BUDESONIDE- budesonide_inhalant

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro The activity of budesonide inhalation suspension is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Inflammation is 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, neutrophils, macrophages, and lymphocytes) and mediators (e. , histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic- and non-allergic-mediated inflammation. The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including an inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85 to 95%) and the low potency of metabolites (see below). The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract. Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks. Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain. Pre-treatment with budesonide administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV 1 HPA Axis Effects The effects of budesonide inhalation suspension on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with budesonide inhalation suspension treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of budesonide inhalation suspension equivalent to 0. 25 mg (n=5), 0. 5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0. 5 mg or 1 mg of budesonide inhalation suspension or placebo. A total of 28, 17, and 31 patients in the budesonide inhalation suspension 0. 5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0. 5 mg, 2 of whom received budesonide inhalation suspension 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (>=500 nmol/L) to a subnormal level (<500 nmol/L) at Week 12. In 4 of these patients receiving budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L. The effects of budesonide inhalation suspension at doses of 0. 5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43 to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period. Budesonide inhalation suspension, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see Warnings and Precautions (5. 5) Absorption: In asthmatic children 4 to 6 years of age, the total absolute bioavailability (i. , lung + oral) following administration of budesonide inhalation suspension via jet nebulizer was approximately 6% of the labeled dose. In children, a peak plasma concentration of 2. 6 nmol/L was obtained approximately 20 minutes after nebulization of a 1 mg dose. Systemic exposure, as measured by AUC and C max Distribution: In asthmatic children 4 to 6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85 to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0. Metabolism: In vitro in vitro in vivo Excretion/Elimination: Budesonide is primarily cleared by the liver. Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine. In asthmatic children 4 to 6 years of age, the terminal half-life of budesonide after nebulization is 2. 3 hours, and the systemic clearance is 0. 5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Special Populations: No differences in pharmacokinetics due to race, gender, or age have been identified. Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults. Nursing Mothers: The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0. 78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0. 014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0. 3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breast-feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0. 02 nmol/L in four infants and <0. 04 nmol/L in one infant) [see Use In Specific Populations (8. 3) Drug-Drug Interactions Inhibitors of cytochrome P450 enzymes Ketoconazole: [see Warnings and Precautions (5. 12) Drug Interactions (7. 1) Cimetidine:.

Budesonide inhalation suspension is an inhaled corticosteroid indicated for: Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age ( 1 Limitations of Use: 1 Budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age. Limitations of Use: Budesonide inhalation suspension is NOT indicated for the relief of acute bronchospasm.

The recommended starting dose and highest recommended dose of budesonide inhalation suspension, based on prior asthma therapy, are listed in the following table. Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators Alone 0. 5 mg total daily dose administered twice daily in divided doses 0. 5 mg total daily dose Inhaled Corticosteroids 0. 5 mg total daily dose administered twice daily in divided doses 1 mg total daily dose Oral Corticosteroids 1 mg total daily dose administered as 0. 5 mg twice daily 1 mg total daily dose Recommended dosing based on previous therapy ( 2 Start with the lowest recommended dose: Bronchodilators alone: 0. 5 mg once daily or 0. 25 mg twice daily Inhaled corticosteroids: 0. 25 mg twice daily up to 0. 5 mg twice daily Oral corticosteroids: 0. 5 mg twice daily In symptomatic children not responding to non-steroidal therapy, a startingdose of 0. 25 mg once daily may be considered. If once-daily treatment does not provide adequate control, the total dailydose should be increased and/or administered as a divided dose. Once asthma stability is achieved, titrate the dose downwards. For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices). Not for injection. 2 Dosing recommendations based on previous therapy are as follows: Bronchodilators alone: 0. 25 mg twice daily Inhaled corticosteroids 0. 5 mg twice daily In symptomatic children not responding to non-steroidal therapy, a starting dose of 0. If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved. Budesonide inhalation suspension should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are NOT recommended. The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Patient Counseling Information,(17. 1) A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U. controlled clinical studies. The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.

Systemic and inhaled corticosteroid use may result in the following: Candida albicans [see Warnings and Precautions (5. 1) Hypersensitivity reactions including anaphylaxis [ see Warnings and Precautions (5. 3) Immunosuppression [ see Warnings and Precautions (5. 4) Hypercorticism and adrenal suppression [see Warnings and Precautions (5. 6) Reduction in bone mineral density [see Warnings and Precautions (5. 7) Growth effects in pediatric patients [see Warnings and Precautions (5. 8) Use in Specific Populations (8. 4) Glaucoma, increased intraocular pressure and cataracts [see Warnings and Precautions (5. 9) Eosinophilic conditions and Churg-Strauss syndrome [see Warnings and Precautions (5. 11) Most common adverse reactions (incidence >3%) are respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Nephron Pharmaceuticals Corporation at 1-800-443-4313 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. Table 1 en dash Adverse Reactions occurring at an incidence of >=3% in at least one active treatment group where the incidence was higher with budesonide inhalation suspension than placebo Adverse Events Vehicle Placebo (n=227) % 0. 25 mg Budesonide Inhalation Suspension Total Daily Dose 0. 5 mg (n=223) % 1 mg (n=317) % Respiratory System Disorder Respiratory Infection 36 34 73 38 Rhinitis 9 7 11 12 Coughing 5 5 9 8 Resistance Mechanism Disorders Otitis Media 11 12 11 9 Viral Infection 3 4 5 3 Moniliasis 2 4 3 4 Gastrointestinal System Disorders Gastroenteritis 4 5 5 5 Vomiting 3 2 4 4 Diarrhea 2 4 4 2 Abdominal Pain 2 3 2 3 Hearing and Vestibular Disorders Ear Infection 4 2 4 5 Platelet, Bleeding and Clotting Disorders Epistaxis 1 2 4 3 Vision Disorders Conjunctivitis 2 < 1 4 2 Skin and Appendages Disorders Rash 3 < 1 4 2 The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one budesonide inhalation suspension treatment group where the incidence was higher with budesonide inhalation suspension than with placebo, regardless of relationship to treatment. Blood and lymphatic system disorders: cervical lymphadenopathy Ear and labyrinth disorders: earache General disorders and administration site conditions: fatigue, flu-like disorder Immune system disorders: allergic reaction Infections and infestations: eye infection, herpes simplex, external ear infection, infection Injury, poisoning and procedural complication: fracture Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders : hyperkinesia Psychiatric disorders: emotional lability Respiratory, thoracic, and mediastinal disorders: chest pain, dysphonia, stridor Skin and subcutaneous tissue disorders: contact dermatitis, eczema, pustular rash, pruritus, purpura The incidence of reported adverse events was similar between the 447 budesonide inhalation suspension treated (mean total daily dose 0. 5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies. The following adverse reactions have been reported during post-approval use of budesonide inhalation suspension. 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. Some of these adverse reactions may also have been observed in clinical studies with budesonide inhalation suspension. Endocrine disorders: [see Warnings and Precautions (5. 6) Eye disorders: [see Warnings and Precautions (5. 9) General disorders and administration site conditions: Immune system disorders: [see Contraindications (4) Warnings and Precautions (5. 10) Infection and Infestation: Musculoskeletal and connective tissue disorders: Nervous system disorders: Psychiatric disorders: Respiratory, thoracic, and mediastinal disorders: Skin and subcutaneous tissue disorders: Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for budesonide inhalation suspension [see Warnings and Precautions (5. 8) Use In Specific Populations,(8.

The use of budesonide inhalation suspension is contraindicated in the following conditions: Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to budesonide or any of the ingredients of budesonide inhalation suspension [see Warnings and Precautions (5. 3) Description (11) Adverse Reactions (6. 2) Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. 1 Hypersensitivity to any of the ingredients in budesonide inhalation suspension ( 4.

Risk Summary Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal risk Labor or Delivery Data Human Data Animal Data In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at doses 0. 2 times the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0. 05 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 5 mcg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0. 5 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 5 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 250 mcg/kg/day). Risk Summary Data Human data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0. 3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see Clinical Pharmacology (12. 2) Adverse Reactions (6. 1) A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0. 5 mg or 1 mg of budesonide inhalation suspension or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received budesonide inhalation suspension versus placebo. However, on an individual basis, 7 patients in this study (6 in the budesonide inhalation suspension treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see Clinical Pharmacology, Pharmacodynamics (12. 2) A dose dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3. 7 cm over 12 weeks compared with 3. 1 cm in the budesonide inhalation suspension 0. 5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and budesonide inhalation suspension 0. 0) and between placebo and budesonide inhalation suspension 1 mg of 0. These findings support that the use of budesonide inhalation suspension in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids. Controlled clinical studies have shown that 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. In a study of asthmatic children 5 to 12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1. 1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with the budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The growth of pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, should be monitored routinely (e. , via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including budesonide inhalation suspension each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2) Warnings and Precautions (5. 8) Of the 215 patients in 3 clinical trials of budesonide inhalation suspension in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients. Formal pharmacokinetic studies using budesonide inhalation suspension have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.

Strong cytochrome P450 3A4 inhibitors (e. , ritonavir): Use with caution. May cause increased systemic corticosteroid effects. 1 The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of budesonide inhalation suspension with long-term ketoconazole and other known strong CYP3A4 inhibitors (e. , ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [ see Warnings and Precautions (5. 12) Clinical Pharmacology (12.

OVERDOSAGE
The potential for acute toxic effects following overdose of budesonide inhalation suspension is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [ see Warnings and Precautions (5.6)
NONCLINICAL TOXICOLOGY
In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 2 2 2 2 In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella Drosophila melanogaster Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m 2 2 2
CLINICAL STUDIES
Three double-blind, placebo-controlled, parallel group, randomized U. clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. 5 mg and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to patients in the 3 U. controlled clinical trials. The co-primary endpoints were nighttime and daytime asthma symptom scores (0 to 3 scale). Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double-blind treatment period in nighttime and daytime asthma symptom scores (scale 0 to 3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization). The double-blind treatment period was defined as the mean over 12 week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U. Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0. 5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at budesonide inhalation suspension doses of 0. 25 mg once daily (one study), 0. 25 mg twice daily, and 0. 5 mg twice daily compared to placebo. Use of budesonide inhalation suspension resulted in statistically significant decreases in either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0. 5 mg once daily (one study). Symptom reduction in response to budesonide inhalation suspension occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of budesonide inhalation suspension studied. Improvements in lung function were associated with budesonide inhalation suspension treatment in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV1 [budesonide inhalation suspension 0. 5 mg once daily and 1 mg once daily (one study); 0. 5 mg twice daily] and morning PEF [budesonide inhalation suspension 1 mg once daily (one study); 0. 25 mg twice daily; 0. 5 mg twice daily] compared to placebo. A numerical reduction in nighttime and daytime symptom scores (0 to 3 scale) of asthma was observed within 2 to 8 days, although maximum benefit was not achieved for 4 to 6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials. Patients Not Receiving Inhaled Corticosteroid Therapy Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline Patients Previously Maintained on Inhaled Corticosteroids The efficacy of budesonide inhalation suspension at doses of 0. 25 mg and 0. 5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 8 years of age, previously maintained on inhaled corticosteroids (mean FEV 1 Statistically significant increases in FEV 1 Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry. Night time Asthma Changes from Baseline p-value :0. 021 Figure 1 Patients Receiving Once-Daily or Twice-Daily Dosing The efficacy of budesonide inhalation suspension at doses of 0. 25 mg once daily, 0. 25 mg twice daily, 0. 5 mg twice daily, and 1 mg once daily was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1. Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 3. Budesonide inhalation suspension at doses of 0. 5 mg twice daily and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores. Budesonide inhalation suspension at a dose of 0. 5 mg twice daily resulted in statistically significant increases compared to placebo in FEV1, and at doses of 0. 5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF. The evidence supports the efficacy of the same nominal dose of budesonide inhalation suspension administered on either a once daily or twice-daily schedule. When all measures are considered together, the evidence is stronger for twice-daily dosing [see Dosage and Administration (2)]. Figure 2: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline.
Patient Information and Instructions for Use
Budesonide (bew DEH so nide) (budesonide) inhalation suspension 2 mL ampules containing 0. 5 mg For inhalation only. Do not swallow. Only use budesonide inhalation suspension with a jet nebulizer machine that is connected to an air compressor. Do not use with an ultrasonic nebulizer. Read the Patient Information that comes with budesonide inhalation suspension before your child starts using it 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 child''s medical condition or treatment. If you have any questions about budesonide inhalation suspension, ask your healthcare provider or pharmacist. What is budesonide inhalation suspension? Budesonide inhalation suspension is an inhaled corticosteroid medicine. Budesonide inhalation suspension is a long-term maintenance medicine used to control and prevent asthma symptoms in children ages 12 months to 8 years. Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms. Budesonide inhalation suspension helps reduce swelling and inflammation in the lungs, and helps keep the airways open to reduce asthma symptoms. Budesonide inhalation suspension does not treat the sudden symptoms (wheezing, cough, shortness of breath, and chest pain or tightness) of an asthma attack. Always have a short-acting beta 2 It is not known if budesonide inhalation suspension is safe or effective in children younger than 12 months or older than 8 years. Who should not use budesonide inhalation suspension? Do not use budesonide inhalation suspension: to treat sudden symptoms of asthma if your child is allergic to budesonide or any of the ingredients in budesonide inhalation suspension. What should I tell my healthcare provider before using budesonide inhalation suspension? Before your child uses budesonide inhalation suspension, tell your healthcare provider if your child: has an allergy. See the section "Who should not use budesonide inhalation suspension?" There is a complete list of ingredients in budesonide inhalation suspension at the end of this leaflet. has or recently had chicken pox or measles, or has recently been near anyone with chicken pox or measles. has or had tuberculosis of the respiratory tract. has certain kinds of infections that have not been treated, including: fungal infections bacterial infections viral infections parasitic infections herpes simplex infection of the eye (ocular herpes simplex) Budesonide inhalation suspension may not be right for children who have had any of these types of infections. has decreased bone mineral density (bone strength). Your child is at risk for decreased bone mineral density if he or she: is inactive for a long period of time has a family history of osteoporosis does not eat well (poor nutrition) takes bone thinning medicines (such as anticonvulsant medicines or corticosteroids) for a long time. has an eye problem such as increased pressure in the eye, glaucoma or cataracts. has liver problems. is planning to have surgery. has any other medical conditions. is pregnant or plans to become pregnant. It is not known if budesonide inhalation suspension will harm your unborn baby. is breast-feeding or plans to breast-feed. Budesonide inhalation suspension can pass into breast milk. You and your healthcare provider should decide if you will use budesonide inhalation suspension or breast-feed. Tell your healthcare provider about all the medicine your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using budesonide inhalation suspension with certain other medicines may affect each other causing side effects. Especially tell your healthcare provider if your child takes: corticosteroids anti-seizure medicine (anticonvulsants) medicines that suppress the immune system (immunosuppressant) ketoconazale (Nizoral) certain medicines that can affect how your liver breaks down medicine Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines your child takes. Keep a list of them and show it to your healthcare provider and pharmacist when your child gets a new medicine. How should I use budesonide inhalation suspension? Use budesonide inhalation suspension exactly as prescribed by your healthcare provider. Your child must use budesonide inhalation suspension regularly for it to work. Budesonide inhalation suspension comes in two strengths. Your healthcare provider has prescribed the strength that is best for your child. Do not stop using budesonide inhalation suspension and do not change your child''s dose of budesonide inhalation suspension without talking to your healthcare provider. Budesonide inhalation suspension is for inhaled use only. Use budesonide inhalation suspension with a jet nebulizer connected to an air compressor set up with a mouthpiece or face mask. Do not use an ultrasonic nebulizer to give budesonide inhalation suspension. Do not mix budesonide inhalation suspension with other nebulizer medicines. If your child uses another medicine by inhalation to treat asthma, talk with your healthcare provider for instructions on when to use the other medicine. If your child misses a dose, just give the next regularly scheduled dose when it is due. Do not use budesonide inhalation suspension more often than has been prescribed. Improvement in the control of asthma symptoms with budesonide inhalation suspension can occur within 2 to 8 days. It may take up to 4 to 6 weeks before maximum improvement is seen. Make sure your child always has a short-acting beta 2 2 Call your healthcare provider right away if: the short-acting rescue medicine does not work as well for relieving asthma symptoms. your child needs to use the short-acting rescue medicines more often than usual. your child''s breathing problems worsen with budesonide inhalation suspension` Rinse your child''s mouth with water and have him or her spit the water out after each budesonide inhalation suspension treatment. Do not swallow the water. This will lessen the chance of getting a fungal infection (thrush) in the mouth. If your child has used long-term corticosteroids and the dose is now being lowered or stopped, a warning card should be carried stating that your child may need corticosteroids during times of stress or during an asthma attack that does not get better with bronchodilator medicines. Your healthcare provider may check your child''s blood, breathing and do eye exams while using budesonide inhalation suspension Read the Patient Information and Instructions for Use at the end of this leaflet for detailed instructions about how to use budesonide inhalation suspension. What are the possible side effects of budesonide inhalation suspension? Budesonide inhalation suspension may cause serious side effects including: Thrush ( candida Worsening of asthma or sudden asthma attacks. Allergic reactions. Tell your healthcare provider or get medical help right away if your child has: skin rash, redness or swelling severe itching swelling of the face, mouth and tongue trouble breathing or swallowing chest pain anxiety (feeling of doom) Immune system effects and a higher chance of infections. Your child is more likely to get infections when taking medicines that weaken the immune system. Symptoms of infection may include: fever, pain, aches, chills, feeling tired, nausea and vomiting. Tell your healthcare provider about any signs of infection while your child uses budesonide inhalation suspension. Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency include tiredness, weakness, nausea and vomiting, and low blood pressure. Decrease in bone mineral density (bone strength). Your healthcare provider may want to check your child for this during treatment with budesonide inhalation suspension. Slowed or delayed growth problems. Your child''s healthcare provider may want to monitor your child''s growth while using budesonide inhalation suspension. Eye problems, including glaucoma and cataracts. Your child''s healthcare provider may suggest eye exams while using budesonide inhalation suspension. Increased wheezing right after taking budesonide inhalation suspension. Always have a fast-acting inhaled bronchodilator medicine with you to treat sudden wheezing. Call your healthcare provider or get medical help right away if your child has any of the serious side effects listed above. The most common side effects of budesonide inhalation suspension include: respiratory infections. Symptoms may include stuffy nose, sore nose and throat. runny nose cough viral infections viral irritation and inflammation of the stomach and intestine (gastroenteritis). Gastroenteritis symptoms may include: stomach area pain, diarrhea, nausea and vomiting, and loss of appetite. ear infections nosebleed pink eye (conjunctivitis) rash Tell your healthcare provider if your child has any side effect that bothers him or her or that does not go away. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. To report SUSPECTED ADVERSE REACTIONS, contact Nephron Pharmaceuticals Corporation at 1-800-443-4313 or FDA at 1-800-FDA-1088 or www. gov/medwatch. How should I store budesonide inhalation suspension? Store budesonide inhalation suspension in an upright position between 68 to 77°F (20 to 25°C) Keep budesonide inhalation suspension in the aluminium foil envelope to protect from light until ready to use. After a budesonide inhalation suspension ampule is opened it should beused right away. Budesonide inhalation suspension ampules can be stored for 2 weeks afteropening the protective aluminum foil envelope. Throw away budesonide inhalation ampules if not used within 2 weeks ofopening the protective aluminum foil envelope. Do not refrigerate or freeze. Keep budesonide inhalation suspension and all medicines out of the reach of children General Information about budesonide inhalation suspension Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use budesonide inhalation suspension for a condition for which it was not prescribed. Do not give budesonide inhalation suspension to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about budesonide inhalation suspension if you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about budesonide inhalation suspension that is written for health professionals. For more information call Nephron Pharmaceuticals Corporation at 1-800-443-4313. What are the ingredients in budesonide inhalation suspension? Active ingredient: budesonide Inactive ingredients: citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection. Patient Instructions for Use Important: Budesonide inhalation suspension is only for use with a jet nebulizer machine. Make sure you know how to use your jet nebulizer machine before your child uses Budesonide inhalation suspension. Budesonide inhalation suspension is a liquid that is turned into a mist by a nebulizer and inhaled into the lungs. The face mask should be properly adjusted to optimize delivery and to avoid exposing the eyes to the nebulized medication. Corticosteroid effects on the skin can be avoided if the face is washed after the use of a face mask. How to use budesonide inhalation suspension. Budesonide inhalation solution comes in a sealed protective aluminum foil envelope. Do not open the sealed pouch until you are ready to use a dose of budesonide inhalation suspension. Open the sealed envelope along the dotted line and take out 1 single-dose ampule from the strip. See Figure 1. Record the date that you opened the foil on the envelope in the space provided. If your prescription was filled with individually wrapped, single-dose ampules, open the sealed aluminum foil envelope and remove the ampule (Figure 1a) Return the unopened budesonide inhalation suspension ampules on the strip back into the foil envelope before storing. Gently shake the budesonide inhalation suspension ampule using a circular motion as shown in Figure 2. Hold the budesonide inhalation suspension ampule upright without squeezing the ampule and open by twisting off the top as shown in Figure 3 4. Place the open end of the budesonide inhalation suspension ampule into the nebulizer cup (reservoir) and slowly squeeze all of the medicine from the ampule into the nebulizer medicine cup as shown in Figure 4. Throw away the empty ampule. Use your jet nebulizer as directed. Manufactured By: For Customer Service, Figure 1 and 1a Figure 2 Figure 3 Figure 4.

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