Asthma patients prefer Respimat Soft Mist Inhaler to Turbuhaler

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3 International Journal of COPD Dovepress open access to scientific and medical research Open Access Full Text Article O R I G I N A L R E S E A R C H Asthma patients prefer Respimat Soft Mist Inhaler to Turbuhaler Rick Hodder 1 Pat Ray Reese 2 Terra Slaton 3 1 Divisions of Pulmonary and Critical Care, University of Ottawa, Ottawa, Ontario, Canada; 2 Reese Associates Consulting LLC, Cary, North Carolina, USA; 3 Consultant, West Columbia, South Carolina, USA Correspondence: Rick Hodder Divisions of Pulmonary and Critical Care, The Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada Tel 1 (613) Fax 1 (613) rhodder@ottawahospital.on.ca Abstract: Device satisfaction and preference are important patient-reported outcomes to consider when choosing inhaled therapy. A subset of adults (n 153) with moderate or severe asthma participating in a randomized parallel-group, double-dummy trial that compared the efficacy and safety of 12 weeks treatment with budesonide delivered via Respimat Soft Mist Inhaler (SMI) (200 or 400 g bd) or Turbuhaler dry powder inhaler (400 g bd), completed a questionnaire on patient device preference and satisfaction (PASAPQ) as part of a psychometric validation. As the study used a double-dummy design to maintain blinding, patients used and assessed both devices, rating their satisfaction with, preference for, and willingness to continue using each device. The mean age of patients was 41 years, 69% were female and the mean duration of disease was 16 years. Total PASAPQ satisfaction scores were 85.5 and 76.9 for Respimat SMI and Turbuhaler respectively (p ); 112 patients (74%) preferred Respimat SMI and 26 (17%) preferred Turbuhaler. Fourteen subjects (9%) indicated no preference for either inhaler. Willingness to continue using Respimat SMI was higher than that for Turbuhaler (mean scores: 80/100 and 62/100, respectively). Respimat SMI was preferred to Turbuhaler by adult asthma patients who used both devices in a clinical trial setting. Keywords: asthma, Respimat Soft Mist Inhaler, Turbuhaler Introduction A patient s satisfaction with and preference for an inhaler device are important outcomes to consider when choosing inhaled therapy for patients with asthma and chronic obstructive pulmonary disease (COPD). Patient satisfaction is important in determining whether patients persist with medication, 1 and has been shown to be influenced by such things as the process of taking or using the product and its subsequent outcomes. 2 Among healthcare professionals, both the ease of use and patient preference for an inhaler device are regarded as amongst the most important considerations when selecting an inhaler for patients. 3,4 Using inhaler devices to treat obstructive lung diseases is by no means a straightforward process for patients, who must learn how to prepare and operate them before being able to take the medication as prescribed. Furthermore, it is also clear that not all patients can use all inhalers equally well. They clearly vary in their preferences for different inhalers 5,6 and frequently do not see devices as being interchangeable. Although a large range of inhaler devices is now available, established devices such as the pressurized metered-dose inhaler (pmdi) and the dry powder inhaler (DPI) are still the most frequently used. The pmdi is robust and can be simple to use, although many patients have trouble using it correctly, submit your manuscript Dovepress International Journal of COPD 2009: Hodder et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

4 Hodder et al particularly in co-ordinating the actuation of the device with inhalation, 7,8 a disadvantage that prompted the development of breath-actuated pmdis. With DPIs, the co-ordination challenge can be avoided, but a minimum inspiratory flow is required which may be limiting for some patients, particularly young children, 9 and some multidose designs need to be stored in a dry place to prevent moisture degrading the powder. One popular multidose design is the Turbuhaler, which has been shown to deliver a high proportion of the inhaled dose in the form of fine particles. 10 Respimat Soft Mist Inhaler (SMI) (Figure 1) is a new type of propellant-free inhaler that generates a fine aerosol cloud which is emitted more slowly and lasts 4 to 10 times longer than the aerosol from pressurized metered-dose inhalers (pmdis). 11 This device has been shown to deliver a higher proportion of the emitted dose to the lungs than a pmdi, and this allows patients to take a lower nominal dose of bronchodilator (relative to pmdi) without affecting efficacy or safety, in both asthma and COPD Lung deposition from Respimat SMI was also found to be greater than from Turbuhaler in asthma patients. 14 In a controlled clinical trial, COPD and asthma patients found Respimat SMI easy to use and preferred it to a hydrofluoroalkane (HFA)-propelled MDI. 6 The objective of the current study was to compare the level of patient satisfaction with Respimat SMI and Mouthpiece Unblock Dose-release button Capillary tube Upper housing Transparent base Spring Cartridge Figure 1 Schematic diagram of Respimat Soft Mist Inhaler. Courtesy of Boehringer Ingelheim GmbH. Dovepress Turbuhaler. This analysis was performed on a subset of patients who had participated in a multicenter clinical trial (Boehringer-Ingelheim study # data on file). The vast majority of patients studied were familiar with and using the pmdi, only a minority having had prior experience with the Turbuhaler and none having used Respimat SMI before. In the original clinical trial, all subjects were instructed in the proper use of the Respimat SMI, Turbuhaler, and pmdi devices. Performance and convenience of the devices were assessed by means of a questionnaire specifically designed to measure patient satisfaction with inhaler devices (Patient Satisfaction and Preference Questionnaire; PASAPQ). 18 In the original trial, peak expiratory flow was the primary clinical endpoint and no clinically significant difference was observed between test groups at end of study. Methods Study design The study presented in this article was undertaken in a subset of adults with clinically stable moderate or severe asthma who had taken part in a randomized, parallel-group, placebocontrolled, double-blind, multicenter clinical trial. The subset chosen for the current analysis consisted of 153 Englishspeaking and German-speaking patients (from study centers in Canada, Germany and South Africa), selected because the PASAPQ questionnaire was only available in those languages. The aim of the primary trial was to compare the efficacy and safety of 12 weeks treatment with budesonide delivered either via Respimat SMI or Turbuhaler. The efficacy and safety results of the clinical trial are reported separately (Boehringer- Ingelheim, study # data on file). As the Respimat SMI and Turbuhaler are different in appearance, a double-dummy design was used; thus, patients used both devices for the full duration of the trial. All patients were randomly allocated to study treatment with budesonide for 12 weeks according to one of the three regimens shown in Table 1. For all regimens, patients took 2 inhalations twice daily from both of the devices, resulting in total daily budesonide dosages of either 400 or 800 g. The order in which patients used the two inhalers on each day of the study was determined by a separate random allocation step. Patients To be enrolled into the screening phase of the clinical study, men and women aged years had to have a diagnosis of moderate or severe asthma of at least 6 months duration, be a non-smoker or ex-smoker (stopped at least 1 year before 226 submit your manuscript Dovepress International Journal of COPD 2009:4

5 Dovepress Table 1 Treatment arms in the clinical study showing the doubledummy design Treatment arm 1 Budesonide 100 g per puff 2 Budesonide 200 g per puff Respimat SMI Turbuhaler Placebo Placebo 3 Placebo Budesonide 200 g per puff screening and with a history of no more than 10 pack-years), and be receiving either a) high-dose inhaled corticosteroids (ICS) plus short-acting beta 2 -agonist as needed, with or without other asthma medications such as long-acting beta 2 - agonists, or b) low-dose ICS plus either inhaled long-acting beta 2 -agonists or oral xanthines. During a run-in period of 1 3 weeks, ICS dosage was standardized to beclomethasone dipropionate 400 g/day delivered via pmdi, plus salbutamol via pmdi for rescue use as needed. To enter the study itself (randomized treatment phase), patients had to fulfill a second set of criteria based on spirometry and record card data. Forced expiratory volume in 1 second (FEV 1 ) had to be 50% to 81% of predicted and either FEV 1 or peak expiratory flow (PEF) had to be at least 10% lower than the screening visit value. In addition, at least one of the following diary card criteria had to be met (for at least 2 out of 7 days, based on the most recent 7 consecutive days of the run-in period): morning PEF 80% predicted; diurnal PEF variability 20%; 6 inhalations/day of beta 2 -agonist, and asthma symptom scores of 2 (day) or 1 (night). Assessments At the end of the 12-week treatment period, all patients rated the two devices using the Patient Satisfaction and Preference Questionnaire (PASAPQ). The PASAPQ is a multi-item measure of satisfaction and preference with inhaler devices that is designed to be easy to understand and administer to asthma and chronic obstructive pulmonary disease (COPD) patients. The items were developed using literature search, focus groups and expert opinion, and the resultant questionnaire has been confirmed to have validity, reliability and responsiveness in psychometric analyses. 18 The PASAPQ is self-administered and contains 13 satisfaction items grouped into two domains, performance and convenience, that together constitute the total score (Table 2). These items are measured on a Likert-type Respimat Soft Mist TM Inhaler for asthma patients Table 2 Items in Patient Satisfaction and Preference Questionnaire (PASAPQ) Device attribute Question Scoring Performance Overall feeling of inhaling Each contributes Inhaled dose goes to lungs equally to total Amount of medication left PASAPQ score Convenience Works reliably Ease of inhaling a dose Using the inhaler Speed medicine comes out Instructions for use Size of inhaler Durability of inhaler Ease of cleaning inhaler Ease of holding during use Convenience of carrying Other Overall satisfaction Stand alone questions Preference (each scored Willingness to continue independently) response scale from 1 (very dissatisfied) to 7 (very satisfied). The three other items are an overall satisfaction question, also measured on the 1 to 7 scale, a question on preference (selection between devices, as well as a no preference option) and a question on willingness to continue using the device in the future, measured on scale of 0 (not willing) to 100 (definitely willing). As this study provided data for the psychometric analyses, 46 additional questions were included for these purposes, 18 but these did not contribute to the total or domain PASAPQ scores reported in this paper. Domain and total scores are first summed and then transformed to scores on a scale from 0 (least) to 100 (most) for patients who complete at least half of the questions. If the patient completes at least half of the items in a domain, values for missing items are imputed using the mean of the completed items in that domain (the half-scale rule ). 19 The total score can be calculated only when both domain scores have computable scores and is calculated as the sum of the 13 items after substitution for missing items at the domain level has taken place. In other research, 18 estimates of the minimal important difference (MID) for the PASAPQ had demonstrated that a score difference between test inhalers of 8 to 10 points on the domain and total scores represented a medium difference in effect, and a difference of 3 to 6 points represented a small difference in effect, depending on which domain was measured. For the current study, therefore, a score difference of 10 points was considered to represent an important difference, and the International Journal of COPD 2009:4 submit your manuscript Dovepress

6 Hodder et al number of patients who scored one inhaler higher than the other by 10 points was recorded for each domain separately and for the total PASAPQ score. For half of the patients, the questionnaires had Respimat SMI listed first and for the other half, the Turbuhaler device was listed first, the order of device listing being randomly allocated. Statistical analysis In addition to descriptive statistics, the mean PASAPQ satisfaction scores and willingness-to-continue ratings (the latter expressed as least squares means) were tested for statistically significant differences between the two devices using a SAS general linear model with a nested design. Comparisons of individual items were tested using a paired t-test. Difference in preference was analyzed using a chi-square test. The 5% level of significance was used (two-tailed test). Results Patient demographics and PASAPQ response rates The mean age of patients in the subset was 41.0 years (standard deviation [SD], 11.5 years), 106 (69.3%) were women and the mean duration of asthma was 16.1 years (SD, 12.5 years). Before entering the trial, 30 patients had previously received inhaled treatment via Turbuhaler and no patients had used Respimat SMI. In the original data set, 306 subjects responded to the PASAPQ and 299 completed Dovepress the full questionnaire (7 subjects left at least one item missing but had computable scores). There were no unusable questionnaires. For the purposes of the comparison between the Respimat SMI and Turbuhaler, PASAPQ satisfaction scores were calculated for all 153 patients in the relevant subset, of whom 152 responded to the preference question. Satisfaction with device performance and convenience For the total PASAPQ score and the performance domain score, mean scores for Respimat SMI were significantly higher than those for Turbuhaler (p , general linear models analysis). The mean scores for the convenience domain also showed a numerical superiority for Respimat SMI, but the difference between devices was not statistically significant (Figure 2). Analysis by country also showed total PASAPQ score and performance domain score to be significantly higher for Respimat SMI in each case (data not shown). Comparison of scores by item showed that in the performance domain, mean scores for Respimat SMI for all questions were significantly higher than those for Turbuhaler (p , paired t-test) with mean differences between device scores ranging from 0.6 to 1.4. In the convenience domain, the mean differences between device scores were smaller (range, 0.2 to 0.2) and generally not of statistical significance, with the difference favoring Respimat SMI for four items and Turbuhaler for two (Table 3) p < p < NS Mean PASAPQ score Total score Performance Convenience Figure 2 Mean patient device preference and satisfaction (PASAPQ) scores for each device (all countries combined), with range of scores transformed to 0 to 100 points; p values for difference between devices from general linear models analysis. Grey bars, Respimat SMI; white bars, Turbuhaler. Abbreviations: NS, not significant. 228 submit your manuscript Dovepress International Journal of COPD 2009:4

7 Dovepress Respimat Soft Mist TM Inhaler for asthma patients Table 3 Satisfaction with inhaler attributes in performance and convenience domains Domain and inhaler attribute Respimat SMI Turbuhaler Difference, Respimat Turbuhaler Performance domain Overall feeling of inhaling the medicine Feeling that the inhaled dose goes to the lungs Can tell amount of medication left in container Inhaler works reliably Ease of inhaling a dose Using the inhaler Speed of medication coming out of inhaler Convenience domain Instructions for using the inhaler Size of the inhaler Durability of the inhaler Ease of cleaning the inhaler Ease of holding inhaler during use Overall convenience of carrying inhaler n Mean (SD) n Mean (SD) n Mean (SD) p value (1.3) 6.3 (1.2) 6.0 (1.4) 6.4 (0.9) 6.3 (1.1) 6.3 (1.1) 6.3 (1.1) 6.1 (1.1) 5.7 (1.4) 6.3 (1.0) 5.9 (1.1) 6.3 (1.0) 5.8 (1.3) (1.6) 4.9 (1.8) 4.7 (1.8) 5.5 (1.6) 5.7 (1.5) 5.7 (1.5) 5.6 (1.5) 6.0 (1.2) 5.9 (1.2) 6.1 (1.2) 5.8 (1.2) 6.1 (1.0) 5.9 (1.2) (2.0) 1.4 (2.0) 1.3 (1.9) 1.0 (1.7) 0.7 (1.7) 0.6 (1.6) 0.7 (1.8) 0.1 (0.9) 0.2 (0.9) 0.2 (0.9) 0.1 (0.8) 0.2 (1.0) 0.1 (0.9) Overall satisfaction with inhaler (1.1) (1.6) (1.7) By paired t-test. Abbreviations: SD, standard deviation; SMI, soft mist inhaler. For the total PASAPQ satisfaction score, 60 patients (39.2%) gave a higher score for Respimat SMI than for Turbuhaler that also exceeded the pre-defined threshold of 10 points representing an important difference. For the performance and convenience domains, the corresponding patient numbers were 79 (51.6%) and 18 (11.8%). This pattern of results was similar across the three countries (data not shown). No patients gave a score for Turbuhaler that exceeded the Respimat SMI score by more than 10 points (Figure 3). Preference and willingness to continue Respimat SMI was preferred by 112 of 152 patients (73.7%) and Turbuhaler preferred by 26 (17.1%), while 14 patients (9.2%) expressed no preference for either inhaler (Figure 4). When these proportions were restated with the subset of patients who indicated a preference for one device as the denominator, 81.2% preferred Respimat SMI and 18.8% preferred Turbuhaler, a difference that was statistically significant (p ). In the small group of patients who had used Turbuhaler previously, preference for Respimat SMI was still markedly higher than for Turbuhaler, with 20% of patients expressing no preference (Table 4). The least squares mean score on the willingness-to-continue question for Respimat SMI was 79.9, significantly higher than the mean score for Turbuhaler (61.8; p ). Discussion In a group of patients with moderate or severe asthma who had just completed a clinical trial, satisfaction with device performance was significantly higher with Respimat SMI than with Turbuhaler as measured by the PASAPQ. Patient satisfaction with the convenience of the two devices was similar. When patients were asked which device they preferred, just over 80% of those who expressed a definite preference preferred Respimat SMI. Our findings are consistent with those of a randomized crossover study in which 224 COPD and asthma patients who were regular users of pmdis received combination bronchodilator therapy (ipratropium plus fenoterol) via Respimat SMI and pmdi for 7 weeks each. 6 In that trial, as in our analysis, both total PASAPQ satisfaction score and performance domain score were significantly higher for Respimat SMI, patient preference significantly favored Respimat SMI (72%, versus 17% for pmdi) and patients were significantly more willing to continue using Respimat SMI after the study than pmdi. 6 The aerosol produced by Respimat SMI is generated mechanically by a spring when the user actuates the inhaler by pressing the dose-release button. Co-ordination of actuation with the patient s inspiratory breath is an easier task than with the standard pmdi, because the aerosol cloud from Respimat SMI is emitted more slowly and International Journal of COPD 2009:4 submit your manuscript Dovepress

8 Hodder et al Dovepress 100 Respimat score higher (by >10 points) Respimat score higher (by </= 10 points) No difference in score Turbuhaler score higher (by </= 10 points) Turbuhaler score higher (by >10 points) Number of patients Total score Performance Convenience Figure 3 Distribution of score differences between inhalers, showing the number of patients for whom differences met the pre-defined criterion for an important difference ( 10 points). so is longer-lasting (1.5 seconds, compared with 0.15 to 0.36 seconds for typical pmdis). 11 No co-ordination of actuation with inhalation is necessary with the Turbuhaler, but as with other DPIs, generation of an aerosol from the device relies on the energy of the patient s own inspiratory effort. This would not normally pose a difficulty to an adult asthma patient with stable disease, even if he or she was experiencing 17.1% 9.2% Preferred Respimat SMI Preferred Turbuhaler 73.7% No preference for either device Figure 4 Proportion of patients (n 152) indicating overall preference for Respimat SMI and Turbuhaler (or no preference). bronchoconstriction. 20 Nevertheless, a comparison of scores for individual items in our study suggested that the difference in aerosol production method between the test devices was apparent to patients. This comparison also confirmed that for all aspects of device performance, patients were significantly more satisfied with Respimat SMI than Turbuhaler. The largest score differences were for the feeling that the inhaled dose goes to the lungs and the ability to tell how much medication remains in the inhaler. Other attributes that scored significantly better for Respimat SMI included the overall feeling of inhaling, the ease of inhaling a dose and the speed at which medication comes out of the inhaler. There was much less difference between the two devices in the level of satisfaction with convenience attributes such as size, portability and handling. The use of patient-reported outcomes (PROs) for assessing the effectiveness of products for regulatory approval is a developing phenomenon. 21 Although device satisfaction and preference is a valid patient-reported outcome, it is less studied than other PROs like quality of life. 22 In a recent review of 30 published inhaler preference studies, only two studies were found to have used robust instruments for measuring preference and satisfaction. 22 The two instruments in question, the Patient Device Experience Assessment (PDEA) 23 and the Patient Satisfaction and Preference Questionnaire (PASAPQ), 18 were developed by experts in psychometric testing and subjected to field testing. Of these, only the PASAPQ has a published validation submit your manuscript Dovepress International Journal of COPD 2009:4

9 Dovepress Respimat Soft Mist TM Inhaler for asthma patients Table 4 Analysis of preference for device according to previous use of Turbuhaler Number preferring each device (n, %) Respimat SMI preferred Turbuhaler preferred No preference Previous use of Turbuhaler 20 (66.7%) 4 (13.3%) 6 (20%) 30 (100%) No previous use of Turbuhaler 92 (75.4%) 22 (18.0%) 8 (6.6%) 122 (100%) Total which also included a determination of the minimum important difference between devices, allowing an assessment of the clinical significance of differences observed in testing. For this reason we chose to use the PASAPQ as the preference assessment tool for the current study. Of 97 patients (63% of the sample) who gave higher total PASAPQ satisfaction scores to Respimat SMI than Turbuhaler, the score difference met the pre-defined criterion for the minimum important difference ( 10 points) in 60 patients, nearly 40% of all those in the study. The score difference did not meet this criterion in any patient who gave Turbuhaler a higher total satisfaction score than Respimat SMI. In our analysis, the mean willingness-to-continue score after the 12-week study period was nearly 80 out of 100 for Respimat SMI, but just over 60 out of 100 for Turbuhaler. The time-honored paradigm that inhaler preference will lead to improved medication adherence and consequently to better clinical outcomes seems plausible, but has been difficult to prove. 21 Treatment satisfaction has been shown to be associated with the probability that patients would persist with a prescribed medication 1 and at least in theory, patients might be able to achieve better inhaler technique with a device they find more satisfying to use, thus improving the effectiveness of the inhaled drug regimen. Recent evidence supporting the preference adherence outcome paradigm is beginning to emerge, as it does appear that in real life conditions, choice of inhaler device can have an impact on treatment adherence and disease control, and that the patient/device interface is crucial, for both asthma and COPD The design of our study reduced the possible sources of bias that could affect the patients assessments of satisfaction with the two devices. The same active ingredient was delivered by both devices, as recommended in a review of device preference and satisfaction studies by Anderson. 22 Deposition of budesonide in asthma patients was shown to be significantly higher with Respimat SMI than Turbuhaler when both were used with optimal technique (51.6 and 28.5% of ex-valve dose respectively), 14 but if this, or the use of two different doses in Respimat SMI had resulted in a discernible efficacy difference over the period of our study, patients could not have attributed the difference to a single device because of the double-dummy design that was employed. In addition, in the original clinical trial, no significant difference in the primary outcome measure of peak expiratory flow was detected between groups. For some patients, the novelty of a new type of inhaler might translate into short-term expressed preference over a familiar device such as the pmdi. However, because the majority of patients in our study were naïve to both Respimat SMI and Turbuhaler, this would probably not have affected the observed preference in favor of the Respimat SMI. The use of the PASAPQ also helped to reduce bias, since the questions in it were designed to be specific to attributes of the inhaler rather than the treatment. In summary, adults with asthma who used Respimat SMI and Turbuhaler devices in a clinical trial setting reported significantly greater satisfaction with the performance of Respimat SMI, and the level of patient satisfaction with convenience of these two devices was very similar. This translated into a higher preference for Respimat SMI, and a greater willingness to continue using it, compared with the Turbuhaler. Acknowledgments The authors would like to acknowledge the help of Chris Kozma, West Columbia, SC, USA for his original work on the PASAPQ, and Roger Nutter, Chester, UK for assistance in drafting the paper. Respimat and Soft Mist are trade marks of the Boehringer Ingelheim group of companies. Turbuhaler is a trade mark of the AstraZeneca group of companies. Research conducted by Reese Associates Consulting and by Ms Slaton was funded by Boehringer Ingelheim. References 1. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2: Shikiar R, Rentz AM. Satisfaction with medication: an overview of conceptual, methodologic, and regulatory issues. Value Health. 2004;7: International Journal of COPD 2009:4 submit your manuscript Dovepress

10 Hodder et al Dovepress 3. Tjwa MKT. Budesonide inhaled via Turbuhaler: a more effective treatment for asthma than beclomethasone dipropionate via Rotahaler. Ann Allergy Asthma Immunol. 1995;75: Fletcher M, Hardy AJ, Karbal B, et al. Effects of asthma training on inhaler device selection and utilization in general practice [abstract]. Eur Respir J. 2004;24(Suppl 48):57s. 5. Lenney J, Innes JA, Crompton GK. Inappropriate inhaler use: assessment of use and patient preference of seven inhalation devices. Respir Med. 2000;84: Schürmann W, Schmidtmann S, Moroni P, Massey D, Qidan M. Respimat Soft Mist Inhaler versus hydrofluoroalkane metered dose inhaler: patient preference and satisfaction. Treat Respir Med. 2005;4: Epstein SW, Manning CP, Ashley MJ, Corey PN. Survey of the clinical use of pressurized aerosol inhalers. Can Med Assoc J. 1979;120: Armitage JM, Williams SJ. Inhaler technique in the elderly. Age Aging. 1988;17: Kamps AW, van Ewijk B, Roorda RJ, Brand PL. Poor inhalation technique, even after inhalation instructions, in children with asthma. Pediatr Pulmonol. 2000;29: Borgström L. The importance of the device in asthma therapy. Respir Med. 2001;95 Suppl B:S26 S Hochrainer D, Hölz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. Comparison of the aerosol velocity and spray duration of Respimat Soft Mist Inhaler and pressurized metered dose inhalers. J Aerosol Med. 2005;18: Newman SP, Steed KP, Reader SJ, Hooper G, Zierenberg B. Efficient delivery to the lungs of flunisolide aerosol from a new portable handheld multidose nebulizer. J Pharm Sci. 1996;85(9): Newman SP, Brown J, Steed KP, Reader SJ, Kladders H. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of Respimat with conventional metereddose inhalers with and without spacer devices. Chest. 1998;113: Pitcairn G, Reader S, Pavia D, Newman S. 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Development and validation of a patient satisfaction and preference questionnaire for inhalation devices. Treat Respir Med. 2005;4: Ware J, Harris W, Gandek B, Rogers B, Reese P. MAP-R for Windows. Multitrait/multi-item analysis program: revised user s guide. Boston MA, USA: Health Assessment Lab; Borgström L. On the use of dry powder inhalers in situations perceived as constrained. J Aerosol Med. 2001;14(3): Hodder R. Design and interpretation of device preference trials: marketing tools or scientific instruments? In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Editors. Respiratory drug delivery X. River Grove, Illinois: Davis Healthcare International; p Anderson P. Patient preference for and satisfaction with inhaler devices. Eur Respir Rev. 2005;14(96): Welch MJ, Nelson HS, Shapiro G, et al. Comparison of patient preference and ease of teaching inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers. J Aerosol Med. 2004;17: Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19: Price D, Thomas M, Mitchell G, Niziol C, Featherstone R. Improvement of asthma control with a breath-actuated pressurised metered dose inhaler (BAI): a prescribing claims study of 5556 patients using a traditional pressurised metered dose inhaler (MDI) or a breath-actuated device. Respir Med. 2003;97: Corden Z, Bosley C, Rees P et al. Home nebulized therapy for patients with COPD: patient compliance with treatment and its relation to quality of life. Chest. 1997;112: Bourbeau J, Bartlett SJ. Patient adherence in COPD. Thorax. 2008;63: Restrepo RD, Alvarez MT, Wittnebel LD, Sorenson H, Wettstein R, Vines DL, Sikkema-Ortiz J, Gardner DD, Wilkins RL. Medication adherence issues in patients treated for COPD. Int J COPD. 2008;3: International Journal of COPD Publish your work in this journal The International Journal of COPD is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in COPD. Special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. Submit your manuscript here: Dovepress This journal is indexed on PubMed Central, MedLine and CAS. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit to read real quotes from published authors. 232 submit your manuscript Dovepress International Journal of COPD 2009:4

11 T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article Tiotropium in Asthma Poorly Controlled with Standard Combination Therapy Huib A.M. Kerstjens, M.D., Michael Engel, M.D., Ronald Dahl, M.D., Pierluigi Paggiaro, M.D., Ekkehard Beck, M.D., Mark Vandewalker, M.D., Ralf Sigmund, Dipl.Math., Wolfgang Seibold, M.D., Petra Moroni-Zentgraf, M.D., and Eric D. Bateman, M.D. A bs tr ac t From the University of Groningen and the Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD all in Groningen, the Netherlands (H.A.M.K.); Therapeutic Area Respiratory Diseases, Boehringer Ingelheim Pharma, Ingelheim am Rhein (M.E., P.M.-Z.), the Medical Department, Institut für Gesundheitsförderung, Rüdersdorf Brandenburg (E.B.), and Biostatistics (R.S.) and Clinical Research (W.S.), Boehringer Ingelheim Pharma, Biberach an der Riss all in Germany; the Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark (R.D.); Cardio Thoracic Department, Pulmonary Unit, University Hospital of Pisa, Pisa, Italy (P.P.); Clinical Trials, Clinical Research of the Ozarks, Columbia, MO (M.V.); and the Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.). Address reprint requests to Dr. Kerstjens at the University of Groningen, Department of Pulmonology, University Medical Center Groningen, P.O. Box , 9700 RB Groningen, the Netherlands, or at h.a.m.kerstjens@umcg.nl. All clinical investigators are listed in the Supplementary Appendix, available at NEJM.org. This article was published on September 3, 2012, at NEJM.org. N Engl J Med 2012;367: DOI: /NEJMoa Copyright 2012 Massachusetts Medical Society. Background Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting betaagonists (LABAs). Methods In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 µg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year. Results The patients had a mean baseline FEV 1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV 1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV 1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P = 0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. Conclusions In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT and NCT ) 1198 n engl j med 367;13 nejm.org september 27, 2012 The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

12 Tiotropium in Poorly Controlled Asthma A substantial proportion of patients with asthma have poorly controlled disease, with recurring symptoms and exacerbations despite the use of preferred controller drugs (i.e., inhaled glucocorticoids with or without inhaled long-acting beta-agonists [LABAs]). For these patients, alternative treatment options may have substantial limitations, including marginal efficacy, cumbersome routes of administration, side effects, and high cost. 1,2 The option of adding a second long-acting inhaled bronchodilator in patients with uncontrolled asthma has been supported by results from recent studies that examined the efficacy of tiotropium, a long-acting anticholinergic bronchodilator approved for the treatment of chronic obstructive pulmonary disease (COPD) but not for the treatment of asthma. 3,4 Three studies with durations ranging from 8 to 16 weeks have shown the efficacy of the addition of tiotropium in patients with asthma who were already receiving standard treatment regimens. 5-7 The effect of tiotropium had not been evaluated in long-term clinical trials of sufficient duration and power to permit assessment of key end points, such as exacerbation frequency, in patients with poorly controlled asthma. We report here the results of two replicate, randomized, placebo-controlled trials, PrimoTinAasthma 1 and PrimoTinA-asthma 2 (hereafter referred to as trial 1 and trial 2), in which we studied the efficacy and safety of adding tiotropium delivered by a soft-mist inhaler, as compared with placebo delivered by the same system, to a treatment regimen of glucocorticoids and LABAs. We evaluated the effects on lung function, exacerbation frequency, and other end points during a 48-week period in patients with poorly controlled asthma. Me thods Patient Characteristics Eligible patients were between the ages of 18 and 75 years and had a 5-year or longer history of asthma that was diagnosed before the age of 40 years. Patients were required to have a score of 1.5 or higher on the Asthma Control Questionnaire 7 (ACQ-7), which consists of seven questions, each scored on a range from 0 (no impairment) to 6 (maximum impairment), with a minimal clinically important difference of 0.5 units 8 ; and to have persistent airflow limitation, which was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) of 80% or less of the predicted value 9 and 70% or less of forced vital capacity (FVC) 30 minutes after the inhalation of four puffs of 100 µg of salbutamol or 90 µg of albuterol at the screening visit, despite daily therapy with inhaled glucocorticoids ( 800 µg of budesonide or the equivalent) and LABAs. Patients were required to have had at least one exacerbation that was treated with systemic glucocorticoids in the previous year and to be either lifelong nonsmokers or to have a smoking history of fewer than 10 pack-years, with no smoking in the year before enrollment. The main exclusion criteria were a past diagnosis of COPD, serious coexisting illnesses, and concurrent use of anticholinergic bronchodilators. Details of inclusion and exclusion criteria and permitted and excluded concomitant medications are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. Trial Design and Oversight The two replicate trials had a randomized, doubleblind, placebo-controlled, parallel-group design, with a 48-week study period. They were conducted between October 2008 and July 2011 in 15 countries (listed in the Supplementary Appendix) and were performed in accordance with the provisions of the Declaration of Helsinki. The protocols were approved by the institutional review board at each participating center. All patients provided written informed consent. After a 4-week screening period, eligible patients underwent randomization. There were nine visits: a visit at the start of the trial (screening), a visit at randomization (baseline), and seven additional visits during the 48-week treatment period. Full trial protocols, including the statistical analysis plans, are available at NEJM.org. All the authors had access to all data and vouch for the accuracy and completeness of the data and for the fidelity of the trials to the final protocols; all the authors were involved in the interpretation of the data and in the writing and editing of the manuscript and made the decision to submit the manuscript for publication. Editorial assistance was provided by International Meetings and Science. Representatives of Boehringer Ingelheim designed and conducted the trial with the first author and collected and analyzed the data. Funding for the trials and editorial assistance was provided by Boehringer Ingelheim and Pfizer. n engl j med 367;13 nejm.org september 27, The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

13 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Trial and Concomitant Medications Patients were randomly assigned to self-administer two puffs of either 2.5 µg (i.e., 5 µg) of tiotropium or matching placebo each morning using a soft-mist inhaler (Respimat) as add-on therapy to individual pretrial maintenance asthma therapy consisting of high-dose inhaled glucocorticoids and LABAs. Continued use of sustained-release theophylline, leukotriene modifiers, anti-ige antibody, and oral glucocorticoids ( 5 mg per day) was also permitted if the dose of each remained stable for at least 4 weeks before study entry and for the duration of the trial. An open-label metered-dose inhaler of salbutamol (100 µg per puff) or albuterol (90 µg per puff) was provided as rescue medication for use during the trials, but the patients were responsible for supplying their own maintenance medications. Trial End Points The two coprimary lung-function end points for each trial were the peak FEV 1 response (within 3 hours after administration of the maintenance and study drugs) and the trough FEV 1 response at week 24 both expressed as the change from the baseline FEV 1. The baseline FEV 1 was measured at the time of randomization (during visit 2) in the morning, 10 minutes before the administration of maintenance and trial medications. In a subgroup of patients, serial measurements of FEV 1 were performed over a 24-hour period at week 24. A prespecified third coprimary end point, the time to the first severe asthma exacerbation (which was defined as a deterioration of asthma necessitating initiation or at least a doubling of systemic glucocorticoids for 3 days), 10 was evaluated from 48-week pooled trial data. Secondary end points included the peak and trough FEV 1 and FVC at each treatment visit, as well as the area under the curve for 3 hours after the administration of the maintenance and study drugs. Also included was the time to the first worsening of asthma (prespecified as the time to the first asthma exacerbation), which was defined as either a progressive increase in symptoms (as compared with usual day-to-day asthma symptoms) or a decline of 30% or more in the best morning peak expiratory flow (PEF) from the mean screening morning PEF for 2 or more consecutive days. Patients recorded morning and evening PEF, asthma symptoms (on the European Quality of Life 5 Dimensions questionnaire, a standardized measure of five dimensions of health status, each rated as no problems, some problems, or severe problems ), and medication use in an electronic diary (Asthma Monitor AM3) twice daily. Measurements were recorded daily and analyzed as means of weekly predose values for morning and evening PEF and asthma symptoms. Asthma control and quality of life were assessed with the use of the ACQ-7 8 and the Asthma Quality of Life Questionnaire (AQLQ), 11 respectively. The AQLQ consists of 32 questions addressing asthma-related symptoms and limitation during the preceding 2 weeks. Each item is scored on a scale of 1 (severely impaired) to 7 (no impairment at all); the minimal clinically important difference is 0.5 units. Adverse events, pulse rate, and blood pressure were assessed routinely. Randomization and Masking After the screening period, patients were randomly assigned in a 1:1 ratio to one of the two study groups. Randomization was performed in blocks of four per center, with no other stratification. The randomization schedule was generated by a validated system (PMX CTM, release HP2, Propack Data) with the use of a pseudo randomnumber generator and a supplied seed number. Statistical Analysis For both trials separately, statistical testing of 24-week lung-function results followed a hierarchical sequence. First, the superiority of treatment with tiotropium to treatment with placebo was tested with respect to peak FEV 1. If significance was determined, the trough FEV 1 was tested next. Ordered one-sided hypotheses (alpha of 0.025) underwent analysis on the basis of adjusted means with the use of a restricted-maximumlikelihood based mixed-effects model with a repeated-measures approach. Analyses included fixed categorical effects of treatment, center, visit, and interaction between treatment and visit, as well as the baseline value of the outcome variable (the pretreatment measure of interest on the day of randomization) and the interaction between baseline and visit measurements. If tiotropium therapy showed superiority with respect to the two primary lung-function end points in each trial, with the type I error rate protected, the third coprimary end point (the time to the first severe exacerbation) was tested on the basis of pooled data after 48 weeks. For the third coprimary end point, a prespecified interim analysis was performed once 1200 n engl j med 367;13 nejm.org september 27, 2012 The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

14 Tiotropium in Poorly Controlled Asthma by an independent data monitoring committee when the total number of patients with at least one severe exacerbation in the two trials combined reached 65; as a result, the sample size was increased to approximately 400 patients per trial, as prespecified in the protocols. The method described by Cui et al. was used to calculate the P value for the third coprimary end point. 12 Initial sample-size calculations are provided in the Supplementary Appendix. All statistical analyses were prespecified, with the exception of the analyses of subgroups defined according to age and smoking status. Statistical comparisons of secondary end points (also analysis of covariance) were exploratory. The statistical analyses were performed with the use of SAS software (SAS Institute). Details regarding the statistical analysis plans are provided in the Supplementary Appendix. R esult s Study Patients Of the 1335 patients who were screened, 912 eligible patients underwent randomization (Fig. 1). A total of 409 patients receiving tiotropium (211 in trial 1 and 198 in trial 2) and 405 patients receiving placebo (202 in trial 1 and 203 in trial 2) completed their respective trial. The primary analyses were performed on the full analysis set, Trial 1 Trial Patients were assessed for eligibility 679 Patients were assessed for eligibility 197 Withdrew after screening 157 Did not meet inclusion criteria or met exclusion criteria 24 Withdrew consent 16 Had other reasons 226 Withdrew after screening 177 Did not meet inclusion criteria or met exclusion criteria 23 Withdrew consent 26 Had other reasons 459 Underwent randomization 453 Underwent randomization 222 Were assigned to placebo 237 Were assigned to tiotropium 234 Were assigned to placebo 219 Were assigned to tiotropium 202 (91.0%) Completed study 20 (9.0%) Discontinued study 6 Had adverse events (3 had worsening asthma) 3 Had compliance issues 1 Was lost to follow-up 3 Declined to continue taking trial medication 7 Had other reasons 211 (89.0%) Completed study 26 (11.0%) Discontinued study 6 Had adverse events (2 had worsening asthma) 1 Had lack of efficacy 3 Had compliance issues 1 Was lost to follow-up 8 Declined to continue taking trial medication 7 Had other reasons 203 (86.8%) Completed study 31 (13.2%) Discontinued study 8 Had adverse events (5 had worsening asthma) 4 Had compliance issues 2 Were lost to follow-up 12 Declined to continue taking trial medication 5 Had other reasons 198 (90.4%) Completed study 21 (9.6%) Discontinued study 2 Had adverse events (1 had worsening asthma) 1 Had lack of efficacy 2 Had compliance issues 7 Declined to continue taking trial medication 9 Had other reasons 456 Were included in per-protocol analysis of exacerbations in the pooled placebo group at 48 wk 456 Were included in per-protocol analysis of exacerbations in the pooled tiotropium group at 48 wk Figure 1. Screening, Randomization, and Study Completion. A total of five patients in trial 2 were excluded because of compliance issues after randomization: two patients in the placebo group and three patients in the tiotropium group. See the Supplementary Appendix for additional information. n engl j med 367;13 nejm.org september 27, The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

15 T h e n e w e ngl a nd j o u r na l o f m e dic i n e which was defined as all 907 patients who underwent randomization and received at least one dose of a study drug and had at least one ontreatment efficacy measurement (Fig. 1). Baseline characteristics were similar in the two trials and well balanced between the study groups (Table 1, and Table S1 in the Supplementary Appendix). Medication used at the time of randomization (visit 2) consisted of inhaled glucocorticoids (median budesonide equipotent dose, 800 µg; interquartile range, 800 to 1600) and LABAs, plus additional protocol-approved treatments, as used Table 1. Baseline Characteristics of the Patients.* Characteristic All Patients (N = 912) Trial 1 Trial 2 Tiotropium (N = 237) Placebo (N = 222) Tiotropium (N = 219) Placebo (N = 234) Female sex no. (%) 551 (60.4) 146 (61.6) 143 (64.4) 127 (58.0) 135 (57.7) Age yr 53.0± ± ± ± ±11.7 Body-mass index 28.2± ± ± ± ±5.9 Race no. (%) White 759 (83.2) 200 (84.4) 187 (84.2) 176 (80.4) 196 (83.8) Other 153 (16.8) 37 (15.6) 35 (15.8) 43 (19.6) 38 (16.2) Never smoked cigarettes no. (%) 692 (75.9) 182 (76.8) 174 (78.4) 158 (72.1) 178 (76.1) Median age of asthma onset yr (range) 26 (0 44) 23 (0 40) 26 (0 39) 29 (0 44) 27 (0 39) Median duration of asthma yr (range) 28 (5 72) 31 (6 70) 28 (6 68) 26 (5 72) 28 (5 69) Severe exacerbations in past year no. (%) <3 738 (80.9) 201 (84.8) 185 (83.3) 179 (81.7) 173 (73.9) (14.0) 27 (11.4) 27 (12.2) 30 (13.7) 44 (18.8) >5 46 (5.0) 9 (3.8) 10 (4.5) 10 (4.6) 17 (7.3) Use of maintenance oral glucocorticoids %** Use of omalizumab % Mean daily no. of puffs of short-acting beta-agonists Use of theophyllines % Use of leukotriene modifiers % Use of antihistamines % ACQ-7 score** 2.6± ± ± ± ±0.7 AQLQ score** 4.6± ± ± ± ±1.1 Forced expiratory volume in 1 sec Value before bronchodilation liters** 1.603± ± ± ± ±0.506 Percent of predicted value before bronchodilation 54.8± ± ± ± ±12.6 Percent of predicted value after bronchodilation 62.2± ± ± ± ±13.0 Reversibility ml 217± ± ± ± ±229 Forced vital capacity liters** 2.744± ± ± ± ±0.851 * Plus minus values are means ±SD. All values were measured during screening (visit 1), unless otherwise stated. There were no significant differences between the two study groups in either trial unless otherwise indicated. P<0.05. The body-mass index is the weight in kilograms divided by the square of the height in meters. Race was self-reported. P<0.01. Exacerbations are expressed as the number of courses of glucocorticoids administered during the previous year. ** This measurement was performed at the time of randomization (visit 2). This measurement reports mean use during the final week before randomization (visit 2). The Asthma Control Questionnaire 7 (ACQ-7) consists of seven questions, each of which is scored on a range from 0 (no impairment) to 6 (maximum impairment). The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 questions addressing asthma-related symptoms and limitations during the preceding 2 weeks. Each item is scored on a scale of 1 (severely impaired) to 7 (no impairment) n engl j med 367;13 nejm.org september 27, 2012 The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

16 Tiotropium in Poorly Controlled Asthma before the trial (Table S1 in the Supplementary Appendix). Glucocorticoids and LABAs, as well as most pulmonary medications, were continued throughout the trial, as detailed in Methods. Primary End Points Lung Function Airflow obstruction was significantly reduced with the addition of tiotropium, as compared with the addition of placebo. At 24 weeks, the mean (±SE) difference between the tiotropium group and the placebo group in the change in the adjusted peak FEV 1 from baseline in the first 3 hours after the administration of tiotropium was 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P<0.001) (Table 2 and Fig. 2A and 2B). The between-group difference in change from baseline in the trough FEV 1 at 24 weeks was also significantly greater for patients in the tiotropium group than for those in the placebo group: 88±31 ml in trial 1 (P = 0.01) and 111±30 ml in trial 2 (P<0.001). Severe Exacerbations The time to the first exacerbation (the primary end point) was increased by 56 days with tiotropium as compared with placebo (282 days vs. 226 days, representing the time until at least 25% of the patients [first quartile] had a first severe Table 2. Mean Difference between Tiotropium and Placebo in the Change from Baseline to Week 24 and Week 48 in the Two Trials.* Measure and Week Trial 1 Trial 2 Forced expiratory volume in 1 sec Peak at 0 3 hr (ml) No. of Patients Difference in Change mean (95% CI) No. of Patients Difference in Change mean (95% CI) 24 wk (20 to 152) (91 to 217) 48 wk (5 to 140) (87 to 217) Trough (ml) 24 wk (27 to 149) (53 to 169) 48 wk ( 21 to 104) (32 to 151) Forced vital capacity Peak (ml) 24 wk (6 to 173) (10 to 177) 48 wk (40 to 210) (29 to 200) Trough (ml) 24 wk (58 to 214) (25 to 186) 48 wk (31 to 190) ( 12 to 153) Peak expiratory flow Morning (liters/min) 24 wk (12.7 to 30.4) (14.5 to 32.1) 48 wk (11.3 to 29.4) (5.1 to 22.9) Evening (liters/min) 24 wk (13.0 to 30.9) (20.7 to 39.1) 48 wk (13.5 to 31.7) (15.1 to 33.8) * All differences are calculated as the adjusted mean change from baseline, as measured at randomization (visit 2), for tiotropium minus placebo. Baseline was defined as the measurement obtained before any study or maintenance medication was administered. Values for forced expiratory volume in 1 second and forced vital capacity have been adjusted for treatment, center, visit, baseline value, and interactions between treatment and visit and between baseline value and visit. This category was a coprimary end point in the two trials. P<0.05. P< P<0.01. All values are means of weekly measurements of peak expiratory flow. n engl j med 367;13 nejm.org september 27, The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

17 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A FEV 1 Change in Trial 1 FEV 1 Change from Baseline (ml) B FEV 1 Change in Trial 2 FEV 1 Change from Baseline (ml) C Severe Exacerbation Patients with at Least One Severe Asthma Exacerbation (%) No. at Risk Placebo Tiotropium ** exacerbation), corresponding to a reduction of 21% in risk (hazard ratio, 0.79; 95% confidence interval [CI], 0.62 to 1.00; P = 0.03) (Fig. 2C). (Since less than 50% of the patients had a severe *** Hours * *** * *** Days Tiotropium Placebo Hours ** *** Tiotropium Placebo ** *** Placebo Tiotropium exacerbation, the median time to the first severe exacerbation cannot be calculated.) Key Prespecified Secondary End Points At week 24, there was significant improvement in spirometric measurements among patients in the tiotropium group, as compared with those in the placebo group (Table 2). In a subgroup of patients in whom 24-hour spirometry was performed, the improvement in FEV 1 was maintained over the full day (Fig. S1A and S1B in the Supplementary Appendix). Improvements in peak FEV 1 were sustained over the 48-week period (Fig. S1C and S1D in the Supplementary Appendix). There were also significantly greater improvements in weekly morning and evening PEF values in the tiotropium group; these improvements were also sustained over the full trial period (Fig. S1E through S1H in the Supplementary Appendix). In the tiotropium group, 122 of 453 patients (26.9%) had at least 1 severe exacerbation, as compared with 149 of 454 patients (32.8%) in the placebo group (Table S2 in the Supplementary Appendix). The total number of severe exacerbations per patient-year was significantly lower in the tiotropium group than in the placebo group (0.53 vs. 0.66, P = 0.046) (Table S2 in the Supplementary Appendix). There were 16 patients hospitalized for asthma in the tiotropium group, Figure 2. Lung Function and Severe Exacerbations. The mean changes in lung function from baseline to 24 weeks, as measured by the forced expiratory volume in 1 second (FEV 1 ) for 3 hours after the administration of the study and maintenance drugs, are shown for trial 1 (Panel A) and trial 2 (Panel B). The baseline FEV 1 was defined as the measurement obtained at randomization (visit 2) before the administration of study and maintenance medications. At subsequent visits during the study period, this measurement was followed immediately by the administration of maintenance and study medications. For Panels A and B, 0 hour denotes the first measurement, taken between 7 and 10 a.m., which was the trough effect of tiotropium or placebo administered 24 hours earlier. Panel C shows the cumulative number of severe exacerbations, with a risk reduction of 21% (hazard ratio, 0.79; P = 0.03 in pooled analysis). One asterisk indicates P<0.05; two asterisks, P<0.01; and three asterisks, P< The I bars represent standard errors. Data have been adjusted for treatment, study center, visit, baseline measurement, and the interactions between treatment and visit and between baseline values and visit n engl j med 367;13 nejm.org september 27, 2012 The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

18 Tiotropium in Poorly Controlled Asthma as compared with 20 patients in the placebo group. The median time to the first worsening of asthma was increased with the addition of tiotropium (315 days, vs. 181 days with placebo), with a reduction of 31% in risk (hazard ratio, 0.69; 95% CI, 0.58 to 0.82; P<0.001) (Fig. S2 and Table S2 in the Supplementary Appendix). There were improvements in scores on the ACQ-7 in the two study groups (Fig. S3A and S3B in the Supplementary Appendix). At week 24, the mean difference in scores between the tiotropium group and the placebo group was significant only in trial 2 ( 0.13 [P = 0.06] and 0.2 [P = 0.003] in trials 1 and 2, respectively) (Table S3 in the Supplementary Appendix). The minimal clinically important difference for the ACQ-7 score was not achieved in either trial. Significant differences in the AQLQ score between the tiotropium group and the placebo group were seen at 24 weeks in trial 2 (0.18 units, P = 0.02), but in trial 1 the difference (0.04 units) was not significant (Fig. S3C and S3D and Table S3 in the Supplementary Appendix). The minimal clinically important difference of 0.5 for the AQLQ score was not achieved in either trial. There were small and nonsignificant betweengroup differences in the number of symptomfree days, as recorded in the AM3 electronic diary. The use of rescue medication was similar in the two study groups; the adjusted mean difference in puffs per day (weekly mean in the 7 days before week 24, tiotropium minus placebo) was 0.09 in trial 1 and 0.26 in trial 2 (Table S3 in the Supplementary Appendix). Between-group differences in other secondary end points were also not significant. Subgroup Analyses The improvements in peak FEV 1 in the tiotropium group, as compared with the placebo group (measured as the interaction between the subgroup and study treatment), tended to be higher in patients with a lower FEV 1 as a percentage of the predicted value (trial 1, P = 0.03; trial 2, P = 0.56), in men (trial 1, P = 0.09; trial 2, P = 0.04), and in former smokers with a history of fewer than 10 pack-years (trial 1, P = 0.14; trial 2, P = 0.047) in post hoc analysis. However, improvements were independent of other factors that were analyzed, including geographic region, level of reversibility, age (post hoc), body-mass index, allergic status, asthma duration, ACQ-7 score at baseline, and use of systemic glucocorticoids in the year before trial enrollment. Similar results were observed in the analysis of the time to the first severe exacerbation. Adverse Events Adverse events were reported in 73.5% of patients in the tiotropium group and 80.3% of patients in the placebo group. Among the adverse events reported by at least 2% of patients in any study group, only allergic rhinitis occurred at a significantly higher rate in the tiotropium group; asthma events and insomnia were significantly more common in the placebo group (Table 3). Adverse events were assessed as drug-related in 26 of 456 patients (5.7%) in the tiotropium group, as compared with 21 of 456 patients (4.6%) in the placebo group. Dry mouth was reported by 11 patients: 8 (1.8%) in the tiotropium group and 3 (0.7%) in the placebo group. Serious adverse events were reported for 77 patients: 37 (8.1%) in the tiotropium group and 40 (8.8%) in the placebo group (Table S4 in the Supplementary Appendix). Of the serious adverse events, 3 events (all in the tiotropium group) were considered to be life-threatening. Two patients had an asthma exacerbation and recovered fully; 1 patient was admitted to the hospital for cerebral infarction. Cardiac adverse events occurred in less than 2% of patients and were well balanced between the study groups. Drug-related cardiac events were reported in 2 patients (0.4%) in the tiotropium group and 1 patient (0.2%) in the placebo group. Changes that were observed in blood pressure and pulse rate and laboratory or electrocardiographic abnormalities were balanced between the study groups. No deaths occurred. Discussion Tiotropium is the most widely used long-acting bronchodilator worldwide for the treatment of COPD. However, its role as a treatment for asthma has only recently been subject to systematic clinical investigation. The results of these two replicate trials confirm that adding tiotropium once daily provided modest sustained bronchodilation over 24 hours. Adding tiotropium also reduced severe exacerbations and episodes of the worsening of asthma in patients who were symptomatic and had persistent airflow limitation despite the use of inhaled glucocorticoids and n engl j med 367;13 nejm.org september 27, The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

19 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 3. Adverse Events.* Event Trial 1 Trial 2 Tiotropium (N = 237) Placebo (N = 222) Tiotropium (N = 219) number of patients (percent) Placebo (N = 234) Any adverse event 167 (70.5) 170 (76.6) 168 (76.7) 196 (83.8) Asthma 91 (38.4) 109 (49.1) 91 (41.6) 123 (52.6) Decreased rate of peak expiratory flow 49 (20.7) 58 (26.1) 44 (20.1) 64 (27.4) Nasopharyngitis 19 (8.0) 20 (9.0) 32 (14.6) 36 (15.4) Headache 12 (5.1) 13 (5.9) 17 (7.8) 20 (8.5) Bronchitis 12 (5.1) 10 (4.5) 13 (5.9) 10 (4.3) Sinusitis 3 (1.3) 10 (4.5) 13 (5.9) 12 (5.1) Upper respiratory tract infection 13 (5.5) 6 (2.7) 8 (3.7) 10 (4.3) Influenza 10 (4.2) 4 (1.8) 10 (4.6) 10 (4.3) Cough 6 (2.5) 5 (2.3) 7 (3.2) 8 (3.4) Back pain 3 (1.3) 7 (3.2) 8 (3.7) 5 (2.1) Oropharyngeal pain 3 (1.3) 5 (2.3) 6 (2.7) 6 (2.6) Pneumonia 7 (3.0) 1 (0.5) 5 (2.3) 6 (2.6) Arthralgia 6 (2.5) 2 (0.9) 4 (1.8) 7 (3.0) Dysphonia 5 (2.1) 4 (1.8) 5 (2.3) 4 (1.7) Diarrhea 4 (1.7) 4 (1.8) 4 (1.8) 6 (2.6) Respiratory tract infection 5 (2.1) 5 (2.3) 2 (0.9) 6 (2.6) Allergic rhinitis 3 (1.3) 2 (0.9) 10 (4.6) 1 (0.4) Hypertension 2 (0.8) 2 (0.9) 4 (1.8) 8 (3.4) Insomnia 0 1 (0.5) 2 (0.9) 9 (3.8) * The listed events were reported in at least 2% of patients who underwent randomization in trials 1 and 2. Events are described according to preferred term classifications in the Medical Dictionary for Drug Regulatory Affairs, version A list of all serious adverse events is provided in Table S4 in the Supplementary Appendix. LABAs and, in some cases, additional controller drugs. The improvements in peak FEV 1 in trials 1 and 2 in patients with asthma who received tiotropium (86 ml and 154 ml, respectively) were similar in magnitude to those reported previously by Kerstjens et al. 7 (139 ml) in patients with asthma receiving inhaled glucocorticoids and LABAs. Although the improvements in FEV 1 were relatively small (<10%), it should be noted that these increases were in patients who were already receiving a long-acting bronchodilator and had fixed airflow limitation. The added benefit of combining two long-acting bronchodilators with different modes of action has also been observed in patients with COPD. 13 Improvements in ACQ-7 and AQLQ scores and other secondary end points in these two replicate trials were small and inconsistent and did not reach the minimal clinically important difference; in light of the fact that episodes of asthma worsening were reduced significantly, this modest symptomatic benefit was surprising. The reduction in severe exacerbations was also significant: in a post hoc calculation, the number needed to treat in order to prevent one severe exacerbation during the 48-week treatment period was 15. The gains observed in trials 1 and 2, though relatively small, should be viewed in the context of the need for additional treatments for this patient population and the limitations of current alternatives. Leukotriene-receptor antagonists and theophylline have shown little, if any, benefit in this patient population; oral glucocorticoids are associated with severe side effects; and other treatments, such as omalizumab, are suitable only for a subgroup of patients. None of the alternatives have shown benefit across more than a few clinical end points. We cannot explain the inconsistency in the 1206 n engl j med 367;13 nejm.org september 27, 2012 The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

20 Tiotropium in Poorly Controlled Asthma results between the two trials. Both trials were performed on several continents in multiple centers, and across the two trials, patient baseline characteristics were similar, and no differences in results according to geographic region were identified in subgroup analyses. A larger placebo response was seen in trial 1 than in trial 2. In our trials, adverse events and serious adverse events were well balanced between study groups in the two trials. Dry mouth, a typical adverse event with anticholinergic agents, was reported in less than 2% of all patients and was reported more frequently in the tiotropium group than in the placebo group (eight patients vs. three patients) a finding that is consistent with the known adverse-event profile of tiotropium. In conclusion, in patients with poorly controlled asthma despite treatment with inhaled glucocorticoids and LABAs, adding tiotropium significantly reduced the risk of episodes of the worsening of asthma and asthma exacerbations requiring treatment with systemic glucocorticoids and provided sustained bronchodilation. The side effects of tiotropium were similar to those previously noted in trials of therapies for COPD. Supported by Boehringer Ingelheim and Pfizer. Dr. Kerstjens reports receiving on behalf of his institution consulting fees or honoraria and support from Boehringer Ingelheim for his travel to meetings or for other purposes connected with this clinical study and support from Boehringer Ingelheim, Pfizer, Nycomed, Novartis, Almirall, and Chiesi for his service on advisory boards and from Boehringer Ingelheim, Pfizer, and Nycomed for consulting work; Dr. Engel, being an employee of Boehringer Ingelheim; Dr. Dahl, receiving consulting fees and travel support from Boehringer Ingelheim connected with this clinical study and receiving on behalf of his institution a grant from Boehringer Ingelheim connected with this clinical study; Dr. Paggiaro, receiving consulting fees from Boehringer Ingelheim in connection with this study, support for service on advisory boards from GlaxoSmithKline, Merck, Novartis, and Takeda/Nycomed, and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Novartis, and Takeda/Nycomed and serving on the board of directors for the Global Initiative for Asthma and receiving on behalf of his institution grant support from Boehringer Ingelheim in connection with this clinical study; Dr. Beck, receiving support for participation in review activities and for travel from Boehringer Ingelheim in connection with this study, support from Almirall and Mundipharma for service on advisory boards, and lecture fees from AstraZeneca, Bayer, Novartis, and Takeda/Nycomed and receiving on behalf of his institution grant support related to this clinical study from Boehringer Ingelheim; Dr. Vandewalker, receiving consulting fees, support to participate in review activities, and travel support and receiving on behalf of his institution a grant from Boehringer Ingelheim connected with this clinical study, receiving grant support from Boehringer Ingelheim, and receiving lecture fees from GlaxoSmithKline, AstraZeneca, and Merck; Drs. Sigmund, Seibold, and Moroni-Zentgraf, being employees of Boehringer Ingelheim; Dr. Bateman, receiving consulting fees and support to review results and receiving on behalf of his institution a grant and travel support from Boehringer Ingelheim related to this clinical study, receiving lecture fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, ALK-Abelló, Chiesi, Novartis, Pfizer, and Takeda/Nycomed, receiving support for service on advisory boards for Almirall, AstraZeneca, Boehringer Ingelheim, Elevation Pharma, Glaxo SmithKline, Napp Pharma, Novartis, Forest, and Merck, receiving consulting fees from Navigant Consulting, IMS Consulting Group, ALK- Abelló, Almirall, and Hoffmann La Roche, receiving support for his participation in educational presentations for Indegene Lifesystems, and being a member of the Task Force on Severe Asthma of the American Thoracic Society and the European Respiratory Society and an advisory board member for the Global Initiative for Asthma. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank all investigators in support of these trials. References 1. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170: Global Initiative for Asthma. Global strategy for asthma management and prevention ( uploads/users/files/gina_report2011_ May4.pdf). 3. Matera MG, Cazzola M. Ultra-longacting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs 2007;67: Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359: Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363: Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16- Arg/Arg patients with asthma. J Allergy Clin Immunol 2011;128: Kerstjens HA, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011;128: Juniper EF, O Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14: Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows: official statement of the European Respiratory Society. Eur Respir J Suppl 1993;16: Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/ European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180: Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 1992;47: Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. Biometrics 1999;55: van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26: Copyright 2012 Massachusetts Medical Society. n engl j med 367;13 nejm.org september 27, The New England Journal of Medicine Downloaded from nejm.org on February 19, For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.

21 JOURNAL OF AEROSOL MEDICINE Volume 18, Number 3, 2005 Mary Ann Liebert, Inc. Pp Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. Deposition of Corticosteroid Aerosol in the Human Lung by Respimat Soft Mist Inhaler Compared to Deposition by Metered Dose Inhaler or by Turbuhaler Dry Powder Inhaler GARY PITCAIRN, Ph.D., 1 SANDIE READER, Ph.D., 2 DEMETRI PAVIA, Ph.D., 3 and STEVE NEWMAN, Ph.D. 1 ABSTRACT Fourteen mild-to-moderate asthmatic patients completed a randomized four-way crossover scintigraphic study to determine the lung deposition of 200 g budesonide inhaled from a Respimat Soft Mist Inhaler (Respimat SMI), 200 g budesonide inhaled from a Turbuhaler dry powder inhaler (Turbuhaler DPI, used with fast and slow peak inhaled flow rates), and 250 g beclomethasone dipropionate inhaled from a pressurized metered dose inhaler (Becloforte pmdi). Mean (range) whole lung deposition of drug from the Respimat SMI (51.6 [46 57]% of the metered dose) was significantly (p 0.001) greater than that from the Turbuhaler DPI used with both fast and slow inhaled flow rates (28.5 [24 33]% and 17.8 [14 22]%, respectively) or from the Becloforte pmdi (8.9 [6 12]%). The deposition pattern within the lungs was more peripheral for Respimat SMI than for Turbuhaler DPI. The results of this study showed that Respimat SMI deposited corticosteroid more efficiently in the lungs than either of two widely used inhaler devices, Turbuhaler DPI or Becloforte pmdi. Key words: lung deposition, gamma scintigraphy, metered dose inhaler, dry powder inhaler, soft mist inhaler, asthma INTRODUCTION THE INHALED ROUTE is generally preferred for delivering inhaled asthma drugs, because it allows the use of small drug doses, which are usually fast-acting, and results in relatively few systemic side effects. (1) The use of inhaled glucocorticosteroids has become first-line therapy for asthma in many parts of the developed world, (2) and the pressurized metered dose inhaler (pmdi) has been the inhalation device of choice for several decades. (3) However, the phasing out of chlorofluorocarbon (CFC) propellants for environmental reasons has resulted in pharmaceutical companies seeking either alternative formulations or new devices for delivering inhaled drugs. (4) While some companies have chosen to reformulate their pmdis with non-cfc propel- 1 Pharmaceutical Profiles Ltd., Nottingham, United Kingdom. 2 Medical Division, Boehringer Ingelheim Ltd., Bracknell, United Kingdom. 3 Medical Division, Boehringer Ingelheim Ltd., Bracknell, United Kingdom. 264

22 DEPOSITION OF CORTICOSTEROID FROM RESPIMAT SOFT MIST INHALER 265 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. lants, (5) others have developed alternative technologies such as dry powder inhalers (DPIs), (6) or liquid based delivery systems. (7) Respimat Soft Mist Inhaler (SMI; Boehringer Ingelheim, Ingelheim, Germany) is a new generation inhaler suitable for patients with asthma or chronic obstructive pulmonary disease (COPD), containing drug as either an aqueous or an ethanolic solution, (8) and is powered mechanically by the energy stored in a tensioned/compressed spring. The device contains up to 112 doses each of 15 L, and delivers a spray cloud that is more slowly moving, of longer duration, (9) and with a smaller droplet size (8) than the spray from a pmdi. The low spray velocity and small droplet size are anticipated to result in lower oropharyngeal deposition and higher lung deposition than a pmdi, while the long spray duration could make coordination between actuating the device and inhalation easier to achieve. Previous studies have shown that Respimat SMI deposits fenoterol and flunisolide in the lungs more efficiently than a CFC pmdi. (10) However, the efficiency with which Respimat SMI deposits inhaled drug in the lungs relative to a DPI has not previously been investigated. In this study, we have compared in asthmatic patients the lung deposition of budesonide via Respimat SMI and Turbuhaler DPI (AstraZeneca, Lund, Sweden), which is one of the most efficient DPIs currently available, (11,12,13) being capable of depositing about 30% of the dose in the lungs with optimal technique. Also, we have included a comparison versus probably the most widely used pmdi corticosteroid formulation at the time the study was undertaken, containing beclomethasone dipropianate (BDP, Becloforte, GlaxoSmithKline, Research Triangle Park, NC). Patients MATERIALS AND METHODS Fourteen patients with mild to moderate stable asthma (six male, eight female) took part in the study. Their ages ranged from 19 to 65 years, and the mean ( SD) forced expiratory volume in one second (FEV 1 ) was 73 12% predicted in males, compared with 78 19% predicted in females. (14) Each patient had demonstrated at least 15% reversibility in FEV 1 to an inhaled 2 -agonist within the preceding 2 years, was either a non-smoker or ex-smoker, and had no change in pulmonary medication within the preceding 4 weeks. Patients were allowed to continue their normal asthma medication throughout the study. Prior to recruitment, the nature of the study was explained both verbally and in writing to each patient, and written informed consent was obtained prior to participation. The study protocol was approved by the Quorn Research Review Committee, Leicestershire, UK, and permission to administer radionuclides to patients was given by the Department of Health, UK. The effective dose equivalent (whole body radiation dose) from taking part in the study was estimated to be 0.6 msv. Study design The study had a randomized four-way crossover open design, in order to compare the pulmonary depositions of the following: 200 g budesonide (single dose) inhaled from Respimat SMI at a targeted average inhaled flow rate of 30 L/min 200 g budesonide (single dose) inhaled from Turbuhaler DPI (Pulmicort, AstraZeneca) at a targeted fast peak inhaled flow rate of 60 L/min 200 g budesonide (single dose) inhaled from Turbuhaler DPI (Pulmicort, AstraZeneca) at a targeted slow peak inhaled flow rate of 30 L/min 250 g beclomethasone dipropionate (single dose) inhaled from a Becloforte pmdi (Glaxo- SmithKline) at a targeted average inhaled flow rate of 30 L/min Radiolabeling Radiolabeling methods using the radionuclide 99m Tc were developed and validated for each of the three products to be investigated, based upon methods used in previous studies with these products. (11,15) In order to validate the radiolabeling methods, particle size distributions of drug and radiolabel were measured using a four-stage high precision multistage impinger (Copley Instruments, Nottingham, UK), (16) operated at a flow rate of 60 L/min. The range of particle sizes trapped on each of the stages of the impinger was as follows: inlet and stage 1: 13 m; stage 2: m; stage 3: m; stage 4: 3.1 m. Measurements were made of the drug distribution within the inhaler before labeling (n 5), the

23 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. 266 drug distribution after labeling (n 5), and the 99m Tc radiolabel distribution (n 5). After radiolabeling the Becloforte pmdi formulation, the metering valve was primed by discarding the first five doses into a filter. Turbuhaler DPI was primed in a similar manner. Respimat SMI was primed by repeatedly firing the device until a steady aerosol plume was emitted. The device was weighed before and after each shot to ensure that the weight of the formulation delivered was at least 12 mg. For in vivo use, the amount of radioactivity in each inhaler was adjusted so that sufficient 99m Tc was deposited in the lungs for good counting statistics, but such that the total amount of activity delivered did not exceed 10 MBq 99m Tc on each study day. Drug inhalations Prior to the administration of radiolabeled drug aerosol, subjects practised the required inhalation manoeuvre with a placebo Respimat SMI, a placebo Turbuhaler DPI, or a placebo Becloforte pmdi. Once the patient s technique was judged competent by an investigator, a single radiolabeled dose was inhaled according to the study randomization. Each inhaler was connected in series with a Compact-MDI Spirometer (Vitalograph, Maids Moreton, UK), which provided visual feedback to the patient of the inhaled flow signal, and allowed them to attain the target flow rate value. The Spirometer provided a record of inhaled volume, breath-holding pause and either average inhaled flow rate (for Becloforte pmdi and Respimat SMI) or peak inhaled flow rate (for Turbuhaler DPI). The Becloforte pmdi and Respimat SMI were actuated by an investigator in the early stages of inhalation. For each regimen, the breath was held for 10 sec, and then the patient exhaled via a low resistance filter to collect exhaled aerosol. Imaging Immediately after dosing, scintigraphic images were recorded using a gamma camera (Maxicamera, General Electric, Milwaukee, WI). Posterior and anterior views of the chest and stomach (duration 100 sec), and a right lateral view of the oropharynx (duration 30 sec) were recorded. After dosing with Respimat SMI, the removable mouthpiece was carefully wiped with a sterile swab containing 70% isopropyl alcohol and 0.5% chlorhexidine acetate (Steret H). These swabs were also used to wipe activity from the outer surface of the nozzle and the surrounding plastic casing. Gamma camera counts from the mouthpiece and swab were combined to give the total mouthpiece deposition. Gamma camera counts were also obtained for Becloforte pmdi actuator, Turbuhaler DPI mouthpiece, and the exhalation filter for all regimens. On one study day a posterior lung ventilation scan was performed using the radioactive inert gas 81m Kr. Data analysis All images were recorded on a Micas V computer system (Park Medical, Farnborough, UK), and were stored on optical disc for subsequent analysis. The lung outlines from the 81m Kr ventilation scan were used to define the edges of the lung fields on the aerosol view. The lungs were subdivided into central, intermediate and peripheral regions of interest. (17) Regions of interest were also drawn around the oropharynx, oesophagus and stomach. Determination of the percentage of the dose deposited in the oropharynx included activity adhering to the mouth and pharynx together with any swallowed activity detected in the esophagus and stomach. All scintigraphic data were corrected for background radiation, radioactive decay, and for the attenuation of gamma rays by overlying tissue where appropriate, (18) but no correction was made for biological clearance of radiotracer. Attenuation correction factors for the lung averaged 1.94, and ranged from 1.82 to 2.05 in individual subjects. Where both anterior and posterior counts had been obtained, the geometric mean count was calculated. The corrected counts in the lungs, oropharynx, mouthpiece/actuator and exhalation filter were summed, and the deposition data expressed as percentage of metered (ex-valve) dose by determining the count in each region as a percentage of the summed count. The percentages of the dose in the central, intermediate and peripheral lung regions were determined, and the peripheral zone/central zone deposition ratio (P/C ratio) was calculated. Lung function testing PITCAIRN ET AL. FEV 1 (Microloop Spirometer, Micro Medical, Rochester, UK) was recorded pre-dosing and at 15, 30, and 60 min post-dosing in order to deter-

24 DEPOSITION OF CORTICOSTEROID FROM RESPIMAT SOFT MIST INHALER 267 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. mine whether any bronchoconstriction occurred as a result of inhaling the study doses. Radiolabeling validation RESULTS The radiolabeling validation data are shown in Figures 1 3 for Respimat SMI, Turbuhaler DPI and Becloforte pmdi, respectively. The match between the distributions of drug before labeling, drug after labeling and radiolabel was closest for Respimat SMI, and was least good for Turbuhaler DPI. However, for each device, there was good agreement between mean fine particle fractions (sum of stages 3 and 4) for the drug before labeling versus radiolabel as follows: Respimat SMI 62.7% versus 58.6%; Turbuhaler DPI 38.7% versus 38.2%; Becloforte pmdi 43.4% versus 40.6%. On the basis of these data, the radiolabeling methods were considered appropriate for use in the in vivo study, since the ratio of fine particle fractions for radiolabel versus drug before labelling fell within the range (19) There was considerable variability for Turbuhaler DPI in the amount of deposition on the inlet throat and on stage 1 of the impinger, but this was considered unimportant since both inlet throat and stage 1 would comprise parts of oropharyngeal deposition in vivo. Deposition data The fractionation of the dose between lungs, oropharynx, device (mouthpiece or actuator) and exhaled air filter is shown in Table 1. Lung deposition averaged 51.6% of the dose for Respimat SMI, and this was significantly (p 0.001) higher than for Turbuhaler DPI with fast flow (mean 28.5%), Turbuhaler DPI with slow flow (mean 17.8%), or Becloforte pmdi (mean 8.9%). Conversely, the percentage of the dose deposited in the oropharynx for Respimat SMI (mean 19.3%) was significantly (p 0.001) lower than those for the other three regimens. A mean 10.5% of the Respimat SMI dose was exhaled, compared to 1% for the other regimens. Typical scintigraphic images for each regimen are shown in Figure 4. Analysis of deposition in central, intermediate and peripheral lung regions showed that deposition occurred in all three regions, but was concentrated in the central lung region for Turbuhaler DPI to a greater extent than for Respimat SMI and Becloforte pmdi. This was reflected in significantly (p 0.01) higher mean peripheral zone/central zone deposition ratios for Respimat SMI (1.34) and Becloforte pmdi (1.27) than for Turbuhaler DPI with fast flow (0.95) or Turbuhaler DPI with slow flow (0.82). Inhalation modes and lung function Patients complied well with the required inhalation techniques, and the inhaled flow rates were close to targeted values (Table 2). One subject recorded a very low inhaled volume (0.7 L) when using the Becloforte pmdi, but this was considered to be an artefact related to the Compact-MDI spirometer. This subject s inhalation de- FIG. 1. Radiolabeling validation data for Respimat SMI, showing percentage distributions of the drug before labeling, drug after labeling and the 99m Tc radiolabel. Data were obtained using a four-stage multistage liquid impinger (MP, mouthpiece; Th, inlet throat; S1 S4, stages 1 4). Data are mean SD.

25 268 PITCAIRN ET AL. Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. FIG. 2. Radiolabeling validation data for Turbuhaler DPI, showing percentage distributions of the drug before labeling, drug after labeling and the 99m Tc radiolabel. Data were obtained using a four-stage multistage liquid impinger (MP, mouthpiece; Th, inlet throat; S1 S4, stages 1 4). Data are mean SD. tails have been excluded from the summary on Table 2. FEV 1 values were virtually unchanged in most patients after drug inhalation, although there were two cases of paradoxical bronchospasm (defined as a fall in FEV 1 of 15% within 30 min of inhalation). One case occurred on a Respimat SMI study day (FEV 1 fell by 20% at 15 min postdose) and the other on a pmdi study day (FEV 1 fell by 29% at 15 min post-dose). Both these events resolved following bronchodilator treatment. DISCUSSION The phasing out of CFC propellants has been a major challenge to the pharmaceutical industry, since companies have needed to develop alternative devices and/or formulations. Some companies have chosen to develop non-cfc products that deposit the same amount of drug in the lungs compared with the CFC products that are being replaced. (20) However, other companies have used the opportunity afforded by the CFC phaseout to develop better products, which target drug to the lungs more efficiently. CFC-based pmdis generally deposit no more than about 15% of the dose in the lungs, (21,22) and this value may be much lower with poor inhaler technique. (23) Improved pulmonary targeting of drugs used to treat asthma and COPD can be achieved using some non-cfc formulations in pmdis. (24) Lung deposition comparable to that seen for Respimat FIG. 3. Radiolabeling validation data for Becloforte pmdi, showing percentage distributions of the drug before labeling, drug after labeling and the 99m Tc radiolabel. Data were obtained using a four-stage multistage liquid impinger (Act, actuator; Th, inlet throat; S1 S4, stages 1 4). Data are mean SD.

26 DEPOSITION OF CORTICOSTEROID FROM RESPIMAT SOFT MIST INHALER 269 TABLE 1. MEAN AND RANGE PERCENTAGE OF THE DOSE DEPOSITED IN LUNGS, OROPHARYNX, DEVICE, AND EXHALED AIR FILTER FOR RESPIMAT SMI, TURBUHALER DPI WITH FAST AND SLOW INHALED FLOWS, AND FOR BECLOFORTE PMDI Respimat SMI Turbuhaler DPI, fast Turbuhaler DPI, slow Becloforte pmdi Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. Lungs (%) 51.6 (46 57) 28.5 (24 33) 17.8 (14 22) 8.9 (6 12) Oropharynx (%) 19.3 (15 24) 49.3 (44 55) 40.5 (35 46) 82.2 (78 86) Device a (%) 17.7 (14 22) 21.2 (17 26) 40.4 (35 46) 8.5 (6 12) Exhaled air (%) 10.0 (9 11) 0.3 ( ) 0.3 ( ) 0.2 ( ) P/C ratio 1.34 ( ) 0.95 ( ) 0.82 ( ) 1.27 ( ) a Mouthpiece for Respimat SMI and Turbuhaler DPI, actuator for Becloforte pmdi. The mean and range peripheral lung zone/central lung zone deposition ratios (P/C ratios) are also shown. SMI has been demonstrated for a BDP pmdi formulated in non-cfc propellant (QVAR, 3M Health Care). (24) Several other pmdi formulations with similar deposition efficiencies are currently in late-stage development. High lung deposition has also been shown for some DPI devices (11 13) or DPI formulations, (25) and by some other novel liquid spray devices. (27,28) Previous studies showed that Respimat SMI deposited drug more efficiently in the lungs than either an Inhacort spacer (Boehringer Ingelheim) (15) or an Aerochamber device (Trudell Medical, London, Ontario). (10,26) The results of this study showed that Respimat SMI deposited significantly more drug in the patients lungs than either Turbuhaler DPI or a Becloforte pmdi. Respimat SMI and the Becloforte pmdi were used with optimal inhalation technique, the inhaler being fired just after the patient began a slow, deep inhalation. If we had chosen to allow the subjects to actuate the devices themselves, then different deposition data might have been obtained. Since drug delivery from Turbuhaler DPI is dependent upon the inspiratory flow rate, (29) it was evaluated using both fast and slow peak inhaled flow rates. FIG. 4. Typical scintigraphic images for Respimat SMI (A), Turbohaler DPI with fast inhaled flow rate (B), Turbuhaler DPI with slow inhaled flow rate (C), Becloforte pmdi (D).

27 270 PITCAIRN ET AL. TABLE 2. MEAN (RANGE) INHALATION PARAMETERS Respimat Turbuhaler Turbuhaler Becloforte SMI DPI, fast DPI, slow pmdi Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. Average inhaled flow rate (L/min) 26 (20 33) n/a n/a 28 (16 41) Peak inhaled flow rate (L/min) n/a 58 (51 78) 29 (20 35) n/a Inhaled volume (L) 2.4 ( ) 2.8 ( ) 2.8 ( ) 2.5 ( ) Breath holding pause (sec) 11 (7 13) 10 (9 11) 11 (9 12) 12 (10 12) n/a, not applicable. Fast inhalation is associated with maximal inspiratory effort, and is considered to represent optimal inhalation technique for most DPIs. (30) An essential prerequisite for performing a scintigraphic study is the validation of the radiolabeling methods used. In the in vitro experiments performed prior to commencing this study, we demonstrated that the radiolabel would act as a valid marker for the in vivo distribution of the drugs, from all three devices tested. The radiolabeling validation data met the recommended criterion that the ratio of fine particle fractions for radiolabel versus drug before labeling should lie within the range of (19) In this study we used a four-stage impinger device for the radiolabeling validation experiments, since it conformed to our normal practice at the time the study was carried out. However, we now use either a five-stage multi-stage liquid impinger or an Andersen cascade impactor, both of which divide the aerosol cloud into a larger number of fractions, and which have better discriminating power for detecting differences between drug and radiolabel size distributions. Whole lung deposition from the Respimat SMI in this study was even higher that that re- ported in previous studies (10,26) involving an aqueous formulation of fenoterol (39.2%), or an ethanolic formulation of flunisolide (44.6%), de- livered by a prototype Respimat SMI device. Oropharyngeal deposition for Respimat SMI (mean 19.3%) was exceptionally low. Lung deposition values comparable to those in the present study have been observed previously for both Turbuhaler DPI, (11,29) and CFC pmdis. (21 23) Turbuhaler DPI is one of several DPIs capable of depositing about 30% of the dose in the lungs. (11 13) The higher lung deposition achieved by the Respimat SMI means that it should be possible to use a lower dose of drug to achieve control in asthma or COPD, and this is desirable in order avoid any risk of over-dosing. Using a lower nominal dose would result in an even lower mass of drug being deposited in the oropharynx, approaching the deposition achieved with some spacer devices. (15) Both phase II dose-ranging studies (31 33) and phase III clinical trials (34 36) have confirmed that Respimat SMI is effective using very low doses of bronchodilators normally used for treatment of asthma and COPD. In one study, (31) a group of 62 adult asthmatics were given inhaled ipratropium bromide (IB, Atrovent, Boehringer Ingelheim) plus fenoterol (F, Berotec, Boehringer Ingelheim) in varying doses, and were randomized to receive five of eight possible treatments. A dose-response relationship was established for Respimat SMI, and it was shown that pmdi doses of 20 g IB 50 g F or 40 g IB 100 g F were required to provide the same improvement in FEV 1 as only 5 g IB 12.5 g F or 10 g IB 25 g F given by Respimat SMI. Respimat SMI deposited drug more peripherally in the lungs than Turbuhaler DPI. The peripheral zone/central zone deposition ratio (P/C ratio) for Respimat SMI averaged 1.34, compared with values of 0.95 and 0.82 for Turbuhaler DPI used with fast and slow inhaled flow rates, respectively. These P/C ratios were similar to those observed previously for Turbuhaler DPI in asthmatic patients. (11) The data suggest that the very small droplets released from Respimat SMI may be better equipped to target inflammation in the lung periphery than particles released from Turbuhaler DPI. In vitro testing carried out as part of the radiolabelling validation procedures showed that the fine particle fractions for Respimat SMI, Turbuhaler DPI and Becloforte pmdi were 62.7%, 38.7%, and 43.4%, respectively. While the difference in fine particle fractions between Respimat SMI and Turbuhaler DPI were reflected in their respective lung depositions (51.6% and 28.5%),

28 DEPOSITION OF CORTICOSTEROID FROM RESPIMAT SOFT MIST INHALER 271 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. there was a much poorer in vitro/in vivo correlation for the Becloforte pmdi (lung deposition 8.9%). These considerations demonstrate the potential limitations of using in vitro data alone to compare inhaler devices. In conclusion, the results of this study showed that the Respimat SMI deposits drug more efficiently in the lungs than either Turbuhaler DPI or Becloforte pmdi. Respimat SMI should allow asthma and COPD maintenance control to be achieved using very low doses of both bronchodilators and corticosteroids. REFERENCES 1. Clark, T.J.H., T. Lee, S. Godfrey, et al Asthma, 4th ed. Edward Arnold Limited, London. 2. Barnes, P.J., S. Pedersen, and W.W. Brusse Efficacy and safety of inhaled corticosteroids: new developments. Am. J. Respit. Crit. Care Med. 157:S1 S O Callaghan, C., and P. Wright The metereddose inhaler. In H. Bisgaard, C. O Callaghan, G.C. Smaldone, eds, Drug Delivery to the Lung. Marcel Dekker, New York, McDonald, K.J., and G.P. Martin Transition to CFC-free metered dose inhalers: into the new millennium. Int. J. Pharm. 211: Partridge, M.R., A.A. Woodcock, A.L. Sheffer, et al Chlorofluorocarbon-free inhalers: are we ready for the change? Eur. Respir. J. 11: Smith, I.J., and M. Parry-Billings The inhalers of the future? A review of dry powder devices on the market today. Pulmonary Pharmacol. Ther. 16: Smart, J.R A brief overview of novel liquidbased inhalation technologies. Drug Deliv. Syst. Sci. 2: Zierenberg, B Optimizing the in vitro performance of Respimat. J. Aerosol Med. 12:S19 S Hochrainer, D., and H. Hölz Comparison of cloud velocities delivered from Respimat soft mist inhaler or MDIs. J. Aerosol Med. 14:386(abst). 10. Newman, S.P Use of gamma scintigraphy to evaluate the performance of new inhalers. J. Aerosol Med. 12:S25 S Thorsson, L., C.J. Kenyon, S.P. Newman, et al Lung deposition of budesonide in asthmatics: a comparison of different formulations. Int. J. Pharm. 168: Pitcairn, G.R., T. Lankinen, O.-P. Seppälä, et al Pulmonary drug delivery from the Taifun dry powder inhaler is relatively independent of the patient s inspiratory effort. J. Aerosol Med. 13: Warren, S.J., and G. Taylor Effect of inhalation flow profiles on the deposition of radiolabelled BDP from a novel dry powder inhaler (Clickhaler), a conventional metered dose inhaler and MDI plus spacer. In R.N. Dalby, P.R. Byron, S.J. Farr, eds, Respiratory Drug Delivery VI. Interpharm Press, Buffalo Grove, IL, Quanjer, P.H., G.J. Tammeling, J.E. Cotes, et al Lung volumes and forced ventilatory flows. Eur. Respir. J. 6: Newman, S.P., K.P. Steed, S.J. Reader, et al Efficient delivery to the lungs of flunisolide from a new portable hand-held multidose nebuliser. J. Pharm. Sci. 85: U.S. Pharmacopeia, USP Multistage liquid impinger. 19: Newman, S.P., P.H. Hirst, G.R. Pitcairn, et al Understanding regional lung deposition in gamma scintigraphy. In Dalby RN, Byron PR, Farr SJ, eds, Respiratory Drug Delivery VI. Interpharm Press, Buffalo Grove, IL, Pitcairn, G.R., and S.P. Newman Tissue attenuation corrections in gamma scintigraphy. J. Aerosol. Med. 3: Snell, N.J.C., and D. Ganderton Assessing lung deposition of inhaled medications. Respir. Med. 93: Smith, I.J The challenge of reformulation. J. Aerosol. Med. 8:S19 S Newman, S.P Scintigraphic assessment of therapeutic aerosols. Crit. Rev. Ther. Drug Carrier Syst. 10: Dolovich, M.B., R. Ruffin, D. Corr., et al Clinical evaluation of a new demand-inhalation MDI aerosol delivery device. Chest 84: Newman, S.P., A.W.B. Weisz, N. Talaee, et al Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax 46: Leach, C.L., P.J. Davidson, and R.J. Boudreau Improved airway targeting with the CFC-free HFAbeclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur. Respir. J. 12: Duddu, S.P., S.A. Sisk, Y.H. Walter, et al Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere powder. Pharm. Res. 19: Newman, S.P., J. Brown, K.P. Steed, et al Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medications. Chest 113: Zimlich, W.C., J.Y. Ding, D.R. Busick, et al The development of a novel electrohydrodynamic pulmonary drug delivery device. In R.N. Dalby, P.R. Byron, S.J. Farr, et al., eds. Respiratory Drug Delivery VII. Serentec Press, Raleigh, NC, Farr, S.J., S.J. Warren, P. Lloyd, et al Comparison of in vitro and in vivo efficiencies of a novel unitdose aerosol generator and a pressurized metered dose inhaler. Int. J. Pharm. 198: Borgström, L., E. Bondesson, F. Morén, et al Lung deposition of budesonide inhaled via Turbuhaler: a comparison with terbutaline sulphate in normal subjects. Eur. Respir. J. 7:69 73.

29 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only Clark, A.R Medical aerosol inhalers: past, present and future. Aerosol Sci. Technol. 22: Goldberg, J., E. Freund, B. Beckers, et al Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler. Eur. Respir. J. 17: Van Noord, J.A., J.J. Smeets, J.P.H.M. Creemers, et al Delivery of fenoterol via Respimat, a novel soft mist inhaler. A randomised double-blind (within device), placebo-controlled, corss-over, dose ranging study in asthmatic patients. Respiration 67: Pavia, D., and D. Moonen Preliminary data from phase II studies with Respimat, a propellant-free soft mist inhaler. J. Aerosol Med. 12:S33 S Hodder, R., B. Dzyngel, N.M. Fagan, et al Comparison of the long-term efficacy and safety of ipratropium bromide delivered by a new soft mist inhaler versus conventional metered dose inhaler in COPD patients. Eur. Respir. J. 18:536s(abst). 35. Vincken, W., F. Gerken, D.M. Moonen, et al Comparison of the efficacy and safety of ipratropium bromide/fenoterol inhaled from a new soft mist inhaler and from a conventional metered dose inhaler in asthma patients. Eur. Respir. J. 18:70s(abst). PITCAIRN ET AL. 36. Kilfeather, S.A., H.H. Ponitz, E. Beck, et al Comparison of the efficacy and safety of ipratropium bromide/fenoterol hydrobromide delivered by a new soft mist inhaler or a conventional metered dose inhaler in COPD patients. Eur. Respir. J. 18:69s(abst). Received on May 26, 2004 in final form, December 23, 2004 Reviewed by: Chester L. Leach, Ph.D. Thomas G. O Riordan, M.D. Address reprint requests to: Gary Pitcairn, Ph.D. Pharmaceutical Profiles Ltd. Mere Way Ruddington Fields Nottingham NG11 6JS, UK gary.pitcairn@pharmprofiles.co.uk

30 RIASSUNTO DELLE CARATTERISTICHE DEL PRODOTTO 1. DENOMINAZIONE DEL MEDICINALE Spiriva Respimat 2,5 microgrammi, soluzione per inalazione 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA La dose rilasciata è di 2,5 microgrammi di tiotropio per erogazione (2 erogazioni costituiscono la dose del medicinale) ed è equivalente a 3,124 microgrammi di tiotropio bromuro monoidrato. La dose rilasciata è la dose che è disponibile per il paziente dopo il passaggio attraverso il boccaglio. Per l elenco completo degli eccipienti, vedere paragrafo FORMA FARMACEUTICA Soluzione per inalazione Soluzione per inalazione trasparente e incolore 4. INFORMAZIONI CLINICHE 4.1 Indicazioni terapeutiche BPCO Tiotropio è indicato per la terapia broncodilatatoria di mantenimento nel sollievo dei sintomi di pazienti affetti da broncopneumopatia cronica ostruttiva (BPCO). Asma Spiriva Respimat è indicato come trattamento broncodilatatore aggiuntivo di mantenimento in pazienti adulti con asma, che sono al momento trattati con la combinazione di mantenimento a base di corticosteroidi per via inalatoria (budesonide 800 mcg/giorno o equivalente) e beta-2-agonisti a lunga durata d azione, che hanno manifestato una o più riacutizzazioni gravi nel corso dell ultimo anno. 4.2 Posologia e modo di somministrazione Posologia Il medicinale è destinato al solo uso inalatorio. La cartuccia può essere inserita ed utilizzata solo per mezzo dell inalatore Respimat (vedere paragrafo 4.2). Due erogazioni tramite l inalatore Respimat costituiscono una dose del medicinale. La dose raccomandata per gli adulti è di 5 microgrammi di tiotropio, somministrati tramite due erogazioni per mezzo dell inalatore Respimat una volta al giorno, alla stessa ora. La dose raccomandata non deve essere superata. Nel trattamento dell asma il beneficio completo si manifesta dopo numerose dosi di medicinale. Popolazioni speciali I pazienti anziani possono utilizzare tiotropio bromuro alla posologia raccomandata. I pazienti con insufficienza renale possono utilizzare tiotropio bromuro alla posologia raccomandata. Per pazienti con insufficienza renale da moderata a severa (clearance della creatinina 50 ml/min) vedere paragrafi 4.4 e

31 I pazienti con insufficienza epatica possono utilizzare tiotropio bromuro alla posologia raccomandata (vedere paragrafo 5.2). Popolazione pediatrica BPCO Non esiste alcuna indicazione per un uso specifico di Spiriva Respimat nei bambini e negli adolescenti al di sotto di 18 anni. Fibrosi cistica L efficacia e la sicurezza di Spiriva Respimat non sono state stabilite (vedere paragrafi 4.4 e 5.1). Asma L efficacia e la sicurezza di Spiriva Respimat nei bambini e negli adolescenti non sono state ancora stabilite. Modo di somministrazione Per assicurare la corretta somministrazione del medicinale, un medico o altro operatore sanitario deve mostrare al paziente come utilizzare l inalatore. Istruzioni per il paziente per l uso e la manipolazione Introduzione Spiriva Respimat (tiotropio bromuro). Leggere queste istruzioni per l uso prima di iniziare ad utilizzare Spiriva Respimat. Questo inalatore dovrà essere utilizzato solo UNA VOLTA AL GIORNO. Ogni volta assumere DUE EROGAZIONI. Se Spiriva Respimat non viene utilizzato per più di 7 giorni, rilasciare un erogazione verso terra. Se Spiriva Respimat non viene utilizzato per più di 21 giorni, ripetere i passi dal 4 al 6 del paragrafo Preparazione per il primo utilizzo fino a che non sia visibile una nuvola. Quindi ripetere ancora tre volte i passi dal 4 al 6. Non toccare l elemento perforante all interno della base trasparente. Manutenzione di Spiriva Respimat Pulire il boccaglio, inclusa la parte di metallo al suo interno, solo con un panno o un fazzoletto di carta umido, almeno una volta alla settimana. 2

32 Un eventuale lieve scolorimento del boccaglio non compromette l efficienza dell inalatore di Spiriva Respimat. Se necessario, pulire l esterno di Spiriva Respimat inalatore con un panno umido. Quando procurarsi una nuova confezione di Spiriva Respimat L inalatore di Spiriva Respimat contiene 60 erogazioni (30 dosi) se utilizzato come indicato (due erogazioni/una volta al giorno). L indicatore della dose mostra approssimativamente quanto medicinale sia rimasto. Quando l indicatore della dose raggiunge l area rossa della scala, è il momento di rivolgersi al medico per una nuova prescrizione; è rimasto medicinale per circa 7 giorni (14 erogazioni). Quando l indicatore della dose raggiunge la fine della scala rossa, Spiriva Respimat si blocca automaticamente - non possono essere erogate ulteriori dosi. A questo punto, la base trasparente non può più essere ruotata oltre. Spiriva Respimat deve essere gettato tre mesi dopo che è stato preparato per il primo utilizzo, anche se non è stato usato completamente o non è stato usato affatto. Preparazione per il primo utilizzo 1. Rimuovere la base trasparente Mantenere chiuso il cappuccio. Premere il fermo di sicurezza sfilando in maniera decisa la base trasparente con l altra mano. 2. Inserire la cartuccia Inserire l estremità stretta della cartuccia nell inalatore. Posizionare l inalatore su una superficie solida e spingere in maniera decisa finchè la cartuccia non sia entrata completamente. Non rimuovere la cartuccia una volta che sia stata inserita nell inalatore. 3

33 3. Reinserire la base trasparente Riposizionare la base trasparente finchè non si sente un clic. Non rimuovere più la base trasparente. 4. Ruotare Mantenere chiuso il cappuccio. Ruotare la base trasparente nella direzione delle frecce presenti sull etichetta finché non si sente un clic (mezzo giro). 5. Aprire Far scattare il cappuccio ed aprire completamente. 6. Premere Rivolgere l inalatore verso terra. Premere il bottone di erogazione della dose. Chiudere il cappuccio. Ripetere i passi 4-6 fino a che non sia visibile una nuvola. Dopo che sia visibile una nuvola, ripetere i passi 4-6 altre tre volte. L inalatore è pronto per l uso. Questi passaggi non influiranno sul numero di dosi disponibili. Dopo la preparazione, l inalatore sarà in grado di rilasciare 60 erogazioni (30 dosi). 4

34 Utilizzo giornaliero RUOTARE Mantenere chiuso il cappuccio. RUOTARE la base trasparente nella direzione delle frecce presenti sull etichetta finché non si sente un clic (mezzo giro). APRIRE Far scattare il cappuccio ed APRIRE completamente. PREMERE Espirare lentamente e completamente. Chiudere le labbra attorno al boccaglio senza coprire i fori di ventilazione. Rivolgere l inalatore verso il fondo della gola. Inspirando lentamente e profondamente dalla bocca, PREMERE il bottone di erogazione della dose e continuare a inspirare lentamente per quanto possibile. Trattenere il respiro per 10 secondi o per quanto possibile. Ripetere i passi Ruotare, Aprire, Premere per un totale di 2 erogazioni. Chiudere il cappuccio fino al successivo utilizzo dell inalatore. 4.3 Controindicazioni Ipersensibilità a tiotropio bromuro o ad uno qualsiasi degli eccipienti elencati al paragrafo 6.1 o all atropina o suoi derivati, per esempio ipratropio o ossitropio. 5

35 4.4 Avvertenze speciali e precauzioni di impiego Tiotropio bromuro, essendo un broncodilatatore di mantenimento da assumere una volta al giorno, non deve essere utilizzato nel trattamento iniziale di episodi acuti di broncospasmo o per il sollievo dai sintomi acuti. Nel caso di un attacco acuto si deve utilizzare un beta-2-agonista a rapida insorgenza d azione. Spiriva Respimat non deve essere utilizzato in monoterapia (come medicinale di prima linea) per l asma. I pazienti asmatici devono essere avvisati che devono mantenere immodificata la terapia antiinfiammatoria, cioè corticosteroidi per via inalatoria, dopo l introduzione di Spiriva Respimat, anche quando i sintomi dovessero migliorare. Dopo la somministrazione di tiotropio bromuro soluzione per inalazione possono verificarsi reazioni di ipersensibilità immediata. In linea con la sua attività anticolinergica, tiotropio bromuro deve essere utilizzato con cautela nei pazienti con glaucoma ad angolo chiuso, iperplasia prostatica od ostruzione del collo della vescica. I medicinali somministrati per via inalatoria possono causare broncospasmo indotto dall inalazione. Tiotropio deve essere utilizzato con cautela nei pazienti con infarto miocardico recente, da meno di 6 mesi; nei pazienti che abbiano manifestato una qualsiasi aritmia instabile o pericolosa per la vita o un aritmia cardiaca che abbia richiesto un intervento o una modifica della terapia farmacologica nell anno precedente; nei pazienti ospedalizzati per insufficienza cardiaca (Classe NYHA III o IV) nell anno precedente. Tali pazienti sono stati esclusi dagli studi clinici e queste condizioni possono essere influenzate dal meccanismo di azione anticolinergico. Poiché la concentrazione plasmatica del medicinale aumenta al diminuire della funzionalità renale, nei pazienti con insufficienza renale da moderata a grave (clearance della creatinina 50 ml/min), tiotropio bromuro deve essere utilizzato solo se i benefici attesi superano i potenziali rischi. Non ci sono dati a lungo termine in pazienti con insufficienza renale severa (vedere paragrafo 5.2). I pazienti devono essere avvisati di evitare che la soluzione spruzzata venga a contatto con gli occhi. Devono essere informati che ciò può avere come conseguenza una precipitazione o peggioramento del glaucoma ad angolo chiuso, dolore o disturbo oculare, temporaneo offuscamento della vista, aloni visivi o immagini colorate associate ad occhi arrossati da congestione congiuntivale ed edema corneale. Se si dovesse sviluppare una qualsiasi combinazione di questi sintomi oculari, i pazienti devono sospendere l utilizzo di tiotropio bromuro e consultare immediatamente uno specialista. La secchezza delle fauci, che è stata segnalata con il trattamento con anticolinergici, a lungo termine può essere associata a carie dentarie. Tiotropio bromuro non deve essere utilizzato più di una volta al giorno (vedere paragrafo 4.9). Spiriva Respimat non è raccomandato nella fibrosi cistica. Se utilizzato in pazienti con fibrosi cistica, Spiriva Respimat può aumentare i segni e i sintomi della malattia (ad esempio gravi eventi avversi, riacutizzazioni polmonari, infezioni del tratto respiratorio). 4.5 Interazioni con altri medicinali ed altre forme di interazione Benché non siano stati effettuati studi formali di interazione farmacologica, tiotropio bromuro è stato utilizzato in concomitanza con altri medicinali comunemente utilizzati nel trattamento della BPCO e dell asma, compresi broncodilatatori simpaticomimetici, metilxantine, steroidi orali e per inalazione, antistaminici, mucolitici, modificatori dei leucotrieni, cromoni, trattamenti anti-ige senza evidenza clinica di interazioni. 6

36 Non è emerso che l uso di LABA o ICS alteri l esposizione a tiotropio. La co-somministrazione di tiotropio bromuro ed altri medicinali contenenti anticolinergici non è stata studiata e pertanto non è raccomandata. 4.6 Fertilità, gravidanza e allattamento Gravidanza I dati relativi all uso di tiotropio in donne in gravidanza sono in numero molto limitato. Gli studi sugli animali non indicano effetti dannosi diretti o indiretti di tossicità riproduttiva a dosi clinicamente rilevanti (vedere paragrafo 5.3). A scopo precauzionale, è preferibile evitare l uso di Spiriva Respimat durante la gravidanza. Allattamento Non è noto se tiotropio bromuro sia escreto nel latte materno. Nonostante studi effettuati su roditori abbiano dimostrato che solo una piccola quantità di tiotropio bromuro è escreta nel latte materno, l uso di Spiriva Respimat non è raccomandato durante l allattamento. Tiotropio bromuro è una sostanza a lunga durata d azione. Deve essere presa la decisione se interrompere l allattamento o interrompere la terapia/astenersi dalla terapia con Spiriva Respimat tenendo in considerazione il beneficio dell allattamento per il bambino e il beneficio della terapia per la donna. Fertilità Non sono disponibili dati clinici sulla fertilità per tiotropio. Uno studio non clinico condotto con tiotropio non ha messo in evidenza alcun effetto avverso sulla fertilità (vedere paragrafo 5.3). 4.7 Effetti sulla capacità di guidare veicoli e sull uso di macchinari Non sono stati effettuati studi sulla capacità di guidare veicoli e di usare macchinari. Il verificarsi di capogiri o visione offuscata può influire sulla capacità di guidare veicoli e di usare macchinari. 4.8 Effetti indesiderati Riassunto del profilo di sicurezza Molti degli effetti indesiderati elencati possono essere attribuiti alle proprietà anticolinergiche di tiotropio bromuro. Tabella riassuntiva delle reazioni avverse La frequenza assegnata agli effetti indesiderati sotto elencati è basata sui tassi grezzi di incidenza delle reazioni avverse al medicinale (cioè eventi attribuiti a tiotropio) osservate nel gruppo trattato con tiotropio, ottenute raggruppando i dati derivanti da 7 studi clinici controllati contro placebo nella BPCO (3.282 pazienti) e da 6 studi clinici controllati contro placebo nell asma (1.256 pazienti) che prevedevano periodi di trattamento compresi tra quattro settimane e un anno. La frequenza è stata definita sulla base della seguente convenzione: Molto comune ( 1/10); comune ( 1/100, <1/10); non comune ( 1/1.000, <1/100); raro ( 1/10.000, <1/1.000); molto raro (<1/10.000); non nota (la frequenza non può essere stabilita sulla base dei dati disponibili). 7

37 Classificazione per sistemi e organi secondo MedDRA Frequenza BPCO Frequenza Asma Disturbi del metabolismo e della nutrizione Disidratazione Non nota Non nota Patologie del sistema nervoso Capogiri Non comune Non comune Cefalea Non comune Non comune Insonnia Raro Non comune Patologie dell occhio Glaucoma Raro Non nota Aumento della pressione intraoculare Raro Non nota Offuscamento della vista Raro Non nota Patologie cardiache Fibrillazione atriale Raro Non nota Palpitazioni Raro Non comune Tachicardia sopraventricolare Raro Non nota Tachicardia Raro Non nota Patologie respiratorie, toraciche e mediastiniche Tosse Non comune Non comune Faringite Non comune Non comune Disfonia Non comune Non comune Epistassi Raro Non nota Broncospasmo Raro Non comune Laringite Raro Non nota Sinusite Non nota Non nota Patologie gastrointestinali Secchezza della bocca Comune Comune Stipsi Non comune Raro Candidosi orofaringea Non comune Non comune Disfagia Raro Non nota Malattia da reflusso gastroesofageo Raro Non nota Carie dentaria Raro Non nota Gengivite Raro Raro Glossite Raro Non nota Stomatite Non nota Raro Ostruzione intestinale, incluso ileo paralitico Non nota Non nota Nausea Non nota Non nota Patologie della cute e del tessuto sottocutaneo, Disturbi del sistema immunitario Eruzione cutanea Non comune Raro Prurito Non comune Raro Edema angioneurotico Raro Raro Orticaria Raro Raro 8

38 Infezione della pelle/ulcera cutanea Raro Non nota Secchezza cutanea Raro Non nota Reazioni di ipersensibilità (comprese le reazioni Non nota Raro immediate) Reazione anafilattica Non nota Non nota Patologie del sistema muscoloscheletrico e del tessuto connettivo Edema articolare Non nota Non nota Patologie renali e urinarie Ritenzione urinaria Non comune Non nota Disuria Non comune Non nota Infezione del tratto urinario Raro Non nota Descrizione delle reazioni avverse selezionate Negli studi clinici controllati sulla BPCO, gli effetti indesiderati comunemente osservati erano di tipo anticolinergico, come secchezza della bocca che si è verificata in circa il 2,9% dei pazienti. Nell indicazione asma l incidenza della secchezza della bocca è stata pari a 1,2%. Nei 7 studi clinici sulla BPCO, la secchezza della bocca ha portato alla sospensione del trattamento in 3 dei pazienti trattati con tiotropio (0,1%). Nei 6 studi clinici sull asma (1.256 pazienti) non è stata riportata alcuna sospensione del trattamento dovuta alla secchezza della bocca. Effetti indesiderati gravi coerenti con gli effetti anticolinergici includono glaucoma, stipsi, ostruzione intestinale, compreso ileo paralitico e ritenzione urinaria. Altre popolazioni speciali Con l aumentare dell età può verificarsi un aumento degli effetti anticolinergici. Segnalazione delle reazioni avverse sospette La segnalazione delle reazioni avverse sospette che si verificano dopo l autorizzazione del medicinale è importante, in quanto permette un monitoraggio continuo del rapporto beneficio/rischio del medicinale. Agli operatori sanitari è richiesto di segnalare qualsiasi reazione avversa sospetta tramite il sistema nazionale di segnalazione all indirizzo Sovradosaggio Dosi elevate di tiotropio bromuro possono indurre la comparsa di segni e sintomi anticolinergici. Comunque, nei volontari sani non sono stati osservati effetti avversi sistemici anticolinergici a seguito dell inalazione di una dose unica fino a 340 microgrammi di tiotropio bromuro. Oltre alla secchezza delle fauci/gola e della mucosa nasale, non sono stati osservati eventi avversi rilevanti dopo 14 giorni di trattamento con una soluzione per inalazione di tiotropio fino a 40 microgrammi in volontari sani, fatta eccezione per una pronunciata riduzione del flusso di saliva a partire dal settimo giorno in poi. 5. PROPRIETÀ FARMACOLOGICHE 5.1 Proprietà farmacodinamiche Categoria farmacoterapeutica: Altri farmaci per le sindromi ostruttive delle vie respiratorie, per inalazione, anticolinergici Codice ATC: R03B B04 9

39 Meccanismo d'azione Tiotropio bromuro è un antagonista specifico a lunga durata d azione dei recettori muscarinici. Presenta un affinità simile per i sottotipi dei recettori muscarinici da M 1 a M 5. Nelle vie aeree, tiotropio bromuro si lega in modo competitivo e reversibile ai recettori M 3 della muscolatura liscia bronchiale, antagonizzando gli effetti colinergici (broncocostrittori) dell acetilcolina, inducendo il rilassamento della muscolatura liscia bronchiale. L effetto è dose-dipendente e dura più di 24 ore. Essendo un anticolinergico N-quaternario, tiotropio bromuro è (bronco-) selettivo a livello topico quando somministrato per via inalatoria, dimostrando un intervallo terapeutico accettabile prima dell insorgenza di effetti sistemici anticolinergici. Effetti farmacodinamici La dissociazione di tiotropio soprattutto dai recettori M 3 è molto lenta mostrando un emivita di dissociazione significativamente maggiore rispetto a quella di ipratropio. La dissociazione dai recettori M 2 è più rapida rispetto ai recettori M 3 e ciò determina negli studi funzionali in vitro, una selettività (cineticamente controllata) per il sottotipo recettoriale M 3 rispetto al sottotipo M 2. L elevata efficacia, la lenta dissociazione dal recettore e la selettività topica dell inalazione si riflettono clinicamente in una broncodilatazione significativa e di lunga durata nei pazienti con BPCO e asma. Efficacia e sicurezza clinica nella BPCO Il programma di sviluppo clinico di Fase III includeva due studi a 1 anno, due studi a 12 settimane e due studi a 4 settimane, randomizzati, in doppio cieco in pazienti con BPCO (1.308 trattati con 5 microgrammi di tiotropio bromuro). Il programma a un anno consisteva in due studi controllati contro placebo. I due studi a 12 settimane erano controllati sia contro un medicinale di controllo attivo (ipratropio) che contro placebo. Tutti e sei gli studi includevano la valutazione della funzionalità polmonare. Inoltre i due studi a 1 anno includevano la valutazione della dispnea, della qualità della vita correlata allo stato di salute e delle riacutizzazioni. Studi controllati verso placebo Funzione polmonare Tiotropio soluzione per inalazione, somministrato una volta al giorno, ha prodotto un miglioramento significativo della funzione polmonare (volume espiratorio forzato in un secondo e capacità vitale forzata) entro 30 minuti dalla prima dose rispetto al placebo (miglioramento medio del FEV 1 a 30 minuti: 0,113 litri; 95% CI: da 0,102 a 0,125 litri, p<0,0001). Il miglioramento della funzione polmonare si è mantenuto, allo stato stazionario, per 24 ore rispetto al placebo (miglioramento medio del FEV 1: 0,122 litri; 95% CI: da 0,106 a 0,138 litri, p<0,0001). Lo stato stazionario farmacodinamico è stato raggiunto entro una settimana. Spiriva Respimat ha significativamente migliorato il PEFR (la velocità del picco di flusso espiratorio) mattutino e serale misurato dalle registrazioni giornaliere dei pazienti rispetto al placebo (miglioramento medio del PEFR: miglioramento medio mattutino 22 l/min; 95% CI: da 18 a 55 l/min, p<0,0001; serale 26 l/min; 95% CI: da 23 a 30 l/min, p<0,0001). L uso di Spiriva Respimat ha determinato, rispetto al placebo, una riduzione dell uso del broncodilatatore di emergenza (riduzione media dello 0,66 delle occasioni d uso al giorno, 95% CI: da 0,51 a 0,81 occasioni al giorno, p<0,0001). Gli effetti broncodilatatori di Spiriva Respimat si sono mantenuti nel corso del periodo di 1 anno di somministrazione senza l insorgenza di problemi di tolleranza. Dispnea, Qualità della vita correlata allo stato di salute, riacutizzazioni della BPCO negli studi a lungo termine della durata di 1 anno Dispnea Spiriva Respimat ha migliorato significativamente la dispnea (valutata utilizzando l indice di dispnea transitorio) rispetto al placebo (miglioramento medio di 1,05 unità; 95% CI: da 0,73 a 1,38 unità, p<0,0001). Per tutto il periodo del trattamento si è mantenuto un miglioramento. 10

40 Qualità della vita correlata allo stato di salute Il miglioramento del punteggio totale medio della valutazione da parte del paziente della propria qualità della vita (misurata utilizzando il questionario respiratorio di St. George) fra Spiriva Respimat e placebo, alla fine dei due studi clinici della durata di 1 anno era pari a 3,5 unità (95% CI: da 2,1 a 4,9, p<0,0001). Una riduzione di 4 unità è considerata clinicamente rilevante. Riacutizzazioni della BPCO In tre studi clinici della durata di un anno, randomizzati, in doppio cieco, controllati con placebo, il trattamento con Spiriva Respimat ha ridotto in modo significativo il rischio di riacutizzazioni della BPCO rispetto a placebo. Le riacutizzazioni della BPCO erano definite come un insieme di almeno due eventi/sintomi respiratori della durata di tre giorni o più che ha richiesto una modifica del trattamento (prescrizione di antibiotici e/o corticosteroidi sistemici e/o un significativo cambiamento del medicinale respiratorio prescritto). Il trattamento con Spiriva Respimat ha comportato un rischio ridotto di ospedalizzazione per riacutizzazione della BPCO (significativo nell ampio studio di riacutizzazioni appropriatamente potenziato). L analisi aggregata di due studi di Fase III e l analisi separata di un ulteriore studio sulle riacutizzazioni sono riportate nella Tabella 1. Tutti i medicinali respiratori ad eccezione degli anticolinergici e dei beta-agonisti a lunga durata d azione erano consentiti come terapia concomitante, cioè beta-agonisti a breve durata d azione, corticosteroidi per via inalatoria e xantine. I beta-agonisti a lunga durata d azione erano consentiti in aggiunta nello studio sulle riacutizzazioni. Tabella 1: Analisi statistica delle Riacutizzazioni della BPCO e delle Riacutizzazioni della BPCO con Ospedalizzazione in pazienti con BPCO di grado da moderato a molto grave. Studio (N Spiriva, N placebo) Studi a 1 anno di Fase III, analisi aggregata d (670, 653) Studio a 1 anno di Fase IIIb sulle riacutizzazioni (1939, 1953) Obiettivi Giorni per la prima riacutizzazione di BPCO Tasso medio di incidenza delle riacutizzazioni per paziente-anno Tempo per la prima riacutizzazione della BPCO con ospedalizzazione Tasso medio di incidenza delle riacutizzazioni con ospedalizzazione per paziente-anno Giorni per la prima riacutizzazione di BPCO Tasso medio di incidenza delle riacutizzazioni per paziente-anno Tempo per la prima riacutizzazione della BPCO con ospedalizzazione Tasso medio di incidenza delle riacutizzazioni con ospedalizzazione per paziente-anno Spiriva Respimat Placebo % Riduzione del Rischio (IC 95%) a 160 a 86 a 29 (da 16 a 40) b 0,78 c 1,00 c 22 (da 8 a 33) c 25 (da -16 a 51) b 0,09 c 0,11 c 20 (da -4 a 38) c 169 a 119 a 31 (da 23 a 37) b 0,69 c 0,87 c 21 (da 13 a 28) c 27 (da 10 a 41) b 0,12 c 0,15 c 19 (da 7 a 30) c p <0,0001 b 0,002 c 0,20 b 0,096 c <0,0001 b <0,0001 c 0,003 b 0,004 c a Tempo per il primo evento: giorni di trattamento entro cui il 25% dei pazienti manifestava almeno una riacutizzazione della BPCO / riacutizzazione della BPCO con ospedalizzazione. Nello studio A il 25% dei pazienti trattati con placebo ha avuto una riacutizzazione entro il giorno 112, mentre con Spiriva Respimat il 25% ha avuto una riacutizzazione entro il giorno 173 (p=0,09);nello studio B il 25% dei pazienti trattati con placebo ha avuto una riacutizzazione entro il giorno 74, mentre con Spiriva Respimat il 25% dei pazienti ha avuto una riacutizzazione entro il giorno 149 (p<0,0001). 11

41 b Gli hazard ratio sono stati stimati con il modello di Cox di rischio proporzionale. La percentuale di riduzione del rischio è 100 (1 - hazard ratio). c Regressione di Poisson. La riduzione del rischio è 100 (1 - rate ratio). d L aggregazione è stata specificata quando gli studi sono stati disegnati. Gli endpoint delle riacutizzazioni erano significativamente migliorati nelle analisi individuali dei due studi a un anno. Studio a lungo termine controllato verso tiotropio È stato condotto uno studio a lungo termine, su larga scala, randomizzato, in doppio cieco, controllato verso trattamento attivo con un periodo di osservazione fino a 3 anni, per confrontare l efficacia e la sicurezza di Spiriva Respimat e Spiriva HandiHaler (5.711 pazienti trattati con Spiriva Respimat; pazienti trattati con Spiriva HandiHaler). Gli endpoint primari erano il tempo alla prima riacutizzazione della BPCO, il tempo alla morte per tutte le cause e, in un sotto studio (906 pazienti), il FEV 1 di valle (pre-dose). Il tempo alla prima riacutizzazione della BPCO era numericamente simile durante lo studio con Spiriva Respimat e Spiriva HandiHaler (hazard ratio (Spiriva Respimat/Spiriva HandiHaler) 0,98 con 95% IC da 0,93 a 1,03). Il numero mediano di giorni alla prima riacutizzazione della BPCO era di 756 giorni per Spiriva Respimat e di 719 giorni per Spiriva HandiHaler. L effetto broncodilatatore di Spiriva Respimat perdurava per 120 settimane ed era simile a quello di Spiriva HandiHaler. La differenza media del FEV 1 di valle di Spiriva Respimat rispetto a quello di Spiriva HandiHaler era di -0,010 l (95% IC da -0,038 a 0,018 l). Nello studio TIOSPIR, successivo alla commercializzazione, che confrontava Spiriva Respimat e Spiriva HandiHaler, la mortalità per tutte le cause (incluso il follow up dello stato vitale) era simile con un hazard ratio (Spiriva Respimat/Spiriva HandiHaler) = 0,96, con 95% IC 0,84-1,09). L esposizione ai rispettivi trattamenti era e anni-paziente. Negli studi controllati verso placebo con il follow up dello stato vitale fino alla fine del periodo previsto di trattamento, Spiriva Respimat ha evidenziato un aumento numerico di mortalità per tutte le cause rispetto al placebo (rate ratio (intervallo di confidenza del 95%) di 1,33 (0,93, 1,92)), con esposizione al trattamento con Spiriva Respimat di anni-paziente; l eccesso della mortalità è stato osservato in pazienti con disturbi del ritmo noti. Spiriva HandiHaler ha evidenziato una riduzione del 13% del rischio di morte (hazard ratio incluso lo stato vitale al follow up (tiotropio/placebo) = 0,87; 95% IC, da 0,76 a 0,99). L esposizione al trattamento con Spiriva HandiHaler era di anni-paziente. Non è stato osservato un eccesso del rischio di mortalità nel sottogruppo di pazienti con disturbi del ritmo noti nello studio con Spiriva HandiHaler controllato verso placebo, come anche nello studio TIOSPIR che ha confrontato Spiriva Respimat verso Spiriva HandiHaler. Efficacia e sicurezza clinica nell asma Il programma clinico di Fase III per l asma persistente ha incluso due studi della durata di 1 anno randomizzati, in doppio cieco, controllati con placebo, su un totale di 907 pazienti asmatici (453 in trattamento con Spiriva Respimat) in terapia con una combinazione di ICS (budesonide 800 mcg/giorno o equivalente) con LABA. Gli studi includevano, come obiettivi primari, le misurazioni della funzione polmonare e le riacutizzazioni gravi. Studi PrimoTinA sull asma Nei due studi della durata di 1 anno in pazienti sintomatici in terapia di mantenimento con almeno ICS (budesonide 800 mcg/giorno o equivalente) più LABA, Spiriva Respimat, quando usato come trattamento aggiuntivo alla terapia di base, ha mostrato miglioramenti clinicamente rilevanti della funzione polmonare rispetto al placebo. 12

42 Alla settimana 24, i miglioramenti medi del FEV 1 di picco e valle sono stati rispettivamente di 0,110 litri (95% CI: da 0,063 a 0,158 litri, p<0,0001) e di 0,093 litri (95% CI: da 0,050 a 0,137 litri, p<0,0001). Il miglioramento della funzione polmonare rispetto a placebo è stato mantenuto per 24 ore. Negli studi PrimoTinA sull asma, il trattamento di pazienti sintomatici (N=453) con ICS più LABA più tiotropio ha ridotto il rischio di riacutizzazioni dell asma grave del 21% rispetto al trattamento di pazienti sintomatici (N=454) con ICS più LABA più placebo. La riduzione del rischio del numero medio di riacutizzazioni di asma grave per anno-paziente è stata pari al 20%. Ciò è stato supportato da una riduzione del 31% del rischio di peggioramento dell asma e da una riduzione del 24% del rischio nel numero medio dei peggioramenti dell asma per paziente-anno (vedere Tabella 2). Tabella 2: Riacutizzazioni in pazienti sintomatici in terapia con ICS (budesonide 800 mcg/giorno o equivalente) più LABA (studi PrimoTinA sull asma) Studio Obiettivi Spiriva Respimat, aggiunto ad almeno ICS a /LABA (N=453) Placebo, aggiunto ad almeno ICS a /LABA (N=454) % Riduzione del Rischio (IC 95%) p due studi di Fase III della durata di 1 anno, analisi aggregata Giorni alla prima riacutizzazione grave di asma Numero medio di riacutizzazioni gravi di asma per pazienteanno 282 c 226 c 21 b (0, 38) 0,530 0, d (0, 36) 0,0343 0,0458 Giorni al primo peggioramento dell asma 315 c 181 c 31 b (18, 42) <0,0001 Numero medio di peggioramenti dell asma per pazienteanno 2,145 2, d (9, 37) 0,0031 a budesonide 800 mcg/giorno o equivalente b L hazard ratio, l intervallo di confidenza e il valore di p sono stati ottenuti con un modello di rischio proporzionale di Cox considerando come effetto il solo trattamento. La percentuale di riduzione del rischio è 100 (1 - hazard ratio). c Tempo al primo evento: giorni di trattamento entro i quali il 25%/50% dei pazienti ha avuto almeno una riacutizzazione grave di asma /peggioramento dell asma d Il rapporto tra tassi è stato ottenuto tramite una regressione di Poisson con esposizione logaritmica (anni) come compensazione. La percentuale di riduzione del rischio è 100 (1 rapporto tra tassi). Popolazione pediatrica BPCO L Agenzia europea dei medicinali ha previsto l esonero dall obbligo di presentare i risultati degli studi con Spiriva Respimat in tutti i sottogruppi della popolazione pediatrica per la BPCO (vedere paragrafo 4.2 per informazioni sull uso pediatrico). 13

43 Asma L Agenzia europea dei medicinali ha rinviato l obbligo di presentare i risultati degli studi con Spiriva Respimat in uno o più sottogruppi della popolazione pediatrica per il trattamento dell asma (vedere paragrafo 4.2 per informazioni sull uso pediatrico). Efficacia e sicurezza clinica nella fibrosi cistica Il programma di sviluppo clinico nella fibrosi cistica includeva 3 studi multicentrici condotti in 959 pazienti di età pari ad almeno 5 mesi. I pazienti di età inferiore a 5 anni hanno utilizzato un distanziatore (AeroChamber Plus ) con maschera facciale e sono stati inclusi solo per la valutazione della sicurezza. I due studi cardine (uno studio di Fase II di individuazione della dose e uno studio di Fase III di conferma) hanno confrontato gli effetti di Spiriva Respimat (tiotropio 5 µg: 469 pazienti) sulla funzione polmonare (FEV 1 espresso come percentuale del predetto AUC 0-4h e FEV 1 di valle) rispetto a placebo (315 pazienti) in periodi di 12 settimane randomizzati in doppio cieco; lo studio di Fase III includeva anche un estensione a lungo termine fino a 12 mesi, in aperto. In questi studi erano permessi come trattamento concomitante tutti i medicinali respiratori, ad eccezione degli anticolinergici, come beta-agonisti a lunga durata di azione, mucolitici e antibiotici. Gli effetti sulla funzione polmonare sono illustrati nella Tabella 3. Non è stato osservato un miglioramento significativo dei sintomi e dello stato di salute (riacutizzazioni valutate tramite il Respiratory and Systemic Symptoms Questionnaire e qualità della vita valutata tramite il Cystic Fibrosis Questionnaire). Tabella 3: Differenza media aggiustata rispetto al placebo per le variazioni assolute rispetto al basale dopo 12 settimane Fase II Fase III Tutti i pazienti Tutti i pazienti 11 anni 12 anni (N Spiriva = 176, N placebo = 168) (N Spiriva = 293, N placebo = 147) (N Spiriva = 95, N placebo = 47) (N Spiriva = 198, N placebo = 100) media (95% CI) valore di p media (95% CI) valore di p media (95% CI) media (95% CI) FEV 1AUC 0-4h (% del predetto) a variazioni assolute FEV 1AUC 0-4h (litri) variazioni assolute FEV 1 di valle (% del predetto) a variazioni assolute FEV 1 di valle (litri) variazioni assolute a Endpoint co-primari 3,39 (1,67, 5,12) 0,09 (0,05, 0,14) 2,22 (0,38, 4,06) 0,06 (0,01, 0,11) <0,001 <0,001 0,018 0,028 1,64 (-0,27, 3,55) 0,07 (0,02, 0,12) 1,40-0,50, 3,30 0,07 (0,02, 0,12) 0,092 0,010 0,150 0,012-0,63 (-4,58, 3,32) 0,01 (-0,07, 0,08) -1,24 (-5,20, - 271) -0,01 (-0,08, 0,06) 2,58 (0,50, 4,65) 0,10 (0,03, 0,17) 2,56 (0,49, 4,62) 0,10 (0,03, 0,17) Tutte le reazioni avverse al farmaco osservate negli studi sulla fibrosi cistica sono effetti indesiderati noti di tiotropio (vedere paragrafo 4.8). Gli eventi avversi più comunemente osservati considerati correlati durante il periodo di 12 settimane in doppio cieco sono stati tosse (4,1%) e bocca secca (2,8%). Il numero e la percentuale di pazienti che hanno riportato eventi avversi di particolare interesse nella fibrosi cistica indipendentemente dalla correlazione sono illustrati nella Tabella 4. Con tiotropio i segni e i sintomi considerati manifestazioni della fibrosi cistica sono aumentati numericamente, sebbene non in modo statisticamente significativo, soprattutto in pazienti di età 11 anni. 14

44 Tabella 4: Percentuale di pazienti con eventi avversi di particolare interesse nella fibrosi cistica suddivisi per gruppo di età oltre 12 settimane di trattamento indipendentemente dalla correlazione (dati di Fase II e Fase III aggregati) 11 anni 12 anni N placebo = 96 N Spiriva = 158 N placebo = 215 N Spiriva = 307 Dolore addominale 7,3 7,0 5,1 6,2 Stipsi 1,0 1,9 2,3 2,6 Sindrome di ostruzione intestinale distale 0,0 0,0 1,4 1,3 Infezioni del tratto respiratorio 34,4 36,7 28,4 28,3 Aumento dell'espettorato 1,0 5,1 5,6 6,2 Riacutizzazioni 10,4 14,6 18,6 17,9 "Sindrome di ostruzione intestinale distale" e "Aumento dell espettorato" sono termini preferiti MedDRA. "Infezioni del tratto respiratorio" è il termine MedDRA di livello più alto del gruppo. "Dolore addominale", "Stipsi" e "Riacutizzazioni" sono raccolte di termini preferiti MedDRA. Trentaquattro (10,9 %) pazienti randomizzati a ricevere placebo e 56 (12,0%) pazienti randomizzati a ricevere Spiriva Respimat hanno manifestato un grave evento avverso. L Agenzia europea dei medicinali ha previsto l esonero dall obbligo di presentare i risultati degli studi con Spiriva Respimat nel sottogruppo della popolazione pediatrica di età inferiore a 1 anno. 5.2 Proprietà farmacocinetiche a) Introduzione generale Tiotropio bromuro è un composto di ammonio quaternario non chirale ed è moderatamente solubile in acqua. Tiotropio bromuro è disponibile come soluzione per inalazione da somministrare mediante l inalatore Respimat. Circa il 40% della dose inalata si deposita nei polmoni, organo bersaglio, il resto nel tratto gastrointestinale. Alcuni dei dati farmacocinetici qui di seguito descritti sono stati ottenuti con dosi superiori rispetto a quelle raccomandate per la terapia. b) Caratteristiche generali del principio attivo dopo somministrazione del medicinale Assorbimento: dopo inalazione da parte di volontari sani giovani, i dati di escrezione urinaria suggeriscono che circa il 33% della dose inalata raggiunge la circolazione sistemica. Le soluzioni orali di tiotropio bromuro hanno una biodisponibilità assoluta del 2-3%. Non è previsto che il cibo influenzi l assorbimento di questo composto dell ammonio quaternario. Le concentrazioni plasmatiche massime di tiotropio sono state osservate 5-7 minuti dopo l inalazione. Allo stato stazionario, nei pazienti con BPCO i livelli plasmatici massimi di tiotropio di 10,5 pg/ml erano raggiunti e diminuivano rapidamente in modo multi-compartimentale. Le concentrazioni plasmatiche minime allo stato stazionario sono state di 1,60 pg/ml. Nei pazienti asmatici, 5 minuti dopo la somministrazione della stessa dose, si raggiungeva una concentrazione plasmatica di picco di tiotropio allo stato stazionario pari a 5,15 pg/ml. L esposizione sistemica a tiotropio conseguente l inalazione di tiotropio tramite il dispositivo Respimat era simile a quella di tiotropio inalato tramite il dispositivo Handihaler. Distribuzione: il farmaco ha un legame alle proteine plasmatiche del 72% e mostra un volume di distribuzione di 32 l/kg. Non sono note le concentrazioni locali nel polmone, ma la modalità di somministrazione suggerisce concentrazioni considerevolmente più elevate nel polmone. Studi condotti nei ratti hanno dimostrato che tiotropio non attraversa la barriera emato-encefalica in misura rilevante. Biotrasformazione: l entità della biotrasformazione è scarsa. Ciò si evince dall escrezione urinaria del 74% del farmaco immodificato dopo somministrazione endovenosa in volontari sani giovani. L estere di tiotropio bromuro è scisso per via non enzimatica nell alcool (N-metilscopina) e nel composto 15

45 acido (acido ditienilglicolico) che sono inattivi sui recettori muscarinici. Esperimenti in vitro con microsomi epatici ed epatociti umani suggeriscono che un ulteriore quantità di farmaco (<20% della dose dopo somministrazione endovenosa) è metabolizzata dal citocromo P450 (CYP) con conseguente ossidazione e successiva coniugazione con glutatione in una varietà di metaboliti di Fase-II. Studi in vitro su microsomi epatici hanno rivelato che la via enzimatica può essere inibita dagli inibitori del CYP 2D6 (e 3A4), chinidina, ketoconazolo e gestodene. Così CYP 2D6 e 3A4 sono coinvolti nella via metabolica che è responsabile dell eliminazione di una parte più piccola della dose. Tiotropio bromuro anche in concentrazioni superiori a quelle terapeutiche non inibisce il CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 o 3A nei microsomi epatici umani. Eliminazione: l emivita effettiva di tiotropio è compresa tra 27 e 45 ore dopo l inalazione in volontari sani e in pazienti con BPCO. L emivita effettiva in pazienti asmatici era di 34 ore. La clearance totale è stata di 880 ml/min dopo somministrazione endovenosa in volontari sani giovani. Somministrato per via endovenosa, tiotropio è principalmente escreto in forma immodificata nelle urine (74%). Dopo assunzione per via inalatoria della soluzione da parte di pazienti con BPCO, allo stato stazionario, il 18,6% (0,93 mcg) della dose è escreto per via urinaria e la quantità rimanente, essendo un farmaco principalmente non assorbito dall intestino, viene eliminata con le feci. Dopo assunzione per via inalatoria della soluzione da parte di volontari sani, il 20,1-29,4% della dose è escreto per via urinaria e la quantità rimanente, essendo un farmaco principalmente non assorbito dall intestino, viene eliminata con le feci. In pazienti asmatici, l 11,9% (0,595 mcg) della dose è escreto immodificato nelle urine, nelle 24 ore successive alla somministrazione al raggiungimento dello steady-state. La clearance renale di tiotropio supera la clearance della creatinina, e ciò indica secrezione nelle urine. Dopo inalazione cronica una volta al giorno da parte di pazienti con BPCO, la farmacocinetica dello stato stazionario è stata raggiunta entro il giorno 7 senza accumuli in seguito. Linearità/non linearità: tiotropio dimostra una farmacocinetica lineare nell'intervallo terapeutico indipendentemente dalla formulazione. c) Caratteristiche nei pazienti Pazienti anziani: come previsto per tutti i medicinali escreti principalmente per via renale, l avanzare dell età è stato associato ad una diminuzione della clearance renale di tiotropio (da 347 ml/min nei pazienti affetti da BPCO di età < 65 anni fino a 275 ml/min in pazienti affetti da BPCO di età 65 anni). Ciò non ha determinato un corrispondente aumento nell'auc 0-6,ss o dei valori della C max,ss. L esposizione a tiotropio non differiva con l età nei pazienti asmatici. Pazienti con insufficienza renale: dopo somministrazione singola giornaliera per via inalatoria di tiotropio allo stato stazionario in pazienti con BPCO, l insufficienza renale lieve (Cl CR ml/min) ha determinato una AUC 0-6,ss lievemente maggiore (tra 1,8 e 30% maggiore) e valori simili della C max,ss rispetto ai pazienti con funzione renale normale (Cl CR > 80 ml/min). Nei pazienti con BPCO con insufficienza renale da moderata a severa (Cl CR < 50 ml/min), la somministrazione endovenosa di una dose singola di tiotropio ha determinato un raddoppio dell esposizione totale (AUC 0-4h maggiore dell 82% e C max maggiore del 52%) rispetto ai pazienti con BPCO e funzione renale normale, che è stato confermato dalle concentrazioni plasmatiche a seguito di inalazione della polvere secca. L inalazione di tiotropio non ha mostrato aumenti rilevanti dell esposizione al farmaco in pazienti asmatici con lieve compromissione renale (Cl CR ml/min) rispetto a pazienti con funzionalità renale normale. Pazienti con insufficienza epatica: si suppone che l insufficienza epatica non abbia influenza rilevante sulla farmacocinetica di tiotropio. Tiotropio è principalmente escreto per via renale (74% nei volontari sani giovani) e attraverso una semplice dissociazione non enzimatica dell estere in prodotti farmacologicamente inattivi. 16

46 Pazienti giapponesi con BPCO: nello studio trasversale di confronto, le medie delle concentrazioni plasmatiche massime di tiotropio 10 minuti dopo la somministrazione allo stato stazionario erano dal 20% al 70% maggiori nei pazienti giapponesi con BPCO rispetto ai pazienti caucasici a seguito della inalazione di tiotropio, ma non c era indicazione di maggior mortalità o rischio cardiaco nei pazienti giapponesi rispetto a quelli caucasici. Per le altre etnie o razze sono disponibili dati di farmacocinetica insufficienti. Pazienti pediatrici: Nel programma della BPCO non erano inclusi pazienti pediatrici (vedere paragrafo 4.2). I pazienti pediatrici sono stati studiati come parte del programma clinico della fibrosi cistica che copre anche gli adulti. Dopo inalazione di 5 mcg di tiotropio, il livello plasmatico di tiotropio nei pazienti con fibrosi cistica e di età 5 anni era 10,1 pg/ml 5 minuti dopo la somministrazione allo steady-state e quindi diminuiva rapidamente. La frazione della dose disponibile nei pazienti con fibrosi cistica e di età <5 anni che utilizzavano il distanziatore e la maschera era approssimativamente da 3 a 4 volte inferiore rispetto a quanto osservato nei pazienti con fibrosi cistica e di 5 anni di età o maggiore. Nei pazienti con fibrosi cistica e di età <5 anni l esposizione a tiotropio era correlata al peso corporeo. d) Relazioni tra farmacocinetica e farmacodinamica Non esiste una correlazione diretta tra farmacocinetica e farmacodinamica. 5.3 Dati preclinici di sicurezza Molti effetti osservati negli studi convenzionali di tollerabilità farmacologica, tossicità per somministrazioni ripetute, tossicità riproduttiva, possono essere spiegati dalle proprietà anticolinergiche di tiotropio bromuro. Negli animali sono stati osservati gli effetti tipici: ridotto consumo di cibo e inibizione dell incremento ponderale, secchezza delle fauci e del naso, lacrimazione e salivazione ridotte, midriasi e aumento della frequenza cardiaca. Altri effetti rilevanti notati negli studi di tossicità per somministrazioni ripetute sono stati: irritazione lieve del tratto respiratorio nel ratto e nel topo evidenziata da rinite e alterazioni dell epitelio della cavità nasale e della laringe, prostatite accompagnata da depositi di natura proteica e litiasi nella vescica del ratto. In ratti giovani esposti dal settimo giorno di vita alla maturità sessuale, sono stati osservati gli stessi cambiamenti farmacologici diretti e indiretti osservati negli studi di tossicità per somministrazioni ripetute come pure rinite. Non è stata constatata tossicità sistemica, non sono stati osservati effetti tossicologicamente rilevanti sui parametri chiave di sviluppo, sullo sviluppo della trachea o degli organi chiave. Effetti dannosi per la gravidanza, lo sviluppo embrionale/fetale, il parto o lo sviluppo post-natale possono essere dimostrati solo a dosaggi tossici per la madre. Tiotropio bromuro non era teratogeno nei ratti o nei conigli. In uno studio generale di riproduzione e fertilità condotto nei ratti, non vi era alcuna indicazione di eventuali effetti avversi sulla fertilità e sulla capacità di accoppiamento sia dei genitori trattati che della loro prole a qualsiasi dosaggio. Dopo esposizione locale o sistemica a dosi più di cinque volte superiori rispetto a quella terapeutica sono state osservate alterazioni respiratorie (irritazione) e urogenitali (prostatite) e tossicità riproduttiva. Studi sulla genotossicità e sul potenziale cancerogeno non hanno rivelato un rischio particolare per l uomo. 17

47 6. INFORMAZIONI FARMACEUTICHE 6.1 Elenco degli eccipienti Benzalconio cloruro Sodio edetato Acqua depurata Acido cloridrico 3,6% (come aggiustatore di ph) 6.2 Incompatibilità Non pertinente. 6.3 Periodo di validità 3 anni Durante l uso: 3 mesi. 6.4 Precauzioni particolari per la conservazione Non congelare. 6.5 Natura e contenuto del contenitore Tipo e materiale del contenitore a contatto con il medicinale: La soluzione è contenuta in una cartuccia di polietilene/polipropilene con una capsula di polipropilene con anello di silicone di saldatura integrato. La cartuccia è inserita all interno di un cilindro di alluminio. Confezioni e dispositivi disponibili. Confezione singola: 1 inalatore Respimat e 1 cartuccia che fornisce 60 erogazioni (30 dosi di medicinale) Confezione doppia: 2 confezioni singole, ciascuna contenente 1 inalatore Respimat e 1 cartuccia che fornisce 60 erogazioni (30 dosi di medicinale) Confezione tripla: 3 confezioni singole, ciascuna contenente 1 inalatore Respimat e 1 cartuccia che fornisce 60 erogazioni (30 dosi di medicinale) Confezione da 8: 8 confezioni singole, ciascuna contenente 1 inalatore Respimat e 1 cartuccia che fornisce 60 erogazioni (30 dosi di medicinale) È possibile che non tutte le confezioni siano commercializzate. 6.6 Precauzioni particolari per lo smaltimento Il medicinale non utilizzato e i rifiuti derivati da tale medicinale devono essere smaltiti in conformità alla normativa locale vigente. 18

48 7. TITOLARE DELL'AUTORIZZAZIONE ALL'IMMISSIONE IN COMMERCIO Boehringer Ingelheim International GmbH Binger Strasse, 173 D Ingelheim am Rhein Germania 8. NUMERO(I) DELL AUTORIZZAZIONE ALL IMMISSIONE IN COMMERCIO ,5 microgrammi, soluzione per inalazione 1 inalatore Respimat + 1 cartuccia PE/PP da 60 erogazioni ,5 microgrammi, soluzione per inalazione 2 inalatori Respimat + 2 cartucce PE/PP da 60 erogazioni ,5 microgrammi, soluzione per inalazione 3 inalatori Respimat + 3 cartucce PE/PP da 60 erogazioni ,5 microgrammi, soluzione per inalazione 8 inalatori Respimat + 8 cartucce PE/PP da 60 erogazioni 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO DELL AUTORIZZAZIONE 12 gennaio 2011/24 luglio DATA DI REVISIONE DEL TESTO 01/

49 Australian Journal of Pharmacy P , 98 : Please follow your local copyright law AJP CPD continuing professional development Respimat Soft Mist Inhaler Nick Wilson BPharm, GradCertPharmPrac, Cert IV TAE, MCPCE, pharmacist, Resource Development, Guild Pharmacy Academy Chronic obstructive pulmonary disease (COPD) is a progressive lung disease which has a significant effect on quality of life factors such as daily activity, sleep patterns and the ability to exercise. This article discusses the role of Spiriva Respimat (tiotropium) and Spiolto Respimat (tiotropium/olodaterol) in COPD therapy and their practical application in pharmacy professional services. Chronic obstructive pulmonary disease (COPD) is a progressive lung disease which has a significant effect on quality of life factors such as daily activity, sleep patterns and the ability to exercise. 1,2 In 2014, COPD was the fifth leading cause of death in Australia. 2 COPD is a common, preventable and treatable condition thought to result from an exaggerated inflammatory response to chronic irritants such as cigarette smoke and other noxious particles. 3 The inflammatory responses that occur in COPD induce lung tissue destruction (resulting in emphysema) and disruption of normal airway repair and defence mechanisms (resulting in fibrosis). The result of these pathological changes is air trapping and progressive airflow limitation. 3 COPD is characterised by symptoms of: chronic and progressive dyspnoea; chronic cough; and sputum production. 3 COPD patients can have severely impaired quality of life, affecting their daily activities, sleep patterns, and ability to exercise. 2 People with COPD rate their health worse than people without the condition. In , 22% of those aged 45 years and older with COPD rated their health as poor, compared to 6% of those aged 55 years and older without it. 2 Epidemiology COPD affects almost 13%, or one in seven, Australians aged 40 years or older, in almost half of whom the disease has progressed to a stage where symptoms are present and may already be impairing quality of life. 4 Cigarette smoking is considered the most important cause of COPD, although around 20% of all COPD cases are among those who have never smoked. 1,3 Many may be unaware that they have COPD until the disease has progressed and symptoms start to impact their daily life, prompting the decision to seek medical help. 4 Case finding A general lack of disease awareness and reporting by patients with COPD, who commonly attribute their symptoms to ageing or trivialise their cough as smoker s cough, as well as being commonly misdiagnosed as asthma, has resulted in substantial rates of underdiagnosis and misdiagnosis of COPD in Australia. 4 Pharmacists have a role in identifying people who may have undiagnosed COPD. Lung Foundation Australia has a referral template for pharmacists to assess high risk patients. 5 See COPD Referral Template for Pharmacists, opposite. Pharmacological interventions for COPD The aim of pharmacological therapy is to prevent and control symptoms, and prevent further lung deterioration by reducing the frequency and severity of exacerbations. 1 Improved exercise AFTER READING THIS ARTICLE, THE LEARNER SHOULD BE ABLE TO: list factors that indicate that a person may have undiagnosed COPD; describe the pharmacological approaches to managing COPD; identify the key characteristics of medications for COPD: Spiriva Respimat and Spiolto Respimat; provide counselling points on the use of Respimat Soft Mist Inhaler; outline the professional services which can be implemented in community pharmacy to assist in patient s COPD management. The 2010 Competency Standards addressed by this activity include (but may not be limited to): 1.3, 4.2, 4.3, 6.1, 6.3, 7.1, 7.2 Accreditation number: CX17005 This activity has been accredited for 0.5 hour of Group One CPD (or 0.5 CPD credit) suitable for inclusion in an individual pharmacist s CPD plan, which can be converted to 0.5 hour of Group Two CPD (or 1 CPD credit) upon successful completion of relevant assessment activities. Expiry date: 01/03/2019 MARCH Page 1 of 5

50 Australian Journal of Pharmacy P , 98 : Please follow your local copyright law EDUCATION PRIMARY CARE COPD REFERRAL TEMPLATE FOR PHARMACISTS 5 Consider COPD in any patient: Aged 35 years or older AND Who meets one or more of the following criteria: Smoker or ex-smoker Works or worked in a job with exposure to dust, gas or fumes Coughs several times most days Coughs up phlegm or mucus on most days Becomes out of breath more easily than others of a similar age Experiences frequent chest infections coordination between actuation and dose inhalation. This translates into higher lung drug deposition and lower oropharyngeal deposition, making it possible to give lower doses of delivered drugs without lowering efficacy. 10 A 2005 study compared the Respimat Soft Mist Inhaler with Turbuhaler (at fast and slow inspiratory rate) and an MDI for mean whole lung deposition. The results showed greater lung deposition for the Respimat Soft Mist Inhaler, as well as a more peripheral pattern of drug delivery. 13 tolerance and quality of life in individuals are secondary aims of therapy. 1 There are two commonly used guidelines for the management of COPD: Lung Foundation Australia s COPD-X, and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy ,3 Although similar in treatment recommendations, the disease severity classifications are different. The COPD-X Guidelines combine symptom descriptions with spirometry results to classify COPD as mild, moderate or severe. The GOLD strategy uses a more multimodal assessment of disease state severity, including symptom burden, and classifies disease state therapy into categories A to D. Lung Foundation Australia recommends a stepwise approach to COPD management, regardless of disease severity, until adequate symptom control has been achieved. 6 Initial therapy Short-acting reliever medications are recommended as initial therapy for mild symptoms of COPD. 3 These include short-acting beta 2 -agonists (SABA) such as salbutamol and terbutaline, or the short-acting muscarinic antagonist (SAMA) ipratropium. 1 Use of shortacting bronchodilators on a regular basis is generally not recommended. 3 Maintenance therapy Long-acting muscarinic antagonists (LAMA) and/or long-acting beta 2 - agonists (LABA) are recommended when mild symptoms are not controlled sufficiently by SABA or SAMA therapy. These medicines also help to prevent exacerbations. 1 The GOLD strategy 2017 has been updated and now positions a combination of a LAMA and a LABA as a mainstay treatment for people with COPD. 7 See Table 1. Bronchodilators are the mainstay of COPD treatment. 7 Inhaled corticosteroids may be initiated if FEV <50% and exacerbations are frequent. 1 Severe COPD Low-dose theophylline may be considered in patients with severe COPD (FEV 1 <40% predicted) in addition to inhaler therapy. 1 Respimat Soft Mist Inhaler The Respimat Soft Mist Inhaler is a device used to deliver tiotropium (Spiriva Respimat) or tiotropium and olodaterol (Spiolto Respimat). 8,9 The inhaler delivers a fine, slow moving soft mist with a long cloud duration for easy inhalation The aerosol cloud generated by Respimat Soft Mist Inhaler contains a higher fraction of fine particles than most pressurised metered dose inhalers (MDIs) and dry powder inhalers (DPIs). The slow moving aerosol also improves TABLE 1: SUMMARY OF THE DIFFERENT LAMA AND LABA INHALERS AVAILABLE AND PBS LISTED IN AUSTRALIA 6 Long-acting muscarinic agonists (LAMAs) Spiriva HandiHaler (tiotropium) Spiriva Respimat (tiotropium) Seebri Breezhaler (glycopyrronium) Bretaris Genuair (aclidinium) Incruse Ellipta (umeclidinium) Long-acting beta 2 -agonists (LABAs) Onbrez Breezhaler (indacaterol) Spiriva Respimat Spiriva Respimat (tiotropium) is a long-acting anticholinergic agent. In the airways, inhibition of muscarinic receptors results in smooth muscle relaxation. 14 The dilation following Spiriva inhalation is primarily a local effect on the airways, not a systemic one. 14 In COPD, Spiriva Respimat is indicated by the Therapeutic Goods Administration (TGA) for: 14 the long-term maintenance treatment of bronchospasm and dyspnoea associated with COPD; and the prevention of COPD exacerbations. The recommended dose of Spiriva Respimat (5µg tiotropium) is two puffs (2 x 2.5µg) from the Respimat inhaler once daily, at the same time each day. Spiriva should not be used more frequently than once daily as the bronchoprotective effect of each dose lasts at least 24 hours. 14 In asthma, Spiriva Respimat is also indicated as add-on maintenance bronchodilator treatment in adult patients with asthma who are currently treated with LAMA/LABA combinations Ultibro Breezhaler (glycopyrronium, indacaterol) Spiolto Respimat (tiotropium, olodaterol) Anoro Ellipta (umeclidinium, vilanterol) Brimica Genuair (aclidinium, eformeterol) 98 MARCH 2017 Page 2 of 5

51 Australian Journal of Pharmacy P , 98 : Please follow your local copyright law AJP CPD continuing professional development Together, tiotropium and olodaterol provide additive bronchodilation due to their different modes of action and different locations of the target receptors in the lungs. FIGURE 1: TYPICAL SCINTIGRAPHIC IMAGES FOR RESPIMAT, TURBUHALER DPI AT SLOW AND FAST INHALED FLOW RATES, AND CFC-pMDI 13 Note: Turbuhaler is referred to as Turbohaler in the United Kingdom. The publisher of this copyrighted material is Mary Ann Liebert, Inc. publishers. Reproduced with permission. the maintenance combination of inhaled corticosteroids ( 800µg budesonide/day or equivalent) and long-acting beta 2 -agonists and who experienced one or more severe exacerbations in the previous year. 14 Spiolto Respimat Spiolto Respimat is a fixed-dose combination of tiotropium and olodaterol, a LABA. Together, tiotropium and olodaterol provide additive bronchodilation due to their different modes of action and different locations of the target receptors in the lungs. 15 Spiolto Respimat has the same daily dose as Spiriva Respimat two puffs once per day. 15 It is not indicated for the relief of acute symptoms of COPD nor for the treatment of asthma. 15 In a 2015 study of once-daily Spiolto in patients with moderate to very severe COPD, Spiolto Respimat significantly improved lung function beyond Spiriva Respimat, Olodaterol Respimat and placebo. 16 Several studies (across mild to very severe COPD) have shown that Spiolto Respimat not only improves lung function in comparison to single ingredient agents, but also patientrelated outcomes like symptom relief and quality of life. Spiolto Respimat is therefore recommended for patients whose COPD is insufficiently managed on a LABA or LAMA alone. 1 Pharmacist s role Pharmacists play an important role in correct inhaler use and this is also the case with the Respimat Soft Mist Inhaler. 17 When patients receive a new pack from their pharmacist each month, either the patient or the pharmacist will need to prepare the Respimat Soft Mist Inhaler for first-time use. First, they will need to insert the cartridge correctly, then prime the device to ensure that the first puff delivers the correct amount of medication. Pharmacists are encouraged to demonstrate the cartridge insertion and priming process to: all patients getting their first few prescriptions filled; patients who have trouble with dexterity; patients who are not yet comfortable completing the insertion and priming themselves. Daily use Inhaling a dose from the Respimat Soft Mist Inhaler is a three-step process. 8,9 Patients should be instructed of the acronym T.O.P. as a reminder of how to correctly inhale their dose. See Figure 2. Spiriva Respimat and Spiolto Respimat are multidose devices with 30 days worth of medication, meaning a new device is dispensed monthly. 8, 9 See Key Counselling Points, opposite. Application in pharmacy professional services There are a number of professional services that pharmacists can implement to improve the health of their customers with COPD, as well as increase revenue for the pharmacy. MARCH Page 3 of 5

52 Australian Journal of Pharmacy P , 98 : Please follow your local copyright law EDUCATION PRIMARY CARE KEY COUNSELLING POINTS Spiriva Respimat and Spiolto Respimat are used in maintenance therapy for COPD. They are not indicated for the relief of acute symptoms of COPD. 14,15 Spiriva may also be indicated as add on therapy for asthma, but will not relieve acute symptoms. 14 Spiriva Respimat and Spiolto Respimat are multidose devices with 30 days worth of medication, meaning a new device is dispensed monthly. 8,9 New devices must be loaded and primed before use. 8,9 The recommended dose of Spiriva Respimat and Spiolto Respimat is given as two puffs from the Respimat inhaler once daily, given at the same time each day. 14,15 The dose should be inhaled slowly to maximise lung deposition. 8,9,13 COPD. As the condition has a significant effect on quality of life and causes progressive deterioration of lung function, pharmacists have the opportunity to provide meaningful interventions to support their patient s lung health. FURTHER READING Spiriva Respimat and Spiolto Respimat online training course, available at mycpd. org.au lunglearning.com.au Smoking cessation program Smoking cessation is the most effective approach in halting or slowing the progression of COPD. Despite this, over a third of patients with advanced COPD continue to smoke. 18 For those with COPD, continuing to smoke can further impair lung function, making it more difficult to cope with day-to-day activities. 1 Pharmacists are in an ideal position to introduce patients to smoking cessation therapies, including nicotine replacement therapy, pharmacotherapy including bupropion and varenicline, and professional counselling services such as QUIT. Clinical interventions Pharmacists are encouraged to review inhaler technique for all airways diseases at every opportunity. Incorrect inhaler technique affects the delivery of active ingredient to the lungs, and therefore efficacy. Pharmacists who identify poor inhaler technique can document this information as a clinical intervention. Screening for undiagnosed cases of COPD and poorly controlled airways disease may also be documented as a clinical intervention if patients are referred to their general practitioner for further investigation. MedsChecks A MedsCheck may identify issues relating to inhaler technique, adverse effects, compliance, or medications which may adversely affect lung function. It also provides the opportunity to assess the immunisation status of COPD patients, who are recommended to have yearly influenza vaccines, and pneumococcal vaccination when necessary. Conclusion Pharmacists play an important role in the screening and ongoing management of ABOUT THE AUTHOR Nick Wilson is resource development pharmacist with the Pharmacy Guild of Australia. He has been a community pharmacist for nearly ten years in many pharmacies across Victoria and the ACT. He also tutors students at undergraduate and postgraduate levels at Monash University. DISCLAIMER The publication of this article has been supported by an educational grant to the Guild Pharmacy Academy from Boehringer Ingelheim. The content is entirely independent and based on the author s opinion. Please consult the full Product Information available at for more information. TURN KEEP CAP CLOSED. TURN BASE IN DIRECTION OF THE ARROWS ON LABEL UNTIL YOU HEAR A CLICK. OPEN FLIP CAP OPEN UNTIL IT CLICKS INTO OPEN POSITION. BREATHE OUT SLOWLY AND FULLY. FIGURE 2: DAILY USE OF RESPIMAT SOFT MIST INHALER PRESS CLOSE YOUR LIPS AROUND THE MOUTHPIECE END. WHILE TAKING IN A SLOW, DEEP BREATH, PRESS DOSE RELEASE BUTTON; KEEP BREATHING IN SLOWLY FOR AS LONG AS YOU CAN. HOLD YOUR BREATH FOR 10 SECONDS, OR AS LONG AS IS COMFORTABLE. CLOSE CAP. REPEAT TURN, OPEN, PRESS (T.O.P.) FOR A TOTAL OF 2 PUFFS. 1. Abramson M, et al. COPD-X concise guide for primary care. Brisbane: Lung Foundation of Australia, Australian Institute of Health and Welfare. COPD chronic obstructive pulmonary disease. Available at: [accessed 22/12/2016]. 3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease (updated 2016). Available at: [accessed 16/01/2017]. 4. Lung Foundation of Australia. Lung Foundation of Australia position paper: COPD case finding in community settings. February Available at: uploads/2014/02/position-paper-1.pdf 5. Lung Foundation Australia. Screening symptom checklist. Available at: com.au/health-professionals/clinical-resources/ copd/primary-care-respiratory-toolkit/ [accessed 25/01/2017]. 6. Lung Foundation Australia. Stepwise management of stable COPD. February Available at: MARCH 2017 Page 4 of 5

53 Australian Journal of Pharmacy P , 98 : Please follow your local copyright law AJP CPD continuing professional development 1 CPD CREDIT GROUP TWO PRIMARY CARE Respimat Soft Mist Inhaler This unit attracts up to 1 Group Two CPD credit. Accreditation number: CX Expiry date: 01/03/2019. Each question has only ONE answer. Case Study 47-year-old Vanessa has been a smoker for the past 25 years. She presents to the pharmacy requesting a chesty cough syrup. She says that she often has a phlegmy smoker s cough which affects her on most days, however her cough has been particularly bad recently. She is concerned that it will progress to a chest infection, which would be her third this year. 1. What advice would be MOST appropriate to provide to Vanessa? A Her cough will go away if she quits smoking. Provide her with a chesty cough syrup and advice on NRT. B Vanessa meets two criteria from the COPD screening checklist, so has a small risk of COPD. C Vanessa meets at least three criteria from the COPD screening, so should see her GP for a more thorough diagnosis. D Vanessa meets at least three criteria from the COPD screening, indicating that she has COPD. A chesty cough syrup would therefore be useless. E Vanessa meets four criteria from the COPD screening. She should be sent to hospital immediately. Six months later Vanessa returns to the pharmacy with confirmation of a COPD diagnosis. Her current medication for COPD is Ventolin (salbutamol) which she uses for symptom relief. Over the past few months, her symptoms have worsened. She reports more difficulty in completing her daily activities, frequent episodes of shortness of breath, and an increase in sputum production and coughing. You discover that Vanessa currently needs to use salbutamol every two to three hours throughout the day. 2. What would you advise Vanessa? A Advise Vanessa that she should be using a short-acting anticholinergic inhaler instead of salbutamol. B Advise Vanessa that she should be using a short-acting anticholinergic inhaler in conjunction with salbutamol. C Refer Vanessa to her GP. She will most likely require a LAMA, LABA, or LAMA/ LABA combination. D Refer Vanessa to her GP. She will most likely require a LABA/ICS combination. E Advise Vanessa to continue managing her symptoms with salbutamol, as her symptoms indicate only mild COPD. Vanessa returns later that week with a new prescription for Spiriva Respimat. 3. Which of these statements about Spiriva Respimat is INCORRECT? A Spiriva Respimat contains tiotropium, a long-acting anticholinergic agent. B Tiotropium causes relaxation of smooth muscle. C Spiriva Respimat is indicated for COPD only. D Spiriva Respimat is a LAMA delivered in a soft mist inhaler. E Priming the Spiriva Respimat does not affect the number of doses. 4. What advice can you provide Vanessa about using Spiriva Respimat? A The dosage is one inhalation daily. B The device must be primed before every use. C Vanessa will need to keep the inhaler once her cartridge has finished, so that she can install the next cartridge into it. D It is easy to remember how to use the device with the acronym POT: press, open, turn. E If Vanessa has trouble inserting the cartridge, the pharmacist will be able to do this for her. 5. Which of these is NOT a potential income stream for the pharmacy based around COPD screening and management? A Clinical interventions B MedsChecks C Using spirometry to diagnose patients with COPD D COPD screening E All of the above are viable income streams in a pharmacy setting. lungfoundation.com.au/wp-content/uploads/2014/02/ LFA-Stepwise-Management-of-COPD_0216_WEB.pdf [accessed 25/01/2017]. 7. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Pulmonary Disease: 2017 Report. Wisconsin, Available at: goldcopd.org/gold-2017-global-strategy-diagnosismanagement-prevention-copd/ 8. Boehringer Ingelheim. Spiriva Respimat Consumer Medicine Information. 9. Boehringer Ingelheim. Spiolto Respimat Consumer Medicine Information. 10. Anderson P. Use of Respimat Soft Mist Inhaler in COPD patients. International Journal of COPD. 2006;1(3): Hochrainer D, et al. Comparison of the aerosol velocity and spray duration of Respimat Soft Mist Inhaler and pressurized metered dose inhalers. J Aerosol Med. 2005;18(3): Zierenberg B. Optimizing the in vitro performance of Respimat. J Aerosol Med. 1999;12(s1):S-19-S Pitcairn G, et.al. Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or Turbuhaler dry powder inhaler. J Aerosol Med. 2005(18): Boehringer Ingelheim. Spiriva Respimat approved product information. 15. Boehringer Ingelheim. Spiolto Respimat approved product information. 16. Beeh KM, et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32: Saini B, et al. Role of community pharmacists in asthma Australian research highlighting pathways for future primary care models. Australas Med J. 2011;4(4): Lung Foundation of Australia. Better living with chronic obstructive pulmonary disease: A patient guide. 2nd edn Available at: au/wp-content/uploads/2014/02/better-living-with- COPD.pdf. MARCH Page 5 of 5

54 JOURNAL OF AEROSOL MEDICINE Volume 12, Supplement 1, 1999 Mary Ann Liebert, Inc. Pp. S-19-S-24 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. Optimizing the in Vitro Performance of Respimat BERND ZIERENBERG, Ph.D. ABSTRACT Aerosolization of a drug solution in a handheld device for inhalation therapy can be achieved either by vibration or extrusion through a fine nozzle. The latter method does not necessitate the use of an electrical power source and has been developed further in Respimat. The device was adapted for mass production, selecting appropriate materials for the desired size and weight as well as for stability and technical performance. After optimization of the nozzle design, Respimat produced encouraging results in its first lung deposition study in volunteers compared with a chlorofluorocarbon-driven metered dose inhaler (CFC-MDI). Respimat is a reusable device with a mode of action that differs from those of other inhalers. The mechanical power from a coiled spring forces a metered volume of drug solution through a nozzle in a unique component, the uniblock. The convergence of two fine jets of liquid generates a slow-moving aerosol of soft mist. The fine particle fraction in the aerosol, determined from experiments with the Anderson Cascade Impactor (Anderson Instruments, Inc., Smyrna, GA), is approximately 66% for an aqueous drug solution and 81% for an ethanolic solution. This value is about 2.5 times higher than the fine particle fractions determined for CFC-MDIs, and the velocity is about five times lower (e.g., 10 m/s for an aqueous solution), with both factors contributing to the improved lung deposition. In addition, the dose release duration from Respimat is considerably longer than that from CFC-MDIs at approximately 1.2 seconds, allowing more time for the patient to coordinate actuation and inspiration. The reliability and consistency of dose delivery from Respimat also have been confirmed. Key words: aerosolization, fine particle fraction, inhalation therapy, particle size, propellantfree, Respimat, soft mist inhaler, uniblock INTRODUCTION a drug solution or suspension, however, and their future is now uncertain. Early pmdis containing chlorofluorocarbon (CFC) propellants are being phased out, and there are also concerns over the global warming potential of alternative propel- lants such as the hydrofluoroalkanes that have been developed to replace the CFCs. Efforts to de- velop alternative devices include various dry inhalers, but these have their own short- NHALATiON provides the most direct noninva- I sive route of administration for treating respiratory disorders, and, historically, pressurized metered dose inhalers (pmdis) have been popular devices for delivering this treatment, mainly by virtue of their convenience and perceived plicity sim- of use. These devices depend on chemical powder propellants to generate an inhalable aerosol from comings as described in the article by Ganderton Boehringer Ingelheim KG, Ingelheim, Germany. S-19

55 S-20 ZIERENBERG Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. in this issue. There is therefore an urgent need for a convenient propellant-free inhaler device to deliver aerosols from solutions. This article describes the development of Respimat (Boehringer Ingelheim, Ingelheim am Rhein, Germany), a novel soft mist inhaler designed both to meet this need and to improve upon existing inhaler performance. GENERAL CONSIDERATIONS FOR SOFT MIST INHALERS The generation of an inhalable aerosol from a drug solution requires the bulk liquid to be converted into appropriately sized droplets. There are two technically feasible methods for achieving this in a pocket-sized device. The first method involves the piezoelectric effect, the use of electrical energy to produce mechanical energy in the form of vibrations. The vibrations are transmitted into the liquid (e.g., by a metallic disk) and result in waves forming in a dosed volume of a drug solution, which propagate to the surface and result in nebulization of the solution into inhalable droplets. This technology was used by Boehringer Ingelheim (Ingelheim am Rhein, Germany) in an early attempt to develop a soft mist inhaler for the treatment of lung diseases/1' The principal disadvantages for this approach are the need for a battery (which has to be recharged by the patient from time to time) and the larger dimensions of the device compared with pmdis. Both of these were considered to be obstacles for Glass Outlet of nozzle patient acceptance of the device by reducing convenience and probably compliance. The second technical approach is based on forcing drug solution through a small hole in a nozzle. During this process, the solution is accelerated and disintegrates into droplets after leaving the nozzle. The efficient production of an inhalable aerosol (i.e., an aerosol with an optimal droplet size distribution generated using only a small amount of mechanical energy) required a technological breakthrough, however. This arrived with the investigation of a two-channel nozzle, whereby the aerosol is generated through the impaction of two converging jets of liquid forced through two small (size range, 5-8 /xm) opposing channels at a carefully controlled angle. MILESTONES IN THE DEVELOPMENT OF RESPIMAT The proof of concept was demonstrated in a prototype model, which consisted of a metal body with a syringe as a solution reservoir. The device was operated by means of a lever arm, which simultaneously tightened the main spring and withdrew a metered volume of drug solution of about 135 /ul from the reservoir. Pressing a button released the spring, forcing the metered dose through the channels as liquid jets that impact 25 /am from the nozzle outlet to produce the aerosol. A feasibility study using aqueous fo-agonist solution showed that the droplet size distribution in the aerosol was in the range suitable for in- Silicon wafer FIG. 1. Filter Schematic drawing of the uniblock/4' (Reproduced by permission rrom uiicipiuuui i'ress, Buffalo Grove, IL).

56 IN VITRO PERFORMANCE OF RESPIMAT S-21 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. halation; the majority of the particle mass was in the range from 1 to 5 /xm. In this first prototype, the nozzle openings were tiny holes pierced into a stainless steel disk; however, a nozzle design better suited for mass production was needed. This was achieved by developing a miniature "sandwich" concept, the uniblock, consisting of a rectangle (2 X 2.5 mm) cut from a glass plate bonded to a silicon wafer. Using photolithographic techniques adapted from the microelectronics industry, multiple copies of the uniblock, each comprising filter structures as well as inlet and outlet channels (Fig. 1), are etched into the silicon wafer with high precision and accuracy. Currently, the accuracy of the photolithographic exposure process is better than 0.1 Lim over a single uniblock bearing the etched nozzle microstructure. Further development of the prototype included exchanging all metal parts for components made from polymers whenever possible and adaptation of all parts of the device for mass production. In addition, the torque required for loading the dose was minimized (approximately 40 cnm) so that the energy needed to generate the aerosol could be easily produced by hand. After initial stability and technical performance tests, the device (referred to as the BINEB or Prototype III) was successfully used in a first lung deposition study in comparison with a CFC metered dose inhaler (MDI) in healthy volunteers/2'3' The experience accumulated with the various and the need to make a functional prototypes practical device with a smaller number of individual components were combined with results of device-handling studies, in which patients evaluated four different design concepts. The resultant device, the Prototype IV, incorporated a radical change in design. Whereas the first prototype design released the dose at an angle of 90 relative to the device exit (i.e., the mouthpiece was at a right angle to the drug cartridge), the new design released the dose in a direction parallel to the exit. This parallel version was used for clinical phase II and phase III studies. The device to be marketed (Fig. 2) contains several further modifications mainly designed to improve the handling of the device by the patient. The visible changes are a hinged cap (color-coded for each drug type), a transparent case for clear identification of the drug product, a remaining dose counter, and a different shape of the doserelease button. This design has been tested by patients in handling studies and has been favorably received. MODE OF ACTION OF RESPIMAT The principal parts of Respimat (Boehringer Ingelheim) are shown in a schematic diagram (Fig. 3). To use the device, the patient removes the transparent case, inserts the cartridge containing the drug solution, and replaces the case. The car- FIG. 2. Respimat soft mist inhaler: market design.

57 S-22 ZIERENBERG Non-return valve Uniblock Capillary tube Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. FIG. 3. Spring Outer casing Drug cartridge Respimat soft mist inhaler: schematic diagram showing key components. tridge is now connected by a capillary tube (containing a nonreturn valve) to the uniblock. To load a dose, the patient simply turns the lower half of the device through 180. The helical cam transforms the rotation into a linear movement, which tightens the spring and moves the capillary with the nonreturn valve to a defined lower position. During this movement, the drug solution is drawn through the capillary into a pump chamber as shown in Figure 3. When the patient actuates the device by pressing the release button, the mechanical power from the spring pushes the capillary with the now closed nonreturn valve to the upper position. This operation drives the metered volume of drug solution the nozzle in the (about 13.5 x<l) through uniblock. Here, two fine jets of liquid are produced at the outlet of the uniblock, which converge at a carefully controlled angle. The resulting impact of the two jets of liquid generates slow-moving a aerosol cloud, or soft mist. When a cartridge is inserted for the first time, the device has to be primed to expel air from its inner parts. The device can be used with three successive cartridges in this way, with each delivering 120 doses. DEVICE PERFORMANCE DATA Respimat is an active system, which means that the aerosol is generated by a constantly available and consistent energy source and that its quality in terms of dose and particle size distribution is independent of the inspiratory flow of the patient. Water, ethanol, or a mixture of both can be used as a solvent for formulating the drug solution. Aqueous drug solutions also contain the two excipients benzalkonium chloride and EDTA as preservatives. The fine particle fraction, defined as the mass percentage of the aerosol consisting of particles smaller than 5.8 /xm, is higher for an ethanolic formulation than for an aqueous formulation generated by the Respimat. Figure 4 shows typical examples for the particle size distribution of aqueous and ethanolic solutions measured in an Anderson Cascade Impactor (Anderson Instruments, Inc., Smyrna, GA). The fine particle fraction amounts to approximately 66% for the aqueous drug solution (ß2 agonist) and 81% for the ethanolic solution (corticosteroid). These values are 2.5 times higher than the corresponding values for aerosols produced by CFC-MDIs. This particle size distribution can also be described in terms of a mass me- diameter value. The mass me- dian aerodynamic dian aerodynamic diameter values with Respimat were 2.0 ± 0.4 /xm for aqueous solution and 1.0 ± 0.3 /xm for ethanolic solution, both of which were determined by measurements using an Anderson Cascade Impactor conducted at a temperature of 22 C ± 2 C and a relative humidity of 50 ± 10% (data on file). The velocity of the aerosol droplets generated

58 i IN VITRO PERFORMANCE OF RESPIMAT S-23 Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. B 5 5H FIG. 4. (B) ethanolic steroid solution Í Particle size fraction (um) Particle size traction (um) Typical particle size distributions for aerosol generated by the Respimat using (A) aqueous ß2 agonist and by Respimat as measured by a high-speed camera or laser Doppler anemometry is about one fifth of the velocity of particles produced by a CFC-MDI independent of drug formulation. These values were 10 m/s with Respimat pared com- with 50 m/s for the CFC-MDI delivering an aqueous ßz agonist. The low particle velocity T3 18-, o Cartridge 1 * Cartridge 2 i + was even more marked for an ethanolic steroid at 7.5 m/s. The solution delivered by Respimat combination of fine particles and low velocity results in a soft mist appearance. Both the size and velocity of the aerosol particles are considered to be important factors in successful drug delivery to the lungs. In addition, the Cartridge 3 i i Number of actuations from each cartridge FIG. 5. Consistency of dose delivery by the Respimat (average daily delivered volume for 20 devices, with each using three cartridges of aqueous drug solution).

59 S-24 ZIERENBERG Downloaded by BOEHRINGER INGELHEIM MULTI SITE from online.liebertpub.com at 10/27/17. For personal use only. relatively long duration of dose release by Respimat (approximately 1.2 and 1.6 seconds for aqueous and ethanolic solutions, respectively) should facilitate maximal inhalation of the dose, allowing the patient time to inhale after pressing the doserelease button, in contrast to the critical need to coordinate actuation and inspiration that is required during the use of pmdis. Ln addition, the soft mist produces a perceptible taste or sensation, providing appropriate feedback to indicate that the dose has been released, in contrast to findings with some powder inhalers. The hypothesis that the soft mist generated by Respimat results in increased inhalation efficiency has been confirmed by findings of greatly improved lung deposition as reported in an article by Newman in this issue. Achieving an improvement in device performance is not sufficient alone. Respimat has also demonstrated consistent performance in laboratory evaluations. These include analysis of the plume geometry (which is performed for every uniblock prior to assembly), Anderson Cascade Impactor and laser diffraction studies of particle characteristics, and measurement of the consistency of the delivered mass (volume). The latter value was determined as the difference in device weight before and after actuation for Respimat devices actuated four times per day over three cartridges, mimicking patient use. The average delivered mass (volume) of 11.0 mg was highly consistent as demonstrated in Figure 5, which shows the averaged delivered volume from four puffs a day for three cartridges used over 3 months. The data were generated with 20 devices. The delivered volume remained within narrow limits over the in-use pe- values at the start of each riod, with slightly higher cartridge as a result of the priming process. The quality of the soft mist in terms of delivered dose and particle size distribution is independent of the range of temperature, humidity, and pressure normally encountered. This may be explained by the small impact of these variables on the physicochemical properties of the drug solution. This impact is probably much smaller than necessary to influence the process of aerosol generation by Respimat. CONCLUSIONS Demonstrating a new approach therapy, Respimat, a propellant-free to inhalation inhaler with a novel mechanism of action, shows distinct advantages over contemporary inhaler devices. Like many other inhalers, Respimat delivers multiple doses of inhalable aerosol from drug solutions; however, in addition, Respimat does this without the use of propellants, employs medication cartridges in a reusable device, and releases accurately metered doses as a soft mist. This soft mist demonstrates improved particle characteristics relative to CFC-MDIs, increasing the targeting of drugs to the lungs. Furthermore, Respimat produces this soft mist in a repeatable and consistent manner independently of temperature, pressure, or humidity. Responding to the needs of patients highlighted in handling studies, refinements to the device have been incorporated, and the resultant product is designed to meet widespread patient acceptance coupled with physician approval of the improved therapeutic targeting. REFERENCES 1. Zierenberg, B The Respimat, a new inhalation system based on the piezoelectric effect. /. Biopharm. Sei. 3: Steed, K.P., B. Freund, L. Towse, and S.P. Newman High lung deposition of fenoterol from BINEB, a novel multiple dose nebuliser device. Eur. Respir. J. 8(Suppl 19):204s. 3. Steed, K.P., B. Zierenberg, S. Reader, and S.P. Newman Lung deposition of flunisolide from BINEB, a novel multiple dose nebuliser, is twice that from a pressurised metered dose inhaler. Eur. Respir. J. 8(Suppl 19):122s. 4. Zierenberg, B., J. Eicher, S. Dunne, and B. Freund Boehringer Ingelheim nebulizer BINEB a new approach to inhalation therapy. In R.N. Dalky, P.R. Byron, and S.J. Farr, eds. Proceedings of Respiratory Drug Delivery V. Interpharm Press, Buffalo Grove, IL, Address reprint requests to: Dr. B. Zierenberg G Devicetechnology/Therapeutic Systems Pharmaceutics Department Boehringer Ingelheim KG BingerStrasse 173 D Ingelheim am Rhein Germany zierenbe@ing.boehringer-ingelheim.com