ALVESCO- ciclesonide_aerosol, metered

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. , mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediators (e. , 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. 6) mcg/day, -4. 03) mcg/day, and -8. 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. 16 mcg/day [95% CI: -15. 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 max max 0-infinity Distribution Elimination 14 max Metabolism 14 Specific Populations Patients with Renal Impairment Patients with Hepatic Impairment max Drug Interaction Studies [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 in vitro In vitro 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.

There are no available data on ALVESCO use in pregnant women to assess a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is low systemic exposure following ALVESCO oral inhalation administration at the recommended dose [see Clinical Pharmacology ( 12. 3 In animal reproduction studies, ciclesonide administered by the oral route to pregnant rats during the period of organogenesis did not cause any evidence of fetal harm at doses up to 15 times the maximum recommended human daily oral inhalation dose (MRHDOID) of 640 mcg/day. Teratogenicity, characteristic of corticosteroids, decreased body weight and/or skeletal variations were observed in rabbit fetuses following administration of ciclesonide to pregnant rabbits by the subcutaneous route during the period of organogenesis at doses 0. 15 times the MRHDOID and higher on a mcg/m 2 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/m 2 2 2 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 2 2 2 2 2 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 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 [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 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 [see Clinical Pharmacology ( 12. 1 Animal Data A study with 14 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 FEV 1 1 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. 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. , 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. 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.

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 [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.

OVERDOSAGE
Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions ( 5.5
NONCLINICAL TOXICOLOGY
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/m 2 2 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 in vivo 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/m 2
CLINICAL STUDIES
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 FEV 1 1 1 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 FEV 1 1 1 1 1 Figure 1 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 FEV 1 The AM pre-dose FEV 1 Figure 2 Statistically significantly more increases in AM pre-dose FEV 1 In the other trial, 257 patients with moderate to severe persistent asthma (mean baseline percent predicted FEV 1 1 Figure 3 Compared to placebo, both ALVESCO doses showed statistically significantly more improvement in pre-dose FEV 1 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 FEV 1 Figure 1 Figure 2 Figure 3.
Patient Information
ALVESCO registered Note: For Oral Inhalation Only Do not 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? 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. 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. It is not known if ALVESCO is safe and effective in children 11 years of age and younger. Who should not use ALVESCO? Do not use ALVESCO: to treat status asthmaticus or other sudden symptoms of asthma. ALVESCO is not a rescue inhaler and should not be used to give you fast relief from your asthma attack. Always use a rescue inhaler such as albuterol, during a sudden asthma attack. if you are allergic to ciclesonide or any of the ingredients in ALVESCO. See the end of this Patient Information leaflet for a complete list of ingredients in ALVESCO. What should I tell my healthcare provider before using ALVESCO? Before you use ALVESCO tell your healthcare provider if you: have or have had eye problems such as increased ocular pressure, glaucoma, or cataracts. have any infections including tuberculosis or ocular herpes simplex. have not had or been vaccinated for chicken pox or measles. are pregnant or plan to become pregnant. It is not known if ALVESCO will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if ALVESCO passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you are using ALVESCO. Tell your healthcare provider about all the medicines you take 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? Read the Instructions for Use at the end of this leaflet for specific information about the right way to use ALVESCO. Use ALVESCO exactly as your healthcare provider tells you to use it. Do not take more of your medicine, or take it more often than your healthcare provider tells you. You must use ALVESCO regularly. It may take 4 weeks or longer after you start using ALVESCO for your asthma symptoms to get better. Do not stop using ALVESCO even if you are feeling better, unless your healthcare provider tells you to. If your symptoms do not improve or get worse, call your healthcare provider. Your healthcare provider may prescribe a rescue inhaler for emergency relief of sudden asthma attacks. Call your healthcare provider if you have: an asthma attack that does not respond to your rescue inhaler or you need more of your rescue inhaler than usual. If you use another inhaled medicine, ask your healthcare provider for instructions on how to use it while you use ALVESCO. What are the possible side effects of ALVESCO? ALVESCO may cause serious side effects, including: Thrush (Candida), a fungal infection of your nose, mouth, or throat. Immune system problems that may increase your risk of infections. fever pain aches chills feeling tired nausea vomiting Adrenal insufficiency. tiredness weakness dizziness nausea that does not go away vomiting that does not go away Decreased bone mass (bone mineral density). Slowed or delayed growth in children. Eye problems such as glaucoma and cataracts. Increased wheezing (bronchospasm) Stop using ALVESCO and use an inhaled fast-acting bronchodilator (rescue inhaler) right away. headache swelling of nose and throat (nasopharyngitis) swelling of the sinuses (sinusitis) throat pain upper respiratory infection joint pain (arthralgia) nasal congestion pain in arms, legs, and back 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. How should I store ALVESCO? Store ALVESCO at room temperature between 59°F to 86°F (15°C to 30°C) Do not Do not Do not Safely throw away medicine that is out of date or no longer needed. Keep ALVESCO Aerosol and dry at all times. Keep ALVESCO and all medicines out of reach of children. General Information About the Safe and Effective use of ALVESCO 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. For more information, go to www. What are the ingredients in ALVESCO? Active ingredient: Inactive ingredients: Instructions for Use registered Read this Instructions for Use for ALVESCO before you start using it and each time you get a refill. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Note: For Oral Inhalation Only Do not The parts of your ALVESCO ALVESCO comes as a canister that fits into an actuator with a dose indicator. Do not Do not Figure A Priming your ALVESCO for use Remove your ALVESCO from its package. Before you use ALVESCO for the first time Remove the plastic cap. Look at the dose indicator on top of the inhaler. Make sure that the dose indicator display window pointer is before the “60” inhalation mark before you use your ALVESCO for the first time. Hold the actuator upright. Spray 3 times into the air away from the face, by pressing down fully onto the center of the dose indicator button. (See Figure B Check the dose indicator display window after the priming sprays and before the first use to make sure it shows that there are 60 sprays left in your ALVESCO unit. If there are not 60 sprays left in your ALVESCO after the first use priming spray, return it to the pharmacy. Make sure the canister is firmly placed in the mouthpiece each time you use your ALVESCO. You do not need to shake your ALVESCO unit before you use it. Using Your ALVESCO Step 1. Figure C Step 2. Figure D Step 3. Figure E Step 4. While breathing in deeply and slowly, press down on the center of the dose indicator with your finger. Press down fully on the canister until it stops moving in the actuator while delivering your dose. When you have finished breathing in, hold your breath for about 10 seconds, or for as long as is comfortable. Note: It is normal to hear a soft click from the indicator as it counts down during use. 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. Do not Cleaning your ALVESCO unit Clean the mouthpiece weekly with a clean dry tissue, both inside and out. (See Figure G Wipe over the front of the small hole where the medicine comes out with a dry, folded tissue. (See Figure H Do not wash or put any part of your ALVESCO unit in water or any other liquids. How to tell if your ALVESCO canister is empty Your ALVESCO unit is fitted with a dose indicator display which shows you how much of your medicine is left after each use. Each canister of ALVESCO contains enough medicine for you to spray your medicine 60 times. This does not count the first sprays used for priming. The dose indicator display counts down by 10 and will move every tenth time you take a puff (i. , 60-50-40, etc. The dose indicator display window will turn red when there are only 20 sprays left. This means that you need to replace your inhaler soon. When the dose indicator display window reads “0” you should throw away your ALVESCO unit. (See Figure I Although your ALVESCO unit is fitted with a dose indicator display to help determine the number of sprays left, you should keep track of the number of sprays used from each canister of your ALVESCO unit. This PPI and Instructions for Use has been approved by the U. Food and Drug Administration. Manufactured for: Covis Pharma ALVESCO is a registered trademark of Covis Pharma. copyright2023 Covis Pharma. All rights reserved. Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I.

Praxis, LLC

ALVESCO- ciclesonide_aerosol, metered Product manual source documgent