Comparable efficacy and tolerability of formoterol (Foradil) administered via a novel multi-dose dry powder inhaler (Certihaler) or the Aerolizer dry powder inhaler in patients with persistent asthma

BACKGROUND: For maximum treatment compliance there is a need to provide asthma patients with devices that suit their particular preferences. The Foradil Certihaler is a novel multi-dose dry powder inhaler developed to increase the choice of devices available. OBJECTIVES: To evaluate the safety and efficacy of formoterol administered via the Foradil Certihaler, or via the single-dose inhaler Foradil Aerolizer. METHODS: This was a randomized, placebo-controlled, double-dummy, incomplete block crossover, dose-ranging and pharmacokinetic study in patients with persistent asthma. Sixty-seven patients (mean 48.0 years) were randomized to formoterol 5, 10, 15 and 30 microg twice daily via the Certihaler, 12 microg formoterol b.i.d. via the Aerolizer, or placebo in four 1-week double-blind treatment periods separated by 1-week single-blind washouts. RESULTS All formoterol doses delivered via the Certihaler or the Aerolizer significantly increased FEV(1) compared with placebo (p < 0.0001). Formoterol demonstrated an onset of action of <3 min. All active treatments were well tolerated. Tremor was the most common adverse event and was more pronounced at high doses. At lower doses the incidence of tremor with the Certihaler was similar to that observed with placebo or the Aerolizer. The pharmacokinetic evaluation comprised 41 patients (mean 45.9 years). Urinary excretion of unchanged formoterol and total formoterol increased with dose delivered via the Certihaler. The optimum dose of formoterol via the Certihaler was 10 microg. Conclusion: Delivery of formoterol via the Certihaler or Aerolizer combines rapid relief with enduring control and provides convenient bronchodilation in patients with persistent asthma.     

Efficacy and safety of high-dose budesonide/formoterol (Symbicort) compared with budesonide administered either concomitantly with formoterol or alone in patients with persistent symptomatic asthma

OBJECTIVE AND BACKGROUND: Budesonide/formoterol 160/4.5 microg, two inhalations bd, is an effective and well-tolerated maintenance therapy for patients not controlled on inhaled corticosteroids alone. The authors assessed the efficacy and safety of a higher dose of budesonide/formoterol in patients with persistent symptomatic asthma. METHODS: This was a 24-week, double-blind, double-dummy randomized study. Budesonide/formoterol 320/9 microg, two inhalations bd (1280/36 microg/day), was compared with corresponding doses of budesonide during weeks 1-12 and budesonide plus formoterol via separate inhalers during weeks 1-24. Efficacy was assessed during weeks 1-12; the primary variable was morning PEF. Safety was assessed over weeks 1-24. RESULTS: Patients (n=456; aged 12-79 years) had a mean reversibility in FEV1 of 28% and mean pre-study inhaled corticosteroid dose of 1038 microg/day. Mean morning PEF increased by 37 L/min and 36 L/min with budesonide/formoterol and budesonide plus formoterol, respectively, versus an increase of 5 L/min with budesonide (P<0.001 for both vs. budesonide). Budesonide/formoterol increased time to first mild exacerbation (P<0.005) versus budesonide. Budesonide/formoterol and budesonide plus formoterol had similar efficacy. All treatments were well tolerated and the incidence of class-related adverse events was similarly low in all groups. Changes in serum potassium and plasma cortisol were comparable across treatments. CONCLUSIONS: High-dose budesonide/formoterol (320/9 microg, two inhalations bd) is effective and well tolerated in patients with persistent symptomatic asthma. The findings also support the safety of regular high-dose formoterol (36 microg/day).     

Single-dose comparison of formoterol (Oxis) Turbuhaler 6 microg and formoterol Aerolizer 12 microg in moderate to severe asthma: a randomised,crossover study

Formoterol inhaled via Turbuhaler (Oxis) or Aerolizer (Foradil) produces fast and long-lasting bronchodilation in asthmatic patients. While formoterol Turbuhaler provides sustained efficacy for > or =12h at a metered dose of 6 microg (delivered dose 4.5 microg), the recommended metered dose for formoterol Aerolizer is 12 microg (delivered dose unknown). This difference may be attributable to improved lung deposition with the Turbuhaler. This open, randomised, crossover study compared the effects of a single metered dose of formoterol Turbuhaler 6 microg and formoterol Aerolizer 12 microg in 16 patients with stable moderate-to-severe asthma. Pulmonary function, assessed by measuring specific airway conductance (sGaw), was determined at intervals of < or =8h post-inhalation of each drug on separate study days. Both inhalers increased sGaw at all time points. There were no significant differences between the two formulations in onset of activity, maximum effect, duration of effect or area under the response curve. Furthermore, both treatments were well tolerated with no differences in adverse events, blood pressure or heart rate; thus the formoterol Turbuhaler may, therefore, have an improved therapeutic index. This pilot study indicates that the same clinical effect can be achieved with half the metered dose (6 microg) of formoterol Turbuhaler compared with formoterol Aerolizer (12 microg).     

Clinically equivalent bronchodilatation achieved with formoterol delivered via Easyhaler and Aerolizer

BACKGROUND: User-friendly devices for the delivery of asthma drugs are needed to enhance treatment compliance. Formoterol inhalation powder has been developed to Easyhaler multidose powder inhaler to enable the treatment of all asthma severities with the same device. OBJECTIVES: This double-blind, double-dummy, single- dose, placebo-controlled, cross-over study aimed to demonstrate the non-inferiority of the bronchodilating effect of formoterol 12 microg delivered via Easyhaler versus via Aerolizer. In addition, dose responses following placebo, 12-microg and 48-microg doses of formoterol via Easyhaler were compared. Furthermore, onset and duration of action, and safety of formoterol inhaled using the two inhalers were compared. METHODS: Sixty-seven adult asthmatic subjects showing >or=15% increase in forced expiratory volume in 1 s (FEV(1)) after short-acting sympathomimetic inhalation were enrolled and completed the study. The study comprised screening and 4 treatment days, with each subject inhaling a single 12-mug dose of formoterol via Easyhaler, a 12-microg dose via Aerolizer, a 48-microg dose via Easyhaler or placebo. Repeat spirometry and vital sign measurements were performed for 12 h during treatment days. The primary efficacy variable was the area under the flow volume curve (AUC(0-12)) of FEV(1). Secondary efficacy variables comprised maximum FEV(1 )(FEV(1max)), forced vital capacity (FVC), and the need of rescue medication during the treatment days. Safety was evaluated by determining blood pressure, heart rate and the number of adverse events (AEs). RESULTS: Results showed the non-inferiority of the bronchodilating effect of 12 microg formoterol via Easyhaler compared to Aerolizer. The Easyhaler-Aerolizer ratio for AUC(0-12) of FEV(1 )was 0.991 (95% confidence interval from 0.969 to 1.013). No statistically significant differences emerged for secondary efficacy variables. A statistically significant dose response was seen following placebo, 12- and 48-microg doses in FEV(1). No safety differences emerged for the 12-microg dose inhaled via Easyhaler or Aerolizer, but the incidence of AEs was higher following formoterol 48 microg and placebo treatments. CONCLUSIONS: Formoterol delivered via Easyhaler was therapeutically equivalent to Aerolizerat the 12-microg dose. The 48-microg dose via Easyhaler demonstrated statistically significantly greater bronchodilation but showed an increased occurrence of AEs.     

Efficacy and safety of formoterol delivered via a new multidose dry powder inhaler (Certihaler) in adolescents and adults with persistent asthma.

Our objective was to compare the efficacy and safety of formoterol (Foradil) delivered via a novel multidose dry powder inhaler (Certihaler) with placebo and albuterol [pressurized metered-dose inhaler (pMDI)], in patients with persistent asthma. After a 2-week run-in phase, 265 patients (13-81 years) previously treated with regular/PRN bronchodilators for persistent asthma were randomized to 12 weeks' double-blind treatment with formoterol 10 microg BID via Certihaler (n = 86), albuterol 180 microg QID via pMDI (n = 88) or placebo (n = 91). The primary efficacy variable was 12-hour AUC of FEV1 after 12 weeks' treatment. Secondary efficacy variables included peak expiratory flow (PEF), rescue bronchodilator medication use, asthma-related quality of life (Juniper Mini Asthma Quality of Life Questionnaire), and asthma symptom scores. Formoterol via the Certihaler had an onset of action within 5 minutes and was associated with a clinically relevant and statistically significant increase in 12-hour AUC of FEV1 after 12 weeks' treatment compared with placebo and albuterol (p < 0.001 and p < 0.05, respectively). Average PEF was significantly superior for formoterol compared with placebo and albuterol (p < 0.001 and p < 0.05, respectively). Compared with placebo, rescue albuterol use during the study was significantly lower for formoterol (p < 0.01) and was accompanied by a trend toward an improvement in asthma-related quality of life (QoL). Asthma symptom scores improved to a similar extent for all treatment groups. Treatment with formoterol via Certihaler was well tolerated. Formoterol 10 microg BID, delivered via the novel Certihaler device, is well tolerated and provides rapid, long-lasting, and clinically superior bronchodilation to placebo and albuterol via pMDI in patients with persistent asthma.     

Efficacy and safety of a new pressurised metered-dose inhaler formulation of budesonide/formoterol in children with asthma: a superiority and therapeutic equivalence study

AIM: This paediatric asthma study evaluated the efficacy and safety of a novel hydrofluoroalkane pressurised metered-dose inhaler (pMDI) formulation of budesonide/formoterol versus budesonide pMDI and budesonide/formoterol dry-powder inhaler (DPI). METHODS: The study was a 12-week, multinational, double-blind trial involving children (aged 6-11 years) with symptomatic asthma on inhaled corticosteroids (375-1000 microg/day), with a history of exercise-induced bronchoconstriction and peak expiratory flow (PEF) > or =50% of predicted. Patients were randomised (two inhalations twice daily) to budesonide pMDI 100 microg, budesonide/formoterol DPI 80/4.5 microg or budesonide/formoterol pMDI 80/4.5 microg. The primary endpoint was change from baseline in morning PEF. RESULTS: Overall, 622 patients were randomised. Increases in morning PEF with budesonide/formoterol pMDI and budesonide/formoterol DPI were therapeutically equivalent (29.5 versus 30.2l/min, respectively; 95% confidence interval: -6.0 to 4.6; P=0.78, also confirmed by per-protocol analysis). Improvements in secondary efficacy endpoints with both budesonide/formoterol formulations were not significantly different. Significantly greater improvement was achieved with budesonide/formoterol pMDI versus budesonide pMDI for morning PEF (+9.6l/min; P<0.001) and other lung function parameters. The safety profile of budesonide/formoterol pMDI was favourable and similar to that of budesonide/formoterol DPI and budesonide pMDI. CONCLUSION: Budesonide/formoterol, administered via the therapeutically equivalent hydrofluoroalkane pMDI or DPI, is an effective and well-tolerated treatment for children with asthma.     

Bronchoprotective and bronchodilator effects of an HFA pMDI vs. a CFC pMDI and a DPI containing formoterol in asthma patients

In this double-blind, placebo-controlled, crossover study we compared the bronchoprotective effects of formoterol 12 microg inhaled via an HFA-134a inhaler (Modulite HFA) versus a CFC and a DPI device in 38 patients with mild-to-moderate persistent asthma. All three formoterol preparations significantly increased methacholine PD20 and FEV1 and improved small airway function parameters compared with placebo (p < 0.001). No significant differences were observed between formoterol formulations. In conclusion, Modulite HFA formoterol was found to be an effective and well tolerated treatment in patients with asthma, with comparable efficacy to current formoterol preparations.     

Safety and tolerability of high-dose formoterol (Aerolizer) and salbutamol (pMDI) in patients with mild/moderate, persistent asthma

This double-blind, double-dummy, crossover study evaluated the tolerability of high-dose formoterol and salbutamol. Sixteen adults with mild/moderate persistent asthma (FEV1 > or = 70% predicted) were randomized to receive either formoterol 36 microg three times daily (TID) at 5-h intervals via Aerolizer (total daily dose 108 microg), or salbutamol 600 microg TID via pressurized metered-dose inhaler (total daily dose 1800 microg) for 3 consecutive days. After a 3-7-day washout period patients received the other treatment. FEV1 was measured 15 min pre-dose and 2 h post-dose. Both formoterol and salbutamol were associated with decreased plasma potassium (mean of minimum values: 3.4 and 3.6 mmol/L, respectively; P<0.001), increased serum glucose (mean of maximum values: 8.3 and 7.9 mmol/L, respectively; P=0.021), and small increases in mean QTc interval (mean of maximum values: 428.8 and 417.4 ms, respectively; P<0.001). However, none of these effects was clinically significant. Both treatments increased FEV1 to a mean maximum of 4.6 L (P=0.613), but the mean FEV1 AUC(0-72)h for formoterol was significantly greater than for salbutamol (302.2 L h, vs. 277.4 L h; P<0.001). No patients discontinued due to treatment-related adverse events. High-dose formoterol via Aerolizer did not produce any clinically significant systemic effects in patients with mild/moderate asthma.     

Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone.

Budesonide/formoterol in a single inhaler was compared with budesonide alone, and with concurrent administration of budesonide and formoterol from separate inhalers, in patients with asthma, not controlled with inhaled glucocorticosteroids alone. In this 12-week, double-blind, randomized, double-dummy study, 362 adult asthmatics (forced expiratory volume in one second 73.8% of predicted, inhaled glucocorticosteroid dose 960 microg x day(-1)) received single inhaler budesonide/formoterol (Symbicort Turbuhaler) 160/4.5 microg, two inhalations b.i.d., or corresponding treatment with budesonide, or budesonide plus formoterol via separate inhalers. There was a greater increase in morning peak expiratory flow (PEF) with single-inhaler (35.7 L x min(-1)) and separate-inhaler (32.0 L x min(-1)) budesonide and formoterol, compared with budesonide alone (0.2 L x min(-1); p<0.001, both comparisons); the effect was apparent after 1 day (p<0.001 versus budesonide, both comparisons). Similarly, evening PEF, use of rescue medication, total asthma symptom scores and percentage of symptom-free days improved more with both single inhaler and separate inhaler therapy than with budesonide alone, as did asthma control days (approximately 15% more, p<0.001 versus budesonide, both comparisons, with a marked increase in the first week). All treatments were well tolerated and the adverse event profile was similar in all three treatment groups. It is concluded that single inhaler therapy with budesonide and formoterol is a clinically effective and well-tolerated treatment for patients with asthma that is not fully controlled by inhaled glucocorticosteroids alone.     

Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial

STUDY OBJECTIVE: To compare a novel asthma management strategy--budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief--with a higher dose of budesonide plus as-needed terbutaline. METHODS: This was a 6-month, randomized, double-blind, parallel-group study in patients with mild-to-moderate asthma (n = 697; mean age, 38 years [range, 11 to 79 years]; mean baseline FEV1, 75% of predicted; mean inhaled corticosteroid [ICS] dosage, 348 microg/d). Following a 2-week run-in period, all patients received two blinded, dry powder inhalers, one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms. Patients were randomized to receive either budesonide/formoterol (80 microg/4.5 microg, two inhalations qd) for maintenance plus additional inhalations as needed for symptom relief, or budesonide (160 microg, two inhalations qd) for maintenance medication plus terbutaline (0.4 mg) as needed. The primary efficacy variable was morning peak expiratory flow (PEF). RESULTS: Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide (increases of 34.5 L/min vs 9.5 L/min, respectively; p < 0.001). The risk of having a severe exacerbation (hospitalization/emergency department [ED] treatment, oral steroids for asthma, or a > or = 30% decrease from baseline in morning PEF on 2 consecutive days) was 54% lower with budesonide/formoterol vs budesonide (p = 0.0011). Budesonide/formoterol patients experienced 90% fewer hospitalizations/ED treatments due to asthma than budesonide patients (1 vs 10, respectively; p = 0.026). The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group (mean dose, 240 microg/d vs 320 microg/d, respectively) and with 77% fewer oral steroid treatment days vs budesonide (114 days vs 498 days, respectively). Both treatments were well tolerated. CONCLUSIONS: Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline.     

Efficacy and safety of formoterol Turbuhaler when added to inhaled corticosteroid treatment in children with asthma

This double-blind, placebo-controlled, randomized, parallel-group, multicenter study was conducted in 302 children aged 6-11 years with asthma not optimally treated with inhaled corticosteroids alone. Patients continued with their existing dose of inhaled corticosteroids and in addition received placebo, formoterol 4.5 microg or formoterol 9 microg b.i.d., for 12 weeks (all delivered via Turbuhaler). Terbutaline was available as reliever medication. The primary efficacy variable was change from baseline in morning peak expiratory flow (PEF); secondary efficacy variables included forced expiratory volume in 1 sec (FEV(1)), serial PEF measured over 12 hr, evening PEF, asthma symptom score, and quality of life. Compared with placebo, formoterol 4.5 microg and 9 microg improved morning PEF by 8 l/min (P = 0.035) and 11 l/min (P = 0.0045), respectively. Evening PEF and FEV(1) were also significantly increased compared with placebo, with no statistically significant difference between formoterol doses. Lung-function improvements compared with placebo were greater in the middle of the day. Twelve-hour average serial PEF after 3 months increased by 24 l/min (95% CI, 9, 39 l/min) in the formoterol 9-microg group, and by 14 l/min (95% CI, 0, 29 l/min) in the formoterol 4.5-microg group. The incidence of severe exacerbations in both formoterol groups was numerically lower than in the placebo group, indicating that formoterol may have the potential to improve exacerbation control in children. Both formoterol doses were well-tolerated, and tolerance to the drug's bronchodilator effect was not observed. Formoterol provided sustained improvements in lung function and was well-tolerated in children with asthma suboptimally treated with inhaled corticosteroids alone.     

Comparison of the effects of salmeterol and formoterol in patients with severe asthma

STUDY OBJECTIVE: Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo. However, to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma. DESIGN: We undertook a randomized, placebo-controlled, crossover study to compare 4 weeks of treatment with inhaled formoterol (12 microg twice daily) or salmeterol (50 microg twice daily) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids (i.e., > or = 1,500 microg daily) or with regular oral corticosteroid treatment. Morning pretreatment peak expiratory flow (PEF) during the last 14 days of the treatment period was the primary outcome variable. Patients recorded morning and evening pretreatment PEF, daytime and nighttime symptom scores, and any use of rescue medication. Spirometry and bronchial reversibility were performed after each treatment. RESULTS: Forty-two nonsmoking patients (29 women; mean age, 45 +/- 2 years; mean [+/- SEM] FEV(1), 61.8 +/- 3.4% of predicted) took part in the trial, and 27 patients completed the trial. The mean morning PEF was greater in patients receiving formoterol (mean increase, 14.4 L/min; 95% confidence interval [CI]. 0.2 to 28.6) or salmeterol (mean increase, 14.8 L/min; 95% CI, 0.5 to 29.1) compared with those receiving placebo, but there was no difference between these treatments. There were no significant treatment effects for any of the secondary outcome variables (i.e., FEV(1,) FVC, mean evening PEF, mean daytime symptom score, or nighttime symptom score). CONCLUSION: We conclude that the long-acting beta(2)-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs.     

Safety of formoterol after cumulative dosing via Easyhaler and Aerolizer

This randomised, double-blind, double-dummy, cumulative dose, multicentre crossover study aimed to demonstrate non-inferiority in safety of formoterol delivered via Easyhaler versus Aerolizer. The secondary objective was to compare the efficacy of the devices. Thirty-three adult asthmatic subjects entered the study and 32 completed it. The study comprised screening and two study days, with each subject inhaling 96 microg (12, 12, 24 and 48 microg) cumulative dose of formoterol via the study inhalers. Serum potassium (S-K+), vital signs and spirometry were performed at baseline, 1h after each dose and additionally 4h after the last dose. The primary safety variable was S-K+. Secondary safety variables were heart rate, corrected QT interval, blood pressure, serum glucose and adverse events. Spirometry was assessed to evaluate efficacy. The results showed non-inferiority in safety of formoterol inhaled via Easyhaler compared to Aerolizer. The adjusted treatment difference in the S-K+ values after 96 microg cumulative dose of formoterol was 0.14 mmol/L being clearly above the pre-determined lower limit of the non-inferiority criterion of -0.2 mmol/L. There were dose-related changes in secondary efficacy variables after both treatments. The changes were comparable in most of the parameters but heart rate was statistically significantly higher and decrease in diastolic blood pressure greater after formoterol via Aerolizer than that via Easyhaler. The occurrence of adverse events was dose-related, the most common events being tremor, hypokalaemia, headache and palpitation. The spirometry results showed no statistically significant difference in efficacy between the treatments. In conclusion, formoterol delivered via Easyhaler was as safe as via Aerolizer.     

The Novolizer®

The Novolizer is a multidose, refillable, breath-actuated dry powder inhaler that delivers up to 200 metered doses of drug from a single cartridge. It has a multiple-feedback control mechanism to ensure that the inhalation was performed correctly. In randomized studies, almost all patients with asthma or COPD using the Novolizer, including those using the device for the first time and children, were able to generate sufficient peak inspiratory flow rates (PIFRs) to overcome the trigger threshold of the device. Comparative studies have shown that patients generate significantly higher PIFR through the Novolizer than through the Turbuhaler. At PIFR of 54-99 L/min through the Novolizer, the median deposition of budesonide in the lungs of healthy volunteers was 19.9-32.1%. Two randomized, double-blind trials in patients with asthma showed that the clinical efficacy of drugs delivered through the Novolizer in terms of improvement in FEV(1) was at least as good as that of an identical treatment regimen delivered through the Aerolizer (for formoterol) or the Sultanol (for albuterol [salbutamol]). Similarly, therapeutic equivalence was also shown between budesonide delivered through the Novolizer and that through the Turbuhaler in patients with COPD or asthma in a randomized, nonblind study. Device-related adverse events were not reported in patients using the Novolizer in therapeutic trials and in a large (n > 3000) post-marketing surveillance study. Overall, the Novolizer was well accepted, with an improved compliance in 80% of patients that was attributable to the control mechanisms of the device.     

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.     

Comparable long-term safety and efficacy of a novel budesonide/formoterol pressurized metered-dose inhaler versus budesonide/formoterol Turbuhaler in adolescents and adults with asthma

Budesonide/formoterol in one inhaler is an established therapy for asthma and chronic obstructive pulmonary disease. The long-term safety and efficacy profile of a novel hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) formulation of budesonide/formoterol was compared with that of budesonide/formoterol in a dry powder inhaler (DPI; Turbuhaler). This multinational, 52-week, randomized, open, parallel-group study included patients aged > or = 12 years with asthma who had a forced expiratory volume in 1s (FEV1)> or = 50% of predicted normal; all patients used inhaled corticosteroids (400-1200 microg/day) and needed additional short-acting beta 2-agonist therapy. Patients were randomized to receive budesonide/formoterol pMDI or DPI 160/4.5 microg, two inhalations twice daily. Safety endpoints included assessment of adverse events and laboratory parameters. Efficacy endpoints included change from baseline in FEV1 and time to first severe asthma exacerbation. Overall, 673 patients (446pMDI, 227DPI) were included. There were no clinically significant differences between treatment groups in the nature, incidence or severity of adverse events or laboratory parameters. The number of patients experiencing adverse events was comparable in the pMDI (332/446 [74%]) and DPI (175/227 [77%]) groups; the most commonly reported adverse event was upper respiratory tract infection. The proportion of patients discontinuing as a result of adverse events was low in both groups (pMDI 12/446 [3%], DPI 2/227 [1%]). Lung function was improved to a similar extent in both groups and there was no detectable difference in time to first severe asthma exacerbation. The novel HFA pMDI formulation of budesonide/formoterol is an equally well tolerated and effective treatment for adults and adolescents with asthma as the budesonide/formoterol DPI.     

Safety and tolerability of high-dose formoterol (via Aerolizer) and salbutamol in patients with chronic obstructive pulmonary disease

To evaluate the safety and tolerability of high-dose formoterol and salbutamol in patients with chronic obstructive pulmonary disease (COPD). In this two-way crossover, double-blind, double-dummy study, 17 adults with mild-to-moderate COPD were randomized to receive either formoterol 24 microg (2 x 12 microg via Aerolizer), or salbutamol 600 microg (6 x 100 microg via metered-dose inhaler), and the appropriate double-dummy q.i.d. at 4-h intervals for 3 consecutive days (total daily dose: 96 and 2400 microg, respectively). After a 4-7-day washout period, patients were switched to the other treatment. Treatment with high-dose formoterol and salbutamol was equally well tolerated, with no reports of serious adverse events. Both agents were associated with decreased plasma potassium (mean minimum values: 3.4 and 3.3 mmol/l for formoterol and salbutamol, respectively; P=0.914), increased serum glucose (mean maximum values: 9.0 and 8.7 mmol/l, respectively; P=0.373), and small increases in mean QTc interval (mean maximum 439 ms with both treatments; P=0.813). No clinically relevant between-treatment differences in adverse events or laboratory values occurred. Both drugs improved lung function (mean maximum forced expiratory volume in 1s [FEV(1)] 2.6 l with both treatments; P=0.624), with the improvement being significantly greater with formoterol than with salbutamol on all 3 days of treatment (mean area under the curve [AUC](0-24 h) of FEV(1) formoterol vs. salbutamol on days 1-3, all P<0.05). High-dose formoterol via Aerolizer (up to 96 microg/day) has a comparable tolerability profile to that of salbutamol in patients with mild-to-moderate COPD.     

A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease

BACKGROUND: Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1s (FEV(1)) were compared for 15 microg nebulized arformoterol and 12 and 24 microg racemic formoterol (containing 6 and 12 microg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI). METHODS: An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV(1) 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 microg) and racemic formoterol DPI (12 and 24 microg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV(1) from baseline on day 14 of each treatment period. RESULTS: At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 microg arformoterol (C(max): 6.5 pg/mL; AUC(0-tau): 56.5 pgh/mL) and 12 microg racemic formoterol DPI (C(max): 6.2 pg/mL; AUC((0-)(tau)()): 46.3 pgh/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C(max) and AUC((0-)(tau)()) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 microg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C(max) (10.8 pg/mL) and AUC((0-)(tau)()) (83.6 pgh/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV(1) was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 microg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV(1). CONCLUSIONS: In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 microg arformoterol and 12 microg racemic formoterol DPI, and 40% lower than 24 microg racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations.     

Once versus twice daily formoterol via Novolizer for patients with moderate to severe COPD--a double-blind, randomised, controlled trial

STUDY OBJECTIVES: To evaluate in patients with moderate to severe COPD whether a single morning dose of 24 microg formoterol from the Novolizer is not inferior to two divided doses of 12 microg formoterol inhaled in the morning and in the evening. DESIGN: Randomised, double blind, active-controlled, parallel-group, multi-centre study with a 2-week run-in period and a 12-week treatment phase. SETTING: Forty-seven outpatient centres in Germany, including private practices. PARTICIPANTS: N=321 symptomatic patients with moderate to severe COPD aged 40-70 years with an FEV1 of 30-80% predicted and the requirement of 3-12 actuations of salbutamol per day on 5 days during the run-in period. TREATMENT: Eligible patients were randomised to inhale formoterol either (a) as a single 24 microg dose in the morning (OD) or (b) in two divided 12 microg doses in the morning and in the evening (b.i.d.). MEASUREMENTS AND RESULTS: The mean age was 60.3 (SD 7.3) years, and mean baseline pre-dose FEV1 was 1.5l (0.5l) or 50% (12%) of predicted, respectively. After 12 weeks of treatment, pre-dose FEV(1) improved in both groups (mean: OD, +104 ml, b.i.d., +135 ml, mean difference between groups: 31 ml). The 95% CI exceeded the pre-determined margin of 100ml by 2 ml, so that the statistical hypothesis of non-inferiority of once daily dosing was not confirmed. No statistically significant differences were seen for improvements in PEF, MEF75, MEF50, and MEF25. COPD symptoms, percentage of symptom-free days and quality of life (SGRQ) improved in both groups to a similar degree. There were no relevant differences in the incidence of adverse events. CONCLUSIONS: Based on a comparable efficacy and tolerability, the dosing schedule with formoterol via Novolizer as once daily in the morning seems to be an alternative compared to twice daily treatment. The primary endpoint suggests the equivalence of both treatment schedules from a clinical perspective. This regimen can be considered as an alternative therapeutic approach for a subgroup of COPD patients and may help to improve patient compliance.     

Once-daily dosing with budesonide/formoterol compared with twice-daily budesonide/formoterol and once-daily budesonide in adults with mild to moderate asthma

Adherence to maintenance therapy is often poor in patients with asthma. Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity. In this 12-week, randomized, double-blind, double-dummy, parallel-group study, 617 patients with mild to moderate persistent asthma (mean forced expiratory volume in 1s [FEV1] 78.5% predicted) who were not optimally controlled on inhaled corticosteroids (200-500 microg/day) were randomized to once-daily budesonide/formoterol (80/4.5 microg, 2 inhalations in the evening), twice-daily budesonide/formoterol (80/4.5 microg, 1 inhalation), or a corresponding dose of budesonide once-daily (200 microg, 1 inhalation in the evening). All patients received budesonide (100 microg twice daily) during a 2-week run-in. Changes in mean morning peak expiratory flow (PEF) were similar for od budesonide/formoterol (23.4 l/min) and twice-daily budesonide/formoterol (24.1 l/min), and both were greater than with budesonide (5.5 l/min; both P<0.001). Evening PEF, symptom-free days, reliever-free days, and asthma control days were improved with budesonide/formoterol therapy vs. budesonide (P<0.05 vs. budesonide for all variables). All treatments were well tolerated. Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma.