Budesonide. An updated review of its pharmacological properties, and therapeutic efficacy in asthma and rhinitis.

DRUG EVALUATION

Drugs 44 (3): 375-407. 1992 0012-666 7/92/0009-0375/$16.50/0 © Adis International Limited. All rights reserved. DRE1116

Budesonide

An Updated Review of its Pharmacological Properties, and Therapeutic Efficacy in Asthma and Rhinitis Rex N. Brogden and Donna McTavish Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: P.J. Barnes, Department of Thoracic Medicine, Royal Brompton Hospital, London, England; N.J. Gross, Departments of Medicine and Molecular Biochemistry, Stritch-Loyola School of Medicine, Hines, Illinois, USA. E. Juniper, Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Center, Hamilton, Ontario, Canada; L.c. Laursen, Bispebjerg Hospital, Kobenhavn, Denmark; S. Lorlfntzson, Vardcentralen, Almhult, Kungsgatan, Sweden; L.G. Olson, Sleep Disorders Centre, Royal Newcastle Hospital, Newcastle, New South Wales, Australia, B. Pedersen, University Hospital of Aarhus, Department of Respiratory Diseases, Aarhus, Denmark; J.H. Toogood, Allergy Clinic, Victoria Hospital, London, Ontario, Canada; A.S. Vathenen, Regional Cardiothoracic Centre and Respiratory Unit, Killingbeck Hospital, Leeds, England.

Contents 376 378 379 379 379 380

381 381 382 382 383 384 384 384 385 385 385 385 386 36 386 387 387

387 387 388

Summary I. Pharmacodynamic Properties 1.1 Topical Glucocorticoid Activity 1.2 Anti-Inflammatory Effect 1.2.1 Effect on Inflammatory Cells and Mediators 1.2.2 ·Effect on Airway Hyperresponsiveness 1.3 Effect on Antigen-Induced Bronchial Reactivity 1.4 Effect on Exercise-Induced Asthma 1.5 Systemic Activity 1.5.1 Effect on Adrenal Function 1.5.2 Effect on Bone 1.5.3 Effect on Growth 1.6 Intranasal Budesonide 1.6.1 Effect on Nasal Allergen Challenge 1.6.2 Effect on Nasal Mucosa 2. Pharmacokinetic Properties 2.1 Absorption 2.2 Distribution 2.3 Elimination 2.3.1 Half-Life 3. Therapeutic Efficacy in Asthma 3.1 Influence of Frequency of Administration 3.1.1 Four Times Daily Versus Less Frequent Administration 3.1.2 Once Daily Administration 3.2 Effect of Delivery System 3.3 Comparisons with Corticosteroids

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388 389 391 392 392 393 395 395 395 396 396 398 398 398 398 399 399 399 399

400 400

4.

5.

6.

7.

3.3.1 Inhaled Budesonide Compared with Inhaled Beclomethasone Dipropionate 3.3.2 Inhaled Budesonide Compared with Oral Corticosteroids 3.4 Comparisons with Bronchodilators 3.5 Efficacy in Childhood Asthma and Persistent Wheezing 3.5.1 Comparisons with Other Drugs 3.5.2 Nebulised Budesonide 3.6 Studies of Effect on Lifestyle Therapeutic Efficacy in Rhinitis 4.1 Seasonal Allergic Rhinoconjunctivitis 4.1.1 Comparisons of Delivery Systems 4.2 Perennial Rhinitis 4.3 Nasal Polyposis Tolerability 5.1 Inhaled Budesonide 5.1 . 1 Local Effects 5.1.2 Miscellaneous Adverse Effects 5.2 Intranasal Budesonide Dosage and Administration 6.1 Asthma 6.2 Rhinitis Place of Budesonide in Therapy

Summary Synopsis Inhaled budesonide is now well established in the management of adult and childhood asthma. and when nebulised. shows considerable promise in recurrent wheezing and in severe asthma in infants. Studies conducted since the drug was previously reviewed in the Journal in 1984 have confirmed the comparable efficacy of equal doses of budesonide and beclomethasone dipropionate. the ability ofbudesonide to reduce oral maintenance corticosteroid requirements. and demonstrated its potential as first-line treatment of mild to moderate asthma. Recent studies have established the usefulness and good tolerability of intranasal budesonide in the treatment of seasonal allergic and perennial rhinitis where the drug is more effective than disodium cromoglycate and at least as effective as beclomethasone dipropionate. Afier up to 10 years of treatment with inhaled budesonide there is no evidence that the drug damages the tracheobronchial lining or the nasal mucosa. Inhaled corticosteroids continue to play an important role in the treatment of asthma with an increasing focus on their role as first-line therapy. and widespread clinical experience has shown budesonide is an effective and well tolerated member ofthis class which should be considered where inhaled or intranasal administration of a corticosteroid is indicated.

Pharmacodynamic Studies Budesonide has a high ratio of topical to systemic activity compared with reference corticosteroids such as beclomethasone dipropionate. In healthy volunteers, high doses of budesonide cause less depression of plasma cortisol urinary free cortisol excretion than equal dosages of beclomethasone dipropionate. The dosage of inhaled budesonide required to suppress fasting plasma cortisol levels in adults varies considerably between individuals. The adrenal suppressive effect of high dosages of inhaled corticosteroids may be reduced by mouth rinsing and use of a large volume spacer device which reduces oropharyngeal deposition and the amount swallowed. Several studies suggest that inhaled budesonide may affect biochemical markers of bone turnover less than similar dosages of beclomethasome dipropionate, and indicate that short term inhalation of budesonide has a less adverse effect on bone metabolism than dosages of oral pred-

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nisolone expected to exert a similar antiasthmatic effect. Long term studies are needed to determine if short term changes observed result in substantial loss of bone mass. Treatment with inhaled budesonide reduces T cell-mediated inflammation in bronchial wall, epithelial eosinophils and lymphocytes in lamina propria, released eosinophilic cationic protein in bronchoalveolar lavage fluid, and plasma leakage into tracheobronchial airways. Reduced numbers of inflammatory cells were present in lung biopsies from patients with asthma treated long term with inhaled budesonide. Regular inhalation of budesonide is associated with improved airway responsiveness and concomitant clinical improvement. Protection against bronchial hyperresponsiveness after corticosteroid withdrawal is dependent on the duration, and possibly the total dosage of corticosteroid treatment. Bronchial antigen challenge in asthmatic patients results in both an immediate and a delayed type of asthmatic reaction. The latter is prevented by acute inhalation of a corticosteroid but the immediate reaction, was historically thought to be unaffected by these drugs. However, the immediate reaction is now known to' be attenuated according to the dosage_and duration of inhaled corticosteroid. Similarly, exercise-induced asthma can be prevented by 3 or 4 weeks' treatment with inhaled budesonide, whereas a single dose is ineffective. The immediate reaction to nasal challenge is also inhibited only after 1 week ot: pretreatment with usual dosages of intranasal budesonide or beclomethasone dipropionate.

Pharmacokinetic Properties Following inhalation or intranasal administration of budesonide, peak plasma concentrations were reached within 15 to 45 minutes. Systemic bioavailability was 73%, which increased to about 100% after instillation of an alcohol (ethanol) solution directly onto nasal mucosa, compared with 10.7% after oral administration, where there was evidence of extensive first-pass metabolism. Volume of distribution of budesonide is about 300L. The concentration of budesonide in lung tissue 1.5 to 4 hours after inhalation of a single 1600~g dose was 15.5 nmoI7h compared with 0.63 nmol/L in plasma at the same time. The major metabolic pathway, 16a, 17a-acetal cleavage, is unique to budesonide among the topical corticosteroids and may increase the overall rate of inactivation. The relatively short elimination half-life following inhalation (about 2 hours) and high plasma clearance (83.7 L/h) highlight the rapid elimination of budesonide.

Therapeutic Efficacy Studies published since the previous review ofbudesonide in the Journal confirm the generally similar efficacy of equal dosages of budesonide and beclomethasone administered by inhalation to adult patients with chronic asthma. These studies also confirm that individualised dosages of budesonide can be substituted for systemic corticosteroids in at least 40 to 50% of patients, often along with an improvement in pulmonary function or symptomatic control, particularly in those patients treated with prednisolone 5 to 7.5mg daily for less than 5 years. Long term treatment of newly diagnosed asthma patients with either inhaled budesonide 12oo~g daily or terbutaline 750~g daily showed the inhaled corticosteroid to be more effective in increasing peak expiratory flow rate (PEFR) and in reducing symptoms, bronchial hyperreactivity and supplemental P2adrenoceptor agonist use. Inhaled budesonide 200 and 400~g daily were better tolerated and tended to be more effective than individually titrated dosages of slow release theophylline on the basis of changes in PEFR and supplemental P2-agonist requirements. These results and the finding that budesonide 400 and 800~g daily improved control of asthma when substituted for oral P2-agonists and/or theophylline, indicate that budesonide may fie an effective first-line treatment for patienfs with mild asthma. The optimum frequency of administration of inhaled budesonide in patients whose asthma was either stable or unstable remains the subject of debate, but in clinical practice it is usually administered twice daily. Initial studies comparing a recently introduced inspiratory flow-driven dry powder inhaler with a ptdssurised inhaler plus a large volume cone spacer suggest that the new delivery system is at least as ,effective as traditional systems, causes less cough immediately after inhalation and is prefeI!ed by patients.

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In the treatment of persistent wheezing in children aged less than 3.5 years, budesonide was effective when inhaled via a large volume spacer fitted with a facemask, but optimum dosage has to be determined individually. Studies in older children reported inhaled budesonide 200 to 400ltg daily to be of similar efficacy to oral prednisolone 10mg, and an equal dose of beclomethasone dipropionate when administered using the same delivery system, and more effective than disodium cromoglycate 8mg daily. Nebulised budesonide from a suspension containing a high concentration of the drug was consistently effective in improving control of childhood severe asthma in anecdotal reports and nonblinded trials, but results of double-blind trials have not always demonstrated superiority over placebo. Further studies are needed to determine optimum dosage via this delivery method and to assess the effect on growth and adrenal function. Intranasal budesonide 400ltg daily used to treat seasonal allergic rhinitis was as at least as effective as the same dose ofbeclomethasone dipropionate, more effective than disodium cromoglycate in relieving nasal symptoms and more effective than oral terfenadine or a single intramuscular injection of methylprednisolone in relieving nasal symptoms. Patients with perennial rhini~is have also been successfully treated with intranasal budesonide, which was more effective than alternative treatments, as have those with recurrent nasal polyposis.

Tolerability Generally budesonide is well tolerated at usual therapeutic dosages, with local effects such as hoarseness (dysphonia), sore throat and local irritation causing cough being reported most commonly. At dosages of 800ltg daily inhaled budesonide does not depress plasma cortisol levels, but individual sensitivity to the adrenocortical suppressive effect of inhaled corticosteroids varies. Initial data indicate no adverse effect on growth and weight gain among children treated for 1 year with inhaled budesonide 200 to 400ltg daily, but the effects of higher dosages are not known. Biopsy specimens from lung mucosa and upper respiratory tract tissues of patients treated with inhaled budesonide for up to 10 years showed reduced numbers of inflammatory cells and no evidence of atrophy after 7 to 15 months. Intranasal budesonide 400ltg daily is well tolerated with infrequent local adverse effects and rare reports of contact allergy.

Dosage and Administration The inhaled dose ofbudesonide for the treatment of asthma in adults should be individualised. The recommended initial dose is 400 to 1600 ltg/day divided into 2 or 4 administrations. Usually 200 to 800 ILg/day is suitable for maintenance but the lowest dose that leaves the patient symptom free should be used. In children with asthma the recommended dose is 200 to 400 ltg/day, divided into 2 or 4 administrations. In treatment of rhinitis the dosage is 400 ILg/day, which can be instilled into each nostril morning and evening or once daily in the morning. Once a good response has been achieved, this dosage can be halved.

Sincebudesonide was previously reviewed in the Journal (Clissold & Heel 1984) clinical experience with the drug has greatly increased, necessitating review of the more recent data, and reassessment of the role of inhaled corticosteroid therapy in the management of asthma in adults and children. This review concentrates on the literature published since 1984 and provides only a brief overview of some pharmacodynamic properties, discussing in more detail only those areas expanded by relatively recent data.

more detail only those areas expanded by relatively recent data.

1. Pharmacodynamic Properties Budesonide, a nonhalogenated glucocorticosteroid derivative structurally related to l6a-hydroxyprednisolone, has a high ratio of local anti-inflammatory to systemic activity, which enables inhalation or intranasal administation oftherapeu-


tically effective dosages in patients with asthma or rhinitis with minimal systemic glucocorticoid effects. 1.1 Topical Glucocorticoid Activity

The topical activity ofbudesonide as evidenced by the human skin vasoconstriction' assay was established in the previous review (Clissold & Heel 1984). In brief, budesonide is more potent than beclomethasone dipropionate, betamethasone valerate, desonide, flunisolide, hydrocortisone butyrate and the acetonidf~s offluocinolone, prednacinolone and triamcinolone (Brattsand et al. 1982a,b; Gruvstad & Bengtsson 1980; Johansson et al. 1982a,b,c). In healthy volunteers, the systemic glucocorticoid activity of budesonide, as determined by changes in plasma cortisol and total or differential white blood cell count, was 2 to 4 times less than that ofbeclomethasone dipropionate following oral administration. However, following inhalation the difference in systemic activity of the 2 drugs was less pronounced (Johansson et al. 1982c; LOfdahl et al. 1984). 1.2 Anti-Inflammatory Effect 1.2.1 Effect on Inflammatory Cells and Mediators Evidence that asthma is associated with airway inflammation has been provided by various methods including bronchoalveolar lavage (BAL), and recently several studies have demonstrated that exposure to, or treatment with, budesonide reduces inflammatory cells in BAL fluid from patients with asthma. In vitro, budesonide caused phenotypic changes within alveolar macrophages obtained by BAL (Marianayagam et al. 1990) and reduced IgE-dependent histamine release from human leucocytes (Bergstrand et al. 1986), possibly by interacting directly with the basophils (Bergstrand et al. 1984), and inhibited monocyte mediated cytotoxicity (Brattsand et al. 1991). Eosinophil survival and activation is stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and budeson-

379

ide has also been shown to inhibit eosinophil survival (Cox et al. 1991) as well as GM-CSF production in vitro, and to increase activity of neutral endopeptase (Borson & Gruenert 1991), an enzyme known to degrade inflammatory mediators. Airway biopsies obtained from patients with mild asthma (mostly atopic) before and after treat~ ment with budesonide 400ILg daily for 4 weeks (Jeffery et al. 1992) or 800ILg daily for 6 months (Burke et al. 1992) revealed reduced T cell-mediated inflammation in bronchial wall (reductions in T cells, memory T cells, dendritic cells and HLA-DR expression) [Burke et al. 1992] and reduced mucosal numbers of mast cells, eosinophils and foci of eosinophil degranulation (Jeffery et al. 1992). Budesonide was more effective in this respect than terbutaline but neither short nor long term treatment with inhaled corticosteroids reduced thickening of the reticular basement membrane (Jeffery et al. 1992). A marked increase in bronchial epithelial eosinophils has been shown to accompany any increase in asthma symptoms and bronchial reactivity (Laitinen et al.' 1991a). Improved spirometry in 7 patients with mild asthma after 3 months' treatment with inhaled budesonide 600ILg twice daily was associated with a decrease in epithelial eosinophi1s and lymphocytes, and mast cells and lymphocytes in lamina propria significantly greater than that achieved after treatment of a parallel group with terbutaline 375ILg twice daily (Laitinen et al. 1991 b). No relationship between airway hyperreactivity to histamine and BAL cell composition in patients with asthma was found by Adelroth et al. (1990) but the percentage of eosinophils was higher in asthmatic patients than in healthy volunteers, and released eosinophilic cationic protein (ECP, an eosinophil-derived cytotoxic protein) in serum and BAL was increased in a subgroup of! patients who had been treated occasionally with inhaled bronchodilators. Treatment of these patibnts with budesonide 400ILg daily for 4 weeks significantly decreased BAL-derived ECP. Reduct~on in serum ECP occurred with budesonide 800 to 1600ILg daily for 4 weeks (Venge et al. 1992; Wempe et al. 1991),

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but not with bambuterol 20mg daily (Wempe et al. 1991), or budesonide 400/Lg daily or theophylline until after 6 months' treatment (Venge et al. 1992). Administration of inhaltld budesonide 800/Lg daily for 8 weeks to 12 healthy smokers with normal lung function did not change absolute or differential cell counts in BAL but reduced the proportion of epithelial cells. Fibronectin levels in BAL were decreased and levels of angiotensin converting enzyme increased, suggesting an effect on the synthesis and/or release of these ploducts by alveolar macrophages (Bergstrand et al. 1990). The proportion of low density eosinophils in peripheral blood (Evans et al. 1991; O'Connor et al. 1991) or of total blood eosinophils (Kraan et al. 1988) in patients with asthma was significantly reduced by treatment with inhaled budesonide 1600/Lg daily for 14 days and 800/Lg daily for 8 weeks, respectively. Glucocorticosteroids inhibit stimulation of inflammatory cells in intrinsic asthma (Persson 1989) as well as allergen-induced effects. Plasma exudation across airway endothelial-epithelial barriers may be a cardinal sign of an ongoing inflammatory process (Persson 1988) and budesonide has been shown to reduce plasma leakage into tracheobronchial airways. Reduced levels of albumin, IgG and ceruloplasmin in BAL fluid and decreased bronchial reactivity to histamine in II patients with intrinsic asthma followed 2 months' treatment with budesonide 400/Lg daily, indicating reduced permeability of the airway epithelium (Jansen et al. 1986). Biopsies obtained from lung mucosa of 6 patients with asthma treated for 10 years with inhaled budesonide or beclomethasone dipropionate 200 to 800/Lg daily showed reduction in inflammatory cells to a level present in volunteers without asthma. Epithelial changes were also less pronounced than at the start of treatment (Lundgren et al. 1988). 1.2.2 Effect on Airway Hyperresponsiveness

Airway hyperresponsiveness in asthma develops as part of a complex inflammatory process (O'Byrne 1986), and is characterised by an in-

Before

treatment

246

8

Weeks 01 treatment

Fig. 1. Effect of 8 weeks' treatment with inhaled budesonide 200!,g daily (light bars) or 800!'g daily (darker bars) on the mean concentration of inhaled methacholine required to produce a fall in FEY I of 20% (PC20) in 30 patients with allergic asthma (after Kraan et al. 1988).

creased sensitivity as well as an increased maximal response to a variety of bronchoconstrictor stimuli (e.g. Barnes 1989; Holgate et al. 1987), both of which can be demonstrated by distinct changes in the dose-response curve to inhaled. histamine or methacholine. Regular inhalation of corticosteroids by steroiddependent asthmatics was shown to be associated with improvement in airway responsiveness (Juniper et al. 1982). This has been confirmed more recently (Juniper et al. 1990a) and also demonstrated in patients with non-steroid-dependent asthma (Juniper et al. 1990b; Kraan et al. 1988; fig. I). The mean improvement in airway responsiveness with inhaled budesonide 400 /Lg/day in 29 patients with mild stable non-sterbid-dependent asthma was 4-fold relative to placeb9, but the rate and extent of improvement varied b~tween patients (Juniper et al. 1990b). The improve~ent in airway responsiveness tended to be dose-rel~!ed in patients already steroid-dependent (Juniper e,t al. 1990b) as well as in those not steroid-dependent (Juniper et al. 1990b; Kraan etal. 1988), and ~as associated


with improvement in clinical asthma severity (Juniper et al. I 990a,b), but airway responsiveness was not influenced by usual dosages of the Ih-adrenoceptor agonist terbutaline (Kerrebijn et al. 1987; Kraan et al. 1985). Short courses of inhaled budesonide 800 to 1200~g daily reduced airway responsiveness to methacholine, sodium metabisulphite and methacholine preceded by leucotriene D4 in healthy volunteers (Bel et al. 1989), and to adenosine-5'monophosphate in patients with asthma (O'Connor et al. 1991). The duration of reduced bronchial hyperresponsiveness induced by inhaled budesonide after withdrawal of the corticosteroid, depends on the duration, and possibly total dosage, of corticosteroid treatment. Thus, the protective effect of budesonide disappeared 3 days after withdrawal in children treated for 2 months with 600~g daily and after I week in adults treated with 1600~g daily for 6 weeks (De Baets et al. 1990; Yathenen et al. 1991), whereas it persisted for up to 3 months after withdrawal in patients treated for I year with 400~g daily (Juniper et al. 1991). 1.3 Effect on Antigen-Induced Bronchial Reactivity Bronchial antigen challenge results in both an immediate and a delayed asthmatic reaction in many patients, and although early studies (Breslin et al. 1973; Pepys et al. 1974) indicated that only the delayed reaction was prevented by acute inhalation of a corticosteroid, it was later shown that like bronchial hyperreactivity, the immediate reaction is also attenuated according to the dosage and duration of inhaled corticosteroid treatment (Dahl & Johansson 1982). Bronchial hyperreactivity to inhalation of histamine in patients with allergic asthma was decreased by treatment with budesonide 400 to 600 ~g/day for 6 to 8 weeks (De Baets et al. 1990; Kraan et al. 1985; Molema et al. 1989), whereas terbutaline 2mg daily (Kraan et al. 1985) and disodium cromoglycate 8mg daily (Molema et al. 1989) had little effect. Administration of budesonide 1600~g

381

daily for 6 weeks reduced bronchial reactivity to histamine, eucapnic dry air hyperventilation and exercise (Yathenen et al. 1991), while short courses of budesonide 1200~g daily were without effect against bronchoconstriction induced by platelet activating factor in healthy volunteers (O'Connor et al. 1990). Long term administration of budesonide 1200 to 1600~g daily for 8 to 12 weeks had no significant effect on lung function, the dose of histamine required to produce a 20% decrease in forced expiratory volume in 1 second (FEY]) [PC20 histamine] or citric acid cough threshold, in nonallergic smokers with chronic obstructive lung disease (Auffarth et al. 1991; Watson et al. 1992). However, the improved symptom score for dyspnoea and a trend towards improvement in FEY 1 with budesonide relative to placebo, suggest that a longer period of treatment in such patients may demonstrate a positive influence of inhaled corticosteroid (Auffarth et al. 1991) as previously shown in some patients with chronic obstructive lung disease treated with budesonide 800 to 2000~g daily for a mean of 2 years (Selroos 1988). Administration of budesonide 800 or 1600~g for 6 or 12 weeks failed to improve airway reactivity to histamine or ventilatory capacity in patients with chronic bronchitis (Engel et al. 1989a, Wesseling et al. 1991), although statistically significant (but limited) effects on respiratory impedance were demonstrated (Wesseling et al. 1991). 1.4 Effect on Exercise-Induced Asthma Historically, inhaled corticosteroids were generally considered to be ineffective in attenuating exercise-induced asthma (Weinberger et al. 1981), but more recent investigations have shown that budesonide, when administered for 3 to 8 weeks, reduces the decrease in FEY 1 caused by exercise in susceptible patients (Henriksen 1988; Henriksen & Dahl 1983; Ostergaard & Pedersen 1986; Yenge et al. 1990), whereas a single dose was ineffective (Dimadi et al. 1989; Yenge et al. 1990). In 14 children, inhaled budesonide 200~g twice daily for 3 weeks reduced the mean exercise-in-

382

duced decrease in FEV 1 from 45 to 17% (Henriksen 1985). In 30 children (Ostergaard & Pedersen 1986) and 22 adults (Molema et al. 1989), 6 or 8 weeks' treatment with inhaled budesonide 400JLg daily was more effective than disodium cromoglycate in protecting against an exercise-induced decrease in lung function. When budesonide 400JLg daily for 4 weeks was combined with terbutaline 32.5JLg, the exercise-related reduction in FEV 1 was attenuated by 84%, whereas the attenuation was 30 and 51 %, respectively, with the same dose of terbutaline or budesonide alone (Henriksen & Dahl 1983). Similarly in adults with exercise-induced· bronchoconstriction, the post-exercise decrease in FEV 1 was reduced to < 50% of pretreatment values in 67% of 13 patients treated for 4 weeks with inhaled budesonide 1000JLg daily, and from 27% to 9% after 6 weeks' treatment with 1600JLg daily (Vathenen et al. 1991). In contrast this level of protection was provided by a single 1000JLg dose of budesonide in only 17% of these patients (Venge et al. 1990). 1.5 Systemic Activity

1.5.1 Effect on Adrenal Function Inhaled doses of 200 to 3200JLg of budesonide and beclomethasone dipropionate cause dose-related suppression of plasma cortisol levels with the latter drug being significantly more suppressive in healthy volunteers (Johansson et al. 1982b). In patients with asthma, however, both budesonide and beclomethasone dipropionate generally had a similar effect on adrenal function when administered in equal dosages to adults (Ebden & Davies 1984) or children (Prahl 1991; Prahl & Jensen 1987; Prahl et al. 1987). Inhalation ofbudesonide 1600JLg dry powder and beclomethasone dipropionate 1000JLg daily via a spacer caused similar suppression of plasma cortisol when followed by mouth rinsing without swallowing (Selroos & Halnie 1991). In a crossover study in 30 children treated with equal dosages ofbudesonide or beclomethasone dipropionate, urinary excretion of free cortisol was significantly higher with budesonide, with the difference being more pronounced in children treated

Drugs 44 (3) 1992

with 1000 to 1200 JLg/day than in those receiving 900JLg daily (Pedersen & Fuglsang 1988). A trend towards a greater suppression of unstimulated diurnal production of steroids with dosages of up to 800JLg daily of beclomethasone dipropionate for 4 weeks than with equal dosages of budesonide in 41 children with asthma, was also reported by Bisgaard et al. (1988). The lack of significant depression of urinary free cortisol during 8 weeks' treatment with budesonide 800JLg daily was confirmed in 33 children subsequently treated by these investigators (Bisgaard et al. 1991). Thus, there are no significant differences between the drugs with respect to their effects on the hypothalamic-pituitary-adrenal axis at low dosages, but at higher dosages (> 1000 JLg/day) budesonKle showed less systemic activity than beclomethasone dipropionate. Large volume spacer devices have been introduced in an attempt to increase intrapulmonary deposition of inhaled corticosteroid and reduce oropharyngeal complications of high doses by decreasing oral deposition of the drug (Newman et al. 1984). In children with asthma receivingbudesonide or beclomethasone dipropionate at dosages of 2100 to 3300 JLg/1.73m 2 body surface via a conventional pressurised inhaler, urinary excretion of free cortisol increased significantly when the same dose was administered via a large volume spacer device incorporating a one-way valve. The change from a conventional inhaler did not result in a significant increase in urinary free cortisol excretion in children receiving either corticosteroid at dosages ranging from 1575 to 1850 JLg/1.73m 2 (Prahl & Jensen 1987). Similarly, the inhalation device used did riot influence urinary free cortisol in 30 children treated with budesonide or beclomethasone at a mean dosage of 900 JLg/day for 6 weeks (Pedersen & Fuglsang 1988). Whether a decrease or increase in systemic glucocorticoid activity occurs on changing from a conventional inhaler to one incorporating a spacer depends not only on the delivery device but also on how the patient uses it. Efficient use of the spacer may slightly increase the systemic effect of the inhaled steroid (Toogood et al. 1984b). The importance of interindividual variations in


the sensitivity to the adrenocortical suppressive effect of inhaled corticosteroids has been shown in children and adults treated with either budesonide and beclomethasone dipropionate or budesonide alone (Gordon et al. 1987; Prahl 1991). In a crossover study in 16 children treated with the same individualised dosage of budesonide or beclomethasone dipropionate via a large volume spacer device for 6 weeks (range 500 to 1800 Jig/day), both drugs had the same negligible effect on fasting morning plasma cortisol levels in 3 patients, while a significant decrease was caused by beclomethasone dipropionate in 3 patients and by budesonide in 2 others (Prahl 1991). The dosage of inhaled budesonide (via a large volume spacer device) required to decrease the fasting morning plasma cortisol level to < 300 nmol/L on 2 consecutive occasions 2 weeks apart in 9 adults, varied considerably. Adrenal suppression occurred in none of the patients at a dosage of 1600 Jig/day, in half at 4000 Jig/day and in all but 1 at 7200 Jlg/day (Gordon et al. 1987). In 9 asthmatic children budesonide 800 Jig/m 2 daily did not significantly affect plasma cortisol or response to adrenocorticotrophic hormone, but increased the ratio of serum insulin to blood glucose and high density lipoprotein (HDL) without altering HDL/total cholesterol ratio. However, metabolic effects were absent at a dosage of 400 Jlgjm 2 (Turpeinen et al. 1991). In a study in 34 adults with asthma, Toogood et al. (1989) concluded that on average inhaled budesonide ~ 1840 Jlg/day/70kg adult exhibited systemic effects (morning serum cortisol and blood eosiniphil count) equivalent to prednisone ~ 15mg administered each morning. However, the level of systemic glucocorticoid activity produced by the dose of budesonide required to control symptoms of asthma was consistently much lower than that produced by the dose of prednisone required to achieve an equivalent antiastllmatic effect in the same patient. 1.5.2 Effect on Bone The short term effects of medium to high dosages of inhaled budesonide (using a large volume cone spacer) on biochemical markers of bone turn-

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over have been studied in healthy volunteers and compared with those of inhaled beclomethasone dipropionate, and with oral prednisolone, at dosages expected to exert a similar systemic effect, rather than producing an equivalent therapeutic effect in the treatment of chronic asthma. Inhaled budesonide at daily doses of up to 3200Jlg had no net effect on several biochemical markers of bone turnover and resorption including intestinal absorption of calcium, serum calcium levels, serum alkaline phosphatase levels, urinary hydroxyproline: creatinine ratio, or levels of vitamin D metabolites or parathyroid hormone (Ali et al. 1991; Hodsman et al. 1991; Jennings et al. 1991a,b; Nadeau et al. 1985; Toogood et al. 1988). In investigations designed to avoid any confounding effects of previous or current corticosteroid treatment, inhaled budesonide 400 to 1600Jlg twice daily and oral prednisolone 5 to 40mg once daily decreased plasma osteocalcin and calcitonin levels (although prednisolone had a more pronounced effect). Unlike prednisolone which decreased alkaline phosphatase levels, budesonide had no effect on this marker, as shown in other studies (Jennings et al. 1991a). While both drugs increased renal phosphate reabsorption and serum phosphate concentration, the increase was more marked with prednisolone (Jennings et al. 1991b). Urinary calcium excretion was increased and renal reabsorption of calcium decreased by prednisolone, whereas budesonide increased renal loss of calcium during the day but was associated with hypocalcuria at night and thus had little effect on 24-hour urinary calcium loss (Jennings et al. 1991 b). Budesonide had less effect on urinary hydroxyproline: creatinine ratio than beclomethasone (Ali et al. 1991; Jennings et al. 1990) but, the effect ofbudesonide and prednisolone on this index of bone resorption did not differ significantly in the healthy volunteers studied by Jennings et al. (1991a). In a comparison of beclomethasone dipropionate and budesonide 800 and 2400Jlg daily, both drugs caused a dose-related decrease in serum osteocalcin and alkaline phosphatase but budesonide had significantly less effect than beclomethasone dipropionate (Jennings et al. 1990).

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Inhalation ofbudesonide 1200 and 2400 ",g/day (twice daily schedule) via a large volume spacer each for 4 weeks, significantly decreased serum osteocalcin, particularly at the higher dosage, but did not increase hydroxyproline output in 30 to 40 healthy volunteers. The magnitude of the inhibition on serum osteocalcin production was reduced by once daily administration in the morning, but it is not clear whether this constitutes a clinically significant advantage (Toogood et al. 1991). Neither 1200 nor 2400",g budesonide daily affected 8am urinary calcium or 24-hour urinary phosphate (Toogood et al. 1991). High dosages of inhaled budesonide (2400 ",g/ day) for 7 days have been reported to suppress the adrenocortical production of androstenedione and dihydroepiandrosterone in 10 healthy adults, with the lowest levels occurring in 4 postmenopausal women (Toogood et al. 1988). Budesonide 800 and 2500JLg daily appear to have less effect on dihydroepiandrosterone levels than an equal dose of beclomethasone dipropionate in healthy volunteers (Jennings et al. 1990). Since these androgens constitute the substrate on which such women depend for their supply of estrogen, and estrogen deficiency is a major risk factor for osteoporosis, it has been suggested that postmenopausal women receiving high-dose inhaled corticosteroid therapy for asthma should also receive an estrogen supplement (Toogood 1989). Thus, short term studies in healthy volunteers suggest that inhaled budesonide has a less adverse effect on bone metabolism than oral prednisolone, and less effect on indicators of bone reabsorption and mineralisation than therapeutically equivalent dosages ofbeclomethasone dipropionate. Long term prospective clinical trials in patients with a~thma taking inhaled corticosteroids are required to determine whether the short term biochemical changes observed translate into substantial loss of bone mass.

1.5.3 Effect on Growth In a double-blind placebo controlled trial in preadolescent mildly asthmatic children, inhaled budesonide 200 to 800",g daily caused a dose-related

reduction of growth velocity, but doses of 200 and 400JLg daily had no clinically relevant effect on lower leg growth measured by knemometry (Wolthers & Pedersen 1991). Uncontrolled studies of the effect of 12 months' treatment with inhaled budesonide 200 to 400JLg daily (via a tube extension or spacer) on height and weight gain in children 3.5 to 16 years of age, have reported that height and weight did not deviate significantly from that expected (Ribeiro 1987; SchUller 1985; Varsano et al. 1990). To dilte there are no studies of the effect on growth of the higher dosage of budesonide (2000 ",g/day) administered by nebuliser to younger children with severe asthma (see section 3.5.2), but it would seem prudent to routinely monitor growth during inhaled corticosteroid use. During treatment with nebulised budesonide 200JLg daily, and 3 months after the last oral dose of prednisolone, 24-hour integrated plasma cortisol and growth hormone levels were close to normal in a 2-year old boy treated for severe asthma (Godfrey et al. 1987). Further ~long term follow-up to assess the effect of budesonide on growth beyond puberty and adrenal function is required in view of the reported adrenal suppression and growth retardation in a few children treated with inhaled beclomethasone dipropionate at dosages of up to 800JLg daily (Littlewood et al. 1988; Priftis et al. 1991; Wales et al. 1991), or inhaled budesonide 800JLg daily (Wolthers & Pedersen 1991). 1.6 Intranasal Budesonide

1.6.1 Effect on Nasal Allergen Challenge Initial studies with beclomethasone dipropionate 200",g indicated that the immediate reaction to nasal challenge was not inhibited by 2 days' pretreatment (Pelikan & Pelikan-Filipek 1982), but longer periods of pretreatment with budesonide or beclomethasone (1 week) inhibit pollen-induced allergic type 1 reactions (Pipkorn 1982; Vilsvik et al. 1975). In contrast, 14 days' intranasal treatment with budesonide 1600JLg daily had little effect on the early response to intranasal ragweed challenge while decreasing reactivity to histamine (Small et

385


al. 1990). Treatment with budes.onide 400~g daily f.or 1 week ab.olished the allergen-induced increase in specific and n.onspecific (histamine) nasal reactivity at rechallenge (Anderss.on et al. 1988, 1989). The late reacti.on specific reactivity was als.o reduced by a single 200~g d.ose administered 2 h.ours bef.ore rechallenge and by ibuprofen 600mg 8-h.ourly beginning 24 h.ours bef.ore initial challenge, suggesting inv.olvement .of cycl.o-.oxygenase metab.olites in nasal reactivity (Klementss.on et al. 1990). The mechanism(s) .of the clinical effect .of intranasal c.ortic.osteroids in allergic rhinitis are still unkn.own but d.oes n.ot appear t.o be due t.o vas.oc.onstricti.on (Bende et al. 1983, Lindqvist et al. 1989), .or alterati.on .of (1:- .or /1-adren.ocept.or sensitivity .or muc.ociliary transp.ort .of n.ormal nasal muc.osa (Lindqvist et al. 1989). F.oll.owing the .observati.on .of decreased nasal muc.osal histamine c.ontent and IgE-mediated histamine release after treatment with intranasal budes.onide f.or 1 week (Pipk.orn & Anderss.on 1982), it was suggested that c.ortic.osteroids may induce a decrease in the mast cell histamine p.o.ol, p.ossibly via inhibiti.on .of the intracellular synthesis .of histamine (Pipk.orn & Enerback 1987). The allergen-pr.ov.oked late increase in nasal lavage ECP c.ontent was inhibited by 2 weeks' pretreatment with budes.onide 400~g daily as was the prechallenge ECP c.oncentrati.on (Bisgaard et al. 1990) alth.ough pretreatment f.or 2 days did n.ot alter levels .of ECP (Anderss.on et al. 1989). Nevertheless, a mechanism .of acti.on in decreasing nasal reactivity may be inhibiti.on .of the increase in this cyt.ot.oxic protein. An.other suggested mechanism in patients with mild allergic rhinitis is attenuati.on .of plasma exudati.on and generati.on .of plasma-derived mediat.ors, since treatment with budes.onide 400~g daily reduced nasal lavage .levels .of bradykinins and fibrin.ogen (Svenss.on et al. 1991).

1.6.2 Effect on Nasal Mucosa N.o hist.opath.ol.ogical changes in the nasal muc.osa were detected in 24 patients with perennial rhinitis treated intranasally with budes.onide 200 t.o 400~g daily f.or peri.ods .of up t.o 5.5 years (Pipk.orn et al. 1988).

2. Pharmacokinetic Properties The pharmac.okinetic pr.operties .of budes.onide have been studied f.oll.owing .oral and intraven.ous administrati.on, inhalati.on and nasal instillati.on. Studies in adults have inv.olved .only healthy v.olunteers; the pharmac.okinetic properties .of budes.onide in children after intraven.ous injecti.on and inhalati.on were studied in patients with asthma. 2.1 Abs.orpti.on In the .original review by Cliss.old and Heel (1984) the systemic bi.oavailability .of budes.onide f.oll.owing .oral administrati.on was 10.7%; since 73% .of the d.ose reaching the lung was systemically available, extensive first-pass metab.olism was suggested. Systemic availability .of inhaled budes.onide may be increased by using a large v.olume spacer c.ompared with a standard metered d.ose inhaler (T.o.og.o.od 1988; T.o.og.o.od et al. 1984), but has als.o been rep.orted t.o decrease (Prahl "& Jensen 1987). Peak plasma c.oncentrati.ons are attained within less than 1 h.our .of inhalati.on. After instillati.on .of [3H]budes.onide 100~g diss.olved in alc.oh.ol (ethan.ol) directly.on t.o the nasal muc.osa in healthy v.olunteers, peak plasma c.oncentrati.ons were reached after 15 t.o 45 minutes. Systemic bi.oavailability was ab.out 100% indicating little .or n.o metab.olism .of the drug during abs.orption through the nasal muc.osa (Edsbacker et al. 1985). In 6 children with asthma, intraven.ous administrati.on .ofbudes.onide 500~g .or inhalati.on .of 100~g (aeros.ol with a tube spacer) resulted in higher plasma c.oncentrati.ons .of the 22S epimer than the 22R epimer (rati.o 1.2 t.o 1.4). Systemic bi.oavailability .of the Sand R epimers was 30 and 25%, respectively, after aeros.ol inhalati.on with a large v.olume spacer but was ab.out 15% when administered as a suspensi.on via a nebuliser (Pedersen et al. 1987). 2.2 Distributi.on The v.olume .of distributi.on .of unchanged budes.onide was rep.orted as 301 L with distributi.on .of the m.ore hydroph.obic epimer 22R (424L) being

386

greater than that of epimer 22S (245L; Ryrfeldt et al. 1982, 1984). Findings were similar in children with asthma: volume of distribution of epimers 22R and 22S was 4.8 and 3.1 L/kg, respectively (Pedersen et al. 1987). Studies in perfused rat lung and trachea models have shown budesonide to have a high affinity for lung and airway tissue (Ryrfeldt et al. 1989; data on file, Astra Draco) and these findings are supported in patients. The mean concentration of budesonide in the lung tissue of II patients undergoing thoracotomy 1.5 to 4 hours after inhalation ofa single dose of 1600llg of the drug was 5.5 nmolj L. Mean plasma concentration was 0.63 nmoljL at about the same time (van den Bosch et al. 1989; data on file, Astra Draco). 2.3 Elimination Budesonide has a high ratio of topical to systemic activity compared with other corticosteroids (see section 1.1). This d~fference probably depends on a more rapid rate of biotransformation of budesonide in the liver as has been shown in in vitro studies reviewed by C}issold and Heel (1984). Such findings have led to the conclusion that budesonide undergoes extensive first-pass hepatic metabolism (Anderson et al. 1982a,b; Brattsand et al. 1982b; Ryrfeldt et al. 1982, 1989). The major metabolic pathway of budesonide, 16a, 17a-acetal cleavage is unique to budesonide among the topical corticosteroids. This biotransformation is catalysed by microsomal mono-oxygenases and proceeds via hydroxylation and subsequent rearrangement to an intermediary ester. The ester is cleaved by hydrolysis to 16a-hydroxyprednisolone and butyric acid (Edsbacker et al. 1987). The latter authors suggested that the acetal cleavage of budesonide increases the overall rate of inactivation and so reduces the risk of systemic side effects. 2.3.1 Half-Life

Total plasma clearance of unchanged budesonide was calculated to be 83.7 L/h (Ryrfeldt et al. 1982), while that of the 22R and 22S epimers was 117 and 68 L/h, respectively (Ryrfeldt et al. 1984).

Drugs 44 (3) 1992

A similar difference in clearance between the Rand S epimers was also noted in children with asthma (2.0 and 1.5 L/h/kg, respectively) [Pedersen et al. 1987], with these values indicating that total plasma clearance in children is about 50% higher than in adults. As established in the original review, recovery of an inhaled dose of budesonide was 41 % in the mouth or inhaler, 32% in the urine and 15% in the faeces. Unchanged budesonide accounted for none or only trace amounts of the total recovered within the first 24 hours (Ryrfeldt et al. 1982, 1984). Plasma half-lives of unchanged budesonide, epimer 22R and 22S were 2.8, 2.7 and 2.7 hours, respectively, after intravenous administration (Ryrfeldt et al. 1982; 1984). A similar (2h) half-life for unchanged budesonide was reported after inhalation (Ryrfeldt et al. 1982).

3. Therapeutic Efficacy in Asthma Clissold and Heel (1984) reviewed the efficacy of budesonide mostly in comparison with equal dosages of beclomethasone dipropionate administered by the same route. More recent studies have confirmed the similar efficacy of these drugs, the superiority of budesonide over placebo, and established in large numbers of patients that inhaled budesonide can be substituted completely for orally administered prednisone or prednisolone in at least 40 to 50% Of patients dependent on systemic corticosteroids for control of their asthma symptoms, without any loss of symptomatic control. Short term studies conducted before 1984 indicated similar effibcy with budesonide inhaled 2 or 4 times daily. More recent longer term trials comparing the relative efficacy of twice and 4 times daily regimens have been conducted in an attempt to delineate optimum frequency of administration. New delivery methods have been developed and comparisons of conventional metered dose inhalers and the more recently introduced dry powder breath-actuated device point to patient preference for, and improved local tolerability of, the newer delivery system. There have also been several studies in children


with asthma. Budesonide has been compared with equal dosages of beclomethasone dipropionate, oral prednisolone in Thai children, and disodium cromoglycate in children with asthma or recurrent wheezing. The efficacy of nebulised budesonide from suspensions containing high concentrations has been studied in infants and young children with severe asthma. 3.1 Influence of Frequency of Administration 3.1.1 Four Times Daily Versus Less Frequent Administration The optimum frequency of administration of inhaled corticosteroids remains a subject of debate despite results from several studies comparing the efficacy and adverse effects of, usually, 4 times daily and twice daily administration. Early studies ofbudesonide addressing this question reviewed previously (Clissold & Heel 1984) have also produced varying results. Some reported that twice daily inhalation was as effective as 4 times daily administration in patients with stable asthma (Nyholm et al. 1984; Stiksa et al. 1982), while others involving patients with unstable asthma (Dahl & Jo~ hansson 1982) or both stable and unstable asthma (Toogood et al. 1982), reported better control of the disease with the 4 times daily dose regimen. All of these studies have been short term (2 to 4 weeks per dose regimen) and of crossover design, thus increasing the likelihood of carryover effects. More recent studies oflonger duration and parallel group design favoured 4 times daily administration in patients whose asthma was either stable (Malo et al. 1989) or unstable (Jenkins et al. 1990), although a short term study in patients with stable asthma reported budesonide 800,ug daily to be similarly effective whether administered once daily, or in 2, or 4 divided doses (Stiksa & Glennow 1985). Thus, in 2 parallel groups of 18 patients with stable moderate to severe asthma whose treatment with beclomethasone dipropionate was replaced with the same daily dose ofbudesonide (800 to 1600,ug daily) administered in 2 or 4 divided doses, efficacy was better with 4 times daily inhalation (Malo et al. 1989). Reflected in the improved symptomatic

387

control (fig. 2), the 4 times daily dosage regimen was associated with fewer relapses requiring oral prednisone over the 6 months of the study. Improved patient compliance has been a stated advantage of reduced dose frequency, but has seldom been measured (Toogood 1985), and in the 6-month study of Malo et al. (1989) compliance, as judged by weighing the aerosol canisters, was equivalent in both groups. In some patients whose asthma is stable and of moderate severity, reduced frequency of administration provides control for a few weeks to a few months. It does appear that twice daily budesonide is less effective than 4 times daily inhalation of the same total daily dose over a period of 6 months in patients with stable moderate to severe asthma, but in clinical practice the majority of patients are successfully treated with twice daily inhaled budesonide and in patients with mild to moderate asthma control has been maintained with once daily administration (section 3.1.2). 3.1.2 Once Daily Administration Recent studies of the relative efficacy of once and twice daily administration of budesonide dry powder delivered by inspiratory flow-actuated inhaler indicate that both regimens are comparable in improving peak expiratory flow rate (PEFR) and reducing asthma symptoms when the same daily dose (400,ug daily) is inhaled as a single dose morning or evening, or in 2 divided doses in patients with mild to moderate stable asthma (data on file, Astra Draco).

3.2 Effect of Delivery System Inhalation of budesonide using a small or large volume spacer device has previously been shown to augment the airway response to the drug in patients with labile moderate airway obstruction (as evidenced by the improved FEV 1 relative to that achieved with a standard inhaler) and to reduce the level of candidiasis (Toogood et al. 1984a,b) [section 5.1.1], although as might be expected, no advantage over a standard actuator was evident in mildly obstructed patients (Reiser et al.

Drugs 44 (3) 1992

388

1986). Following the recent introduction of an inspiratory flow driven dry powder inhaler (that delivers budesonide without carrier powder, fluorocarbons or lubricants), studies comparing the efficacy of budesonide inhaled with this device compared with that achieved using a conventional inhaler plus a 750ml cone spacer, reported improved morning PEFR (Engel et al. 1989b; Damste et al. 1989), reduced frequency of cough (Engel et al. 1989b) and greater patient preference (Boe et al. 1992; Engel et al. 1989b; Hetta et al. 1989; Sinninghe et al. 1989; Tjwa 1990) with the dry powder inhaler. In patients with mild to moderate asthma symptoms budesonide 400JLg once daily via a dry powder inhaler was superior to placebo in increasing PEFR, alleviating symptoms (Campbell et al. 1991; Lee et al. 1991) and reducing i32-agonist use (Cam pbell et al. 1991). Nebulised budesonide 2 to 8mg daily has also been used to treat adults whose asthma was not adequately controlled using a metered-dose inhaler. Efficacy was dose-related and superior to that achieved with 1600JLg daily from the conventional inhaler in a double-blind crossover study (Bisgaard 1989), while in an uncontrolled trial, nebulised bu-

3.3 Comparisons with Corticosteroids 3.3.1 Inhaled Budesonide Compared with Inhaled Beclomethasone Dipropionate Double-blind crossover studies in generally small numbers of patients with chronic asthma of varying severity conducted since the earlier review of budesonide in the Journal (Clissold & Heel 1984) have confirmed that budesonide and beclomethasone dipropionate are of similar efficacy when administered in equal, or approximately equal, dosages by inhalation via a press uri sed aerosol (table I). High dosages of budesonide (1600 JLg/day) and beclomethasone dipropionate (1500 JLg/day) were compared by Ebden et al. (1986) who found budesonide to reduce daytime wheeze symptoms and daily bronchodilator use more than beclomethasone, but the effect of the drugs on lung function

o Twice daily • Four times daily

2000

..'"

desonide improved lung function and reduced prednisolone requirements and hospital admissions for acute exacerbations in 18 patients with steroid-dependent severe asthma (Otulana et al. 1992).

p

>.

U

C Q)

1600

,c::.

'~

0.

(5

~

C

1200

*

E

c. ~

::l

c: (ij

(5

800

6

{:::

I-

*

t:=/

,c::.

400

Dayllme asthma

Nocturnal asthma

Daytime cough

Noctumal cough

f

..

Disability

Fig. 2. Total number of patient days of asthma symptoms during treatment with inhaled budesonide 800-1600 /Lg/day administered twice or 4 times daily in a total of 36 patients with stable moderate to severe asthma studied for 6 months; • = p < 0.0001 (after Malo et al. 1989).


389

Table I. Summary of results of short to medium term double-blind crossover therapeutic trials comparing the efficacy of budesonide (Bud) and beclomethasone dipropionate (BDP) in adult patients with chronic asthma

Reference

Boe et al. (1989)C Ebden et al. (1986) Keelan et al. (1984) Rafferty et al. (1985)

No. of patientsa

Duration of treatment b (weeks)

Total daily dosage (frequency of administration) Bud

4

400l'g (bid) 800l'g (bid)

400l'g (bid) 1OOOl'g (bid)

26

6

1600l'g (bid)d

1500l'g (bid)

28

4

400l'g (qid)

400l'g (qid)

14-16

400l'g (qid)

Overall efficacy

PEFR, diary cards .suppl. bronchodilators PEFR, FEV1, FVC, diary cards PEFR, FEV1, diary cards PEFR, FEV1, FVC, diary cards, supp. bronchodilators

Bud"'" BDP

BDP

100

26

Assessment criteria

400l'g (qid)

Bud

~

BDP

Bud"'" BDP BDP

~

Bud

a Number of patients who completed the trial. b Duration of treatment with each active regimen. c Placebo-controlled multicentre study. d Administered via a tube spacer. Abbreviations and symbols: bid = twice daily; co = crossover; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PEFR = peak expiratory flow rate; qid = 4 times daily; suppl. = supplementary; Bud"'" BDP signifies that both drugs were of similar efficacy; Bud ~ BDP indicates a tendency towards better efficacy with budesonide; BDP ~ Bud indicates a trend towards better efficacy with beclomethasone dipropionate.

and adrenal function did not differ. Patients were receiving beclomethasone dipropionate at an average dosage of 890~g daily before the trial but there was no clear advantage in increasing the dosage of inhaled corticosteroid. Patients studied in crossover fashion by Keelan et al. (1984) were receiving beclomethasone dipropionate 400~g daily in addition to bronchodilators at the start of the trial. PEFR increased significantly in the group treated with budesonide 400~g (lOO~g 4 times daily) during the first 4 weeks of the trial, but the higher baseline pEFR in the group treated with. beclomethasone suggested that this group was optimally treated, leaving little scope for improvement. It is well established that inhaled corticosteroids, including budesonide, can be substituted for part or whole of maintenance oral corticosteroid requirements in patients dependent on systemic steroids for management of their asthmatic symptoms, without diminution of the quality of symptomatic control (see section 3.3.2). The relative 'prednisolone sparing' efficacy of

400~g daily (100~g 4 times daily) of either budesonide or beclomethasone dipropionate was studied by Rafferty et al. (1985). The reduction in the dosage of prednisolone (2.65mg) during adminstration of beclomethasone dipropionate was significantly greater than that achieved during treatment with budesonide (1.8mg) although effects of the drugs on lung function and bronchodilator requirements were similar and the difference in their ability to facilitate prednisone withdrawal not clinically important.

3.3.2 Inhaled Budesonide Compared with Oral Corticosteroids It is now widely accepted that inhaled cortico-

steroids such as budesonide are an effective substitute for oral steroids in patients with relatively severe steroid-dependent chronic asthma whether oral steroids are administered daily or on alternate days. Adrenal function usually improves when inhaled corticosteroids are substituted for daily oral steroids at dosages providing an equivalent or bet-

Drugs 44 (3) 1992

390

ter degree of antiasthmatic response (see section 1.2). Thus, it appears clinically appropriate to substitute high dosages of inhaled corticosteroids for oral steroids in patients with severe asthma rather than continuing to treat them systemically (Toogood et al. 1989). It was shown by Adelroth et al. (1985) that budesonide could be substituted for prednisolone in patients dependent on systemic steroids. Subsequent long term studies in which inhaled budesonide 1600ILg daily has been added to existing therapy, including oral prednisolone/prednisone before a gradual reduction in dosage of the oral steroid, have confirmed that systemic steroids could be completely withdrawn in 40 to 50% of patients (Adelroth et al. 1985; Laursen et al. 1986). Over a 2 -year period, Adelroth et al. (1985) were able to substitute inhaled budesonide 800 to 1600ILg daily (via a tube spacer) for oral prednisolone, 5 to 15mg daily or 5 to 20mg on alternate days in 18 of the 36 patients who completed the study (fig. 3). Previous attempts to reduce the dosage of prednisolone in these patients had failed, indicating that patients were receiving about the minimum effective dose

of oral steroid at the start of the study. About half the ultimate reduction in prednisolone dosage was achieved during the first 3 months of budesonide therapy and withdrawal was complete after about 6 months. Withdrawal of oral steroid was most readily achieved in patients receiving alternate day therapy, those on low dosages and in patients treated with prednisolone for < 5 years (fig. 4). Similar results were reported by Laursen et al. 1986) in patients requiring generally high dosages of oral prednisone. Prestudy attempts to reduce the dosage of oral steroid had failed. However, the mean dosage of prednisone was decreased from 13.9 to 8.5 and 14 to 6.5mg after 15 weeks' therapy with inhaled budesonide 400 and 1600ILg daily, respectively, via a large volume spacer. During the subsequent 36 weeks, complete withdrawal of oral prednisone was achieved in 18 (40%) of 45 patients treated with inhaled budesonide 1600ILg daily, and 1 year after completion of the study, mean dosage of prednisone was 4mg and 40% of patients still required no oral steroids. Mean plasma cortisol increased after substitution of budesonide for oral prednisone, 31 and 63% of patients had a normal

o Nil o 2.5mg

4

5.0mg .7.5mg .10.0mg

fA

C Q> .~

a.

a

3

.2i

E :>

z

5mg (10)

7.5mg {7l

10mg (13)

15mg (1 )

Pretrial daily dosage of prednisolone (number of patients)

Alternate day

5·20mg

(5)

Fig. 3. Dosages of prednisolone required to control asthma before and after 2 years' treatment with inhaled budesonide 800 to 1600!,g daily in 38 adult patients with steroid-dependent chronic asthma (after Adelroth et al. 1985).

391


o 100% reduction .;;'50% • for symptoms Bud > BOP for PEFR Bud == BOP

Bud 400"g +Tb 2000"g Tb 2000"g + placebo Bud via large spacer, Tb via small spacer

8 (d, r, pi)

PEFR, symptoms, bronchial hyperresponsiveness, diurnal variation

Bud + Tb > Tb for nocturnal PEFR, wheeze, bronchial hyperresponsiveness

Bud 400"g OSCG 8mg both MOl

8 (db, r, pi)

PEFR, bronchial hyperresponsiveness, exercise-induced asthma

Bud > OSCG for PEFR, exerciseinduced asthma Bud == OSCG for bronchial hyperresponsiveness

Number of patients completing study. Bud > indicates that the efficacy of budesonide was statistically significantly greater than that of the comparative regimen for the criteria indicated; Bud == indicates equivalent changes were produced by budesonide and the comparative regimen. Abbreviations: co = crossover; db = double-blind; MOl = metered dose inhaler; pc = placebo-controlled; PEFR = peak expiratory flow rate; pi = parallel; r = randomised.


ported that nebulised budesonide 2000,ug daily was superior to placebo in reducing the requirement for oral prednisolone, whereas Van Bever et al. (1990) found no significant differences between budesonide. 1000,ug daily and placebo in 23 children aged 3 to 17 months with severe asthma. The reason for the different findings in these studies is not clear, but could possibly be associated with the lower dosage used by Van Bever et al. (1990) in severely affected patients or the use of different nebuliser equipment (Newman et al. 1988). 3.6 Studies of Effect on Lifestyle The effect on quality of life of augmenting existing bronchodilator therapy with inhaled budesonide 400 or 800,ug daily was studied in 2 large nonblinded multicentre trials involving over 3100 evaluable general practice patients with mild to moderate asthma (Gay et al. 1989; Nankani et al. 1990). Existing therapy provided less than optimum control of asthma symptoms; the addition of inhaled budesonide improved mean PEFR, alleviated asthma symptoms and reduced bronchodilator requirements in both studies. The effect of treatment with budesonide on lifestyle was assessed by self-administered questionnaire covering broad aspects of sleep quality and daytime activity. 'Quality of life' was reported to be improved after 4 weeks' treatment with budesonide 400 or 800,ug daily inhaled with or without a spacer. The usual clinical and laboratory measures used to assess drug effect on lifestyle provide only crude estimates of the effect of treatment on quality of life (Ganz 1990) which require more complex validated scales of assessment (Hyland et al. 1991) and since only a few aspects were assessed in these uncontrolled trials of budesonide, they are of limited value of life in patients with mild to moderate asthma.

4. Therapeutic Efficacy in Rhinitis The efficacy of intranasal budesonide in patients with seasonal allergic rhinitis or perennial rhinitis was evident at the time of the previous review in

395

the J oumal and has been confirmed by studies published since, as has the formerly demonstrated effect in improving symptoms and reducing polyp size in patients with recurrent nasal polyposis. 4.1 Seasonal Allergic Rhinoconjunctivitis Because of the spontaneous variation in the intensity of symptoms during periods of fluctuating atmospheric allergen levels, it is desirable that trials of any medication for controlling symptoms of seasonal allergic rhinoconjunctivitis should be controlled, conducted during a period when daily pollen counts indicate risk of exposure, and of parallel group design. Studies comparing budesonide with other treatments were of parallel group design, although not all obtained pollen counts during the study. Entry to the trials was mostly based on a history of seasonal allergic rhinitis and positive skin prick tests rather than the more reliable nasal provocation test. Since there is no proven simple and reliable objective method of measuring the severity of allergic rhinoconjunctivitis symptoms at clinic visits, reliance is placed on subjective assessment of changes in severity as recorded by the patients on daily diary cards, on patient preference and on the requirement for supplementary antiallergic drugs. Nasal peak inspiratory flow rate has been used as a measure of nasal airway resistance in a few studies. It has recently been shown that the clinical effect ofbudesonide in patients with seasonal allergic rhinitis is dependent on local nasal application, oral administration being ineffective (Lindqvist et al. 1989). Comparisons with placebo have confirmed the superiority of intranasal budesonide' over placebo in relieving nasal symptoms (blockage, discharge and sneezing) in adults (Pedersen et al. 1990) and children (WoIthers & Pedersen 1990), and studies comparing budesonide with various other treatments have also been conducted. In the study of Pedersen et al. (1990), intranasal administration of budesonide 400,ug twice daily from a 750ml spacer fitted with a nozzle was more effective than placebo in relieving both nasal and bronchial symp-

Drugs 44 (3) 1992

396

toms in 30 patients with allergic rhinitis and asthma. On the basis of alleviation of nasal symptoms and overall efficacy (table IV), intranasal budesonide 200~g twice daily was at least as effective (McArthur & Higgins 1988) or more effective than beclomethasone dipropionate (Vanzieleghem & Juniper 1987), superior to disodium cromoglycate 26 or 31.2 mg/dayadministered 5 or 6 times daily in relieving nasal symptoms (Bjerrum & Illum 1985; Fisher & Higgins 1988; Salomonsson et al. 1986), at least as effective as a single 80mg intramuscular injection of a depot preparation of methylprednisolone acetate (Pichler et al. 1988), and better than terfenadine 120mg daily orally (Ramsdale & Kline 1990). In one comparison of intranasal budesonide and beclomethasone (Vanzieleghem & Juniper 1987), patients were instructed to use their allocated treatment as required to control symptoms. The clinical potency ofbudesonide was greater than that of beclomethasone dipropionate in that fewer applications of budesonide were required to control nasal symptoms based on recorded use. Drug use indicated from canister weights showed more favourable results with budesonide. In an interesting comparison of intranasal budesonide administered during the ragweed pollen season and a course of hyposensitisation injections administered during the 6 weeks before the season, blinding was difficult to maintain because of local reaction to the allergen injection, but the investigator who performed the assessments remained blinded (Juniper et al. 1990a). Since the study aimed to compare the 2 different approaches to treatment, an 'intention to treat' analysis was used. However, only 14 of the 30 patients allocated to the allergen injections received the full course, and the group may have benefited more had all patients been able to complete the course of 4 injections (Juniper et al. 1990a), although it is doubtful that this study can be considered an appropriate test of the potential therapeutic activity of immunotherapy (JH Toogood, personal communication). . Budesonide 400~g once daily in the morning was as effective as 200~g twice daily in reducing total )

daily nasal symptom score and was preferred by patients (Ross et al. 1991). Generally, as expected, budesonide and the comparative treatment regimen provided little benefit against eye symptoms. However, eye symptoms were significantly alleviated by budesonide relative to disodium cromoglycate in the study of Bjerrum and IlIum (1985) and appeared to be better controlled by budesonide than oral terfenadine in patients treated by Ramsdale and Kline (1990). However, pollen counts were not performed by Bjerrum and Illum (1985) and since the severity of eye symptoms is not clear in either study, there may have been a pretreatment difference in eye symptom severity in the treatment groups.

4.1.1 Comparisons of Delivery Systems The standard metered-dose pressurised intranasal device has been compared with an aqueous suspension nasal pump (Irander et al. 1984) and a more recently introduced device which delivers pure budesonide powder when actuated by nasal inspiration (Pedersen et al. 1991). In the latter study, 112 patients were allocated to receive budesonide powder 400 or 800~g, budesonide aerosol 400~g or placebo once daily in the morning. There were no statistically significant differences between the aerosol and either dose of the powder (Pedersen et al. 1991) or between an aqueous suspension and an aerosol (Irander et al. 1984) with respect to changes in nasal symptoms, supplemental antiallergic drug requirements, overall efficacy or nasal peak inspiratory flow. Active preparations were more effective than placebo for these criteria but not in alleviating eye symptoms. Dose-related efficacy was noted by Irander et al. (1984) with the '400~g twice daily dosage being more effective thllD half this dosage; in contrast, Pedersen et al. (1991) found no difference between budesonide powder 800 or 400~g once daily, pointing to an optimum dose of 400~g daily. 4.2 Perennial Rhinitis Budesonide has been compared with placebo in children and adults with allergic perennial rhinitis, with intranasal beclomethasone dipropionate or

397


Table IV. Summary of studies comparing the therapeutic efficacy of intranasal budesonide (Bud) with that of intranasally administered beclomethasone dipropionate (BOP), or disodium cromoglycate (OSCG), systemic methylprednisolone acetate (MPA), oral terfenadine In or allergen injection therapy (AIT) in patients with seasonal allergic rhinoconjunctivitis Reference

No. of patients8 (design)

Daily dosage (formulation)

Duration Relative efficacy (weeks) nasal supplementary eye symptom symptom antiallergy score score drugs

Beclomethasone dipropionate McArthur & 3 88 Bud 400"g Higgins (1988) nb, pi BOP 300"g (ANS) 7 Vanzieleghem 56 Bud 50"g & Juniper db, r, pi per BOP (1987) actuation used as required (MOl) Disodium cromoglycate 3 Bjerrum & 42 Bud 400"g db, r, pi OSCG 26mg ilium (1985) Fisher & 56 Bud 4OO1L9 3 Higgins (1988) nb, pi OSCG 341.2mg 4 Salomonsson 42 Bud 400"g et al. (1986) db, r, pi OSCG 31.2mg Methylprednisolone acetate Pichler et al. 30 3 Bud 400"g db, r, pi MPA 80mg (1988). single 1M injection Oral terfenadine Ramsdale & 44 6 Bud 400"g Kline (1990) db, r, pi (ANS) T 120mg Simpson & 143 3 Bud 400"g Higgins (1988) db, r, pi, T 120mg Bud +T pc

Allergan injection therapy 57 Juniper et al. (1990) db, r, pi

Bud 400"g (ANS) AIT

7

Bud> BOP

Bud == BOP Bud

Bud> OSCG Bud> OSCG

~

BOP

overall efficacy

nasal overall airway tolerability resistance

Bud == BOP

Bud == BOP

Bud> BOP

Bud> BOP

Bud == OSCG

Bud> OSCG Bud == OSCG

Bud> OSCG

Bud == OSCG Bud == OSCG

Bud == MPA

Bud == MPA

Bud> OSCG

Bud

~

MPA

Bud == MPA

MPA

~

Bud

Bud> T

Bud

Bud == T == Bud +

~T

Bud+T> Bud or T

Bud> AIT Bud == AIT Bud> AIT

Bud + T > Bud or T

T

Bud + T == Bud

Bud AIT

==

a Number of patients who completed the study, except Juniper et al. (1990) who performed 'intention to treat' analysis. Abbreviations and symbols: ANS = aqueous nasal spray; db = double-blind; 1M = intramuscular; nb = nonblind; MOl = metered dose inhaler; pc = placebo-controlled; pi = parallel; r = randomised; Bud> indicates that the efficacy of budesonde was statistically significantly greater than that of the comparative regimen for the critria indicated; Bud ~ indicates a tendency for better efficacy with budesonide; Bud == indicates equivalent changes or tolerability were associated with each treatment.

Drugs 44 (3) 1992

398

flunisolide, and with oral terfenadine or astemizole. In 37 children with perennial symptoms of allergic rhinitis and concomitant asthma who were mouth breathers because of chronic nasal obstruction, intranasal budesonide 400~g daily for 4 weeks alleviated cough and wheeze, reduced asthma severity, mouth breathing, nasal obstruction and secretion, eosinophilia, nasal airway resistance and attenuated exercise-induced asthma (Henriksen & Wenzel 1984). However, there was no significant improvement in PEFR. In another comparison with placebo, intranasal budesonide 400~g daily significantly reduced nasal symptom scores in 57 children and 48 adults and the requirement for supplemental terfenadine in children. Objective assessment revealed a decrease in hypertrophy of the nasal conchae, oedema, secretion and obstruction (Day et al. 1990). Brief reports of crossover trials comparing intranasal budesonide 400~g daily with other intranasally administered corticosteroids have shown that budesonide is more effective than the same dosage of beclomethasone dipropionate in reducing the score for nasal blockage (McGivern et al. 1985; Synnerstad & Lindqvist 1985), sleep disturbance, and in increasing nasal PEFR (McGivern et al. 1985), and of similar efficacy to flunisolide 200~g daily (SipiHi & Sorri 1984). In a recent study involving 130 patients, budesonide 400~g daily alone or with oxymetazoline nasal drops added for the first 3 days of the 3-week study, was more effective than terfenadine 120 mg/day orally in relieving nasal symptoms. Budesonide/oxymetazoline provided the most rapid relief of nasal blockage (Lau et al. 1990). Budesonide 200~g twice daily for 4 weeks was more effective than astemizole lOmg once daily orally in alleviating nasal and eye symptoms in 69 adult patients (Bunnag & Jareoncharsri 1992). 4.3 Nasal Polyposis Recent placebo-controlled trials have confirmed that intranasal administration of budesonide 400 or 800~g daily for periods of 4 weeks or 6 months

results in improvement in symptoms, regression of polyp size and an increase in nasal peak inspiratory flow in patients with recurrent nasal polyposis (Hartwig et al. 1988; Ruhno et al. 1990). In both studies nasal symptoms. (obstruction score, discharge, itch) improved when budesonide was substituted for placebo in patients initially allocated to placebo treatment.

5. Tolerability 5.1 Inhaled Budesonide Generally, inhaled budesonide is well tolerated at usual therapeutic dosages in clinical trials, and long term studies have not shown any adverse events not expected from short term clinical experience with the drug. However, long term effects of medium to high (1600 to 2400~g daily) dosages of inhaled budesonide on bone composition have still to be determined (see section 1.5.2) as has the effect on the attainment of adult height in children treated long term. 5.1.1 Local Effects Local adverse effects most commonly associated with inhaled corticosteroids, including budesonide, include hoarseness (dysphonia), oropharyngeal candidiasis, stomatitis, sore throat, and local irritation causing cough. Dysphonia has been reported to be due to mucosal irritation caused by the freon propellants and drying action of the spray, although a bilateral adductor vocal cord deformity has also been observed which appeared to be caused by the active drug rather than the propellant (Williams et al. 1983). Dysphonia can be alleviated by reducing the amount of the inhaled steroid deposited around the larynx by decreasing the daily dosage or inhalation via a large volume spacer (Toogood 1990). Oropharyngeal candidiasis is an infrequent adverse effect of usual dosages of budesonide and other inhaled corticosteroids, but is more common with high dose therapy, particularly in patients receiving oral corticosteroids concomitantly. However, the incidence of candidiasis can be greatly reduced by decreasing the daily frequency of administration


from 4~ to 2 doses while maintaining the same daily dosage, or by use of a large or small volume spacer (Toogood et al. 1984), although thrush occurred with similar frequency in patients treated with 2 or 4 times daily budesonide over a period of 6 months in the study of Malo et al. (1989). Coughing on inhalation has been reported in a variable proportion of patients treated with a conventional budesonide metered dose aerosol, but initial studies suggest that cough is less of a problem with a dry powder inhaler than a pressurised metered dose inhaler (Engel et al. 1989b; Selroos et al. 1991). Systemic absorption of budesonide delivered from a dry powder inhaler can be reduced by mouth rinsing without swallowing, immediately after inhalation (Selroos & Halme 1991). In a large general practice trial of inhaled budesonide, local adverse effects· reported in 0.5 to 0.9% of the 1661 patients included throat/mouth irritation, dysphonia, and cough, while the overall rate of withdrawal due to adverse effects was 0.8% (Nankani et al. 1990). 5.1.2 Miscellaneous Adverse Effects Rarely reported adverse effects of clinical importance include severe bronchoconstriction in a patient following inhalation of budesonide aerosol or beclomethasone aerosol or dry powder (Poh & Wang 1986). As reported in the earlier review this also occurred in a patient whose pulmonary function decreased substantially after inhalation of both budesonide and its propellants, but was not adversely affected by beclomethasone dipropionate or betamethasone aerosol (McGivern & MacFarlane 1984). Acute adrenal insufficiency occurred in a 38-year-old man who had been treated with inhaled budesonide 4.8 mg/day for 4 months followed by 6.4 mg/day for 2 weeks before a reduction in dose to 3.2 mg/day over 2 weeks and to 2.4 mg after a further 6 weeks. He had also received intranasal beclomethasone dipropionate 200~g daily before the increase in dose of budesonide (Wong & Black 1992). Behavioural disturbances during treatment with inhaled budesonide have been reported in young children (2 to 5 years) treated with 800 to 1200~g

399

daily for periods of 2 days to 3 months (Connett & Lenney 1991; Lewis & Cochrane 1983), in a 9year-old boy treated with 200~g daily for a few days, and in his father 2 days after beginning treatment with budesonide 400~g daily (Meyboom & DeGraaf-Breederveld 1988). Hyperactive behaviour was the most frequent finding in the children, none of whom had a history of psychological disturbance. 5.2 Intranasal Budesonide At the usual dosage of 400~g daily, intranasal budesonide is well tolerated with adverse effects usually confined to nasal irritation causing sneezing immediately after use, nasal dryness, crusting, localised stinging, itching, nasal secretion and epistaxis during either short or longer term administration. Sneezing appears to be caused by the propellants used in the pressurised nasal spray, since a higher incidence has been reported in placebo recipients than in those treated with budesonide (Henriksen & Wenzel 1984). Newer preparations which deliver the active drug in aqueous suspension or as a dry powder also appear to be particularly well tolerated (Bhatia et al. 1991; Pedersen et al. 1991) with no apparent difference in tolerability when administered once or twice daily (Bhatia et al. 1991). Contact allergy to budesonide nasal spray on the nose and cheek or upper lip has been reported on rare occasions (Gamboa et al. 1991; Meding & Dahlberg 1986; Peris-Tortajada et al. 199 n. Crosssensitivity to other corticosteroids is rare (Gamboa et al. 1991; Noda et al. 1991), but a cross-reaction between budesonide and hydrocortisone butyrate has been reported (Dunkel et al. 1991). No histopathological changes in the nasal mucosa were detected in patients treated intranasally with budesonide for periods of up to 5.5 years (Pipkorn et al. 1988).

6. Dosage and Administration 6.1 Asthma The dosage ofbudesonide delivered by pres surised aerosol or as a dry powder, is individual. Initially it is normally 400 to 1600 ~g/day divided

400

into 2 or 4 administrations. The maintenance dosage is usually 200 to 800ILg daily and should also be individualised to the lowest dosage adequately controlling symptoms. In children the usual dosage is 200 to 400 ILg/day divided into 2 or 4 administrations. Administration via an inspiratory flowdriven dry powder device has been shown to be as effective as with a metered dose inhaler and a spacer when administered twice or once daily, and to be preferred by patients. Special care should be observed in patients with pulmonary tuberculosis, fungal infections of the airways, those transferring from systemic steroids, in pregnancy, and patients exposed to chicken pox. 6.2 Rhinitis The usual daily dosage in the treatment of seasonal and perennial allergic rhinitis is 400lLg. Dosage may be reduced to 200 ILg/day after a good response has been achieved. As with other corticosteroids the full effect of budesonide may not be apparent for a number of days and the patient must understand that the treatment is not intended for rapid relief and must be used regularly.

7. Place of Budesonide in Therapy Asthma, even when mild, is considered an inflammatory disease as has been demonstrated from studies of the cellular composition of bronchoalveolar lavage and endobronchial biopsies (Beasley et al. 1989; Jeffery et al. 1989; Laitinen et al. 1985). Airway hyperresponsiveness is now viewed as a secondary consequence of the inflammation that narrows the lumen anatomically and increases the responsiveness of neuromuscular control of airways through the action of the mediators of inflammation. Thus, treatment should be directed at reversing the underlying inflammation, not simply at relieving bronchospasm (Reed 1991). It has recently been recommended in a report on guidelines for diagnosis and management (National Heart and Blood Institute Information Center 1991) that the regimen for the treatment of patients with anything

Drugs 44 (3) 1992

more than mild occasional asthma should include an anti-inflammatory medication along with bronchodilators for symptomatic relief Following widespread clinical use over a period of several years, inhaled budesonide has become established as an effective and safe therapy for the management of moderate-to-severe asthma when used in conjunction with bronchodilators. Studies conducted since budesonide was previously reviewed in the Journal have confirmed that inhaled budesonide is of similar efficacy to an equal dose of inhaled beclomethasone dipropionate in adults and children with chronic asthma. Initial studies suggest that inhaled budesonide may be more effective than individually titrated doses of slow release theophylline, or oral bronchodilators and/or theophylline during short term administration in chronic asthma, and is also more effective than inhaled terbutaline during long term treatment of newly detected asthma, and there is evidence that inhaled budesonide at dosages greater than 800ILg daily has less effect on adrenal activity and bone metabolism than beclomethasone dipropionate. Short term studies in children with chronic asthma have shown inhaled budesonide 200 to 400ILg daily to be similar in efficacy to the same dosage of beclomethasone dipropionate, or prednisolone lOmg daily administered orally. Nebulised budesonide from a suspension containing a high concentration of the drug has been consistently effective in improving the control of severe asthma in infants and young children treated under nonblind conditions. However, results have varied in double-blind studies and more such studies are required. to determine the optimum dosage, efficacy, and effect on growth and adreljlal function of the higp. dosages (2000lLg daily) usually administered via a nebuliser, although short term linear growth in preadolescent mildly asthmatic children is not influenced by low dosages of 200 and 400ILg daily. Generally, inhaled corticosteroids have been used in adults in the management of asthmatic patients not adequately controlled by intermittently administered bronchodilators (usually inhaled .ih-agonists) with or without disodium


cromoglycate, or nedocromil sodium. However, since extensive inflammatory changes have been found in bronchial biopsy specimens from patients with mild asthma only, and since corticosteroids can suppress inflammatory processes, inhaled corticosteroids including budesonide are increasingly seen as fIrst-line therapy in the full spectrum of adult asthma patients. However, more data is required regarding the effect of inhaled budesonide and other corticosteroids on the attainment of adult height before these drugs can be recommended for the long term treatment of children with mild asthma, and further study is also needed on the effects of inhaled steroids in bone metabolism and the clinical implications of these effects in terms of possible risk of osteoporosis and fracture in elderly patients. Widespread use of intranasal budesonide over several years has shown that at a standard dosage of 400ILg daily it has become an established treatment for seasonal allergic rhinitis, perennial rhinitis and may be used as prophylaxis in patients with recurrent nasal polyposis. In the treatment of seasonal allergic rhinoconjunctivitis intranasal budesonide was at least as effective as beclomethasone dipropionate or a single intramuscular injection of methylprednisolone acetate, and more effective than disodium cromoglycate and oral terfenadine. Similarly, in patients with perennial rhinitis, intranasal budesonide was of similar efficacy to intranasal flunisolide, at least as effective as beclomethasone dipropionate administered by the same route and more effective than oral terfenadine. Widespread clinical experience has shown budesonide to be an effective and well tolerated treatment for asthma and rhinitis when administered by inhalation and intranasally, respectively. While the anti-inflammatory properties of available corticosteroid esters vary quantitatively, there is still no clear efficacy advantage for any of these drugs. However, pharmacodynamic studies indicate that budesonide has a more favourable ratio of antiasthmatic to systemic glucocorticoid activity than beclomethasone dipropionate and budesonide is

401

preferred where high dosages of inhaled corticosteroids are needed to control asthma.

References Adelroth E, Rosenhall L, Glennow C. High dose inhaled budesonide in the treatment of severe steroid-dependent asthmatics. Allergy 40: 58-64, 1985 Adelroth E, Rosenhall L, Johansson S-A, Liridon M, Venge P. Inflammatory cells and eosinophilic activity in asthmatics investigated by bronchoalveolar lavage. American Review of Respiratory Disease 142: 91-99, 1990 Ali NJ, Capewell S, Ward MJ. Bone turnover during high dose inhaled corticosteroid treatment. Thorax 46: 160-164, 1991 Andersson M, Andersson P, Pipkorn U. topical glucocorticosteroids and allergen-induced increase in nasal reactivity: relationship between treatment time and inhibitory effect. Journal of Allergy and Clinical Immunology 82: 1019-1026, 1988 Andersson M, Andersson P, Pipkorn U. Allerge-induced specific and non-specific nasal reactions. Acta Otolaryngologica 107: 270-277, 1989 Andersson P, Brattsand R, Edsbacker S, Kiillstriim L, Ryrfeldt A. Biotransformation rate (in vitro) and systemic potency (in vivo) of the topical glucocorticoid budesonide in male and female rats. Journal of Steroid Biochemistry 17: 703-706, 1982a Andersson P, Edsbiicker S, Ryrfeldt S, von Bahr C. In vitro biotransformation of glucocorticoids in liver and skin homogenate fraction from man, rat and hairless mouse. Journal of Steroid Biochemistry 16: 787-795, 1982b Auffarth B, Postma DS, de Monchy JGR, van der Mark ThW, Boorsma M, et al. Effects of inhaled budesonide on spirometric values, reversjbillity, airWay responsiveness, and cough threshold in smQRers with chronic obstructive lung disease. Thorax 46: 372-377, 1991 Baran D. A companson of inhaled budesonide and beclomethasone dipropionate:in childhood asthma. British Journal of Diseases of the Che~t,81: 170-175, 1987 Barnes PJ. New conCepts in the pathogenesis' of bronchial hyperresponsiveness'and asthma. Journal of Allergy and Clinical Immunology 83: ;1 013-1026, 1989 Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in' mild asthma and after bronchial provocation. American Review of Respiratory Disease 139: 806-817,1989 Bel EH, Yen Der V~en H, Dijkman JH, Sterk PJ. The effect of inhaled budesonide on the maximal degree of airway narrowing to leukotriene D4 and methacholine in normal subjects in vivol-3. American Review of Respiratory DiSease 139: 427-431, 1989 Bende M, Lindqvist N, Pipkorn U. Effect of a topical glucocorticoid, budesonide, on nasal mucosal blood flow as measured with I33Xe wash-out technique. Allergy 38: 461-464, 1983 Bergstrand H, BjprI)sson A, Lindquist B, Nilsson A, Brattsand R. Inhibitory effecti:or glucocorticosteroids on anti IgE-induced histamine relellse from human basophilic ledkocytes. Evidence for a dual mefhilnism of action. Allergy 39: 317-230, 1984 Bergstrand H, Bjiirtison A, Blaschke E, Brattsand R, Eklund A, et al. Effects ~f ~n inhaled corticosteroid, budesonide, on alveolar macropMIi:!:' function in smokers. Thorax 45: 362-368, 1990 " Bergstrand H, Limdqist B, Petersson B-A. The glucocorticosteroid, budesonidefpartially blocks histamine release from human lung tissl.te :~n vitro. Allergy 41: 319-326, 1986 Berube D, Spier Sj 'Lapierre G, Marcotte JE, Lamarre A. Effects ofbudesonide: ini'irifantile asthma. Abstract. American Review ofRespiratory;qlsease 141: A905, 1990 Bhatia M, Ross JRM, Taylor Md, Peers EM. Intranasal bu4e1

402

son ide once daily in seasonal allergic rhinitis. Current Medical Research and Opinion 12: 287-295. 1991 Bisgaard H. Gmnborg H. Hygind N. Dahl R. Lindqvist N. et a!. Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide. Journal of Allergy and Clinical Immunology 85: 891-895. 1990 Bisgaard H. Nebulised budesonide in adult asthmatics. Paper presented at a workshop on budesonide nebulising suspension. Zurich. January. 1989 Bisgaard H. Nielsen MD. Andersen B. Andersen P. Foged N. et a!. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. Journal of Allergy and Clinical Immunology 81: 1088-1095. 1988 Bisgaard H. Pedersen S. Damkjaer Nielsen M. Osterballe O. Adrenal function in asthmatic children treated with inhaled budesonide. Acta Paediatrica Scandinavica 80: 213-217. 1991 Bjerrum P. IlIum P. Treatment of seasonal allergic rhinitis with budesonide and disodium cromoglycate. Allergy 40: 65-69, 1985 Boe J. Rosenhall L, Alton M. Carlsson L-G, Carlsson U. et a!. Comparison of dose-response effects of inhaled beclomethasone dipropionate and budesonide in the management of asthma. Allergy 44: 349-355, 1989 Boe J, Stiksa G. Svensson K, Asbrink E. New method of evaluating patient preference for different inhalation delivery systems. Annals of Allergy 68: 255-260, 1992 Borson DB. Gruenert DC. Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. American Journal of Physiology 260: L83-L89. 1991 Bjerrum p. IlIum P. Treatment of seasonal allergic rhinitis with budesonide and disodium cromoglycate. Allergy 40: 65069. 1985 Brattsand R. Delander E-L. Petersn C. Wieslander E. Cytotoxicity of human phagocytes studied in vitro in a novel model based on neutral red absorption. Agents and Actions 34: 35-37. 1991 Brattsand R, Thalen A Roempke K, Kallstrom L, Gruvstad E. Development of new glucocorticoids with a very high ratio between topical and systemic activities. European Journal of Respiratory Diseases 63 (Supp!. 122): 62-73. 1982b Brattsand R, Thalen A. Roempke K. Kallstrom L. Gruvstad E. Influence of 16a-17a-acetal substitution and steroid nucleus fluorination on the topical and systemic activity ratio of glucocorticoids. Journal of Steroid Biochemistry 16: 779-786, 1982a Breslin ABX. Pepys J. Davies RJ. Hendrick DJ. Effect of beclomethasone dipropionate on antigen bronchial challenge in asthmatic patients. Australian and New Zealand Journal of Medicine 3: 324. 1973 Bundgaard A, Schmidt A. A comparison of oral slow release theophylline and inhaled budesonide in adult asthmatics. Atemwegs-und Lungenkrankheiten 16 (Supp!.): S36-S41. 1990 Bunnag C. Jareonscharsri P. A double-blind comparison of budesonide nasal spray and astemizole in patients with perennial rhinitis. Abstract. 2nd National Congress of the Indonesian Society for Allergy and Immunology and the 1st Asian Pacific Symposium on Allergy and Immunology, 1992 Burke C, Poulter LW, Norris A. Schmekal B. Effect of inhaled steroid therapy on bronchial immunopathology in asthma. Abstract. American Review of Respiratory Disease 141: A876, 1990 Burke C. Power CK, Norris A, Condez A. Schmekel B, et a!. Lung function and immunopthological changes after inhaled corticosteroid .therapy in asthma. European Respiratory Journal 5: 73-79, 1992 Campbell LM, Watson DG, Venables TL, Taylor MD, Richardson PDI. Once daily budesonide turbohaler compared with placebo as initial prophylactic therapy for asthma. British Journal of Clinical Research 2: 111-122. 1991 Clissold SP, Heel RC. Budesonide. A preliminary review of its pharmacodynamic properties and therapeutic efficac in asthma and rhinitis. Drugs 28: 485-518. 1984

Drugs 44 (3) 1992

Connett G, Lenney W. Inhaled budesonide and behavioural disturbances. Lancet 338: 634-635. 1991 Cox G, Ohtoshi T. Vancheri C. Denburg JA, Dolovich J. et a!. Promotion of eosinophil survival by human bronchial epithelial cells and its modulation by steroids. American Journal of Respiratory Cell and Molecular Biology 4: 525-531, 1991 Crowe M. Gay AL, Keelan P. Prednisolone sparing effect of high dose budesonide aerosol in the management of chronic systemic steroid dependent asthmatics. Irish Medical Journal 79: 39-41, 1986 Dahl R. Johansson s-A. Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction. European Journal of Respiratory Diseases 63: 167-175. 1982 Dahl R, Pedersen B, Hgglof B. Nocturnal asthma: effect of treatment with oral sustained-release terbutaline. inhaled budesonide, and the two in combination. Journal of Allergy and Clinical Immunology 83: 811-815, 1989 Damste's D, Oostinga HP, Heeringa A. Inhaled budesonide administered via turbohaler or via pressurized metered dose inhaler in patients with bronchial asthma. Rovaniemi Seminar June 15-17. 1989 Day JH. Andersson CB. Briscoe MP. Efficacy and safety of intranasal budesonide in the treatment of perennial rhinitis in adults and children. Annals of Allergy 64: 445-450. 1990 De Baets FM. Goeteyn M. Kerrebijn KF. The effect of two months of treatment with inhaled budesonide on bronchial responsiveness to histamines and house-dust mite antigen in asthmatic children. American Review of Respiratory Disaease 142: 581-586. 1990 de Jongste Jc. Duiverman EJ. Nebulised budesonide in severe childhood asthma. Correspondence. Lancet: 1388. 1989 Dimadi M, Lammers J-WJ. van Herwaarden CLA. Effects ofnedocromil and budesonide on exercise-induced bronchoconstriction. European Respiratory Journal 2 (Supp!. 5): 399s. 1989 Dunkel FG, Elsner P, BUrg G. Contact allergies to topical costico steroids: 10 cases of contact dermatitis. Contact Dermatitis 25: 97-103, 1991 Ebden P, Davies BH. High-dose corticosteroid inhalers for asthma. . Lancet 2: 576, 1984 Ebden P, Jenkins A, Houston G, Davies BH. Comparison of two high dose corticosteroid aerosol treatments. beclomethasone dipropionate (1500 I'g/day) and budesonide (1600 I'g/day) for chronic asthma; Thorax 41: 869-874. 1986 Edsbacker S, Andersson KE, Ryrfeldt A. Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man. European Journal of Clinical Pharmacology 29: 477-481, 1985 Edsbacker S, Andersson P, Lindberg C. Paulson J. Ryrfeldt A. et a!. Liver metabolism of budesonide in rat. mouse. and man. Drug Metabolism and Disosition 15: 403-411. 1987 Engel T. Heinig JH, Madsen 0, Hansen M. Weeke ER. A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. European Respiratory Journal 2: 935939, 1989a Engel T, Heinig JH, Mailing H-J. Scharling B, Nikander K, et a!. Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or Turbuhaler R Allergy 44: 220-225, 1989b Evans PM. O'Connor BJ, Fuller RW, Chung Kf, Barnes PJ. Effect of inhaled budesonide on eosinophil density in asthma. British Journal of Clinical Pharmacology 31: 616P, 1991 Fisher WG, Higgins AJ. A comparison ofbudesonide and disodium cromoglycate (DSCG) in children with hayfever. XIII International Congress of Allergology and Clinical Immunology, Montreux, Switzerland, October 16-21, 9: 382, 1988 Gamboa PM, Jauregui I, Antepara I. Contact dermatitis from budesonide in a nasal spray without cross-reactivity to amcinom ide. Contact Dermatitis 24: 227-228, 1991


Ganz PA. Methods of assessing drug therapy on quality of life. Drug Safety 5: 233-242. 1990 Gay AL. Richardson PDI. Howarth NJ. The influence of budesonide (Pulmicort) on patients' lifestyles in the management of asthma. A multicentre trial in general practice. Clinical Trials Journal 26: 175-180. 1989 Gleeson JGA. Price JF. Controlled trial of budesonide given by the Nebuhaler in preschool children with asthma. British Medical Journal 297: 163-166. 1988 Gordon ACH. McDonald CF. Thomson SA. Frame MH. Pottage A. et al. Dose of inhaled budesonide required to produce clinical suppression of plasma cortisol. European Journal of Respiratory Disease 71: 10-14. 1987 Godfrey S. Avital A. Rosier A. Mandelberg A. Uwyyed K. Ne, bulised budesonide in severe infantile asthma. Correspondence. Lancet 2: 851-852. 1987 Gruvstad E. Bengtsson B. A comparison of a new steroid. budesonide. with other topical corticosteroids in vasoconstriction assay. Drugs Under Experimental and Clinical Research 6: 385390. 1980 Haahtela T. Jarvinen M. Kava T. Kiviranta K. Koskinen S. et al. Comparison of a il2-agonist. terbutaline with an inhaled corticosteroid. budesonide. in newly detected asthma. New England Journal of Medicine 325: 388-392. 1991 Hartwig S. Linden M. Laurent C, Vargo A-K. Lindqvist N. Budesonide nasal spray as prophylactic treatment after polypectomy. Journal of Laryngology and Otology 102: 148-151. 1988 Henriksen JM. Dahl R. Effects of inhaled budesonide alone and in combination with low dose terbutaline in children with exercise-induced asthma. American Review of Respiratory Disease 128: 993-9971 1983 Henriksen JM. Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction. mouth breathing. and asthma. American Review of Respiratory Disease 130: 1014-1018. 1984 Hetta L. Larsson L-G. Nikander K. A comparative clinical study of inhaled budesonide delivered either via a pressurised metered dose inhaler or via TurbuhalerR . Abstract 887. European Respiratory Journal 2 (Suppl. 8): 8332s. 1989 Hodsman AB. Toogood JH. Jennings B. Fraher U. Baskerville Jc. Differential effects on inhaled budesonide and oral prednisolone on serum osteocalcin. Journal of Clinical Endocrinology and Metabolism 72: 530-540. 1991 Holgate ST. Besley R. Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clinical Science 73: 561-572. 1987 Hyland ME. Finnis S. Irvine SH. A scale for assessing quality of life in adult asthma sufferers. Journal of Psychosomatic Research 35: 99-110. 1991 Irander K. Geterud A. Lindqvist N. Pipkorn U. A single blind clinical comparison between 2 preparations of budesonide in the treatment of seasonal allergic rhinitis. Clinical Otolaryngology 9: 235-242. 1984 Jansen HM. Out T A. de Nooyer M. Roos CM. Zuyderhout F. The effect of corticosteroid (budesonide) inhalation therapy on the hyperpermeability of the respiratory membrane in patients with bronchial hyperreactivity. American Review of Respiratory Disese 133 (Suppl.): 50, 1986 Jeffery PK. Godfrey W. Adelroth E. Nelson F. Rogers A. et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. American Review of Respiratory disease 145: 890-899. 1992 Jeffery PK, Wardlaw AJ. Nelson FC, Collins JV. Kay AB. Bronchial biopsies in asthma. An ultrastructural quantitative study and correlation with hyperreactivity. American Review of Respiratory Disease 140: 1745-1753. 1989 Jenkins PK. Woolcock A. Thompson P. Musk AW. Armstrong J. et al. a comparison of the efficacy and safety of a BID vs QID regimen of inhaled budesonide in moderate to severe un-

403

stable asthmatics. Abstract 3132. Thoracic Society ot Australia and New Zealand 20: 541. 1990 Jennings BH. Andersson K-E. Johansson S-A. The assessment of the systemic effects of inhaled glucocorticosteroids. The effects of inhaled budesonide vs oral prednisolone on calcium metabolism. European Journal of Clinical Pharmacology 41: 1116.1991b Jennings BH, Andesson K-E. Johansson SA. Assessment of systemic effects of inhaled glucocorticosteroids: comparison of the effects of inhaled budesonide and oral prednisolone on adrenal function and markers of bone turnover. European Journal of Clinical Pharmacology 40: 77-82. 1991a Jennings BH. Larsson B. Anderson K-E. Johansson S-A. The assessment of systemic effects of inhaled glucocorticosteroids: A comparison of budesonide and beclomethasone in healthy volunteers. VII 1.-14 Department of Clinical Pharmacology. University of Lund. Sweden. 1990 Johansson S-A. Andersson K-E. Brattsand R. Gruvstad E. Hedner P. Topical and systemic glucorticoid potencies of budesonide and beclomethasone dipropionate in man. European Academy of Allergology and Clinical Immunology 2: 709-715. 1982a Johansson S-A, Andersson K-E, Brattsand R, Gruvstad E. Hedner P. Topical and system glucocorticeid potencies of budesonide. beclomethasone dipropionate and prednisolone in man. European Journal of Respiratory Diseases 63 (Suppl. 122): 7482, 1982b Johansson S-A. Andersson K-E. Brattsand R. Gruvstad E, Hedner P. Topical and systemic glucocorticoid potencies of budesonide and beclomethasone dipropionate in man. European Journal of Clinical Pharmacology 22: 523-529. 19.82c Johansson sA, Dahl R. A double-blind dose-response study of budesonide by inhalation in patients with bronchial asthma. Allergy 43: 173-178, 1988 Juniper EF. Kline PA, Vanzieleghem MA. Hargreave FE. Reduction of budesonide after a year of increased use: a randomized controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained. Journal of Allergy and Clinical Immunology 87: 483-489. 1991 Juniper EF. Frith PA. Hargreave FE. Long term stability of airway responsiveness to histamine. Thorax 37:,288-291. 1982 Juniper EF, Kline PA. Ramsdale EH. Hargreave FE; Comparison of the' efficacy and side effects of aqueous steroid nasal spray (budesonide) on a allergen-injection therapy (Pollinex-R) in the treatment of seasonal allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 85: 606-61'1, 1990a Juniper EF, Kline PA,:Vanzieleghem MA. Ramsilale EH. O'Byrne PM, 'e,t al. Effect of long-term treatment with an inhaled corticosteroid (Budesonide) on airway hyperre~ponsiveness and clinical ;asthma in nonsteroid-dependent asthmatics. American Review of Respiratory Diseases 142: 832-836, 1990b JuniperEF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, et al. Long-term effects of budesonide on airway responsivemiss and clinical asthma severity in inhaled steroid-dependent' asthmatics. European Respiratory Journal 3: 11221127, 1990c Keelan P, Frame M, Gray P, Kelly P. Comparison of a new corticosteroid aerosol, budesonide, with beclomethasone dipropionate' in the treatment of chronic asthma. Irish Medical Journal 7: 244-247, 1984 Kerrebijn 'KF, van essen-Zandvliet EEM, Neijens HJ. Effect of long-teit)! treatment with inhaled corticosteroids and betaagonists! on the' bronchial responsiveness in children with asthma. Journal of Allergy and Clinical Immunology 79: 653659, 19~7 Klementsson H, Lindqvist N, Andersson M, Pipkorn U. Effect of a single dose qf a topical glucocorticoid and a cyclo-oxygenase inhibitor on allergen-induced changes'iin nasal reactivity. Allergy 45: 604-611, 1990

404

Kraan J, Koeter GH, v.d. Mark ThW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treament with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. Journal of Allergy and Clinical Immunology 76: 628-636, 1985 Kraan J, Koeter GH,Van Der Mark ThW, Boorsma M, Kukler J, et al. Dosage and time effects of inhaled budesonide on bronchial hyperreactivity. American Review of Respiratory Disease 137: 44-48, 1988 Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. American Review of Respiratory Disease 131: 599-606, 1985 Laitinen LA, Laitinen A, Haahtela T. Treatment of eosinophilic airway inflammation with inhaled corticosteroid, budesonide, in newly diagnosed asthmatic patients (Abstract). European Respiratory Journal 4 (Suppl. 14): 342S, 1991b Laitinen LA, Laitinen A, Heino M, Haahtela T. Eosinophilic airway inflammation during exacerbation of asthma and its treatment with inhaled corticosteroid. American Review of Respiratory Disease 143: 423-427, 1991a Lau SK, Wei WI, Van Hasselt CA,Sham CL, Woo J, et al. A clinical comparison of budesonide nasal aerosol, terfenadine and a combined therapy of budesonide and oxymetazoline in adult patients with perennial rhinitis. Asian Pacific Journal of Allergy and Immunology 8: 109-115, 1990 Laursen LC, Taudorf E, Borgeskov S, Kobayasi T, Jensen H, et al. Fiberoptic bronchoscopy and bronchial mucosal biopsies in asthmatics undergoing long-term high-dose budesonide aerosol treatment. Allergy 43: 284-288, 1988 Laursen LC, TaudorfE, Weeke B. High-dose inhaled budesonide in treatment of severe steroid-dependent asthma. European Journal of Respiratory Diseases 68: 19-28, 1986 Lee PS, Campbell LM, Watson DG, Venables T, Parry-Billings KS, et al. Budesonide Turbohaler once daily in mild asthma. Abstract. Thorax 46: 769P, 1991 Lewis LD, Cochrane GM. Psychosis in a child inhaling budesonide. Lancet 2: 634, 1983 Lindqvist N, Andersson M, Bede M, Loth S, Pipkorn U. The clinical efficacy of budesonide in hay fever treatment is dependent on topical nasal application. Clinical and Experimental Allergy 19: 71-76, 1989 Lindqvist N, Holmberg K, Pipkorn U. Intranasally administered budesonide, a glucocorticoid, does not exert its clinical effect through vasoconstriction. Clinical Otolaryngology 14: 519-523, 1989 Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Correspondence. Lancet 1: 115-116, 1988 LOfdahl CoG, Mellstrand T, Svedmyr N. Glucocorticoids and asthma. Studies of resistance and systemic effects of glucocorticoids. European Journal of Respiratory Diseases 65 (Suppl. 136): 69-79, 1984 Lorentzson S, Boe J, Eriksson G, Persson G. Use of inhaled corticosteroids in patients with mild asthma. Thorax 45: 733-735, 1990 Lundgren R, SOderberg M, Horstedt P, Stenling R. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years of treatment with inhaled steroids. European Respiratory Journal I: 883-889, 1988 MacDonald GF, Knight A, Fleetham J, Sproule B, Dales R. A comparison of budesonide and placebo in oral-steroid-dependent asthmatics: a preliminary analysis. In Hargreave FE, et al. (Eds) Glucocorticoids and mechanisms of asthma. Clinical and experimental aspects. pp. 111-124, Amsterdam 1989 Malo J-L, Cartier A, Merland N, Ghezzo H, Burek A, et al. Fourtimes-a-day dosing frequency is better than a twice-a-day regimen in subjects requiring a high-dose inhaled steroid, bude-

Drugs 44 (3) 1992

sonide, to control moderate to severe asthma. american Review of Respiratory Disease 140: 624-628, 1989 Marianayagam L, Spiteri M, Poulter LW. Budesonide induces distinct phenotypic changes in alveolar populations. American Review of Respiratory Disease 141: 1990 McArthur JG, Higgins AJ. A comparison ofbudesonide and BDP aqueous sprays in the treatment of hayfever. Allergy 43 (Suppl.): 114, 1988 McCarthy TP, Nebulised budesonide in severe childhood asthma. Lancet I: 379-380, 1989 McGivern DV, Basran GS, Handley S, Davies D. A comparison of budesonide and beclomethasone dipropionate in perennial rhinitis. European Academy of Allergology and Clinical Immunology 239: 215, 1985 McGivern DV, MacFarlane JT. Severe bronchoconstriction after inhalation ofbudesonide.British Medical Journal 288: 477, 1984 Meding B, Dahlberg E. Contact allergy to budesonide in a nasal spray. Contact Dermatitis 14: 253-254, 1986 Meyboom RHB, de Graaf-Breedenveld N. Budesonide and psychic side effects. Correspondence. Annals of Internal Medicine 109: 683, 1988 Molema J, van Hervaarden CLA, Folgering HThM. Effects'of long term treatment with inhaled cromoglycate and budesonide on bronchial hyperresponsiveness in patients with allergic asthma. European Respiratory Journal 2: 308-316, 1989 Nadeau J, Toogood JH, Crilly R. Effect of inhaled budesonide on calcium and phosphate metabolism. Abstract 128. Annals of Allergy 55: 257, 1985 Namsirikul P, Chaisupamongkollarp S, Chantadisai N, Bamberg P. Comparison of inhaled budesonide with oral prednisolone at two dose-levels commonly used for the treatment of moderate asthma. European Respiratory Journal 2: 317-324, 1989 Nankani IN, Northfield M, Beran YM, Richardson PDL Changes in asthmatic patients; smptoms and lifestyles on institution on inhaled budesonide therapy. Current Medical Research and Opinion 12: 198-206, 1990 Narendra-Nathan P, Godfrey S, Pedersen S, Nakander K, Noviski N, et al. Prednisolone-sparing effects of nebulised budesonide suspension in asthmatic children. Abstract 220. Journal of Allergy in Clinical Immunology 85: 198, 1990 Newman SP, Miller AB, Johnes TR, Moren F, Clarke SW. Improvement of pressurised aerosol deposition with Nebuhaler spacer device. Thorax 39: 935-941, 1984 Newman SP, Talaee N, Nikander K, Berg E, Clarke SW. Evaluation of nebulisers and compressors for use with budesonide nebuliser suspension. Abstract. European REspiratory Journal 1 (Suppl. 2): 211 s, 1988 Noda H, Nishida T, Ihaa Y, Fukaya Y, Abe M, et al. Contact dermatitis due to budesonide. Contact Dermatitis 25: 72-7, 1991 Nyholm E, Frame MH, Cayton RM. Therapeutic advantages of twice-daily over four-time daily inhalation budesonide in the treatment of chronic asthma. European Journal of Respiratory Diseases 65: 339-345, 1984 O'Byrne PM. Airway inflammation and airway responsiveness. Chest 90: 575-577, 1986 O'Connor BJ, Evans PM, Ridge SM, Fuller RW, Barnes PJ. Effect of an inhaled steroid (budesonide) on indirect airway responsiveness (AR) and eosinophils in astha. Abstract 71630. American Review of Respiratory Disease 143: A442, 1991 O'Connor BJ, Fuller RW, Chung KF, Barnes PH. Effect of budesonide on responses to inhaled platelet activating factor in normal subjects. Abstract P694. European Respiratory Journal 3 (Suppl. 10): 203s, 1990 0stergaard PA, Pedersen S. The effect of inhaled disodium cromoglycate and budesonide on bronchial responsiveness to histamine and exercise in asthmatic children: a clinical comparison. In: Glucocorticosteroids in childhood Asthma. Xiiith Congress of the European Academy of Allergology and Clinical Immunology. Budapest, May 6: 55-65, 1986


Otulana BA, Varma N, Bullock A, Higenbottam T. High dose nebulised steroid in the treatment of chronic steroid-dependent asthma. Respiratory Medicine 86: 105-108, 1992 Pedersen B. Bundgaard Larsen B, Dahl R, Lindqvist N. Mygind N. Powder administration of pure budesonide for the treatment of seasonal allergic rhinitis. Allergy 46: 582-587, 1991 Pedersen B. Dahl R, Lindqvist N, Mygind N. Nasal inhalation of the glucocorticoid budesonide from a spacer for the treatment of patients with pollen rhinitis and asthma. Allergy 45: 451-456, 1990 Pedersen S, Fuglsang G. Urine cortisol excretion in children treated with high doses of inhaled corticosteroids: a comparison of budesonide and beclomethasone. European Respiratory Journal I: 433-435, 1988 Pedersen S, Steffensen G, Ekman I, Tonnesson M, Borga O. Pharmacokinetics of budesonide in children with asthma. European Journal of Clinical Pharmacology 31: 579-582. 1987 Pelikan Z, Pelikan-Filipek M. The effects of disodium cromoglycate and beclomethasone dipropionate on the immediate response of the nasal mucosa to allergen challenge. Annals of Allergy 49: 283-282. 1982 Pepys J, Davies RJ, Breslin ABX, Hendrick DJ, Hutchcroft BJ. The effect of inhaled becIomethasone dipropionate (becotide) and sodium cromoglycate on asthmatic reactions to provocation tests. Clinical Allergy 4: 13-24, 1974 Peris-Tortajada A, Giner A, Perez C Hernandez D, Basomba A. Contact allergy to topical budesonide. Journal of Allergy and Clinical Immunology 87: 597-598. 1991 Persson CGA. Antiinflammatory therapy with glucocorticoids in intrinsic asthma. Agents and Actions 28 (Suppl.): 279-291, 1989 Persson CGA. Plasma exudation and asthma. Lung 166: 1-23, 1988 Phanichyakan P. Wong ECK. Inhaled budesonide aerosols in treatment of childhood asthma. Asian Pacific Journal of Allergy and Immunology 6: 111-115, 1988 Phanichyakarn P, Wong ECK. Budesonide aerosols in Thai Asthmatic children. Journal of the Medical Association of Thailand 72 (Suppl.): 1989 Pichler WJ. Klint Th, Blaser M. GrafW. Sauter K, et al. Clinical comparison of systemic methylprednisolone acetate versus topical budesonide in patients with pollinosis. Schweizerischen Gesellschaft fur lillergologie und Immunologie, Lugano, June 26-27, 5285, 1986 Pichler WJ, Klint T, Blaser M, Graf W. Sauta K, et al. Clinical comparison of systemic methylprednisolone acetate versus topical budesonide in patients with seasonal allergic rhiitis. Allergy 43: 87-92, 1988 Pichler WJ, Lkint T, Blaser M, GrafW, Sauter K, et al. Clinical comparison of systemic methylprednisolone acetate versus topical budesonide in patients with seasonal allergic rhinitis. Allergy 43: 87-92. 1988 Pipkorn U. Andersson P. Budesonide and nasal mucosal histamine content and anti-IgE induced histamine release. Allergy 37: 591-595, 1982 Pipkorn U, Enerback L. Nasal mucosal mast cells and histamine in hay fever. International Archives of Allergy and Applied Immunology 84: 123-128. 1987 Pipkorn U, Pukander J. Suonpaa J, Makinen J; Lindqvist N. Longterm safety of budesonide nasal aerosol: a 5.5-year follow-up study. Clinical Allergy 18: 253-259, 1988 Pipkorn U. The effect of budesonide on the immediate reaction to allergen challenge - a rhinomanometric study. European Journal of Respiratory Diseases 63 (Suppl. 122): 185-191, 1982 Poh SC Wang YT. Severe bronchoconstricti'on after inhalation of beclomethasone and budesonide. Singapore Medical Journal 27: 247-249, 1986 Prahl P. Adrenocortical suppression following treatment with beclomethasone and budesonide. Clinical and Experimental Allergy 21: 145-146, 1991

405

Prahl P, Jensen T, Bjerregaard-Andesen H. Adrenocortical function in children on high-dose steroid aerosol therapy. Allergy 42: 541-544, 1987 Prahl P, Jensen T. Decreased adreno-cortical supression utilizing the Nebuhaler for inhalation of steroid aerosols. Clinical allergy 17: 393-398. 1987 Priftis K. Everard ML, Milner AD. Unexpected side-effects of inhaled steroids: a case report. European Journal of Pediatrics 150: 448-449. 1991 Rafferty P, Tucker LG, Frame MH, Fergusson RJ, Biggs B-A, et al. Comparison ofbudesonide and beclomethasone dipropionate in patients with severe chronic asthma: assessment ofprednisolone-sparing effects. British Journal of Diseases of the Chest 79: 244, 1985 Ramsdale EH. Kline PA. Comparison of an intranasal steroid (budesonide) with terfenadine in the treatment ofragweed-induced rhinoconjunctivitis. Abstract 402. Journal of Allergy and Clinical Immunology 85: 1990 Reed CEo Aerosol steroids as primary treatment of mild asthma. Editorial. New England Journal of Medicine 325: 425-426, 1991 Reiser J. Frame MH, Warner JO. The potential value of 750-ml spacer for the administratio f inhaled corticosteroids to children. Pediatric Pulmonology 2: 237-243, 1986 Ribeiro LB. A 12-month tolerance study with budesonide in asthmatic children. In Godfrey S (Ed.) Glucocorticoids in Childhood Asthma. pp. 95-108, Excerpta Medica. Amsterdan, 1987 Ross JRM, Mohan G, Anderson B. Taylor MD, Richardson POI. Budesonide once-daily in seasonal allergic rhinitis. Current Medical Research and Opinion 12: 507-515, 1991 Ruhno J, Andersson B, Denburg J. Anderson M, Hitch 0, et al. a double-blind comparison of intranasal budesonide with placebo for nasal polyposis. Journal of Allergy and Clinical Immunology 86: 946-953. 1990 Ryrfeldt A, Andersson P, Edsbacker S. Tonnesson M. Davies D. et al. Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. European Journal of Respiratory Diseases 63 (Suppl. 122): 86-95. 1982 Ryrfeldt A, Edsbacker S, Pouwels R. Kinetics of epimeric glucocorticoid budesonide. Clinical Pharmacology and Therapeutics 35: 525-530. 1984 Ryrfeldt A, Persson G, Nilsson E. Pulmonary disposition of the potent glucocorticoid budesonide, evaluated in an isolated perfused net lung model. Biochemical Pharmacology 38: 17-22. 1989 Salomonsson P, Gottberg L. Pegelow K-O. A clinical comparison of budesonide nasal-spray versus disodium chromoglycate (DSCG) in birch-pollen induced hay-fever. 13th Congress of the European Academy of Allergology and Clinical Immunology. budapest, May 4-10, 1986 Schuller CF. A prospective twelve months tolerance study of inhaled budesonide in children. Presented at the 4th Congress on Bronchitis and Emphysema, September 23-28. Milano. 1985 Selroos OB. Inhaled corticosteroids in COPD and interstitial lung disease. 34th Nordic Congress on Diseases of the Chest, Aarhus. Absract, pp. 33-34. 1988 Selroos 0, Backman R, Lofroos A-B, Niemisto' M. Aikiis C. turbuhaler does not increase the frequency of local side-effects compared to other inhalation devices for corticosteroids. Abstract. European Respiratory Journal 4 (Suppl. 14): 1316. 1991 Selroos 0, Halme M. Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler. Thorax 46: 891-894, 1991 Selroos O. The effects of inhaled corticosteroids on the natural history of obstructive lung diseases. European Respiratory Review I (5): 354-365. 1991 Simpson RJ, Higgins AJ. Budesonide and terfenadine separately and in combination in the treatment of hayfever. Abstract. Allergy 43 (Suppl. 7): 112. 1988

406

Sipilii P, Sorri M. Budesnide and flunsolide in perennial allergic rhinitis: an open trial. Allergy 39 (Suppl. 2): 1984 Small P, Barrett D, Biskin N. The effects of high doses oftopicai steroids on both ragweed and histamine induced nasal provocation. Abstract 75. Journal of Allergy and Clinical Immunology 35: 162, 1990 Small P, Barrett D. Effects of high doses of topical steroids on both ragweed and histamine-induced nasal provocation. Annals of Allergy 67: 520-524, 1991 Springer C, Avital A, Maayan Ch, Rosier A, Godfrey S. Comparison of budesonide and beclomethasone dipropionate for treatment of asthma. Archives of Disease in Childhood 62: 815-819, 1987 Stiksa G, Gennow C, Johannesson N. An open cross-over trial with budesonide and beclomethasone dipropionate in patients with bronchial asthma. European Journal of Respiratory Diseases 63 (Suppl. 122): 266-267, 1982 Stiksa G, Glennow C. Once daily inhalation ofbudesonide in the treatment of chronic asthma: a clinical comparison. Annals of Allergy 55: 49-51, 1985 Svensson C, Klementsson H, Alkner U, Pipkorn U, Persson CGA. A topical glucorticoid reduces the levels of fibrinogen and bradykinins on the allergic nasal mucosa during natural pollen exposure. Abstract 35. Journal of Allergy and Clinical Immunology 87: 147, 1991 Synnerstad B, Lindqvist N. Budesonide and beclomethasone dipropionate in the treatment of perennial rhinitis - a 12 months comparison. Abstract. EAACI Stockholm, June 2-5, p 239, 1985 Tan WC, Chan TB, Lim TK, Wong ECK. The efficacy of high dose inhaled budesonide in replacing oral corticosteroid in Asian patients with chronic asthma. Singapore Medical Journal 31: 142-146, 1990 Tjwa MKT. Budesonide Turbohaler (BUD) vs beclomethasone Rotahaler (BDP) on histamine PC20 and FEV I. Abstract p499. Eueopean Respiratory Journal 3 (Suppl. 10): 161s, 1990 Toogood JH. An appraisal of the influence of dose frequency on the antiasthmatic activity of inhaled corticosteroids. Annals of Allergy 55: 2-4, 1985 Toogood JH, Baskerville JC, Jennings B, Lefcoe NM, Johansson SA. Influence of dosing frequency and schedule on the response of chronic asthmatics to the aerosol steroid, budesonide. Journal of Allergy and Clinical Immunology 70: 288-298, 1982 Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S-A. Use of spacers to facilitate inhaled corticosteroid treatment of asthma. American Review of Respiratory Disease 129: 723-729, 1984a Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson SA. Use of spacers to facilitte inhaled corticosteroid treatment of asthma. American Review of Rspiratory Disease 129: 723729, 1984b Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S-A. Bioequivalent doses of budesonide and prednisone in moderate and severe asthma. Journal of Allergy and Clinical Immunology 84: 688-700, 1989 Toogood JH. Budesonide in children with asthma. Correspondence. European Journal ofClinial Pharmacology 34: 113-114, 1988 Toogood JH. Complications of topical steroid therapy for asthma. American Review of Respiratory Disease 141: S89-S96, 1990 Toogood JH, Crilly RG, Jones G, Nadeau J, Wells GA. Effect of high-dose inhaled budesonide on calcium and phosphate metabolism and the risk of osteoporosis. American Review of Respiratory Disease 138: 57-61, 1988 Toogood JH, Frankish CW, Jennings BH, Baskerville JC, Borga 0, et al. A study ofthe mechanism of the antiasthmatic action of inhaled budesonide. Journal of Allergy and Clinical Immunology 85: 872-880, 1990

Drugs 44 (3) 1992

Toogood JH. High-dose inhaled steroid therapy for asthma. Journal of Allergy and Clinical Immunology 83: 528-536, 1989 Toogood JH, Jennings B, Baskerville J, Anderson J, Johansson SA. dosing regimen of budesonide and occurence of oropharyngeal complications. European Journal of Respiratory Diseases 65: 35-44, 1984 Toogood JH, Jennings B, Baskerville J, Johanssn SA. Which asthmatic patients respond best to a spacer (Sp)? Abstract 50. Journal of Allergy and Clinical Immunology 73: 1984 Toogood JH, Jennings B, Hodsman AB, Baskerville J, Fraher U. Effects of dose and dosing schedule of inhaled budesonide on bone turnover. Journal of Allergy and Clinical Immunology 88: 572-580, 1991 Turpeinen M, Sorva R, Juntunen-Backman K. Changes in carbohydrate and lipid metabolism in children with asthma inhaling budesonide. Journal of Allergy and Clinical Immunology 88: 384-389, 1991 Van Bever HP, Schuddinck L, Wojciechowski M, Stevens WJ. Aerosolized budesonide in asthmatic infants: a double blind study. Pediatric Pulmonology 9: 177-180, 1990 Vanzieleghem MA, Juniper EF. A comparison ofbudesonide and beclomethasone dipropionate nasal aerosols in ragweek-induced rhinitis. Journal of Allergy and Clinical Immunology 79: 887-892, 1987 Varsano I, Volovitz B, Malki H, Amir Y. Safety of 1 year of treatment with budesonide in young children with asthma. Journal of Allergy and Clinical Immunology 85: 914-920, 1990 Vathenen AS, Knox AJ, Wisnieski A, Tattersfield AE. Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. Thorax 46: 811-816, 1991 Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. American Review of Respiratory Diseases 143: 1317-1321, 1991 Vaz de Azevedo M, Coelho M, Mendes JAP, de Almeida AB. Can a low or moderate dose of inhaled budesonide replace oral non-steroidal anti-asthma treatment? Journal of International Medical research 19: 280-288, 1991 Venge P, Dahl R, Karlstr60m R, Pedersen B, Peterson GGB. Eosinophil and neutrophil activity in asthma in a one-year double blind trial with theophylline and two doses of inhaled budesonide. Abstract. Journal of Allergy and Clinical Immunology 89: 190, 1992 Venge P, Henriksen J, Dahl R, Hakansson L. Exercise-induced asthma and the generation of neutrophil chemotactic activity. Journal of Allergy and Clinical Immunology 85: 498-504, 1990 Vilsvik JS, Jensen AO, Wahlstad R. The effect ofbeclomethasone dipropionate aerosol on allergon-induced nasal stenosis. Clinical Allergy 5: 291-294, 1975 van den Bosch JMM, Westermann CJJ, Aumann J, Edsbiicker S, Tonnesson M, et al. Concentration in lung tissue of inhaled budesonide. Rovaniemi Seminar June 15-17, 1989 Waalkens HJ, Gerritsen J, Koeter GH, Krouwels FH, van Aalderen WMC, et al. Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow. Thorax 46: 499-503, 1991 Wales JKH, Barnes ND, Swift PGF. Growth retardation in children on steroids for asthma. Lancet 338: 1535, 1991 Watson A, Lim TK, Joyce H, Pride NB. Failure of inhaled corticosteroids to modify bronchoconstrictor responsiveness in middle-aged smokers with mild airflow obstruction. Chest 101: 350-355, 1992 Weinberger M, Hendeles L, Ahrens R. Clinical pharmacology of drugs used for asthma. Pediatric Clinics of North America 28: 47-75, 1981 Wempe JB, Tammeling EP, Kiiter Gh, Postma DS. Effects of budesonide and bambuterol on circadian variation of eosi-


nophil count and serum ECP. Abstract. European Respiratory Journal 4 (Suppl. 4): 476s, 1991 Wesseling GJ, Puaedvlieg M, Wouters EFM. Inhaled budesonide in chronic bronchitis. Effects on respiratory impedance. European Resiratory Journal 4: 1101-1105, 1991 Williams AJ, Baghat MS, Stableforth DE, Caytn RM,Shenoi PM, et al. Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormality. Thorax 38: 813-821, 1983 Wolthers OD, Pedersen S. Efficacy and safety of budesonide in the treatment of children with seasonal rhinitis. XVII Nordiske Kongress i Allergologi, Arhus, May 17-19, 1990 Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double-blind trial. British Medical Journal 303: 163-165, 1991

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Wong J, Black P. Acute adrenal insufficiency associated with high dose inhaled steroids. Correspondence. British Medical Journal 304: 1415, 1992 Zimmerman B, Tremblay D, Naus F. Nebulized inhaled steroid (budesonide): prolonged high dose therapy in children less than age 5. Abstact 460. Journal of Allergy and clinical Immunology 85: 258, 1990

Correspondence: Rex N. Brogden. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand.

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