "text": "\nStep 6. Replace the cap to keep the mouthpiece clean. " }

Step 7. Rinse your mouth with water and spit it out. Do not swallow.

{ "type": "p", "children": [], "text": "\nStep 7. Rinse your mouth with water and spit it out. Do not swallow. " }

Cleaning your ALVESCO unit

{ "type": "p", "children": [], "text": "\nCleaning your ALVESCO unit\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

How to tell if your ALVESCO canister is empty

{ "type": "p", "children": [], "text": "\nHow to tell if your ALVESCO canister is empty\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

This PPI and Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "\nThis PPI and Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Manufactured for: Covis Pharma Zug, 6300 SwitzerlandMade in United Kingdom

{ "type": "p", "children": [], "text": "Manufactured for: \nCovis Pharma\nZug, 6300 SwitzerlandMade in United Kingdom" }

ALVESCO is a registered trademark of Covis Pharma.

{ "type": "p", "children": [], "text": "ALVESCO is a registered trademark of Covis Pharma." }

©2023 Covis Pharma. All rights reserved.

{ "type": "p", "children": [], "text": "©2023 Covis Pharma. All rights reserved. " }

{ "type": "", "children": [], "text": "" }

NDC 70515-711-01         Net Contents: 6.1 g

{ "type": "p", "children": [], "text": "NDC 70515-711-01         Net Contents: 6.1 g" }

Alvesco® ciclesonide   Inhalation Aerosol

{ "type": "p", "children": [], "text": "\nAlvesco®\n\nciclesonide  \nInhalation Aerosol\n" }

80 mcg/actuation

{ "type": "p", "children": [], "text": "\n80 mcg/actuation\n" }

60 Metered Actuations

{ "type": "p", "children": [], "text": "\n60 Metered Actuations\n" }

FOR ORAL INHALATION WITH ALVESCO® INHALATION AEROSOL ACTUATOR ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION WITH ALVESCO®\nINHALATION AEROSOL ACTUATOR ONLY" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

COVIS

{ "type": "p", "children": [], "text": "\nCOVIS\n" }

Alvesco® ciclesonide  Inhalation Aerosol

{ "type": "p", "children": [], "text": "\nAlvesco®\n\nciclesonide  Inhalation Aerosol\n" }

80 mcg/actuation

{ "type": "p", "children": [], "text": "\n80 mcg/actuation\n" }

GTIN: 00370515711013S/N: XXXXXXXXXXXXXXEXP: MM/YYYYLOT: YYXXXX

{ "type": "p", "children": [], "text": "GTIN: 00370515711013S/N: XXXXXXXXXXXXXXEXP: MM/YYYYLOT: YYXXXX" }

Pharmacist: Dispense with Patient’s Instructions for Use from package insert inside.

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense with Patient’s Instructions for Use from package insert inside." }

WARNING: Keep out of reach of children. Avoid spraying in eyes.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of reach of children. Avoid spraying in eyes." }

COVIS Manufactured for:Covis PharmaZug, 6300 Switzerland

{ "type": "p", "children": [], "text": "\nCOVIS\nManufactured for:Covis PharmaZug, 6300 Switzerland" }

Made in the United Kingdom

{ "type": "p", "children": [], "text": "Made in the United Kingdom" }

Each 6.1 g canister of ALVESCO® Inhalation Aerosol contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. The 80 mcg strength of ALVESCO® Inhalation Aerosol delivers 100 mcg from the valve and 80 mcg of ciclesonide from the actuator.

{ "type": "p", "children": [], "text": "Each 6.1 g canister of ALVESCO® Inhalation Aerosol contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. The 80 mcg strength of ALVESCO®\nInhalation Aerosol delivers 100 mcg from the valve and 80 mcg of ciclesonide from the actuator." }

Dosage and Administration: See package insert for dosage information.

{ "type": "p", "children": [], "text": "\nDosage and Administration:\nSee package insert for dosage information." }

CONTENTS UNDER PRESSURE. Do not puncture.

{ "type": "p", "children": [], "text": "\nCONTENTS UNDER PRESSURE. Do not puncture." }

Do not use or store near heat or open flame.

{ "type": "p", "children": [], "text": "Do not use or store near heat or open flame. " }

Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator.

{ "type": "p", "children": [], "text": "Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator." }

Store at 25°C (77°F); excursions between 15–30°C (59–86°F) are permitted [see USP]. For optimal results, canister should be at room temperature when used.

{ "type": "p", "children": [], "text": "\nStore at 25°C (77°F);\nexcursions between 15–30°C (59–86°F) are permitted [see USP]. For optimal results, canister should be at room temperature when used." }

{ "type": "", "children": [], "text": "" }

NDC 70515-712-01           Net Contents: 6.1 g

{ "type": "p", "children": [], "text": "NDC 70515-712-01           Net Contents: 6.1 g" }

Alvesco® ciclesonide   Inhalation Aerosol

{ "type": "p", "children": [], "text": "\nAlvesco®\n\nciclesonide  \nInhalation Aerosol\n" }

160 mcg/actuation

{ "type": "p", "children": [], "text": "\n160 mcg/actuation\n" }

60 Metered Actuations

{ "type": "p", "children": [], "text": "\n60 Metered Actuations\n" }

FOR ORAL INHALATION WITH ALVESCO® INHALATION AEROSOL ACTUATOR ONLY

{ "type": "p", "children": [], "text": "FOR ORAL INHALATION WITH ALVESCO®\nINHALATION AEROSOL ACTUATOR ONLY" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

COVIS

{ "type": "p", "children": [], "text": "\nCOVIS\n" }

Alvesco® ciclesonide   Inhalation Aerosol

{ "type": "p", "children": [], "text": "\nAlvesco®\n\nciclesonide  \nInhalation Aerosol\n" }

160 mcg/actuation

{ "type": "p", "children": [], "text": "\n160 mcg/actuation\n" }

GTIN: 00370515712010S/N: XXXXXXXXXXXXXXEXP: MM/YYYYLOT: YYXXXX

{ "type": "p", "children": [], "text": "GTIN: 00370515712010S/N: XXXXXXXXXXXXXXEXP: MM/YYYYLOT: YYXXXX" }

Pharmacist: Dispense with Patient’s Instructions for Use from package insert inside.

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense with Patient’s Instructions for Use from package insert inside." }

WARNING: Keep out of reach of children. Avoid spraying in eyes.

{ "type": "p", "children": [], "text": "\nWARNING: Keep out of reach of children. Avoid spraying in eyes." }

COVIS Manufactured for:Covis PharmaZug, 6300 Switzerland

{ "type": "p", "children": [], "text": "\nCOVIS\nManufactured for:Covis PharmaZug, 6300 Switzerland" }

Made in the United Kingdom

{ "type": "p", "children": [], "text": "Made in the United Kingdom" }

Each 6.1 g canister of ALVESCO® Inhalation Aerosol contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. The 160 mcg strength of ALVESCO® Inhalation Aerosol delivers 200 mcg from the valve and 160 mcg of ciclesonide from the actuator.

{ "type": "p", "children": [], "text": "Each 6.1 g canister of ALVESCO® Inhalation Aerosol contains a solution of ciclesonide in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. The 160 mcg strength of ALVESCO®\nInhalation Aerosol delivers 200 mcg from the valve and 160 mcg of ciclesonide from the actuator." }

Dosage and Administration: See package insert for dosage information.

{ "type": "p", "children": [], "text": "\nDosage and Administration:\nSee package insert for dosage information." }

CONTENTS UNDER PRESSURE. Do not puncture.

{ "type": "p", "children": [], "text": "\nCONTENTS UNDER PRESSURE. Do not puncture." }

Do not use or store near heat or open flame.

{ "type": "p", "children": [], "text": "Do not use or store near heat or open flame. " }

Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator.

{ "type": "p", "children": [], "text": "Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator." }

Store at 25°C (77°F); excursions between 15–30°C (59–86°F) are permitted [see USP]. For optimal results, canister should be at room temperature when used.

{ "type": "p", "children": [], "text": "\nStore at 25°C (77°F); excursions between 15–30°C (59–86°F) are permitted [see USP]. For optimal results, canister should be at room temperature when used." }

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.

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.

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).

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).

OMNARIS Nasal Spray is a metered-dose, manual-pump spray formulation containing a hypotonic aqueous suspension of ciclesonide. Once primed, each actuation of the pump delivers 50 mcg ciclesonide in a volume of 70 microliters from the nasal actuator.

{ "type": "p", "children": [], "text": "OMNARIS Nasal Spray is a metered-dose, manual-pump spray formulation containing a hypotonic aqueous suspension of ciclesonide. Once primed, each actuation of the pump delivers 50 mcg ciclesonide in a volume of 70 microliters from the nasal actuator." }

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)].

{ "type": "p", "children": [], "text": "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)]." }

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.

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.

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.

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.

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.

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.

<div class="scrollingtable"><table cellpadding="3.6pt" width="75%"> <caption> <span>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</span> </caption> <col width="27%"/> <col width="30%"/> <col width="27%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule" valign="top"> <p class="First">Adverse Event</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">OMNARIS Nasal Spray<br/>200 mcg Once Daily<br/>(N = 546) %</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo<br/> <br/>(N = 544) %</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">6.0</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">4.6</p> </td> </tr> <tr> <td valign="top"> <p class="First">Epistaxis</p> </td><td align="center" valign="top"> <p class="First">4.9</p> </td><td align="center" valign="top"> <p class="First">2.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nasopharyngitis</p> </td><td align="center" valign="top"> <p class="First">3.7</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Ear Pain</p> </td><td align="center" valign="top"> <p class="First">2.2</p> </td><td align="center" valign="top"> <p class="First">0.6</p> </td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table cellpadding="3.6pt" width="75%"> <caption> <span>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</span> </caption> <col width="29%"/> <col width="28%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule" valign="top"> <p class="First">Adverse Event</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">OMNARIS Nasal Spray<br/>200 mcg Once Daily<br/>(N = 380) %</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo<br/> <br/>(N = 369) %</p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">6.6</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">5.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nasopharyngitis</p> </td><td align="center" valign="top"> <p class="First">6.6</p> </td><td align="center" valign="top"> <p class="First">5.4</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Pharyngolaryngeal pain</p> </td><td align="center" valign="top"> <p class="First">3.4</p> </td><td align="center" valign="top"> <p class="First">3.3</p> </td> </tr> </tbody> </table></div>

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.

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.

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)].

{ "type": "p", "children": [], "text": "\nIn 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)].

{ "type": "p", "children": [], "text": "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)]." }

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/m2 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.

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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 bases at maternal oral doses up to 900 mcg/kg/day).

There are no data on the presence of ciclesonide in human milk, the effects on the breastfed child, or on milk production. It is not known whether nasal spray 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 mother’s clinical need for OMNARIS Nasal Spray, and any potential adverse effects on the breastfed child from OMNARIS Nasal Spray, or from the underlying maternal condition.

The pharmacokinetics of intranasally administered ciclesonide have not been assessed in patient subpopulations because the resulting blood levels of ciclesonide and des-ciclesonide are insufficient for pharmacokinetic calculations [see Clinical Pharmacology (12.3)].

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 a nursing infant are unknown, however, like all corticosteroids, suppression of the HPA function is a potential complication.

Human Data

At recommended doses, the intranasal 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 a lower limit of quantification of 25 pg/mL and 10 pg/mL, for ciclesonide and des-ciclesonide, respectively.

In healthy adults treated for 2 weeks with 50 to 800 mcg of ciclesonide nasal spray daily (n = 6 in each treatment group), the peak serum concentrations of des-ciclesonide in all subjects were found to be below 30 pg/mL. Of those treated with 800 mcg and 400 mcg daily, 100% and 67% had detectable levels of des-ciclesonide, respectively. With daily doses of ≤ 200 mcg, detectable serum levels of des-ciclesonide were not observed. The low systemic exposure following ciclesonide nasal spray administration was confirmed in a crossover study in 29 healthy adults. The median maximum observed concentration was less than 10 pg/mL and 602 pg/mL following a single dose of ciclesonide nasal spray (300 mcg) and orally inhaled ciclesonide (320 mcg), respectively.

Animal Data

A study with 14C-ciclesonide showed milk exposure of rat pups to 0.006% of the dose secreted in milk.

The safety and effectiveness for seasonal and perennial allergic rhinitis in children 12 years of age and older have been established. The efficacy of OMNARIS Nasal Spray in patients 6 to 11 years of age for treatment of the symptoms of seasonal allergic rhinitis was demonstrated in one study in patients 6 to 11 years of age with seasonal allergic rhinitis. The efficacy of OMNARIS Nasal Spray for the treatment of the symptoms of seasonal allergic rhinitis in patients 5 years of age and younger has not been established. The efficacy of OMNARIS Nasal Spray for the treatment of the symptoms of perennial allergic rhinitis in patients 11 years of age and younger has not been established [see Clinical Studies (14.1)]. The safety of OMNARIS Nasal Spray in children 2 to 11 years of age was evaluated in 4 controlled clinical studies of 2 to 12 weeks duration [see Clinical Pharmacology (12.2), Clinical Studies (14.1), and Adverse Reactions (6)].

Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including OMNARIS Nasal Spray, should be monitored routinely (e.g., via stadiometry). A 52-week, multicenter, double-blind, randomized, placebo-controlled parallel-group study was conducted to assess the effect of orally inhaled ciclesonide on growth rate in 609 pediatric patients with mild persistent asthma, aged 5 to 8.5 years. Treatment groups included orally inhaled ciclesonide 40 mcg or 160 mcg or placebo given once daily. Growth was measured by stadiometer height during the baseline, treatment and follow-up periods. The primary comparison was the difference in growth rates between ciclesonide 40 and 160 mcg and placebo groups. Conclusions cannot be drawn from this study 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 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.

Clinical studies of OMNARIS Nasal Spray did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Chronic overdosage may result in signs or symptoms of hypercorticism [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Chronic overdosage may result in signs or symptoms of hypercorticism [see Warnings and Precautions (5.4)]." }

There are no data available on the effects of acute or chronic overdosage with OMNARIS Nasal Spray.

{ "type": "p", "children": [], "text": "There are no data available on the effects of acute or chronic overdosage with OMNARIS Nasal Spray." }

The active component of OMNARIS Nasal Spray is ciclesonide, a 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)-,(11β,16α)-. 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:

{ "type": "p", "children": [], "text": "The active component of OMNARIS Nasal Spray is ciclesonide, a 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)-,(11β,16α)-. 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 a white to yellow-white powder, practically insoluble in water and freely soluble in ethanol and acetone. OMNARIS Nasal Spray is a metered-dose, manual-pump spray formulation containing a hypotonic aqueous suspension of ciclesonide. OMNARIS Nasal Spray also contains microcrystalline cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and edetate sodium; and hydrochloric acid to adjust the pH to 4.5.

{ "type": "p", "children": [], "text": "Ciclesonide is a white to yellow-white powder, practically insoluble in water and freely soluble in ethanol and acetone. OMNARIS Nasal Spray is a metered-dose, manual-pump spray formulation containing a hypotonic aqueous suspension of ciclesonide. OMNARIS Nasal Spray also contains microcrystalline cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and edetate sodium; and hydrochloric acid to adjust the pH to 4.5." }

Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120-times higher than the parent compound.

The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation.

Adrenal Function: In a 6-week trial in adolescents and adults 12-73 years of age with perennial allergic rhinitis, a daily dose of 200 mcg of OMNARIS Nasal Spray was compared to placebo nasal spray. Dexamethasone 6 mg was used as an active control during the last 4 days of the treatment period. Adrenal function was assessed by measurement of 24-hour serum cortisol levels before and after 6 consecutive weeks of treatment. The difference from placebo for the change from baseline in serum cortisol AUC(0-24) was 10.4 mcg•hour/dL (95% CI: -4.7, 25.5) for 200 mcg of OMNARIS Nasal Spray. The effects observed with the active control (dexamethasone, n=18) validate the sensitivity of the study to assess the effect of ciclesonide on the HPA axis.

In a 12-week study in children 6 to 11 years of age with perennial allergic rhinitis, daily doses of 200 mcg, 100 mcg, and 25 mcg of OMNARIS Nasal Spray were compared to placebo nasal spray. Adrenal function was assessed by measurement of 24-hour urinary-free cortisol (in 32 to 44 patients per group) and morning plasma cortisol levels (in 45 to 61 patients per group) before and after 12 consecutive weeks of treatment. The ciclesonide-treated groups had a numerically greater decline in 24-hour urinary-free cortisol compared to the placebo-treated group. The differences (and 95% confidence intervals) from placebo in the mean change from baseline to 12 weeks were -0.81 (-4.0, 2.4), -0.08 (-3.1, 2.9), and ‑2.11 (‑5.3, 1.1) mcg/day for 200 mcg, 100 mcg, and 25 mcg dose groups, respectively. The mean AM plasma cortisol value did not show any consistent treatment effect with differences (and 95% confidence intervals) from placebo in the mean change from baseline to 12 weeks of 0.35 (‑1.4, 2.1), 0.12 (-1.5, 1.7), and -0.38 (-2.1, 1.3) mcg/dL for 200 mcg, 100 mcg, and 25 mcg dose groups, respectively. In this study, serum was assayed for ciclesonide and des‑ciclesonide [see Clinical Pharmacology (12.3)].

In a 6-week study in children 2 to 5 years of age with perennial allergic rhinitis, daily doses of 200 mcg, 100 mcg, and 25 mcg of OMNARIS Nasal Spray were compared to placebo nasal spray. Adrenal function was assessed by measurement of 24-hour urinary-free cortisol (in 15 to 22 patients per group) and morning plasma cortisol levels (in 28 to 30 patients per group) before and after 6 consecutive weeks of treatment. The ciclesonide-treated groups had a numerically greater decline in 24-hour urinary-free cortisol compared to the placebo-treated group. The differences (and 95% confidence intervals) from placebo in the mean change from baseline to 6 weeks were ‑2.04 (-4.4, 0.3), -1.96 (-4.5, 0.6), and ‑1.76 (‑4.3, 0.8) mcg/day for the 200 mcg, 100 mcg, and 25 mcg dose groups, respectively. The plasma cortisol also decreased numerically after treatment with ciclesonide. The differences (and 95% confidence intervals) from placebo in the mean change in plasma cortisol from baseline to 6 weeks were ‑1.04 (‑2.7, 0.7), -0.36 (-2.1, 1.4), and ‑0.12 (‑1.8, 1.6) mcg/dL for the 200 mcg, 100 mcg, and 25 mcg dose groups, respectively. In this study, serum was assayed for ciclesonide and des-ciclesonide [see Clinical Pharmacology (12.3)].

Absorption: Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide. However, the known active metabolite (des-ciclesonide) is detected in the serum of some patients after nasal inhalation of ciclesonide. The bioanalytical assay used has a lower limit of quantification of 25 pg/mL and 10 pg/mL, for ciclesonide and des-ciclesonide, respectively.

In healthy adults treated for two weeks with 50 to 800 mcg of ciclesonide nasal spray daily (n=6 in each treatment group), the peak serum concentrations of des-ciclesonide in all subjects were found to be below 30 pg/mL. Of those treated with 800 mcg and 400 mcg daily, 100% and 67% had detectable levels of des‑ciclesonide, respectively. With daily doses of 200 mcg or less, detectable serum levels of des-ciclesonide were not observed. The low systemic exposure following ciclesonide nasal spray administration was confirmed in a crossover study in twenty-nine healthy adults. The median Cmax was less than 10 pg/mL and 602 pg/mL following a single dose of ciclesonide nasal spray (300 mcg) and orally inhaled ciclesonide (320 mcg), respectively.

Distribution: Following intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide were approximately 2.9 L/kg and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug detected in the systemic circulation. Des‑ciclesonide is not significantly bound to human transcortin.

Metabolism: Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. Des-ciclesonide undergoes further metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. The full range of potentially active metabolites of ciclesonide has not been characterized. After intravenous administration of 14C-ciclesonide, 19.3% of the resulting radioactivity in the plasma is accounted for by ciclesonide or des-ciclesonide; the remainder may be a result of other, as yet, unidentified multiple metabolites.

Elimination: Following intravenous administration of 800 mcg of ciclesonide, the clearance values of ciclesonide and des-ciclesonide were high (approximately 152 L/h and 228 L/h, respectively). 14C-labeled 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: The pharmacokinetics of intranasally administered ciclesonide have not been assessed in patient subpopulations because the resulting blood levels of ciclesonide and des-ciclesonide are insufficient for pharmacokinetic calculations. However, population pharmacokinetic analysis showed that characteristics of des-ciclesonide after oral inhalation of ciclesonide were not appreciably influenced by a variety of subject characteristics such as body weight, age, race, and gender.

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

Pediatric: In pediatric subjects treated with 25 to 200 mcg of ciclesonide nasal spray daily, serum concentrations of des-ciclesonide were below 45 pg/mL, with the exception of one value of 64.5 pg/mL. In a 12-week study in children 6 to 11 years of age with perennial allergic rhinitis, des-ciclesonide was detected in 50% of the subjects treated with 200 mcg and in 5% of those treated with 100 mcg ciclesonide nasal spray daily. In a 6-week study in children 2 to 5 years of age with perennial allergic rhinitis, des-ciclesonide was detected in 41%, 22%, and 13% of the subjects treated with 200 mcg, 100 mcg, and 25 mcg ciclesonide nasal spray daily, respectively.

Drug-Drug Interactions: Based on in vitro studies in human liver microsomes, des-ciclesonide appears to have no inhibitory or induction potential on the metabolism of other drugs metabolized by cytochrome P450 enzymes. The inhibitory potential of ciclesonide on cytochrome P450 isoenzymes has not been studied. In vitro studies demonstrated that the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating no potential for protein binding-based drug interactions.

In a drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, a strong inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of the active metabolite of ciclesonide, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged.

In another drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin.

Two-year carcinogenicity studies in B6C3F1 mice and Wistar rats were conducted to assess the carcinogenic potential of ciclesonide. Ciclesonide demonstrated no tumorigenic potential in a study with mice that received oral doses up to 900 mcg/kg/day (approximately 20 and 10 times the MRHDID in adults and adolescents ≥ 12 years of age and children 6 to 11 years of age, respectively, on a mcg/m2 basis) and a study with rats that received inhalation doses up to 193 mcg/kg/day (approximately 9 and 4 times the MRHDID in adults and adolescents ≥ 12 years of age and children 6 to 11 years of age, respectively, on a mcg/m2 basis).

Ciclesonide was not mutagenic in an Ames test or in the Chinese hamster lung V79 cell/hypoxanthine-guanine phosphoribosyl transferase (HGPRT) forward mutation assay and was not clastogenic in a human lymphocyte chromosomal aberration assay or in an in vitro micronucleus test. However, ciclesonide was clastogenic in an in vivo mouse micronucleus test. The concurrent reference corticosteroid (dexamethasone) in this study showed similar findings.

Fertility and reproductive performance were unaffected in male and female rats dosed by the oral route up to 900 mcg/kg/day (approximately 45 times the MRHDID in adults based on mcg/m2).

Adults and Adolescent Patients 12 Years of Age and Older: The efficacy of OMNARIS Nasal Spray was evaluated in 3 randomized, double‑blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 6 weeks duration conducted in the United States and Canada in adolescents and adults with allergic rhinitis. The three trials included a total of 1524 patients (495 males and 1029 females) of whom 79 were adolescents, ages 12 to 17 years. The racial distribution in these three trials included 1374 Caucasians, 69 Blacks, 31 Asians, and 50 patients classified as Other. Of the 1524 patients, 546 patients received OMNARIS Nasal Spray 200 mcg once daily administered as 2 sprays in each nostril. Patients enrolled in the studies were 12 to 86 years of age with a history of seasonal or perennial allergic rhinitis, a positive skin test to at least one relevant allergen, and active symptoms of allergic rhinitis at study entry. Assessment of efficacy in these trials was based on patient recording of four nasal symptoms (runny nose, nasal itching, sneezing, and nasal congestion) on a 0-3 categorical severity scale (0=absent, 1=mild, 2=moderate, and 3=severe) as reflective or instantaneous scores. Reflective scoring required the patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity at the time of recording. The results of these trials showed that patients treated with OMNARIS Nasal Spray 200 mcg once daily exhibited statistically significantly greater decreases in total nasal symptom scores than placebo-treated patients. Secondary measures of efficacy were also generally supportive.

Dose-Ranging Trial: One of the three trials was a 2-week dose-ranging trial that evaluated efficacy of four doses of OMNARIS Nasal Spray in patients with seasonal allergic rhinitis. The primary efficacy endpoint was the difference from placebo in the change from baseline of the sum of morning and evening reflective total nasal symptom score averaged over the 2-week treatment period. Results of the primary efficacy endpoint are shown in Table 3. In this trial OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo, but the lower doses were not statistically significantly different from placebo.

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <caption> <span>Table 3 Mean change in reflective total nasal symptom score over 2 weeks in patients with seasonal allergic rhinitis</span> </caption> <col width="18%"/> <col width="8%"/> <col width="11%"/> <col width="17%"/> <col width="15%"/> <col width="19%"/> <col width="12%"/> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="7" valign="top">* Sum of AM and PM Scores; Maximum score = 24<br/>** Estimates, 95% Confidence Intervals, and p-values were obtained from repeated measures ANCOVA analysis with treatment, baseline, day, and treatment by day interaction effects included in the model.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Treatment</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Baseline*</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Change from Baseline</span> </p> </td><td align="center" class="Botrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Difference from Placebo**</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Estimate</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">95% CI</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">p-value</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Seasonal Allergic Rhinitis Trial – Reflective total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">144</p> </td><td align="center" valign="top"> <p class="First">18.8</p> </td><td align="center" valign="top"> <p class="First">-5.73</p> </td><td align="center" valign="top"> <p class="First">-1.35</p> </td><td align="center" valign="top"> <p class="First">(-2.43, -0.28)</p> </td><td align="center" valign="top"> <p class="First">0.014</p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 100 mcg</p> </td><td align="center" valign="top"> <p class="First">145</p> </td><td align="center" valign="top"> <p class="First">18.7</p> </td><td align="center" valign="top"> <p class="First">-5.26</p> </td><td align="center" valign="top"> <p class="First">-0.88</p> </td><td align="center" valign="top"> <p class="First">(-1.96, 0.19)</p> </td><td align="center" valign="top"> <p class="First">0.11</p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 50 mcg</p> </td><td align="center" valign="top"> <p class="First">143</p> </td><td align="center" valign="top"> <p class="First">18.4</p> </td><td align="center" valign="top"> <p class="First">-4.82</p> </td><td align="center" valign="top"> <p class="First">-0.44</p> </td><td align="center" valign="top"> <p class="First">(-1.52, 0.63)</p> </td><td align="center" valign="top"> <p class="First">0.42</p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 25 mcg</p> </td><td align="center" valign="top"> <p class="First">146</p> </td><td align="center" valign="top"> <p class="First">18.7</p> </td><td align="center" valign="top"> <p class="First">-4.74</p> </td><td align="center" valign="top"> <p class="First">-0.35</p> </td><td align="center" valign="top"> <p class="First">(-1.42, 0.71)</p> </td><td align="center" valign="top"> <p class="First">0.51</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Placebo</p> </td><td align="center" valign="top"> <p class="First">148</p> </td><td align="center" valign="top"> <p class="First">17.8</p> </td><td align="center" valign="top"> <p class="First">-4.38</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> </tbody> </table></div>

Seasonal Allergic Rhinitis Trial: The second trial was a 4-week single dose level trial conducted in patients with seasonal allergic rhinitis. The primary efficacy endpoint in the seasonal allergic rhinitis trial was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score averaged over the first 2 weeks of treatment. In this trial, OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo (Table 4). 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.

Perennial Allergic Rhinitis Trial: The third trial was a 6-week single dose level trial conducted in patients with perennial allergic rhinitis. The primary efficacy endpoint in the perennial allergic rhinitis trial was the difference from placebo in the change from baseline of the average of morning and evening reflective total nasal symptom score averaged over the 6 weeks of treatment. In this trial, OMNARIS Nasal Spray 200 mcg once daily was statistically significantly different from placebo (Table 4). 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.

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <caption> <span>Table 4 Mean changes in reflective total nasal symptom score and instantaneous total nasal symptom score in allergic rhinitis trials</span> </caption> <col width="16%"/> <col width="6%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="14" valign="top">* Mean of AM and PM score from reflective total nasal symptom score; Mean of AM score for instantaneous total nasal symptom score; Maximum = 12<br/>** Estimates, 95% Confidence Intervals, and p-values were obtained from repeated measures ANCOVA analysis with treatment, baseline, day, and treatment by day interaction effects included in the model.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Treatment</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Baseline*</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Change from Baseline</span> </p> </td><td align="center" class="Botrule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Difference from Placebo**</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Estimate</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">95% CI</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">p-value</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Seasonal Allergic Rhinitis Trial – Reflective total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">162</p> </td><td align="center" valign="top"> <p class="First">8.96</p> </td><td align="center" valign="top"> <p class="First">-2.40</p> </td><td align="center" valign="top"> <p class="First">-0.90</p> </td><td align="center" valign="top"> <p class="First">(-1.36, -0.45)</p> </td><td align="center" valign="top"> <p class="First">&lt;0.001</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">162</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.83</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-1.50</p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Seasonal Allergic Rhinitis Trial – Instantaneous total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">162</p> </td><td align="center" valign="top"> <p class="First">8.45</p> </td><td align="center" valign="top"> <p class="First">-1.87</p> </td><td align="center" valign="top"> <p class="First">-0.84</p> </td><td align="center" valign="top"> <p class="First">(-1.30, -0.39)</p> </td><td align="center" valign="top"> <p class="First">&lt;0.001</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">162</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.33</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-1.03</p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Perennial Allergic Rhinitis Trial – Reflective total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">232</p> </td><td align="center" valign="top"> <p class="First">7.59</p> </td><td align="center" valign="top"> <p class="First">-2.51</p> </td><td align="center" valign="top"> <p class="First">-0.62</p> </td><td align="center" valign="top"> <p class="First">(-0.97, -0.28)</p> </td><td align="center" valign="top"> <p class="First">&lt;0.001</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">229</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">7.72</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-1.89</p> </td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Perennial Allergic Rhinitis Trial – Instantaneous total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">232</p> </td><td align="center" valign="top"> <p class="First">7.05</p> </td><td align="center" valign="top"> <p class="First">-1.99</p> </td><td align="center" valign="top"> <p class="First">-0.53</p> </td><td align="center" valign="top"> <p class="First">(-0.90, -0.17)</p> </td><td align="center" valign="top"> <p class="First">0.004</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Placebo</p> </td><td align="center" valign="top"> <p class="First">229</p> </td><td align="center" valign="top"> <p class="First">7.05</p> </td><td align="center" valign="top"> <p class="First">-1.46</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> </tbody> </table></div>

Onset of action: Onset of action was evaluated in two environmental exposure unit studies in patients with seasonal allergic rhinitis receiving a single dose of OMNARIS Nasal Spray 200 mcg. Results from these two studies did not demonstrate a replicate onset of action within the assessment period. Onset of action was also evaluated in the 4-week seasonal allergic rhinitis and in the 6-week perennial allergic rhinitis trial by frequent recording of instantaneous symptom score after the first dose. In these trials, onset of effect was seen within 24 to 48 hours with further symptomatic improvement observed over 1 to 2 weeks in seasonal allergic rhinitis and 5 weeks in perennial allergic rhinitis.

Pediatric Patients Aged 6 to 11 Years: The efficacy of OMNARIS Nasal Spray was evaluated in two randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials in 1282 patients 6 to 11 years of age with allergic rhinitis. Of the two trials, one was 2 weeks in duration conducted in patients with seasonal allergic rhinitis that evaluated efficacy of 200 mcg and 100 mcg of OMNARIS Nasal Spray once daily. The other trial was 12 weeks in duration conducted in patients with perennial allergic rhinitis that evaluated efficacy of 200 mcg, 100 mcg, and 25 mcg of OMNARIS Nasal Spray once daily. Of the total number of patients enrolled in the 2 studies, 380 were treated with 200 mcg of OMNARIS Nasal Spray once daily. 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 averaged over 2 weeks of treatment in the seasonal allergic rhinitis trial and over the first 6 weeks of treatment in the perennial allergic rhinitis trial. In the 2-week trial in patients with seasonal allergic rhinitis, the OMNARIS Nasal Spray 200 mcg once daily dose was statistically significantly different from placebo, but the 100 mcg once daily dose was not statistically significantly different from placebo. The efficacy results for the seasonal allergic rhinitis trial are shown in Table 5.

<div class="scrollingtable"><table cellpadding="3.6pt" width="100%"> <caption> <span>Table 5 Mean changes in reflective total nasal symptom score in 1 seasonal allergic rhinitis trial in children 6 to 11 years of age</span> </caption> <col width="16%"/> <col width="6%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <col width="16%"/> <tfoot> <tr class="First Last"> <td align="left" class="Botrule" colspan="21" valign="top">* Mean of AM and PM score from reflective total nasal symptom score; Maximum = 12<br/>** Estimates, 95% Confidence Intervals, and p-values were obtained from repeated measures ANCOVA analysis with treatment, baseline, day, and treatment by day interaction effects included in the model.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Treatment</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Baseline*</span> </p> </td><td align="center" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Change from Baseline</span> </p> </td><td align="center" class="Botrule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Difference from Placebo**</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Estimate</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">95% CI</span> </p> </td><td align="center" class="Botrule Toprule" valign="middle"> <p class="First"> <span class="Bold">p-value</span> </p> </td> </tr> <tr> <td class="Toprule" colspan="7" valign="top"> <p class="First"> <span class="Bold">Reflective total nasal symptom score</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 200 mcg</p> </td><td align="center" valign="top"> <p class="First">215</p> </td><td align="center" valign="top"> <p class="First">8.25</p> </td><td align="center" valign="top"> <p class="First">-2.46</p> </td><td align="center" valign="top"> <p class="First">-0.39</p> </td><td align="center" valign="top"> <p class="First">(-0.76, -0.02)</p> </td><td align="center" valign="top"> <p class="First">0.040</p> </td> </tr> <tr> <td valign="top"> <p class="First">Ciclesonide 100 mcg</p> </td><td align="center" valign="top"> <p class="First">199</p> </td><td align="center" valign="top"> <p class="First">8.41</p> </td><td align="center" valign="top"> <p class="First">-2.38</p> </td><td align="center" valign="top"> <p class="First">-0.32</p> </td><td align="center" valign="top"> <p class="First">(-0.69, 0.06)</p> </td><td align="center" valign="top"> <p class="First">0.103</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Placebo</p> </td><td align="center" valign="top"> <p class="First">204</p> </td><td align="center" valign="top"> <p class="First">8.41</p> </td><td align="center" valign="top"> <p class="First">-2.07</p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> </tbody> </table></div>

In the 12-week trial in patients with perennial allergic rhinitis, none of the ciclesonide doses were statistically significantly different from placebo. The means and 95% confidence intervals for the differences (OMNARIS Nasal Spray minus placebo) between OMNARIS Nasal Spray 200 mcg, 100 mcg, and 25 mcg treatment groups and placebo were ‑0.31 (-0.75, 0.13), 0.02 (-0.41, 0.46), and 0.09 (-0.35, 0.53), respectively.

Pediatric Patients Aged 2 to 5 Years: Efficacy of OMNARIS Nasal Spray in patients 2 to 5 years of age has not been established [see Pediatric Use (8.4)].

OMNARIS is supplied in an amber glass bottle and provides for nasal delivery with a manual metered pump. OMNARIS Nasal Spray is supplied with an oxygen absorber sachet and enclosed in a foil pouch. The contents of one 12.5 gram bottle provide 120 actuations, after initial priming. Each spray delivers 50 mcg of ciclesonide from the nasal actuator. Prior to initial use, OMNARIS Nasal Spray must be gently shaken and then the pump must be primed by actuating eight times. The OMNARIS Nasal Spray bottle has been filled with an excess to accommodate the priming activity. The bottle should be discarded after removal from the foil pouch either after 120 sprays following initial priming (since the amount of ciclesonide delivered per spray thereafter may be substantially less than the labeled dose) or after 4 months. Patient instructions are also provided.

{ "type": "p", "children": [], "text": "OMNARIS is supplied in an amber glass bottle and provides for nasal delivery with a manual metered pump. OMNARIS Nasal Spray is supplied with an oxygen absorber sachet and enclosed in a foil pouch. The contents of one 12.5 gram bottle provide 120 actuations, after initial priming. Each spray delivers 50 mcg of ciclesonide from the nasal actuator. Prior to initial use, OMNARIS Nasal Spray must be gently shaken and then the pump must be primed by actuating eight times. The OMNARIS Nasal Spray bottle has been filled with an excess to accommodate the priming activity. The bottle should be discarded after removal from the foil pouch either after 120 sprays following initial priming (since the amount of ciclesonide delivered per spray thereafter may be substantially less than the labeled dose) or after 4 months. Patient instructions are also provided." }

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Do not freeze. Shake gently before use. Keep out of reach of children.

{ "type": "p", "children": [], "text": "\nStore at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Do not freeze. Shake gently before use. Keep out of reach of children.\n" }

Omnaris Nasal Spray 50 mcg, 120 metered sprays; net fill weight 12.5 g. NDC 70515-701-01

{ "type": "p", "children": [], "text": "\nOmnaris Nasal Spray 50 mcg, 120 metered sprays; net fill weight 12.5 g. NDC 70515-701-01\n" }

Patients should be informed that treatment with OMNARIS Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with OMNARIS Nasal Spray. In addition, nasal corticosteroids are associated with nasal septal perforation and impaired wound healing. Avoid spraying OMNARIS Nasal Spray directly onto the nasal septum. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use OMNARIS Nasal Spray until healing has occurred [see Warnings and Precautions (5.1)].

Patients should be informed that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. The patient should inform his/her health care provider if a change in vision is noted while using OMNARIS Nasal Spray [see Warnings and Precautions (5.2)].

Patients who are on immunosuppressive doses of corticosteroids should be warned to avoid exposure to chickenpox or measles, and if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.3)].

Patients should use OMNARIS Nasal Spray at regular intervals since its effectiveness depends on its regular use. In clinical trials, the onset of effect was seen within 24 to 48 hours with further symptomatic improvement observed over 1 to 2 weeks in seasonal allergic rhinitis and 5 weeks in perennial allergic rhinitis. Initial assessment of response should be made during this time frame and periodically until the patient’s symptoms are stabilized. The patient should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve by a reasonable time or if the condition worsens.

Patients should be informed to avoid spraying OMNARIS Nasal Spray in their eyes.

It is important that the bottle is gently shaken prior to use to ensure that a consistent amount is dispensed per actuation. The bottle should be discarded after 120 actuations following initial priming or after 4 months after the bottle is removed from the foil pouch, whichever occurs first.

Manufactured forCovis PharmaZug, 6300 SwitzerlandMade in Germany© 2018 Covis Pharma and AstraZeneca group of companies. All rights reserved

OMNARIS is a registered trademark of AstraZeneca group of companies and is used under license.

May 2019

OMNARIS® [Ŏm-nĕ’-rĭs]      (ciclesonide) Nasal Spray, 50 mcg

{ "type": "p", "children": [], "text": "\nOMNARIS® [Ŏm-nĕ’-rĭs]      (ciclesonide) Nasal Spray, 50 mcg\n" }

Important Note: For Intranasal Use Only. Avoid spraying in eyes or directly onto the nasal septum (the wall between the two nostrils).

{ "type": "p", "children": [], "text": "\nImportant Note: For Intranasal Use Only. Avoid spraying in eyes or directly onto the nasal septum (the wall between the two nostrils).\n" }

Read this leaflet before you start using OMNARIS Nasal Spray and each time you refill your prescription. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about OMNARIS Nasal Spray, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Read this leaflet before you start using OMNARIS Nasal Spray and each time you refill your prescription. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about OMNARIS Nasal Spray, ask your healthcare provider or pharmacist." }

What is OMNARIS Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat is OMNARIS Nasal Spray?\n" }

OMNARIS Nasal Spray contains a medicine called ciclesonide, which is a synthetic corticosteroid (a substance that reduces inflammation). This medicine is used to treat nasal symptoms (i.e., runny nose, itchy nose, sneezing, and nasal congestion) that happen with:

{ "type": "p", "children": [], "text": "OMNARIS Nasal Spray contains a medicine called ciclesonide, which is a synthetic corticosteroid (a substance that reduces inflammation). This medicine is used to treat nasal symptoms (i.e., runny nose, itchy nose, sneezing, and nasal congestion) that happen with: " }

{ "type": "", "children": [], "text": "" }

How do I use OMNARIS Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow do I use OMNARIS Nasal Spray?\n" }

Use your nasal spray exactly as prescribed by your healthcare provider.

{ "type": "p", "children": [], "text": "Use your nasal spray exactly as prescribed by your healthcare provider." }

Seasonal allergy symptoms may improve over 1 to 2 weeks; year-round allergy symptoms may improve over 5 weeks. If your symptoms do not improve or get worse, call your healthcare provider.

{ "type": "p", "children": [], "text": "Seasonal allergy symptoms may improve over 1 to 2 weeks; year-round allergy symptoms may improve over 5 weeks. If your symptoms do not improve or get worse, call your healthcare provider." }

Dosage

{ "type": "p", "children": [], "text": "\nDosage\n" }

{ "type": "", "children": [], "text": "" }

Before using OMNARIS Nasal Spray, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore using OMNARIS Nasal Spray, tell your healthcare provider about all of your medical conditions, including if you:\n" }

{ "type": "", "children": [], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements." }

OMNARIS Nasal Spray and other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take antifungal or anti-HIV medicines.

{ "type": "p", "children": [], "text": "OMNARIS Nasal Spray and other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take antifungal or anti-HIV medicines." }

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine." }

What are the possible side effects of OMNARIS Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of OMNARIS Nasal Spray?\n" }

OMNARIS Nasal Spray may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nOMNARIS Nasal Spray may cause serious side effects, including:\n" }

{ "type": "", "children": [], "text": "" }

The most common side effects of OMNARIS Nasal Spray include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of OMNARIS Nasal Spray include:" }

{ "type": "", "children": [], "text": "" }

These are not all the possible side effects of OMNARIS Nasal Spray. Tell your healthcare provider about any side effects that bother you or do not go away.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of OMNARIS Nasal Spray. Tell your healthcare provider about any side effects that bother you or do not go away." }

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "\nCall your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n" }

What are the ingredients in OMNARIS Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in OMNARIS Nasal Spray?\n" }

Active ingredient: ciclesonide

{ "type": "p", "children": [], "text": "Active ingredient: ciclesonide" }

Inactive ingredients: purified water, microcrystalline cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and edetate sodium; and hydrochloric acid to adjust the pH to 4.5.

{ "type": "p", "children": [], "text": "Inactive ingredients: purified water, microcrystalline cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and edetate sodium; and hydrochloric acid to adjust the pH to 4.5." }

This leaflet does not contain all of the information about your medicine. If you have any questions, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "This leaflet does not contain all of the information about your medicine. If you have any questions, ask your healthcare provider or pharmacist." }

You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine.

{ "type": "p", "children": [], "text": "You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine.\n\n" }

Patient’s Instructions for Use

{ "type": "p", "children": [], "text": "\nPatient’s Instructions for Use\n" }

OMNARIS Nasal Spray is supplied in an amber glass bottle in a protective plastic sleeve and should be handled with care.

{ "type": "p", "children": [], "text": "\nOMNARIS Nasal Spray is supplied in an amber glass bottle in a protective plastic sleeve and should be handled with care. \n" }

Preparing for Use

{ "type": "p", "children": [], "text": "\nPreparing for Use\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

Using the Spray

{ "type": "p", "children": [], "text": "\nUsing the Spray\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

How do I store OMNARIS Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow do I store OMNARIS Nasal Spray?\n" }

{ "type": "", "children": [], "text": "" }

How do I know when the OMNARIS Nasal Spray bottle is empty?

{ "type": "p", "children": [], "text": "\nHow do I know when the OMNARIS Nasal Spray bottle is empty?\n" }

Each bottle of OMNARIS Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times. Do not use a bottle of OMNARIS Nasal Spray after 120 sprays (not counting the priming sprays) have been used or after the “discard by date” you wrote on the sticker when you opened the foil pouch. You may still see some medicine in the bottle. Talk with your healthcare provider before your supply of OMNARIS Nasal Spray runs out to see if you should get a refill of your medicine.

{ "type": "p", "children": [], "text": "Each bottle of OMNARIS Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times. Do not use a bottle of OMNARIS Nasal Spray after 120 sprays (not counting the priming sprays) have been used or after the “discard by date” you wrote on the sticker when you opened the foil pouch. You may still see some medicine in the bottle. Talk with your healthcare provider before your supply of OMNARIS Nasal Spray runs out to see if you should get a refill of your medicine." }

Applicator Cleaning Instructions

{ "type": "p", "children": [], "text": "\nApplicator Cleaning Instructions\n" }

Wipe the applicator tip with a clean tissue and replace the dust cap, after you use your nasal spray each day (See Figure 5).

{ "type": "p", "children": [], "text": "Wipe the applicator tip with a clean tissue and replace the dust cap, after you use your nasal spray each day (See Figure 5)." }

{ "type": "", "children": [], "text": "" }

If the applicator is clogged or needs more thorough cleaning, use the following cleaning instructions; (Do not try to unblock the tiny spray hole on the applicator with a pin or other sharp object. Do not twist or try to remove the white plastic pump attached to the medicine bottle.)

{ "type": "p", "children": [], "text": "If the applicator is clogged or needs more thorough cleaning, use the following cleaning instructions; (Do not try to unblock the tiny spray hole on the applicator with a pin or other sharp object. Do not twist or try to remove the white plastic pump attached to the medicine bottle.)\n" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "", "children": [], "text": "" }

Manufactured for Covis Pharma. Zug, 6300 SwitzerlandMade in Germany© 2018 Covis Pharma and AstraZeneca group of companies. All rights reserved.

{ "type": "p", "children": [], "text": "Manufactured for\nCovis Pharma.\nZug, 6300 SwitzerlandMade in Germany© 2018 Covis Pharma and AstraZeneca group of companies. All rights reserved." }

OMNARIS is a registered trademark of AstraZeneca group of companies and is used under license.

{ "type": "p", "children": [], "text": "OMNARIS is a registered trademark of AstraZeneca group of companies and is used under license." }

Revised: June 2018

{ "type": "p", "children": [], "text": "Revised: June 2018" }

{ "type": "", "children": [], "text": "" }

NDC 70515-701-01

{ "type": "p", "children": [], "text": "NDC 70515-701-01" }

Net Contents: 12.5 g

{ "type": "p", "children": [], "text": "Net Contents: 12.5 g" }

omnaris® (ciclesonide) Nasal Spray, 50 mcg

{ "type": "p", "children": [], "text": "\nomnaris®\n\n(ciclesonide) Nasal Spray, 50 mcg" }

120 Metered Actuations

{ "type": "p", "children": [], "text": "\n120 Metered Actuations\n" }

FOR INTRANASAL USE ONLY

{ "type": "p", "children": [], "text": "FOR INTRANASAL USE ONLY" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

FRAGILE: Glass bottle inside.

{ "type": "p", "children": [], "text": "\nFRAGILE: Glass bottle inside." }

Attention Pharmacist: Dispense with accompanying Patient’s Instructions for Use.

{ "type": "p", "children": [], "text": "\nAttention Pharmacist:\nDispense with accompanying Patient’s Instructions for Use." }

Attention Patient: See Patient’s Instructions for Use and cleaninginstructions before using this product.

{ "type": "p", "children": [], "text": "\nAttention Patient:\nSee Patient’s Instructions for Use and cleaninginstructions before using this product." }

Discard OMNARIS® 4 months after opening foil pouch.

{ "type": "p", "children": [], "text": "Discard OMNARIS® 4 months after opening foil pouch." }

COVIS

{ "type": "p", "children": [], "text": "\nCOVIS\n" }

GTIN: 00370515701014

{ "type": "p", "children": [], "text": "GTIN: 00370515701014" }

LOT: XXXXXX

{ "type": "p", "children": [], "text": "LOT: XXXXXX" }

EXP: MM-YYYY

{ "type": "p", "children": [], "text": "EXP: MM-YYYY" }

SERIAL NO:XXXXXXXXXXXXXX

{ "type": "p", "children": [], "text": "SERIAL NO:XXXXXXXXXXXXXX" }

Discard OMNARIS® 4 months after openingfoil pouch.

{ "type": "p", "children": [], "text": "\nDiscard OMNARIS®\n4 months after openingfoil pouch.\n" }

Discard After Date:

{ "type": "p", "children": [], "text": "\nDiscard After Date:\n" }

___/___/___

{ "type": "p", "children": [], "text": "___/___/___" }

Peel off andplace directly onnasal spray bottle.

{ "type": "p", "children": [], "text": "\nPeel off andplace directly onnasal spray bottle.\n" }

Manufactured forCovis PharmaZug, 6300 SwitzerlandMade in Germany

{ "type": "p", "children": [], "text": "Manufactured forCovis PharmaZug, 6300 SwitzerlandMade in Germany" }

© 2019 Covis PharmaAll rights reserved.

{ "type": "p", "children": [], "text": "© 2019 Covis PharmaAll rights reserved." }

Contents: A manualmetered pump sprayunit containing ahypotonic aqueoussuspension of ciclesonide;microcrystalline cellulose,carboxymethylcellulosesodium, hypromellose,potassium sorbate,edetate sodium adjustedto a target pH of 4.5 withhydrochloric acid.

{ "type": "p", "children": [], "text": "\nContents: A manualmetered pump sprayunit containing ahypotonic aqueoussuspension of ciclesonide;microcrystalline cellulose,carboxymethylcellulosesodium, hypromellose,potassium sorbate,edetate sodium adjustedto a target pH of 4.5 withhydrochloric acid." }

Usual Dosage: Seepackage insert.

{ "type": "p", "children": [], "text": "\nUsual Dosage: Seepackage insert." }

Avoid spraying in eyes.

{ "type": "p", "children": [], "text": "\nAvoid spraying in eyes.\n" }

Keep out of reach ofchildren.

{ "type": "p", "children": [], "text": "\nKeep out of reach ofchildren.\n" }

Shake gently before use.

{ "type": "p", "children": [], "text": "\nShake gently before use.\n" }

Store at 25°C (77°F);excursions permittedto 15°–30°C (59°–86°F)[see USP ControlledRoom Temperature].Do not freeze.

{ "type": "p", "children": [], "text": "\nStore at 25°C (77°F);excursions permittedto 15°–30°C (59°–86°F)[see USP ControlledRoom Temperature].Do not freeze.\n" }