Alvesco Drug Information

ALVESCO is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 12 years of age and older. Limitations of Use: ALVESCO is not indicated for the relief of acute bronchospasm. ALVESCO is not indicated for children under 12 years of age.

Administration Information Administer ALVESCO by the orally inhaled route. After administration, rinse the mouth with water and spit out without swallowing to help reduce the risk of oropharyngeal candidiasis. 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.

Recommended Dosage

The recommended starting dosage and the highest recommended dosage of ALVESCO are listed in Table 1 Table 1: Recommended Dosages for Adults and Pediatric Patients 12 Years and Older 1 Prednisone should be reduced gradually, no faster than 2.5 mg/day on a weekly basis, beginning after at least 1 week of therapy with ALVESCO. Patients should be carefully monitored for signs of asthma instability, including monitoring of serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy. 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.

Clinical Trial Experience

The safety data described below for adult and pediatric patients 12 years of age and older reflect exposure to ALVESCO in doses ranging from 80 mcg to 640 mcg twice daily in five double-blind placebo-controlled clinical trials. Studies with once daily dosing are omitted from the safety database because the doses studied once daily are lower than the highest recommended twice daily doses. The five studies were of 12 to 16 weeks treatment duration, one of which included a safety extension follow-up of one year.

In the 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. 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. Table 2 includes adverse reactions for the recommended doses of ALVESCO that occurred at an incidence of ≥ 3% in any of the ALVESCO groups and which were more frequent with ALVESCO compared to placebo. Table 2: Adverse Reactions with ≥ 3% Incidence Reported in Patients ≥ 12 Years of Age with ALVESCO in US Placebo-Controlled Clinical Trials in Patients Previously on Bronchodilators and/or Inhaled Corticosteroids 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. The safety profile from the one-year follow-up was similar to that seen in the 12- and 16-week treatment studies.

Post-marketing Experience

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. In vitro studies and clinical pharmacology studies suggested that des-ciclesonide has no potential for metabolic drug interactions or protein binding-based drug interactions. 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.

Pregnancy Risk Summary There are no available data on ALVESCO use in pregnant women to assess a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is low systemic exposure following ALVESCO oral inhalation administration at the recommended dose. In animal reproduction studies, ciclesonide administered by the oral route to pregnant rats during the period of organogenesis did not cause any evidence of fetal harm at doses up to 15 times the maximum recommended human daily oral inhalation dose (MRHDOID) of 640 mcg/day.

Teratogenicity, characteristic of corticosteroids, decreased body weight and/or skeletal variations were observed in rabbit fetuses following administration of ciclesonide to pregnant rabbits by the subcutaneous route during the period of organogenesis at doses 0.15 times the MRHDOID and higher on a mcg/m 2 basis (see Data). No evidence of fetal harm was observed in rabbits at doses of 0.03 times the MRHDOID. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre‑eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Animal Data In an embryo-fetal development study in pregnant rats dosed by the oral route during the period of organogenesis from gestation days 6 to 15, ciclesonide did not cause any evidence of fetal harm at doses up to approximately 15 times the MRHDOID in adults (on a mcg/m 2 basis with maternal oral dose up to 900 mcg/kg/day). Maternal toxicity, as evidenced by decreased body weight gain, was observed at approximately 15 times the MRHDOID in adults (on a mcg/m 2 basis at a maternal dose of 900 mcg/kg/day); however, no adverse effects were observed at doses 5 times the MRHDOID and lower (on a mcg/m 2 basis with maternal oral doses of 300 mcg/kg/day and lower).

In two embryo-fetal development studies in pregnant rabbits dosed by the subcutaneous route during the period of organogenesis from gestation days 6 to 18, ciclesonide caused acampsia (flexures of legs) in fetuses at doses 0.15 times the MRHDOID and higher (on a mcg/m 2 basis with maternal oral doses of 5 mcg/kg/day and higher), decreased body weight, cleft palate, enlarged fontanelle, parchment-like skin, and incomplete ossification of bones in fetuses at doses 0.76 times the MRHDOID (on a mcg/m 2 basis with a maternal subcutaneous dose of 25 mcg/kg/day), and embryo-fetal death at doses 3 times the MRHDOID and higher (on a mcg/m 2 basis with maternal subcutaneous doses of 100 mcg/kg/day and higher). No evidence of fetal harm was observed at a dose 0.03 times the MRHDOID in adults (on a mcg/m 2 basis at a maternal subcutaneous dose of 1 mcg/kg/day). Maternal toxicity was observed at doses 3 times the MRHDOID in adults (on a mcg/m 2 basis with maternal subcutaneous doses of 100 mcg/kg/day and lower); however, no evidence of toxicity was observed at doses 0.76 times the MRHDOID and lower (on a mcg/m 2 basis with maternal subcutaneous doses of 25 mcg/kg/day and lower).

In a prenatal and postnatal development study in pregnant rats dosed by the oral route from gestation day 6 to lactation day 20, ciclesonide produced no adverse developmental effects on offspring at doses up to approximately 15 times the MRHDOID (on a mcg/m 2 basis at maternal oral doses up to 900 mcg/kg/day).

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

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 FEV 1 of 68%. The primary efficacy endpoint was morning pre-dose FEV 1.

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. The primary efficacy endpoint was time to the first severe asthma exacerbation 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.

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

Chronic overdosage may result in signs/symptoms of hypercorticism.