Drugs

, Volume 60, Issue 5, pp 1141–1178

Budesonide Inhalation Suspension

A Review of its Use in Infants, Children and Adults with Inflammatory Respiratory Disorders
Adis Drug Evaluation
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Summary

Abstract

Budesonide, a topically active corticosteroid, has a broad spectrum of clinically significant local anti-inflammatory effects in patients with inflammatory lung diseases including persistent asthma.

In infants and young children with persistent asthma, day- and night-time symptom scores, and the number of days in which β2-agonist bronchodilators were required, were significantly lower during randomised, double-blind treatment with budesonide inhalation suspension 0.5 to 2 mg/day than placebo in 3 multicentre trials. Significantly fewer children discontinued therapy with budesonide inhalation suspension than with placebo because of worsening asthma symptoms in a study that included children who were receiving inhaled corticosteroids at baseline.

Recent evidence indicates that budesonide inhalation suspension is significantly more effective than nebulised sodium cromoglycate in improving control of asthma in young children with persistent asthma.

At a dosage of 2 mg/day, budesonide inhalation suspension significantly reduced the number of asthma exacerbations and requirements for systemic corticosteroids in preschool children with severe persistent asthma. In children with acute asthma or wheezing, the preparation was as effective as, or more effective than oral prednisolone in improving symptoms.

In children with croup, single 2 or 4mg dosages of budesonide inhalation suspension were significantly more effective than placebo and as effective as oral dexamethasone 0.6 mg/kg or nebulised L-epinephrine (adrenaline) 4mg in alleviating croup symptoms and preventing or reducing the duration of hospitalisation.

Early initiation of therapy with budesonide inhalation suspension 1 mg/day appears to reduce the need for mechanical ventilation and decrease overall corticosteroid usage in preterm very low birthweight infants at risk for chronic lung disease.

In adults with persistent asthma, budesonide inhalation suspension ≤8 mg/day has been compared with inhaled budesonide 1.6 mg/day and fluticasone propionate 2 mg/day administered by metered dose inhaler. Greater improvements in asthma control occurred in patients during treatment with budesonide inhalation suspension than with budesonide via metered dose inhaler, whereas fluticasone propionate produced greater increases in morning peak expiratory flow rates than nebulised budesonide. Several small studies suggest that the preparation has an oral corticosteroid-sparing effect in adults with persistent asthma and that it may be as effective as oral corticosteroids during acute exacerbations of asthma or chronic obstructive pulmonary disease.

The frequency of adverse events was similar in children receiving budesonide inhalation suspension 0.25 to 2 mg/day or placebo in 12-week studies. During treatment with budesonide inhalation suspension 0.5 to 1 mg/day in 3 nonblind 52-week studies, growth velocity in children was generally unaffected; however, a small but statistically significant decrease in growth velocity was detected in children who were not using inhaled corticosteroids prior to the introduction of budesonide inhalation suspension. Hypothalamic-pituitary-adrenal axis function was not affected by short (12 weeks) or long (52 weeks) term treatment with nebulised budesonide.

In conclusion, budesonide inhalation suspension is the most widely available nebulised corticosteroid, and in the US is the only inhaled corticosteroid indicated in children aged ≥1 year with persistent asthma. The preparation is suitable for use in infants, children and adults with persistent asthma and in infants and children with croup.

Pharmacodynamic Properties

Budesonide is a topically active corticosteroid with anti-inflammatory properties. In patients with asthma, the drug suppresses the number of inflammatory cells in the lungs, inhibits synthesis and release of cytokines, reduces bronchial hyper-responsiveness to a variety of substances and attenuates both the early and late asthmatic response.

A single 4mg dose of nebulised budesonide inhalation suspension did not perturb serum cortisol levels in healthy adult volunteers. Similarly, budesonide inhalation suspension 1 to 4 mg/day had no significant effect on plasma markers of systemic corticosteroid activity in bone, blood or adrenal tissue in adult patients with asthma. In contrast, significant dose-related suppression of eosinophil counts and both osteocalcin and morning plasma cortisol levels occurred during treatment with oral prednisolone 5 to 20 mg/day in this randomised, double-blind, crossover study.

No pharmacodynamic studies have been conducted in children with asthma during treatment with budesonide inhalation suspension. However, when administered as a dry powder, inhaled budesonide produced significant improvement in markers of inflammation in inhaled corticosteroid-naive children that were correlated with reductions in use of as-needed β-agonist bronchodilators and improvements in asthma symptom scores and pulmonary function tests.

Pharmacokinetic Properties

The mass median aerodynamic diameter of the droplets in budesonide inhalation suspension is ≈3 to 5μm when the preparation is administered via jet nebuliser with compressor. In adults, the lung deposition of budesonide from the nebulised suspension was ≈15% of the nominal dose when delivered by 3 commonly used jet nebulisers. The systemic bioavailability of budesonide was 6% after a single 1000μg dose of budesonide inhalation suspension in children aged 3 to 6 years with persistent asthma; in adults, the systemic bioavailability of budesonide was 13%. The volume of distribution at steady state, terminal elimination half-life and clearance of budesonide were 3 L/kg, 2.3 hours and 32.2 L/h, respectively, in children and 2.7 L/kg, 2.3 hours and 80.4 L/h, respectively, in adults.

Therapeutic Use

In Children

Budesonide inhalation suspension has been evaluated in infants and young children aged 6 months to 8 years with symptomatic persistent asthma in 3 multicentre, randomised, double-blind, placebo-controlled, parallel-group trials. After 12 weeks of treatment, daytime and night-time asthma symptom scores, the primary efficacy variables in these studies, were significantly lower among infants and children treated with budesonide inhalation suspension 0.5 to 2 mg/day than among those receiving placebo. The number of days during which β2-agonist bronchodilators were required for breakthrough asthma symptoms was also reduced significantly in children treated with budesonide compared with placebo. In 1 study, in which all children were receiving inhaled corticosteroids prior to enrolment, the proportion of children who discontinued therapy because of worsening of asthma symptoms was significantly greater in placebo than budesonide 0.5 to 2 mg/day recipients.

Budesonide inhalation suspension 1mg twice daily significantly reduced the number of asthma exacerbations and the requirements for systemic corticosteroids in preschool children with severe persistent asthma in 2 small, randomised, double-blind studies.

Recent data indicate that budesonide inhalation suspension is significantly more effective than nebulised sodium cromoglycate in improving control of asthma symptoms in young children with persistent asthma.

In randomised trials, nebulised budesonide was as effective as or more effective than oral prednisolone in improving symptoms in children with acute asthma or wheezing.

Budesonide inhalation suspension is an effective and well tolerated alternative to systemic corticosteroids in children with mild to severe croup. The formulation, given as a 2 or 4mg single dose, was more effective than placebo and as effective as oral dexamethasone 0.6 mg/kg in alleviating croup symptoms and reducing the duration of hospital stay in several studies. In 1 small study, budesonide inhalation suspension was as effective as nebulised L-epinephrine 4mg in young children with moderately severe croup.

Several published studies with budesonide have failed to demonstrate a beneficial effect on the symptoms of acute bronchiolitis or the prevention of post-bronchiolitic wheezing during the 6-month to 1-year period after treatment. Two-year follow-up results from arecently published prospective, nonblind study suggests that administration of budesonide inhalation suspension during and for 2 months after respiratory syncytial virus-bronchiolitis may reduce the development of subsequent respiratory symptoms. Double-blind studies with long term follow-up (≥2 years) are needed to confirm these results.

In very low birthweight infants (median birthweight 805g) born prior to 30 weeks of gestation, nebulised budesonide 0.5mg twice daily for 14 days significantly reduced overall requirement for corticosteroids and facilitated discontinuation of mechanical ventilation compared with placebo. There was, however, no significant difference in supplemental oxygen requirements at 28 days of age between the 2 groups in this randomised, double-blind study.

In Adults

Improvements in asthma control were significantly greater in patients with asthma during treatment with budesonide inhalation suspension 2 or 8 mg/day than inhaled budesonide 1.6 mg/day administered by a metered dose inhaler plus spacer device in a randomised, double-blind, crossover study. Greater improvements in morning and evening peak expiratory flow and greater reductions in as-needed β2-agonist use occurred in patients during treatment with budesonide 8 mg/day than budesonide via metered dose inhaler. Greater increases in evening peak expiratory flow rates were documented during treatment with a lower dosage of budesonide inhalation suspension (2 mg/day) than budesonide via metered dose inhaler in this 4-week crossover study.

High dosages of fluticasone propionate via metered dose inhaler provided greater improvements in asthma control than budesonide inhalation suspension 2 or 4 mg/day in a randomised, nonblind, multicentre, crossover trial. Morning peak expiratory flow rates increased by a significantly greater extent after switching from nebulised budesonide 2 or 4 mg/day to inhaled fluticasone propionate 2 mg/day. There were, however, no differences in the number of 24-hour symptom-free intervals during 4 weeks of treatment with fluticasone propionate or budesonide inhalation suspension. Systemic effects on hypothalamic-pituitary-adrenal axis function were not quantified in this study.

Several small studies suggest that budesonide inhalation suspension has an oral corticosteroid-sparing effect in some adults with persistent asthma. The mean dosage of prednisolone was reduced by 59% (from 12.6 mg/day) in 55% of patients after 12 weeks’ treatment with budesonide inhalation suspension 2 mg/day in a noncomparative study.

Nebulised budesonide may be as effective as oral corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). In a randomised, double-blind, multicentre study, forced expiratory volume in 1 second increased by a similar amount in 188 hospitalised patients with acute exacerbations of COPD during 3 days’ treatment with budesonide inhalation suspension 2mg every 6 hours or oral prednisolone 30mg every 12 hours. Both active treatments were significantly more effective than placebo in increasing post-bronchodilator forced expiratory volume in 1 second.

Tolerability

Budesonide inhalation suspension was generally well tolerated in clinical studies in infants and children. The frequency of adverse events was similar in children receiving budesonide inhalation suspension 0.25 to 2 mg/day or placebo in 12-week studies. Growth velocity was generally unaffected in children who had prior exposure to inhaled corticosteroids during 3 nonblind 52-week studies in which patients received budesonide inhalation suspension 0.5 to 1 mg/day or standard asthma care. Children with persistent asthma who were not using inhaled corticosteroids prior to receiving budesonide inhalation suspension experienced a small but significant decrease in growth velocity compared with those who received standard asthma care. There was no evidence of hypothalamic-pituitary-adrenal axis suppression after 12 weeks’ double-blind and 52 weeks’ nonblind treatment with budesonide inhalation suspension.

In adults with oral and inhaled corticosteroid-dependent asthma, reduced dosages of oral prednisolone after the introduction of budesonide inhalation suspension for 12 weeks resulted in the resolution of systemic adverse events in 24% of patients, and reduced the overall incidence of purpura, moon face, skin thinning and weight gain.

Dosage and Administration

In the US, budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in children aged 12 months to 8 years. In children receiving treatment with inhaled bronchodilators and/or inhaled corticosteroids, the recommended initial dosage is 0.5 mg/day. In those receiving oral corticosteroids, a higher initial dosage (1 mg/day) is recommended. The maximum recommended dosage in children is 0.5 mg/day in those previously receiving bronchodilators and 1 mg/day in those who were receiving inhaled or oral corticosteroids.

In the UK and elsewhere, budesonide inhalation suspension is indicated for use in children and adults with asthma. The recommended dosage in infants and children aged 3 months to 12 years with asthma is 1 to 2 mg/day when starting treatment, during an asthma exacerbation or during withdrawal of oral corticosteroids; maintenance doses are typically 50% lower than the starting dose. In adults and children aged >12 years, the starting dosage of budesonide inhalation suspension is 2 to 4 mg/day, although higher doses may be necessary in very severe cases of asthma.

In children with croup the usual dose of budesonide inhalation suspension is 2mg given as a single inhalation or as two 1mg doses 30 minutes apart.

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  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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