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Synopsis: Inhaled beclomethasone dipropionate1 is now well established in the management of asthma. Studies conducted over the last decade, and since the drug was previously reviewed in the Journal, have confirmed that inhaled beclomethasone dipropionate 400 to 800μg daily can reduce the need for oral maintenance corticosteroids in the majority of asthmatic patients requiring such therapy, and that increasing the dosage to 2000μg daily may provide additional clinical benefit in some patients unresponsive to usual therapeutic dosages. Follow-up over a period of several years has confirmed that the initial response to inhaled beclomethasone can be maintained in most patients. Recent studies indicate that beclomethasone dipropionate 400μg daily is equally effective when administered in 2 or 4 divided doses in patients with stable asthma, but it is likely that the lower frequency of administration will be less effective when the asthma is unstable.
Recent studies have established the usefulness and good tolerability of intranasal beclomethasone dipropionate in the treatment of perennial and seasonal rhinitis, where the drug has been shown to be more effective than intranasal sodium cromoglycate and similar in efficacy to flunisolide. Nasal polyps decrease in size during continuous treatment with intranasal beclomethasone dipropionate, but enlarge again during periods of respiratory infection.
After a decade of treatment with inhaled and intranasal beclomethasone dipropionate, there is no evidence that the drug damages the tracheobronchial lining or the nasal mucosa. Thus, the initial promise of beclomethasone dipropionate has been fulfilled. It has had an important role in asthma therapy over the past decade, which will continue into the future.
Pharmacodynamic Studies: Beclomethasone dipropionate has high topical activity but low systemic activity. In asthmatic patients, the inhaled drug has little immunosuppressive effect and causes minimal changes in circulating leucocytes and eosinophils. Although antigen-induced type I immediate asthmatic and nasal reactions are not inhibited by prechallenge administration of single doses of beclomethasone dipropionate, regular treatment for 1 week prior to antigen challenge inhibits such reactions in some patients.
Substitution of inhaled beclomethasone dipropionate for oral maintenance corticosteroids in patients with asthma generally results in an improvement in adrenal function when the oral steroids have been administered daily, but there is less evidence of improved adrenal function when inhaled beclomethasone dipropionate is substituted for alternate-day oral steroids. However, other systemic adverse effects associated with long term use of oral steroids rarely occur with inhaled beclomethasone dipropionate. Some recent studies have demonstrated that usual therapeutic doses of inhaled beclomethasone dipropionate may cause some adrenal suppression in children compared with that in asthmatic patients not receiving corticosteroid therapy, although the findings have not been consistent between studies. There was no evidence of adrenal suppression in patients with rhinitis who were treated with intranasal beclomethasone dipropionate.
Histological and electron microscope studies of the bronchial mucosa, and histological studies of the nasal mucosa, of patients treated for several years with topical beclomethasone dipropionate showed no evidence of mucosal damage due to administration of the drug.
Pharmacokinetic Studies: Beclomethasone dipropionate, although well absorbed by the oral route, possesses relatively low systemic activity after oral administration because of metabolic inactivation during its passage through the liver.
Therapeutic Trials: Studies published since inhaled beclomethasone dipropionate was first reviewed in the Journal have confirmed its efficacy in the treatment of asthma in steroid-dependent asthmatics and in patients with asthma not requiring maintenance oral corticosteroids. Long term controlled studies and open follow-up studies have demonstrated that the initial response achieved after several weeks of treament with inhaled beclomethasone dipropionate is maintained in most patients and that reinstitution of continuous maintenance systemic corticosteroids is seldom necessary in previously steroid-dependent patients once they have been replaced by the inhaled steroid.
In comparative trials, inhaled beclomethasone dipropionate 400μg daily in 4 divided doses was similar in efficacy to budesonide 200μg twice daily (when compared at a time when the asthma was stable), betamethasone valerate 400μg daily or dexamethasone isonicotinate 1000/μg daily. However, dexamethasone caused more adrenal suppression than beclomethasone dipropionate.
Although early studies generally failed to record any objective benefit from an increase in the dose of inhaled beclomethasone to 800μg daily or above, more recent trials have adequately demonstrated that some adult patients with severe chronic asthma whose disease is not satisfactorily controlled by beclomethasone dipropionate 400μg daily derive further clinical benefit from an increase in dosage of the inhaled steroid. The higher doses were in some instances associated with evidence of adrenal suppression, particularly in patients treated with beclomethasone dipropionate 2000μg daily, but this was often outweighed by the improvement in the control of their asthma.
Studies in patients with stable asthma have failed to show any objective benefit from administration of salbutamol before each dose of inhaled beclomethasone dipropionate or from concurrent administration of sodium cromoglycate. Similarly, dry-powder inhalation of beclomethasone dipropionate generally appeared to offer no advantages over the aerosol preparation in adults or children, including those patients with a mediocre or poor technique with the conventional aerosol, although some investigators considered the powder preparation to be more effective in some patients. Formal studies indicate that twice daily administration of inhaled beclomethasone dipropionate is similar in efficacy to the same dose administered 4 times daily in adults and children with stable asthma adequately controlled by beclomethasone dipropionate 400μg daily in addition to their usual bronchodilator therapy. However, there is evidence that it may not be assumed that twice daily doses of the drug are as effective as more frequent administration when the asthma is unstable.
The efficacy of intranasal beclomethasone dipropionate in the treatment of perennial and allergic seasonal rhinitis has been studied in numerous placebo-controlled trials and in comparisons with sodium cromoglycate, flunisolide and budesonide. On the basis of subjective changes in the severity of nasal symptoms, intranasal beclomethasone dipropionate has consistently been more effective than placebo or sodium cromoglycate, not significantly different from flunisolide and, in 1 study, less effective than an equal dose of budesonide. A decrease in the size of nasal polyps has been noted in patients treated for several months with intranasal beclomethasone dipropionate, but the drug was ineffective in relieving symptoms of severe rhinosinusitis or in diminishing persistent middlear effusion. There was no significant difference in the efficacy of intranasal beclomethasone dipropionate administered as a powder or an aerosol in nasal polyposis or when given once, twice or 4 times daily in patients with seasonal rhinitis. However, further studies are needed to determine the optimum frequency of administration in perennial rhinitis and in nasal polyposis.
Side Effects: The most frequent side effects associated with long term use of inhaled beclomethasone dipropionate have been oropharyngeal candidiasis, hoarseness and/or sore throat. Clinical thrush has seldom become a major problem as it has usually been readily controlled with topical antifungal drugs, and has only occasionally necessitated withdrawal of therapy. The incidence of hoarseness and sore throat, like that of oropharyngeal candidiasis, has varied considerably between studies, due in part to the different methods of eliciting side effect data.
In the first few years after the introduction of inhaled beclomethasone dipropionate, there was some concern that the drug may increase the incidence of respiratory infections. However, suitably designed studies have revealed no evidence of an increase in chest infections during long term treatment.
Symptoms indicative of systemic corticosteroid withdrawal and exacerbation of atopic conditions continue to occur when inhaled beclomethasone dipropionate is substituted for oral maintenance steroids, but atopic conditions can usually be controlled by appropriate topical therapy and seldom necessitate reinstitution of oral corticosteroids. The appearance of such side effects attests to the lack of systemic effect of usual therapeutic doses of inhaled beclomethasone dipropionate.
Experience with ‘high dose’ inhaled beclomethasone dipropionate indicates that long term treatment with doses higher than 1000μg daily may cause some adrenal suppression, but this is generally outweighed by the additional symptomatic benefit.
Intranasal beclomethasone dipropionate 400μg daily is well tolerated when used to treat perennial rhinitis, allergic seasonal rhinitis or nasal polyposis. The most commonly reported side effects of nasal irritation, sneezing, slight epistaxis and headache have generally occurred with similar frequency during treatment with either the active drug or its vehicle.
Dosage and Administration: The usual maintenance dose of inhaled beclomethasone dipropionate in the treatment of asthma is 10μg (2 inhalations) 2, 3 or 4 times daily in adults and 50 to 100μg 2, 3 or 4 times daily in children. In adults whose asthma is not adequately controlled with usual doses, daily doses of up to 2000μg have been used from an aerosol delivering 250μg per actuation.
In the treatment of perennial or seasonal rhinitis, the recommended dosage in children and adults is 50μg in each nostril 4 times daily, although 100μg twice daily is often used.
KeywordsAsthma Budesonide Beclomethasone Nasal Polyposis Beclomethasone Dipropionate
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