Inhaled Mometasone Furoate

Summary Abstract Mometasone furoate is a corticosteroid with relatively high in vitro potency. Recent randomised, double-blind, multicentre trials have assessed the efficacy of mometasone furoate delivered by dry powder inhaler over 12 weeks in adults and adolescents with mild to severe persistent asthma. Mometasone furoate 200µg twice daily or 400µg once daily in the morning or 200µg once daily in the evening improved lung function, asthma symptom scores and use of rescue medication to a significantly greater extent than placebo in patients who had previously received only short-acting inhaled β 2 -adrenoceptor agonists alone as treatment in 3 trials (n = 195 to 306). In studies in 227 to 733 patients with mild to moderate asthma who were receiving ongoing treatment with inhaled corticosteroids prior to enrolment, mometasone furoate 100 to 400µg twice daily was consistently better at improving the above indicators of asthma than placebo. Mometasone furoate 100 to 200µg twice daily was as effective as beclomethasone dipropionate 200µg twice daily or budesonide 400µg twice daily and mometasone furoate 200µg twice daily was as effective as fluticasone propionate 250µg twice daily. Mometasone furoate 400 or 800µg twice daily was also consistently more effective than placebo in reducing oral corticosteroid dosages and improving lung function and asthma symptoms in 132 patients with oral corticosteroid-dependent asthma. Once daily administration of mometasone furoate 400µg appears to be as effective at improving indicators of asthma as twice daily administration of 200µg. Patients receiving mometasone furoate ≤800 µg/day and recipients of placebo experienced a similar overall incidence of adverse events considered to be related to treatment. The most common of these events were oral candidiasis, headache, pharyngitis and dysphonia. Mometasone furoate 100 to 400µg twice daily, beclomethasone dipropionate 200µg twice daily, budesonide 400µg twice daily or fluticasone propionate 250µg twice daily were similarly tolerated. Conclusion : Inhaled mometasone furoate is well tolerated, with minimal systemic activity and is equally effective when administered as a divided dose or as a single daily dose. Use of the drug can result in a decrease in requirements for oral corticosteroids in patients with oral corticosteroid-dependent asthma and is as effective as other inhaled corticosteroids currently used in the treatment of mild to moderate persistent asthma. Thus mometasone furoate is suitable for the control of mild to severe persistent asthma in adults or adolescents. Pharmacodynamic Properties Mometasone furoate binds to the corticosteroid receptor with greater affinity than fluticasone propionate, budesonide, triamcinolone acetonide and dexamethasone. Studies of cells derived from humans show that mometasone furoate is similar in in vitro anti-inflammatory potency to fluticasone propionate and more potent than budesonide, beclomethasone dipropionate and triamcinolone acetonide. In patients with mild to moderate persistent asthma, treatment with mometasone furoate 50 or 100µg delivered by dry powder inhaler (DPI) twice daily significantly reduced bronchial hyper-responsiveness induced by adenosine monophosphate or an allergen. Mometasone furoate ≤1200 µg/day has a minimal effect on HPA axis function in patients with mild to moderate asthma as measured by the mean serum cortisol area under the plasma concentration-time curve determined over 24 hours (AUC24). All patients receiving mometasone furoate or placebo in 3 randomised, evaluator-blind, placebo-controlled trials had a normal response to an injection of tetracosactide 0.25mg. Mometasone furoate ≤1600 µg/day produced less reduction in serum cortisol AUC 24 than prednisone 10 mg/day or fluticasone propionate 880µg daily (delivered dose). Administration of mometasone furoate by DPI may lower serum cortisol AUC 24 to a greater extent than administration by metered dose inhaler (MDI), although no direct comparisons have been carried out. Pharmacokinetic Properties Very little mometasone furoate is absorbed systemically after it has been inhaled in healthy volunteers. The mean bioavailability of a single dose of mometasone furoate 400µg (delivered by DPI) is <1%. Mean plasma concentrations after this dose are below the lower limit of quantification (0.05 µg/L), the mean area under the plasma concentration-time curve from Oh to the final measurable sampling time is 0.09 µg/L · h and the peak plasma concentration is 0.05 µg/L. Systemic exposure to the drug after multiple dose administration of mometasone furoate 200 to 800 µg/day by DPI (as measured by plasma mometasone furoate concentrations) is also minimal. Most inhaled mometasone furoate is swallowed and excreted unabsorbed and unchanged in faeces. Any drug that is absorbed appears to be extensively metabolised by cytochrome P450 3A4 in the liver and excreted in the urine and/or bile. The systemic clearance of mometasone furoate 400µg after intravenous administration is 53.5 L/h, which is similar to that of other inhaled corticosteroids. Therapeutic Efficacy In patients with mild to moderate persistent asthma who had previously been using short-acting inhaled β 2 -adrenoceptor agonists alone, mometasone furoate 200µg twice daily, 400µg once daily in the morning or 200µg once daily in the evening for 12 weeks produced significantly greater improvements in forced expiratory volume in 1 second (FEV 1 ), morning peak expiratory flow rate (PEF), asthma symptom scores and use of rescue medication than placebo in 3 randomised, double-blind, multicentre trials (n = 195 to 306). Significant improvements in some parameters were seen as early as 24 hours after initiation of mometasone furoate 400µg once daily in the morning. Mometasone furoate 100 to 400µg twice daily consistently improved FEV 1 , PEF, symptom scores and rescue medication use to a significantly greater extent than placebo in randomised, double-blind, multicentre studies (n = 227 to 365) in patients with mild to moderate asthma who had received inhaled corticosteroids before study enrolment. In a similar patient group, mometasone furoate 200 or 400µg twice daily was significantly more effective than budesonide 400µg twice daily in improving some indicators of asthma in a randomised, evaluator-blind, multicentre trial (n = 731) and mometasone furoate 100 and 200µg twice daily was generally as effective as beclomethasone dipropionate 200µg twice daily in a well designed study (n = 365). Mometasone furoate 200µg twice daily was as effective as fluticasone propionate 250µg twice daily in a randomised, evaluator-blind study (n = 733). In another well designed, 12-week study (n = 132) conducted in adults and adolescents with moderate to severe persistent asthma dependent on oral corticosteroid treatment, mometasone furoate 400 or 800µg twice daily was consistently more effective than placebo in reducing oral prednisone dosages and improving lung function and asthma symptoms. Further reductions in oral corti-costeroid dosages were observed for the duration of a 9-month, noncomparative extension of this study where all patients were initially switched to mometasone furoate 800µg twice daily. Administering mometasone furoate 400µg once daily in the morning is generally as effective at improving indicators of asthma as administering 200µg of the drug twice daily in patients with mild to moderate persistent asthma who had previously received short-acting inhaled β 2 -adrenoceptor agonists or inhaled corticosteroid therapy. Evening administration of once daily mometasone furoate 200µg appears to be more effective than administration of this dosage in the morning. Tolerability Mometasone furoate delivered by DPI is well tolerated: the overall incidence of treatment-related adverse events was generally similar in patients receiving mometasone furoate ≤800 µg/day (18 to 28%) and patients receiving placebo (19 to 22%) in 3 well designed studies. Mometasone furoate 200µg twice daily or 400µg once daily produced the same incidence of adverse events. Patients receiving mometasone furoate ≤800 µg/day for 12 weeks most commonly experienced oral candidiasis (1 to 15%), headache (2 to 11%), pharyngitis (1 to 10%) and dysphonia (1 to 5%). Fewer than 3% of mometasone furoate or placebo recipients withdrew from studies because of an adverse event possibly or probably related to treatment. The overall incidence of adverse events related to treatment was similar with mometasone furoate 100 to 400µg twice daily and beclomethasone dipropionate 200µg twice daily, budesonide 400µg twice daily or fluticasone propionate 250µg twice daily in comparative trials. Mometasone furoate ≤1600 µg/day is well tolerated for up to 1 year of treatment according to a noncomparative study. Dosage and Administration Mometasone furoate administered by Twisthaler™ DPI is recommended for the prophylactic management of mild to severe asthma in adults and adolescents ≥12 years. Mometasone furoate 400µg once daily (metered dose) is the recommended starting dosage in patients previously maintained on bronchodilators alone or inhaled corticosteroids. Some patients may maintain better control if they receive mometasone furoate in divided doses (200µg twice daily). The drug should be titrated to the lowest dose at which effective control of asthma is maintained. Patients with severe asthma receiving systemic corticosteroids can initially receive mometasone furoate at a dosage of 400µg twice daily (the maximum recommended dose). At intervals of 1 to 2 weeks, the systemic corticosteroid can then be slowly withdrawn by no more than 2.5 mg/day of prednisone (or equivalent) at a time, in conjunction with patient monitoring. Once reduction of systemic corticosteroid is complete, mometasone furoate can be titrated to the lowest effective dose.