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Beclomethasone Dipropionate Inhaler: A Review of its Pharmacology, Therapeutic Value and Adverse Effects

Research paper by R. N. Brogden, R. M. Pinder, Phyllis R. Sawyer, T. M. Speight, G. S. Avery

Indexed on: 15 Nov '12Published on: 15 Nov '12Published in: Drugs



Abstract

Synopsis: Beclomethasone dipropionate2 is a topically active corticosteroid used as an adjuvant in the control of chronic asthma when given by inhalation as an aerosol. It is not intended for treatment of acute attacks.It appears that the main difference between beclomethasone dipropionate and other corticosteroids previously used by inhalation is its high topical activity together with a lower systemic activity due to metabolic inactivation of the swallowed portion of the dose.Clinical experience has shown that at doses of 200 to 600μg daily, beclomethasone dipropionate inhaler is preferable to oral corticosteroids, because of lack of side-effects, when adult patients and children who are inadequately controlled by full doses of sodium cromoglycate and bronchodilators, are first considered to need maintenance corticosteroids. Inhaled beclomethasone dipropionate can allow a worthwhile reduction in maintenance doses of systemic corticosteroids in many patients already receiving these drugs and can replace systemic steroids entirely in some patients, particularly when their initial dose of steroids is less than 10mg daily of prednisone or its equivalent. Substitution should be attempted when the patient’s asthma is well controlled on their usual doses of systemic steroids and full doses of other adjuvant therapy. Withdrawal of systemic corticosteroids should be performed slowly and carefully. Because recovery from impaired adrenocortical function caused by prolonged systemic steroid therapy is usually slow, special care is necessary for 9 to 12 months after transfer to beclomethasone dipropionate aerosol until the hypothalamo-pituitary-adrenal axis has sufficiently recovered to cope with emergencies such as trauma, surgery, severe infections or an acute attack of asthma. It is essential that additional therapy including high doses of systemic corticosteroids be used immediately to control any acute exacerbation of asthma which occurs during maintenance therapy with beclomethasone dipropionate aerosol.Tests of adrenal function suggest that beclomethasone dipropionate at dosages of 400 to 800μg daily has little or no adverse effect.The most common side-effect associated with the continuous use of beclomethasone dipropionate inhaler has been oropharyngeal candidiasis, which appears to be dose-related and more common in women than in men. Systemic steroid withdrawal effects, like being generally unwell, and exacerbation of underlying allergic diseases such as allergic rhinitis, have been reported after substitution of beclomethasone dipropionate inhaler for systemic steroids. However, systemic withdrawal effects seldom occur if systemic steroids are withdrawn slowly.Pharmacological Studies: Preliminary investigations indicated that beclomethasone dipropionate possessed certain pharmacological features suited to topical administration in asthma. An alcoholic solution applied under occlusive dressing is about 500 times more active in producing vasoconstriction of normal skin than dexamethasone or betamethasone. At doses normally used in the treatment of asthma, several weeks of therapy with inhaled beclomethasone dipropionate causes no significant suppression of early morning plasma cortisol, or plasma cortisol response to tetracosactrin stimulation in normal subjects.Beclomethasone dipropionate is well absorbed when given orally, but possesses relatively low systemic activity by this route, apparently because of metabolic inactivation during its passage through the liver. This is supported by the finding that whereas an oral dose of 4 to 8mg of beclomethasone dipropionate is required to cause a marked suppression of plasma cortisol, 1mg intravenously causes complete suppression of plasma cortisol in normal subjects.Thus it appears that the high topical activity of beclomethasone dipropionate, together with a relatively low systemic activity due to metabolic inactivation of the swallowed portion of the dose, are the main reasons why therapeutic doses of inhaled beclomethasone dipropionate control asthma without causing important glucocorticoid effects.Therapeutic Trials: Clinical experience with beclomethasone dipropionate inhaler in steroid-dependent asthmatic patients and in those not receiving systemic corticosteroids, indicates that beclomethasone dipropionate inhaler is preferable to oral corticosteroids when patients who are inadequately controlled by full doses of a bronchodilator and sodium cromoglycate are first considered to require maintenance corticosteroids. Inhaled beclomethasone dipropionate can allow a worthwhile reduction in maintenance doses of systemic corticosteroids in many patients already receiving these drugs and can replace systemic steroids entirely in some patients, without causing a deterioration in their asthma, particularly when their initial dose of steroids is less than 10mg daily of prednisone. Substitution should be attempted when the patient’s asthma is well controlled on usual doses of systemic steroids and full doses of other adjuvant therapy. Exacerbations of asthma should be controlled by immediate therapy with systemic corticosteroids.In double-blind comparisons of oral prednisolone and beclomethasone dipropionate inhaler in steroid-dependent asthmatics, the efficacy of 300μg daily of beclomethasone dipropionate was indistinguishable from that of 7.5mg daily of prednisolone and tended to be more effective than 5mg daily of the oral corticosteroid.It appears that increasing the dose of beclomethasone dipropionate above 400μg daily may benefit some selected patients who fail to respond to usual therapeutic doses. A dose of 800μg daily of beclomethasone dipropionate inhaler may allow a greater reduction in maintenance doses of systemic steroids than 400μg daily in patients whose initial dose of oral corticosteroids exceeds 16mg daily (prednisone). However, as oral candidiasis seems to occur more frequently at the higher dosage, there appears to be little advantage in using maintenance doses of beclomethasone dipropionate inhaler greater than 400μg daily in patients receiving 15mg or less of prednisone.As might be expected, there is a tendency for response to beclomethasone dipropionate to be better in patients who have previously shown a good response to systemic corticosteroids than in patients in whom beclomethasone dipropionate was used to supplement oral corticosteroids in the hope of avoiding an increase in maintenance dosage. These patients were generally on a higher maintenance dose of corticosteroids.Although long-term studies to date suggest that there is no loss of control after substitution of beclomethasone for systemic corticosteroids, short-term courses of systemic steroids are required to control occasional exacerbations of asthma.It appears that sodium cromoglycate can be withdrawn in some patients once they are established on beclomethasone dipropionate inhaler, but others appear to benefit from combined therapy.Therapeutic trials in children, suggest that adequate doses of beclomethasone dipropionate inhaler can replace corticosteroids or corticotrophin in most asthmatic children requiring maintenance therapy with these drugs. Many of the children treated with beclomethasone dipropionate inhaler have not been adequately controlled by sodium cromoglycate plus maintenance corticosteroids, but their asthma status has usually been maintained or sometimes improved when beclomethasone dipropionate aerosol has been substituted for systemic steroids. Substitution of beclomethasone dipropionate aerosol for systemic corticosteroids does not generally appear to result in either suppression or acceleration of growth or in obvious suppression of adrenal function.Studies to date have been unable to explain why some patients fail to respond to beclomethasone dipropionate. In some such cases a short course of oral steroid in relatively high dosage before starting beclomethasone has allowed control to be maintained thereafter with beclomethasone dipropionate inhaler alone.The initial maintenance dose of systemic corticosteroids seems to influence the ease with which these drugs can be withdrawn, particularly when fixed doses of 400 to 600μg daily of beclomethasone dipropionate inhaler have been used. Generally, withdrawal of maintenance corticosteroids in steroid-dependent asthmatics treated with beclomethasone dipropionate inhaler has been easier when the daily dose has been 10mg or less of prednisone or its equivalent. The response to beclomethasone dipropionate may also be influenced by the initial lung function and by the inability to inhale effectively, and to some extent, by age. Overall response in children appears to be at least equal to that in adults.Results of insulin stress tests conducted in one study suggest that at usual therapeutic doses the drug has little effect on the hypothalamo-pituitary-adrenal function. Less definitive measurements such as the tetracosactrin stimulation test and resting early morning plasma cortisol levels have generally failed to detect any obvious suppression of adrenal function at usual therapeutic doses. However, adrenal suppression is apparent at dosages exceeding 1,600μg daily. There has been a clear trend for plasma cortisol levels to return towards normal after substitution of beclomethasone dipropionate for systemic corticosteroids.Side-effects: In clinical experience to date there have been no confirmed reports of systemic side-effects with doses of beclomethasone of up to 600μg daily. The most common side-effect associated with the continuous use of beclomethasone dipropionate inhaler has been oropharyngeal fungal infection with Candida albicans. This effect seems to be dose-related and to be more common in women than in men, but has usually cleared readily with appropriate topical antifungal therapy.Steroid-withdrawal effects such as nausea, vomiting, malaise and muscle and joint pains have been reported in many studies in which systemic corticosteroids have been replaced by beclomethasone dipropionate inhaler. The frequency of such symptoms has tended to be greater in studies in which systemic steroids have been rapidly withdrawn. Exacerbation of underlying allergic diseases, such as allergic rhinitis and atopic eczema, formerly controlled by systemic steroids, has occurred in many studies.Dose: The usual adult maintenance dose is 2 inhalations (100μg) 3 or 4 times daily. In children 1 or 2 inhalations should be given 2, 3 or 4 times daily according to the response. Patients with severe asthma should be given a systemic corticosteroid preparation until the asthma is brought under control, and treatment then continued with beclomethasone dipropionate aerosol.