Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BackgroundBudesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.AimThe aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.MethodsData from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.ResultsA similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.ConclusionsThis integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis

Combination formoterol and inhaled steroid versus beta(2)-agonist as relief medication for chronic asthma in adults and children (Review)

Background Formoterol has a fast onset of action and can therefore be used to relieve symptoms of asthma. A combination inhaler can deliver formoterol with different doses of inhaled corticosteroid; when used as a reliever both drugs will be delivered more frequently when asthma symptoms increase. This has the potential to treat both bronchoconstriction and inflammation in the early stages of exacerbations. Objectives To assess the efficacy and safety of combined inhalers containing both formoterol and an inhaled corticosteroid when used for reliever therapy in adults and children with chronic asthma. Search methods We last searched the Cochrane Airways Group trials register in April 2009, and no new studies were found for inclusion in the review. Selection criteria Randomised trials in adults and children with chronic asthma, where a combination inhaler containing formoterol and inhaled corticosteroid is compared with fast-acting beta2-agonist alone for the relief of asthma symptoms. This should be the only planned difference between the trial arms. Data collection and analysis Two review authors independently extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. Main results Three trials involving 5905 participants were included. In patients with mild asthma who do not need maintenance treatment, no clinically important advantages of budesonide/formoterol as reliever were found in comparison to formoterol as reliever. Two studies enrolled patients with more severe asthma who were not controlled on high doses of inhaled corticosteroids (around 700 mcg/day in adults), and had suffered a clinically important asthma exacerbation in the past year. Hospitalisations related to asthma in the two studies comparing budesonide/formoterol for maintenance and relief with the same dose of budesonide/formoterol for maintenance with terbutaline for relief yielded an odds ratio of 0.68 (95% CI 0.40 to 1.16), which was not a statistically significant reduction. In adults there was a reduction in exacerbations requiring oral corticosteroids compared to terbutaline, odds ratio 0.54 (95% CI 0.44 to 0.65), which translates into a number needed to treat over 12 months of 15 (95% CI 13 to 21). The study in children found less serious adverse events with budesonide/formoterol used for maintenance and relief. There was no significant difference in annual growth in children using budesonide/formoterol reliever in comparison to terbutaline. Authors’ conclusions In mild asthma it is not yet known whether patients who use a budesonide/formoterol inhaler for relief of asthma symptoms derive any clinically important benefits. In more severe asthma, two studies enrolled patients who were not controlled on inhaled corticosteroids, and had suffered an exacerbation in the previous year, and then had their maintenance inhaled corticosteroids reduced in both arms of the study. Under these conditions the studies demonstrated a reduction in the risk of exacerbations that require oral corticosteroids with budesonide/formoterol for maintenance and relief in comparison with budesonide/formoterol for maintenance and terbutaline or formoterol for relief. The incidence of serious adverse events in children was also less using budesonide/formoterol for maintenance and relief in one study, which similarly enrolled children who were not controlled on inhaled corticosteroids, and who had their maintenance inhaled corticosteroids reduced at the start of the study. This study also compared an explorative maintenance dose of budesonide/formoterol that is not approved for treatment

Combination fluticasone and salmeterol versus fixed dose combination budesonide and formoterol for chronic asthma in adults and children

BackgroundCombination therapies are frequently recommended as maintenance therapy for people with asthma, whose disease is not adequately controlled with inhaled steroids. Fluticasone/salmeterol (FP/SAL) and budesonide/formoterol (BUD/F) have been assessed against their respective monocomponents, but there is a need to compare these two therapies on a head-to-head basis.ObjectivesTo estimate the relative effects of fluticasone/salmeterol and budesonide/formoterol in terms of asthma control, safety and lung function.Search strategyWe searched the Cochrane Airways Group register of trials with prespecified terms. We performed additional hand searching of manufacturers' web sites and online trial registries. Searches are current to May 2008.Selection criteriaRandomised studies comparing fixed dose FP/SAL and BUD/ F were eligible, for a minimum of 12 weeks. Crossover studies were excluded. Our primary outcomes were: i) exacerbations requiring oral steroid bursts, ii) hospital admission and iii) serious adverse events.Data collection and analysisTwo authors independently assessed studies for inclusion in the review. We combined continuous data outcomes with a mean difference (MD), and dichotomous data outcomes with an odds ratio (OR).Main resultsFive studies met the review entry criteria (5537 participants). Primary outcomes: The odds of an exacerbation requiring oral steroids did not differ significantly between treatments (OR 0.89; 95% CI 0.73 to 1.09, three studies, 4515 participants). The odds of an exacerbation leading hospital admission were also not significantly different (OR 1.29; 95% CI 0.68 to 2.47, four studies, 4879 participants). The odds of serious adverse events did not differ significantly between treatments (OR 1.47; 95% CI 0.75, 2.86, three studies, 4054 participants). Secondary outcomes: Lung function outcomes, symptoms, rescue medication, exacerbations leading ED visit/hospital admission and adverse events were not significantly different between treatments.Authors' conclusionsThe evidence in this review indicates that differences in the requirement for oral steroids and hospital admission between BUD/F and FP/SAL do not reach statistical significance. However, the confidence intervals do not exclude clinically important differences between treatments in reducing exacerbations or causing adverse events. The width of the confidence intervals for the primary outcomes justify further trials in order to better determine the relative effects of these drug combinations. Although this review sought to assess the effects of these drugs in both adults and children, no trials were identified in the under-12s and research in this area is of a high priority

Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice.

Inhaled glucocorticoids form the mainstay of asthma treatment because of their anti-inflammatory effects in the lung. Exposure to the air pollutant ozone (O3) exacerbates chronic airways disease. We and others showed that presence of the epithelial-derived surfactant protein-D (SP-D) is important in immunoprotection against inflammatory changes including those induced by O3 inhalation in the airways. SP-D synthesis requires glucocorticoids. We hypothesized here that O3 exposure impairs glucocorticoid responsiveness (including SP-D production) in allergic airway inflammation. The effects of O3 inhalation and glucocorticoid treatment were studied in a mouse model of allergic asthma induced by sensitization and challenge with Aspergillus fumigatus (Af) in vivo. The role of O3 and glucocorticoids in regulation of SP-D expression was investigated in A549 and primary human type II alveolar epithelial cells in vitro. Budesonide inhibited airway hyperreactivity, eosinophil counts in the lung and bronchoalveolar lavage (BAL) and CCL11, IL-13, and IL-23p19 release in the BAL of mice sensitized and challenged with Af (p < 0.05). The inhibitory effects of budesonide were attenuated on inflammatory changes and were completely abolished on airway hyperreactivity after O3 exposure of mice sensitized and challenged with Af. O3 stimulated release of pro-neutrophilic mediators including CCL20 and IL-6 into the airways and impaired the inhibitory effects of budesonide on CCL11, IL-13 and IL-23. O3 also prevented budesonide-induced release of the immunoprotective lung collectin SP-D into the airways of allergen-challenged mice. O3 had a bi-phasic direct effect with early (<12 h) inhibition and late (>48 h) activation of SP-D mRNA (sftpd) in vitro. Dexamethasone and budesonide induced sftpd transcription and translation in human type II alveolar epithelial cells in a glucocorticoid receptor and STAT3 (an IL-6 responsive transcription factor) dependent manner. Our study indicates that O3 exposure counteracts the effects of budesonide on airway inflammation, airway hyperreactivity, and SP-D production. We speculate that impairment of SP-D expression may contribute to the acute O3-induced airway inflammation. Asthmatics exposed to high ambient O3 levels may become less responsive to glucocorticoid treatment during acute exacerbations

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.

BACKGROUND: Inhaled corticosteroids (ICS) are anti-inflammatory drugs that have proven benefits for people with worsening symptoms of chronic obstructive pulmonary disease (COPD) and repeated exacerbations. They are commonly used as combination inhalers with long-acting beta2-agonists (LABA) to reduce exacerbation rates and all-cause mortality, and to improve lung function and quality of life. The most common combinations of ICS and LABA used in combination inhalers are fluticasone and salmeterol, budesonide and formoterol and a new formulation of fluticasone in combination with vilanterol, which is now available. ICS have been associated with increased risk of pneumonia, but the magnitude of risk and how this compares with different ICS remain unclear. Recent reviews conducted to address their safety have not compared the relative safety of these two drugs when used alone or in combination with LABA. OBJECTIVES: To assess the risk of pneumonia associated with the use of fluticasone and budesonide for COPD. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), clinicaltrials.gov, reference lists of existing systematic reviews and manufacturer websites. The most recent searches were conducted in September 2013. SELECTION CRITERIA: We included parallel-group randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies were included if they compared the ICS budesonide or fluticasone versus placebo, or either ICS in combination with a LABA versus the same LABA as monotherapy for people with COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics, numerical data and risk of bias information for each included study.We looked at direct comparisons of ICS versus placebo separately from comparisons of ICS/LABA versus LABA for all outcomes, and we combined these with subgroups when no important heterogeneity was noted. After assessing for transitivity, we conducted an indirect comparison to compare budesonide versus fluticasone monotherapy, but we could not do the same for the combination therapies because of systematic differences between the budesonide and fluticasone combination data sets.When appropriate, we explored the effects of ICS dose, duration of ICS therapy and baseline severity on the primary outcome. Findings of all outcomes are presented in 'Summary of findings' tables using GRADEPro. MAIN RESULTS: We found 43 studies that met the inclusion criteria, and more evidence was provided for fluticasone (26 studies; n = 21,247) than for budesonide (17 studies; n = 10,150). Evidence from the budesonide studies was more inconsistent and less precise, and the studies were shorter. The populations within studies were more often male with a mean age of around 63, mean pack-years smoked over 40 and mean predicted forced expiratory volume of one second (FEV1) less than 50%.High or uneven dropout was considered a high risk of bias in almost 40% of the trials, but conclusions for the primary outcome did not change when the trials at high risk of bias were removed in a sensitivity analysis.Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I(2) = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate. Budesonide also increased non-fatal serious adverse pneumonia events compared with placebo, but the effect was less precise and was based on shorter trials (OR 1.62, 95% CI 1.00 to 2.62; six more per 1000 treated over nine months; moderate quality). Some of the variation in the budesonide data could be explained by a significant difference between the two commonly used doses: 640 mcg was associated with a larger effect than 320 mcg relative to placebo (subgroup differences: I(2) = 74%, P value 0.05).An indirect comparison of budesonide versus fluticasone monotherapy revealed no significant differences with respect to serious adverse events (pneumonia-related or all-cause) or mortality. The risk of any pneumonia event (i.e. less serious cases treated in the community) was higher with fluticasone than with budesonide (OR 1.86, 95% CI 1.04 to 3.34); this was the only significant difference reported between the two drugs. However, this finding should be interpreted with caution because of possible differences in the assignment of pneumonia diagnosis, and because no trials directly compared the two drugs.No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to permit conclusions to be drawn. AUTHORS' CONCLUSIONS: Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison.Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations such as fluticasone furoate, for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

Background An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. Objectives We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment.Search strategyTrials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. Selection criteria Controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. Data collection and analysis Two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. Main results Eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I(2) = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I(2) = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions.No studies were found in children. Authors' conclusions The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children.Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone

A new formulation of oral viscous budesonide in treating of paediatric eosinophilic oesophagitis: a pilot study

OBJECTIVES: Oral viscous budesonide is a recent therapeutic option for eosinophilic oesophagitis (EoE) compared with dietary restriction and inhaled steroids. This single-centre, open-label, not blinded study aims to evaluate the efficacy and safety of a new, preprepared oral viscous budesonide suspension (PVB) in children and adolescents with EoE. METHODS: We treated 36 children with PVB (29 boys; median age 12 years) with EoE diagnosed according to European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines. Patients <150 and >150 cm height received 2 and 4 mg PVB daily, respectively, for 12 weeks. Upper gastrointestinal endoscopy was performed at baseline, after 12 weeks of therapy and 24 weeks after the end of therapy. Baseline and post-treatment scores were calculated for symptoms, endoscopy, and histology. Serum cortisol was performed at baseline, 12, and 36 weeks. RESULTS: At the end of PVB trial, endoscopy showed macroscopic remission in 32 patients (88.9%), whereas at histology median pre- and post-treatment peak eosinophil count/high power field (HPF) markedly decreased from 42.2 (range: 15-100) to 2.9 (range: 0-30); moreover, mean symptom and histology scores impressively improved compared with baseline (P < 0.01). At 24 weeks after the end of PVB therapy, endoscopy showed oesophageal relapse in 21 patients (58.3%), whereas 15 (41.7%) were still in remission. Seven children (19.4%) with positive multichannel intraluminal impedance-pH were treated also with proton pump inhibitors. No significant difference between pre-/post-treatment morning cortisol levels occurred. CONCLUSIONS: The new PVB suspension presented in the present study is effective and safe for treating children with proven EoE. Larger placebo-controlled clinical trials would provide more information about dosing, efficacy, and long-term safety of this formulation, specifically designed for the oesophagus

The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis

Objective. To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). Methods. Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were > 2 SD below the pretreatment value in the entire group of study patients. Results. Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. Conclusion. Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further

Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users

Inhaled corticosteroids versus long-acting beta -agonists for chronic obstructive pulmonary disease (Review).

Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear