Budesonide

Summary

Synopsis: Budesonide¹ is a non-halogenated glucocorticosteroid which has been shown to possess a high ratio of topical to systemic activity compared with a number of reference corticosteroids such as beclomethasone dipropionate, flunisolide, and triamcinolone acetonide. It appears to undergo extensive first-pass metabolism to metabolites of minimal activity which accounts for the low level of systemic activity.

The majority of therapeutic trials in asthma have been of short term duration and have demonstrated that conventional doses of inhaled budesonide (200 to 800 µg/day) and beclomethasone dipropionate (400 to 800 µg/day) are of similar efficacy in both adults and children with moderate to severe asthma. Other studies have compared high doses of inhaled budesonide (400 to 3200 µg/day in 4 divided doses) with both alternate day (7.5 to 60mg) and daily (7.5 to 40mg) oral prednisone in patients with severe or unstable asthma. In the small number of such trials to date, inhaled budesonide was superior to prednisone with respect to the level of asthma control and the lesser influence on adrenal function. Long term open studies have similarly shown that inhaled budesonide can be gradually substituted for oral prednisone in steroid-dependent patients, often with a concomitant improvement in pulmonary function and asthma control.

Intranasal budesonide (200 to 400 µg/day) relieves nasal symptoms in patients with seasonal allergic, perennial allergic and vasomotor rhinitis. In comparative studies in patients with seasonal rhinitis it has been shown to be of similar efficacy as intranasal flunisolide and intranasal beclomethasone dipropionate and superior to intranasal sodium cromoglycate (cromolyn sodium) and the antihistamine dexchlorpheniramine.

Following inhalation, the most commonly reported side effects have been candidiasis, dysphonia and sore throat, while after intranasal administration the most frequent adverse reactions have been nasal stinging, throat irritation, dry nose and slight nasal bleeding. At usual dosages, both formulations of budesonide appear to have little or no effect on adrenal function.

Thus, at this stage in its development budesonide has been shown to offer an effective alternative to oral or other inhaled corticosteroids in the management of asthma and rhinitis. However, its relative efficacy and tolerability during long term use, compared with beclomethasone dipropionate, remains to be clarified.

Pharmacodynamic Studies: In animals budesonide has a high ratio of topical to systemic activity compared with reference corticosteroids such as beclomethasone dipropionate, flunisolide and triamcinolone acetonide. In man, budesonide was shown to have 1.6 to 3 times greater local anti-inflammatory activity using a skin vasoconstriction assay, and between 2 and 4 times less systemic activity than beclomethasone dipropionate. The reduction in systemic potency in healthy volunteers should augur well for the clinical usefulness of budesonide, and trials in patients with asthma have not revealed any significant differences between conventional doses of budesonide and beclomethasone dipropionate. In practice, usual doses of inhaled or intranasal budesonide have caused only minimal changes in hypothalamic-pituitary-adrenal (HPA) function, although a doseresponse relationship with plasma cortisol concentrations has been documented. When inhaled therapy was substituted for oral prednisolone there was a gradual increase in plasma cortisol concentrations, highlighting the lower adrenal suppressive activity of budesonide compared with oral steroid.

Even after single doses, inhaled budesonide produced a rapid improvement in pulmonary function in patients with asthma, characterised by a dose-response relationship with peak expiratory flow rate. A divided daily regimen gave a more pronounced and longlasting increase in lung function at a reduced total daily dosage compared with a single daily dose.

The mechanism of action of budesonide, like that for other glucocorticoids, remains obscure. However, it has been noted that as long as pretreatment was sufficiently long, inhaled budesonide inhibited both the immediate and late reactions provoked by bronchial allergen challenge. Similarly, intranasal budesonide inhibited the type 1-mediated immediate nasal reaction and this may be related to suppression of histamine release in nasal biopsy samples in vitro.

Following intranasal administration of budesonide for up to 1 year in patients with rhinitis, no adverse morphological changes in the nasal mucosa occurred. However, no studies evaluating the histological characteristics of the bronchial mucosa after inhaled budesonide have been reported.

Pharmacokinetic Studies: In man, peak plasma concentrations of unchanged budesonide occurred within 1 hour of inhalation and approximately 3 hours after oral ingestion, thus reflecting the rapid rate of absorption from the lung. Systemic bioavailability was calculated to be 10.7% after oral administration, with evidence of extensive first-pass metabolism.

The volume of distribution of budesonide is comparatively large (301L), which is indicative of wide tissue distribution. Budesonide has been shown to be extensively bound to plasma proteins (88.3%) with negligible binding to transcortin. The relatively short elimination half-life (approximately 2 hours) and high plasma clearance (83.7 L/hour) highlight the rapid systemic elimination of budesonide. In vitro studies have corroborated the involvement of the liver in the rapid biotransformation of budesonide; 2 major metabolites with minimal activity have been isolated and identified. Only trace amounts of budesonide are excreted unchanged in the urine.

Therapeutic Trials: The majority of clinical trials with inhaled budesonide have been crossover studies designed to evaluate the effectiveness of different dosage regimens, or its comparative efficacy with that of inhaled beclomethasone dipropionate. Most were of short duration (2 to 4 weeks) and, when peak expiratory flow rate was measured, demonstrated a dose-response relationship over a wide range of inhaled dosages (100 to 1600 µg/day in divided doses) in patients with moderately severe and severe (steroiddependent) asthma. The dose-response relationship was maintained whether budesonide was administered twice or 4 times daily.

In short term comparative trials inhaled budesonide (400 to 3200 µg/day in 4 divided doses) was found to be superior to alternate-day oral prednisone (7.5 to 60mg) in patients with moderate to severe asthma, and was able to produce as effective control of unstable asthma as daily oral prednisone (7.5 to 40mg once daily). In this latter study, at doses producing equivalent control of the asthmatic condition, inhaled budesonide had significantly less effect on adrenal function. In other comparative trials, inhaled budesonide (200 to 800 µg/day) was of approximately equal efficacy as inhaled beclomethasone dipropionate (400 to 800 µg/day) in both adults and children with asthma. In long term open trials gradual substitution of inhaled budesonide for oral steroid has often resulted in an improvement in pulmonary function and asthma control. Oral steroid dosage was usually markedly decreased during budesonide administration, and 1600 µg/day of inhaled budesonide reduced mean oral prednisone usage by half.

Intranasal budesonide has been used in the treatment of seasonal allergic, perennial allergic and vasomotor rhinitis. In seasonal rhinitis doses of 200 to 400 µg/day were significantly better than placebo in relieving nasal symptoms and reducing the need for supplemental antiallergy medication, but had no effect on eye symptoms. In patients with seasonal allergic rhinitis, intranasal budesonide was as effective as intranasal beclomethasone dipropionate and intranasal flunisolide, and significantly superior to both intranasal sodium cromoglycate and the oral antihistamine dexchlorpheniramine. Short term comparisons in patients with perennial rhinitis, with or without an allergic component, have shown budesonide to be significantly better than placebo in relieving nasal symptoms when doses of 200 to 400 µg/day were administered. In long term open trials in patients with perennial rhinitis, intranasal budesonide (200 to 400 µg/day) has consistently produced a significant reduction in all nasal symptoms with a low incidence of mild and transient side effects.

In patients with nasal polyposis, budesonide was significantly more effective than placebo in reducing total symptom scores and increasing nasal peak flow rates, while rhinoscopy revealed a distinct decrease in nasal congestion, a decrease in polyp size, and a significant reduction in the number of polyps. However, only 10 patients received the active drug in this study and a well-designed trial in a greater number of patients is required to confirm the usefulness of intranasal budesonide in this condition.

Side Effects: Generally, budesonide has been well tolerated and few trials have reported adverse reactions associated with treatment. However, the majority of these studies have been of short term duration (2 to 4 weeks). Longer term trials in greater numbers of patients are required to fully evaluate the tolerability of budesonide.

Using the inhaled preparation, the most commonly reported side effects have been oropharyngeal candidiasis, hoarseness and sore throat, as is also the case with other inhaled corticosteroids. The reported incidence of candidiasis varied widely among studies, but was reduced by using a spacing device or by reverting to a less frequent dosing regimen. Gradual substitution of inhaled budesonide for oral prednisolone resulted in a number of side effects such as hoarseness, sore throat, arthralgia, myalgia, exacerbation of eczema and pulmonary eosinophilia and sarcoidosis, which can all be explained in terms of a local reaction or are indicative of systemic corticosteroid withdrawal. Administration of inhaled budesonide, up to 800 µg/day, appears to have a minimal effect on adrenal function as assessed by basal plasma cortisol concentrations and their increase after tetracosactrin stimulation. Nevertheless, during substitution of inhaled budesonide for oral corticosteroid, recovery of hypothalamic-pituitary-adrenal integrity can take up to 12 months after long term oral steroid therapy, and it is essential to take special care during this period.

Intranasal budesonide has been well tolerated, and in both long and short term trials in patients with rhinitis the most common side effects have been local reactions such as nasal stinging, throat irritation, dry nose and nasal bleeding. In comparative studies, intranasal budesonide has produced fewer adverse effects than the antihistamine dexchlorpheniramine, significantly less nasal irritation than flunisolide, and equivalent incidences of minor transient reactions as intranasal beclomethasone dipropionate and intranasal sodium cromoglycate. No evidence of adrenal suppression has been reported with this formulation.

Dosage and Administration: The inhaled dose of budesonide for the treatment of asthma in adults should be individualised. The recommended initial dose is 400 to 1600 µg/day divided into 2 or 4 administrations. The maintenance dose is usually 200 to 400 µg/day — using the lowest dose that leaves the patient symptom free. In children with asthma the recommended dose is 200 to 400 µg/day, divided into 2 or 4 administrations.

In the treatment of rhinitis the recommended dosage is 100µg (2 actuations of 50µg each) into each nostril morning and evening (400 µg/day). This dosage can be halved once a good response has been achieved.