Chlorofluorocarbon Metered-dose Inhaler Research Articles

Inhaled corticosteroids in children with persistent asthma: effects of different drugs and delivery devices on growth.

Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. Although treatment with ICS is generally considered to be safe in children, the potential adverse effects of these drugs on growth remains a matter of concern for parents and physicians. To assess the impact of different inhaled corticosteroid drugs and delivery devices on the linear growth of children with persistent asthma. We searched the Cochrane Airways Trials Register, which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, Embase, CINAHL, AMED and PsycINFO. We handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases, or contacted the manufacturer, to search for potential relevant unpublished studies. The literature search was initially conducted in September 2014, and updated in November 2015, September 2018, and April 2019. We selected parallel-group randomized controlled trials of at least three months' duration. To be included, trials had to compare linear growth between different inhaled corticosteroid molecules at equivalent doses, delivered by the same type of device, or between different devices used to deliver the same inhaled corticosteroid molecule at the same dose, in children up to 18 years of age with persistent asthma. At least two review authors independently selected studies and assessed risk of bias in included studies. The data were extracted by one author and checked by another. The primary outcome was linear growth velocity. We conducted meta-analyses using Review Manager 5.3 software. We used mean differences (MDs) and 95% confidence intervals (CIs ) as the metrics for treatment effects, and the random-effects model for meta-analyses. We did not perform planned subgroup analyses due to there being too few included trials. We included six randomized trials involving 1199 children aged from 4 to 12 years (per-protocol population: 1008), with mild-to-moderate persistent asthma. Two trials were from single hospitals, and the remaining four trials were multicentre studies. The duration of trials varied from six to 20 months.One trial with 23 participants compared fluticasone with beclomethasone, and showed that fluticasone given at an equivalent dose was associated with a significant greater linear growth velocity (MD 0.81 cm/year, 95% CI 0.46 to 1.16, low certainty evidence). Three trials compared fluticasone with budesonide. Fluticasone given at an equivalent dose had a less suppressive effect than budesonide on growth, as measured by change in height over a period from 20 weeks to 12 months (MD 0.97 cm, 95% CI 0.62 to 1.32; 2 trials, 359 participants; moderate certainty evidence). However, we observed no significant difference in linear growth velocity between fluticasone and budesonide at equivalent doses (MD 0.39 cm/year, 95% CI -0.94 to 1.73; 2 trials, 236 participants; very low certainty evidence).Two trials compared inhalation devices. One trial with 212 participants revealed a comparable linear growth velocity between beclomethasone administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) and beclomethasone administered via chlorofluorocarbon-metered dose inhaler (CFC-MDI) at an equivalent dose (MD -0.44 cm/year, 95% CI -1.00 to 0.12; low certainty evidence). Another trial with 229 participants showed a small but statistically significant greater increase in height over a period of six months in favour of budesonide via Easyhaler, compared to budesonide given at the same dose via Turbuhaler (MD 0.37 cm, 95% CI 0.12 to 0.62; low certainty evidence). This review suggests that the drug molecule and delivery device may impact the effect size of ICS on growth in children with persistent asthma. Fluticasone at an equivalent dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less adverse effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this systematic review of head-to-head trials is not certain enough to inform the selection of inhaled corticosteroid or inhalation device for the treatment of children with persistent asthma. Further studies are needed, and pragmatic trials and real-life observational studies seem more attractive and feasible.

Nonprescription Racemic Epinephrine for Asthma

Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug Administration rule. It contains 11.25 mg RE in 0.5 mL and is delivered by a handheld electronic nebulizer. In 2001, we conducted a pilot study that was never published. Now that the product is promoted as a replacement for epinephrine chlorofluorocarbon metered-dose inhaler (Primatene), we provide the results of that study. Methacholine challenge was used as a bioassay. To determine the dose of RE that is equivalent to nebulized albuterol. Four subjects, 18 to 45 years old, with mild stable asthma completed the pilot study. Methacholine challenge was performed on the first screening day, without pretreatment, and then on different days, 15 minutes after 1.25 mg albuterol and 2.5, 5, 10, and 20 mg RE delivered by a Pari LC Plus nebulizer. The end point was the provocative concentration of methacholine that caused a 20% decrease in FEV1. Data were log transformed and analyzed by an ANOVA for repeated measures. There was a significant dose response for RE. The geometric mean provocative concentration of methacholine that caused a 20% decrease in FEV1 was 44 mg/mL (95% CI, 23-85 mg/mL) after albuterol, and 10.2 mg/mL (95% CI, 3.5-30 mg/mL) after the 10-mg dose of RE (approximate nonprescription dose) (P = .001). There were no adverse effects. RE provides less bronchoprotection from methacholine than does albuterol and may be less effective in treating acute bronchospasm.

Clinical effectiveness of the Respimat® inhaler device in managing chronic obstructive pulmonary disease: evidence when compared with other handheld inhaler devices

Objectives:Medication for the management of chronic obstructive pulmonary disease (COPD) may be delivered by a number of different inhaler devices. This study was undertaken to determine the clinical effectiveness of the Respimat® handheld inhaler device compared with other handheld inhaler devices for the delivery of medication in stable COPD.Methodology:A systematic review of high-quality randomized controlled clinical trials comparing Respimat with other inhaler devices using the same medication was performed. Studies were searched for in the Cochrane Central Register of Controlled Trials as well as other relevant electronic databases. Manufacturers of inhaled COPD medication were also contacted for potential trials.Results:Seven studies of high methodological quality with 3813 participants were included in the review. Three trials used Handihaler® as the comparator inhaler, three used a chlorofluorocarbon metered-dose inhaler (CFC-MDI), and one trial used a hydroflouroalkane (HFA)-MDI. When Respimat was compared with Handihaler, the following reported outcomes were not significantly different: trough forced expiratory volume in 1 second (FEV1) (weighted mean difference [WMD] 0.01 L; P = 0.14), trough forced vital capacity (FVC) (WMD 0.001 L: P = 0.88), peak FEV1 (WMD 0.01 L: P = 0.08), peak FVC (WMD 0.01 L: P = 0.55), morning peak expiratory flow rate (PEFR) (WMD 5.06 L/min: P = 0.08), and evening PEFR (WMD 4.39 L/min: P = 0.15). Furthermore, there were no differences when Respimat was compared with Handihaler for risk of exacerbations (relative risk [RR] 0.94: P = 0.81), dry mouth (RR 1.57: P = 0.34), or nasopharyngitis (RR 1.42: P = 0.22). For Respimat compared with CFC-MDI, the only outcome for which data were available for meta-analysis was exacerbations, which were not significantly different (RR 1.20: P = 0.12). In addition, five trials with 2136 patients showed that there was no difference in risk of exacerbations or nasopharyngitis when Respimat was compared with all other handheld inhaler devices (RR 1.18: P = 0.13 and RR 1.33: P = 0.19, respectively). None of the clinical outcome measures reported was significantly different when the same, higher, or lower doses of medication were used in the inhaler devices being compared. Unfortunately, none of the included trials reported mortality as an outcome measure.Conclusions:Evidence from high-quality trials published to date suggests that the Respimat inhaler does not provide any additional clinical benefit to that provided by other inhaler devices in the management of COPD. Although in vitro studies have reported differences between the Respimat inhaler device and other handheld devices, we found no difference in any clinical outcome measures, including lung function and adverse events. Although recent reports have highlighted concerns of increased mortality with the Respimat inhaler device, none of the included trials reported mortality as an outcome. Only a small number of trials reported data that could be used in this systematic review, and a limited number of studies have been published that compare Respimat with other inhaler devices using the same drug and strength. Therefore, further trials comparing Respimat with other handheld inhaler devices using the same drug and dose are required before firm conclusions can be drawn. The concern with increased mortality with Respimat use should be investigated urgently.

Effects of fluticasone propionate and salmeterol hydrofluoroalkane inhalation aerosol on asthma-related quality of life

Current asthma guidelines emphasize domains of impairment and risk for assessing severity and control, noting the need to consider separately the effects of asthma on asthma quality of life and functional capacity. Proper treatment to control asthma should result in improvements in patient well-being and functional status. To assess asthma-related quality of life after treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane 134a metered-dose inhaler compared with the individual components alone. Asthma-related quality of life was assessed as part of two 12-week, randomized, double-blind, placebo-controlled clinical trials comparing the fluticasone propionate-salmeterol combination administered via a single metered-dose inhaler with salmeterol, fluticasone propionate, and placebo administered via traditional chlorofluorocarbon metered-dose inhaler. The Asthma Quality of Life Questionnaire was completed at baseline and end point. Score changes, overall and for the 4 separate domains, were compared within and among the treatment groups. A total of 720 of 725 patients completed a baseline Asthma Quality of Life Questionnaire and were included in the analyses. In both studies, all mean scores improved significantly from baseline with the fluticasone propionate-salmeterol combination, with significantly greater improvement in the overall score compared with salmeterol alone, fluticasone propionate alone, and placebo groups. Improvements with the combination were also clinically meaningful compared with changes with salmeterol and placebo in both studies and with fluticasone propionate in study 1. Treatment with combination fluticasone propionate and salmeterol delivered via hydrofluoroalkane metered-dose inhaler resulted in significantly greater improvements in asthma-related quality of life compared with individual components and placebo administered via traditional chlorofluorocarbon metered-dose inhaler.

Albuterol HFA for the management of obstructive airway disease

Albuterol (salbutamol outside the USA) is used to acutely relieve symptoms related to airway obstruction and prevent exercise-induced bronchospasm. Albuterol is most commonly administered by metered-dose inhaler (MDI). MDIs had used chlorofluorocarbon (CFC) propellants, but CFCs accumulate in the stratosphere and contribute to ozone catabolism. Loss of the ‘ozone layer’, which filters UVB rays, has public health concerns. Albuterol has been reformulated in MDIs using hydrofluoroalkane (HFA) propellants, which do not affect the ozone layer. Albuterol HFA MDIs deliver the same amount of drug per puff with similar particle size distributions as albuterol CFC MDIs, resulting in comparable bronchodilator efficacy of the two products. The highly favorable safety profile of albuterol has not been altered with reformulation. The propellant HFA-134a appears to be devoid of safety concerns.

Acute Local Tolerability of Acidic Aqueous Vehicles Delivered via Respimat® Soft Mist™ Inhaler in Hyperreactive Asthma Patients

Background:Acidic inhalers can be associated with increased adverse reactions. Objectives: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat® Soft Mist™ Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI).Methods: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV₁) from baseline to 0–30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV₁ ≧15% below baseline within 30 min of dosing), cough episodes and adverse events.Results: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV₁ was comparable between treatment groups: –1.6% (Respimat SMI pH 2.7), –1.8% (Respimat SMI pH 7.0), –1.9% (CFC-MDI), and –2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. Conclusions: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.

Short‐term growth and adrenal function in children with asthma treated with inhaled beclomethasone dipropionate hydroflouroalkane‐134a

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluoroalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)-formulated metered dose inhalers (MDI). The aim was to assess whether BDP HFA MDI 100 microg twice daily was equivalent to BDP CFC MDI 100 microg twice daily in terms of effects on short-term lower leg growth rate (LLGR) and measures of hypothalamic-pituitary-adrenal (HPA) function. The study consisted of a randomized double-blind cross-over trial with three active, a run-in and two wash-out periods each consisting of 2 wk. The place of study was a secondary referral outpatient clinic. The subjects involved were 14 boys and 10 girls with asthma, aged 7-12 yr. They were all administered BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily. The outcome measures included LLGR and 24-h urine-free cortisol (UFC) and total cortisol metabolites (TCM). Mean (SD) LLGR during run-in and BDP HFA 100 microg, BDP CFC 100 microg and 200 microg twice daily periods were 0.43 (0.23), 0.09 (0.29), 0.10 (0.45) and 0.08 (0.27) mm/wk. The one-sided 97.5% confidence interval for the difference in LLGR between BDP HFA 100 microg and BDP CFC 100 microg was 0.24, thus, below the predefined criterion of 0.20 mm/week. Inter-period comparisons of active treatments showed no differences between means of LLGR, UFC or TCM. Though non-inferiority between BDP HFA and CFC 100 microg twice daily in terms of effects on LLGR was not found, equivalence was suggested by comparisons of LLGR during run-in and active treatments and by HPA function measures.

Systemic Activity of Inhaled Hydrofluoroalkane-134a Metered Dose Inhaler with Beclomethasone Dipropionate in Children with Asthma

Inhaled beclomethasone dipropionate (BDP) with the propellant hydrofluororoalkane-134a (HFA) has been designed to be equivalent in terms of safety to chlorofluorocarbon (CFC)- formulated metered dose inhalers (MDI). The purpose of this study was to assess whether inhaled BDP HFA MDI 100 µg b.i.d. was equivalent to BDP CFC MDI 100 µg b.i.d in terms of effects on short-term lower leg growth rate (LLGR) in children with asthma. Secondary aims were to assess effects on measures of hypothalamic-pituitary-adrenal (HPA) function. Seventeen boys and 13 girls with a mean age of 9.3 years were studied in a randomized double- blind cross over trial with three active, a run-in, and two wash-out periods, each of 2 weeks duration. Interventions were BDP HFA 100 µg, BDP CFC 100 µg, and BDP CFC 200 µg b.i.d delivered by the Volumatic™ spacer device. LLGR as measured by knemometry, 24-hour urine-free cortisol (UFC)/creatinine, and total cortisol metabolites (TCM)/creatinine were assessed. Mean (SD) LLGRs during run in and BDP HFA 100 µg, BDP CFC 100 µg, and 200 µg b.i.d. were 0.45 (0.44), 0.29 (0.24), 0.33 (0.26), and 0.31 (0.22) mm/week. The mean difference in LLGR between BDP HFA 100 µg and BDP CFC 100 µg b.i.d. was 0.02 mm/week with a one-sided 97.5% confidence interval lower end for the difference of 0.15 mm/week, thus, above the predefined noninferiority margin of –0.20 mm/week. UFC/creatinine and TCM/creatinine data showed no consistent variations. The systemic activity of BDP HFA 100 is equivalent to CFC 100 µg b.i.d., and children can be switched to the new HFA formulation without any risk of enhanced adverse systemic effects. (Pediatr Asthma Allergy Immunol 2006; 19[3]:172–179).

The Effect of Reducing the Fine-Particle Mass of Salmeterol from Metered-Dose Inhalers on Bronchodilatation and Bronchoprotection Against Methacholine Challenge: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study

This study examined the clinical relevance of fine-particle mass (FPM) delivered from metered dose inhalers (MDIs) to bronchodilatation and bronchoprotection against methacholine challenge by comparing a marketed chlorofluorocarbon (CFC) formulation of salmeterol with an investigational hydrofluoroalkane (HFA)formulation. This was a randomized, double-blind, placebo-controlled, 3-way crossover study in patients with mild to moderate asthma who had a forced expiratory volume in 1 second (FEV (1)) of > or =60% predicted and a base-line provocation dose of inhaled methacholine required to produce a 20% decrease in FEV(1) (PD (20) [methacholine]) of < or =3.2 mg. On separate occasions, patients received 2 inhalations of salmeterol 25 microg from either the CFC MDI (FPM 14 microg), the investigational HFA MDI (FPM 7 microg), or placebo via CFC MDI. Serial measurements of FEV(1) were made over 90 minutes after dosing, followed by methacholine challenge. Efficacy end points were PD(20) (methacholine) and FEV(1) AUC (inc) (incremental area under the FEV(1) curve) over 15 to 90 minutes. The study was designed to demonstrate non-inferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness; for PD(20) (methacholine), noninferiority was predefined as 1.0 doubling dose of methacholine. The study enrolled 40 patients (65% men; mean age, 36.9 years). Both active treatments were significantly better than placebo in terms of PD(20) (methacholine) (P < 0.001). In the per-protocol population, the mean (SE) difference in bronchoprotection between the CFC MDI and placebo was 2.7888 (0.3432) doubling doses of methacholine (n = 32), and the difference between the investigational HFA MDI and placebo was 1.8268 (0.3418) doubling doses(n = 33). The adjusted mean (SE) treatment difference between the CFC MDI and HFA MDI was 0.9621 (0.3454) doubling doses. The upperlimit of the 95% CI (0.2714-1.6527) was greater than the predefined limit for noninferiority. There was no significant difference in FEV(1) AUC(inc) between formulations (mean treatment difference, 1.895 L . min; 95% CI, -4.893 to 8.684); however, both active treatments were significantly different from placebo (P < 0.001). FPM from different MDI formulations may affect the bronchoprotective properties of salmeterol. In this study, the formulation with the smaller FPM was associated with less-effective bronchoprotection, although there was no difference in bronchodilatation. This study did not demonstrate noninferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness.

Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat ® soft mist™ inhaler

Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat SMI and CFC-MDI. Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: 'bronchospasm', 'other respiratory adverse events', 'rescue medication use' and 'asymptomatic drop in FEV(1) 15% from baseline'. In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks' treatment. Delivery of bronchodilators by Respimat SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.

Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metered-dose inhaler in healthy subjects

Inhaled corticosteroids may cause oropharyngeal side effects if deposited in the oropharynx in active form. Ciclesonide, an inhaled corticosteroid with low glucocorticoid receptor affinity, is activated primarily in the lung by esterases to an active metabolite, desisobutyryl-ciclesonide (des-CIC), with high glucocorticoid receptor affinity. We studied oropharyngeal deposition of ciclesonide, des-CIC, and budesonide. In an open-label, randomized, two-treatment (administered in sequence), five-period study, 18 healthy subjects received 800 microg (ex-valve) inhaled ciclesonide via a hydrofluoroalkane-pressurized, metered-dose inhaler followed by 800 microg budesonide (Pulmicort) by a chlorofluorocarbon-pressurized, metered-dose inhaler (four puffs of 200 microg each, ex-valve) or vice versa. Oropharyngeal cavity rinsing was performed immediately, or 15, 30, 45, or 60 min after inhalation (one rinsing per study period), and the solutions were analyzed using liquid chromatography with tandem mass spectrometric detection. Ciclesonide and budesonide were detected in most oropharyngeal wash samples. Maximal concentration of each inhaled corticosteroid was reached immediately post-inhalation; maximal concentrations of ciclesonide and des-CIC were 30% and 0.67%, respectively, of budesonide. Oropharyngeal deposition of ciclesonide and budesonide decreased rapidly within 15 min post-inhalation, and less rapidly thereafter. Less than 10% of the residual ciclesonide in the oropharynx was converted to des-CIC. The molar dose-adjusted amount of des-CIC was 4% of budesonide (P < 0.0001). There were no significant adverse events. Oropharyngeal deposition of des-CIC was more than one order of magnitude lower than that of budesonide when administered by the respective metered-dose inhalers. This may explain the low frequency of oropharyngeal side effects of ciclesonide in clinical studies.

Salmeterol HFA is as effective as salmeterol CFC in children and adults with persistent asthma

In accordance with the Montreal Protocol 1987, initiatives to phase out and replace ozone-depleting chlorofluorocarbon (CFC) propellants with non-ozone-depleting propellants in metered-dose inhalers (MDIs) in the treatment of asthma and chronic obstructive pulmonary disease are underway. In view of this, two multi-centre, randomised, parallel-group, double-blind studies were conducted to compare the safety and efficacy of salmeterol xinafoate delivered by an MDI using the hydrofluoroalkane (HFA) 134a propellant with the licensed CFC formulation (Serevent) in asthmatic populations of children (4-11 years) and adults (12 years). Patients on a stable dose of inhaled corticosteroids with a scope for improvement based on mean morning peak expiratory flow (PEF) and symptoms were randomised to receive salmeterol HFA MDI 50 microg twice daily or salmeterol CFC MDI 50 microg twice daily for 12 weeks. The primary efficacy variable was mean morning PEF and secondary variables included other lung function parameters, symptom scores, use of relief medication and safety assessments. The difference between the treatments in adjusted mean morning PEF (salmeterol HFA-salmeterol CFC) were 2.5 and -3.2 L/min for per-protocol populations of children and adults, respectively. The lower limit of 95% confidence intervals for both populations was within the pre-defined limit (-15 L/min) set for non-inferiority. Similar results were observed in intent-to-treat (ITT) populations. In children, the two formulations resulted in a lack of any statistically significant difference in secondary efficacy parameters. A significant difference at endpoint in clinic forced expiratory volume in 1s was reported in favour of the HFA formulation in the adult population, although the magnitude of this effect was not considered clinically significant. The incidences of adverse events (AEs) were similar for both formulations and populations, and no safety concerns were generated. Together these data demonstrate salmeterol HFA MDI to be as effective as salmeterol CFC MDI in adults and children.

Development and performance of a new hydrofluoroalkane (HFA 134a)-based metered dose inhaler (MDI) of salmeterol

In response to the Montreal Protocol, a salmeterol (Serevent) metered dose inhaler (MDI) has been developed containing the non-chlorofluorocarbon propellant, hydrofluoroalkane 134a (HFA), to replace the marketed Serevent chlorofluorocarbon (CFC) propellant MDI. This paper details the pharmaceutical assessment of salmeterol HFA MDI and confirms that this product meets the current Committee for Proprietary Medicinal Products regulatory requirements, and is comparable to the CFC MDI in product performance. Criteria investigated included fine particle mass (FPM), dose delivery and uniformity, priming requirements and simulated-use-testing. Dose delivery was unaffected by changing product orientation during storage. The mean dose delivered per actuation ranged from 21.3 to 22.4 microg, and all individual doses were within the +/-25% defined limits of the target ex-actuator dose of 21 microg. The FPM results, defined as the mass of particles between 1.1 and 4.7 microm in diameter (the sum of the mass deposited on stages 3-5 of the Andersen Cascade Impactor), were similar for the HFA and CFC products. The mean FPM values of the two HFA clinical batches were 8.7 and 10.1 microg, covering the values obtained during the development, and the one of the CFC clinical batch was 10.0 microg. Comparability in aerosol characteristics was also demonstrated when the salmeterol HFA inhaler was tested using a large volume spacer (Volumatic).

Fenoterol Delivery by Respimat® Soft Mist Inhaler Versus CFC Metered Dose Inhaler: Cumulative Dose-Response Study in Asthma Patients

Objectives. Respimat® (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Design. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 µg/actuation, RMT50; or 100 µg/actuation, RMT100) and MDI (100 µg/actuation; MDI100). Patients and interventions. A total of 41 asthma patients received cumulative doses of fenoterol 600 µg (RMT50) or 1200 µg (RMT100 and MDI100) on 3 test days. Measurements and results. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of ± 0.15 L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30 minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. Conclusions. The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.

Clinical equivalence of salmeterol/fluticasone propionate in combination (50/100 μg twice daily) when administered via a chlorofluorocarbon-free metered dose inhaler or dry powder inhaler to patients with mild-to-moderate asthma

This multi-centre, randomized, double-blind, double-dummy, parallel-group study was designed to investigate the hypothesis of equivalent efficacy and comparable safety of two inhaled presentations of salmeterol/fluticasone propionate combination product (SALM/FP) 50/100 μg administered twice daily to patients with mild-to-moderate asthma for 12 weeks. The delivery systems were a 25/50 μg strength hydrofluoroalkane (HFA) metered-dose inhaler (MDI) and a DiskusTMinhaler (50/100 μg strength). A third group received FP 100 μg twice daily via a chlorofluorocarbon MDI (50 μg strength). A total of 497 patients aged 11–79 years with reversible airways obstruction who were symptomatic on inhaled corticosteroid (ICS) therapy and had room for improvement in lung function were randomized to treatment in a double-blind, parallel-group design (SALM/FP MDI: n=165; SALM/FP DiskusTM: n=167; FP MDI:n =165) for 12 weeks. A total of 383 patients completed the study according to the protocol.According to the primary efficacy variable, increase in mean morning PEF over weeks 1–12, the two inhaled presentations of SALM/FP were clinically equivalent (adjusted mean increases 43 and 46 l min−1; treatment difference 3 l min−1; 95% confidence interval: −6 to 11 l min−1). Equivalence was also demonstrated by all secondary efficacy measures. The SALM/FP MDI was significantly superior to the FP MDI for increase in mean morning PEF (treatment difference 19 l min−1;P<0·001) and for all secondary measures except FEV1and symptom-free nights. There was no significant difference between the groups with respect to adverse events and serum cortisol levels.These results demonstrate that the SALM/FP 25/50 μg HFA MDI (two inhalations twice daily) is clinically equivalent to the SALM/FP 50/100 μg DiskusTM(one inhalation twice daily). Patients switching to SALM/FP from other MDI-based asthma treatments may now do so without a change of delivery device.

Switching from chlorofluorocarbon-beclomethasone dipropionate to a hydrofluoroalkane-134a beclomethasone dipropionate metered-dose inhaler: Study of patient preferences

Objective The aims of this study were to assess the acceptability of a new hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP) metered-dose inhaler (MDI) and the ease with which patients switched from a chlorofluorocarbon (CFC) BDP MDI to the new MDI. Background BDP has been reformulated in a new CFC-free MDI that uses HFA as the propellant. Methods A total of 385 adult patients with asthma who already used inhaled corticosteroids completed a questionnaire about the MDI they had used before entering the study. They also assessed a CFC-BDP MDI during a 2-week run-in period. After the run-in period, 267 patients were assigned randomly to 1 month of treatment with the HFA-BDP MDI. Results At the end of the 1-month treatment period, patients assessed the HFA-BDP MDI and indicated their preference for the CFC or HFA MDI. Patients reported no major differences between the 2 MDIs in terms of adapter size and style or mouthpiece size and shape. Overall, 235 of the 267 participants (88%) found the HFA-BDP MDI to be an acceptable replacement for the CFC-BDP MDI, whereas 150 patients (56%) reported that the HFA-BDP MDI had advantages over the CFC-BDP MDI. These advantages included the lower number of puffs per day, the lack of CFCs, and the better or more comfortable mouthpiece. Most patients (256 [96%]of 267) found it easy to switch from the CFC-BDP to the HFA-BDP MDI. In all, 160 (60%) of the 267 patients indicated that they preferred the HFA-BDP MDI to the CFC-BDP MDI. Conclusions Results of this study confirm that the HFA-BDP MDI is an acceptable replacement for the CFC-BDP MDI and that most patients find the switch from a CFC-BDP MDI to the HFA-BDP MDI to be easy.

Systemic Exposure to Fluticasone Propionate Administered via Metered-Dose Inhaler Containing Chlorofluorocarbon or Hydrofluoroalkane Propellant

The pharmacokinetic profile of a single dose of inhaled fluticasone propionate (FP) administered via a metered-dose inhaler (MDI), containing either a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant was investigated in healthy volunteers. Two randomised, double-blind, crossover studies were conducted, each in 12 male volunteers. Both studies compared pharmacokinetic data after a single inhaled dose of FP 1000 microg from a MDI containing either CFC (CFC MDI) or HFA (HFA MDI) with a single intravenous dose of FP 250 microg. The maximum plasma FP concentrations after inhalation via the 2 types of MDI were almost identical (0.56 and 0.54 microg/L for CFC MDI and HFA MDI, respectively); bioavailability values of inhaled FP from the 2 MDIs were also similar (geometric mean values: 26.4% via the CFC MDI and 28.6% via the HFA MDI). Inhalation of FP via both MDI formulations produced similar reductions in urinary cortisol excretion over 12 and 24 hours postdose. The bioavailability values of FP after inhalation via a CFC MDI and an HFA MDI are similar. The 2 formulations deliver comparable amounts of FP, and systemic exposures to FP from the 2 devices, measured by urinary cortisol excretion, are not significantly different.

Aerosol therapy for asthma.

Inhaled drugs play an important role in asthma management. The correct use of an appropriate delivery device is necessary to achieve the desired therapeutic effects of the drug. Currently, chlorofluorocarbon-propelled metered-dose inhalers, with or without spacers, are the most popular aerosol delivery devices. With the planned phase out of the chlorofluorocarbon metered-dose inhalers, the use of other delivery devices is being emphasized. To achieve optimal therapeutic effects, the drug and the delivery device should be considered a "couple". Aerosol delivery devices should provide an adequate "drug dose to the lung", be cost effective, simple to operate, minimize oropharyngeal deposition and systemic side effects, and match the patient's requirements. A new generation of aerosol delivery devices, incorporating the latest advances in aerosol technology, is likely to fulfill many of the goals mentioned above.

Advances in Metered Dose Inhaler Technology with the Development of a Chlorofluorocarbon-Free Drug Delivery System

The impending phaseout of chlorofluorocarbon (CFC)-containing metered dose inhalers (MDIs) has challenged the pharmaceutical industry to rethink and redesign many components of the technology involved in delivering asthma medication to the lungs. Along with the emergence of the first formulation using the nonozone-depleting propellant, hydrofluoroalkane (HFA) 134a to replace CFC propellants, advances in drug delivery technology have improved the performance characteristics of the MDI itself. Although MDIs have remained the mainstay of asthma therapy for 40 years, MDI technology still presents challenges. Some of the shortcomings of existing CFC MDIs affect the reliability of dosing. These challenges have been addressed in the development of the first CFC-free beta-agonist for the treatment of asthma. Airomir CFC-free (salbutamol sulfate; 3M Pharmaceuticals, St. Paul, MN), which is currently available in over 30 countries and was recently approved in the United States (Proventil HFA; Schering-Plough, Madison, NJ), incorporates numerous design and technological improvements which together with the introduction of CFC-free propellants mark the beginning of the next generation of asthma therapy. Although the new generation of CFC-free MDIs incorporates several improvements in dose reproducibility, these changes should be virtually transparent to the patient switching from a CFC MDI to a CFC-free MDI. What may be noticeable is a "softer puff," which is the result of valve and actuator redesign. The taste of the new CFC-free product may also be a little different yet totally acceptable to users.