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Efficacy and Safety of Mometasone Furoate Administered Once-Daily in the Evening in Patients With Persistent Asthma Dependent on Inhaled Corticosteroids

Posted on: Tuesday, 11 October 2005, 03:00 CDT

By D'Urzo, Anthony; Karpel, Jill P; Busse, William W; Boulet, Louis- Philippe; Et al

Key words: Adherence - Evening dosing - Mometasone furoate - Once daily - Quality of life - Steroid tapering

ABSTRACT

Background: Once-daily dosing with an inhaled corticosteroid (ICS) may simplify asthma management and improve patient compliance. Since asthma is frequently worse at night, evening dosing appears to be a more obvious choice to accommodate the chronobiology of asthma than morning dosing.

Objective: The primary study objective was to compare the efficacy and safety of mometasone furcate (MF) dry powder inhaler (MF-DPI) 400 μg qd PM (one 400 μg inhalation) with placebo for the treatment of asthma in patients previously dependent on twice a day (bid, bis in die) ICS therapy. We also compared different regimens of MF-DPI with each other and with placebo.

Methods: This 12-week, multicenter, double-blind, placebo- controlled study evaluated lung function and asthma symptoms in 400 subjects with persistent asthma randomized to MF-DPI 200 μg qd (once a day, quaque die) PM, 400 μg qd PM as one inhalation from a 400 μg device, 400 μg qd PM as two inhalations from a 200 μg device, 200 μg twice daily (bid), or placebo. Evening doses were to be taken in the late afternoon or early evening, preferably before dinner time.

Results: Mean changes from baseline at endpoint in FEV, (forced expiratory volume in 1s) were similar for MF-DPI 400 μg qd PM (one inhalation; 0.41 L), MF-DPI 400 μg qd PM (2 inhalations; 0.49L), MF-DPI 200 μg qd PM (0.41 L), and MF-DPI 200 μg bid (0.51L); and all were significantly improved compared with placebo (0.16L; p < 0.001). Secondary efficacy variables, including nocturnal awakenings and use of rescue albuterol, were also significantly improved with MF-DPI treatment compared with placebo. All treatments were generally safe and well tolerated, with adverse events of mild to moderate severity.

Conclusions: Once-daily evening dosing of MF-DPI at doses of 400 and 200 μg restored lung function and improved nocturnal and daytime symptom control in subjects with asthma previously dependent on bid ICS therapy. Comparable effectiveness of a total daily dose of 400 μg was demonstrated between once daily in the evening and twice-daily administration. The results also confirm the effectiveness of MF-DPI 200 μg qd PM, the lowest dose studied.

Introduction

Inhaled corticosteroids (ICS) are considered to be the first- line therapy for patients with persistent asthma1"4. Their effects include improvements in lung function and quality of life, and reduction in hospitalization and mortality5,6. In an attempt to simplify treatment regimens which may improve treatment adherence7, studies have evaluated asthma control with the use of once-daily dosing of ICS compared with more frequent dosing schedules. Studies of fluticasone (FP)8 and budesonide (BUD)9 have been unable to establish comparable efficacy of once a day (qd, quaque die) and twice a day (bid, bis in die) dosing with these agents. Mometasone furoate (MF) dry powder inhaler (MF-DPI) is an effective once-daily controller therapy for patients with mild to moderate persistent asthma at a dose as low as 200 μg qd PM10-12, and studies have demonstrated the comparability of once-daily and twice-daily dosing with MF-DPI10,13.

In the present study (double-blind, placebocontrolled), we evaluated the safety and efficacy of MF-DPI using a number of treatment regimens (200 μg qd PM, 400 μg qd PM [administered as one 400 μg inhalation or two 200 μg inhalations], and 200 μg bid) in patients with asthma requiring ICS therapy. We wanted to assess if qd PM dosing with MF-DPI could result in control comparable to bid dosing and maintain this control over the duration of the trial, by using lung function and other asthma control parameters. We compared all active treatments to placebo and to each other. Specifically, we were interested in knowing whether MF-DPI 400 μg qd PM (administered as one 400 μg inhalation) was superior to placebo treatment.

Methods

Patient population

Adults and adolescents (≥ 12 years old) with a diagnosis of persistent asthma for ≥ 12 months, and who required daily maintenance treatment with ICS for ≥ 12 weeks immediately prior to the screening visit, were eligible for this study. For ≥ 2 weeks immediately prior to the screening visit, subjects must have been on a stable regimen within the following dose ranges μg/day) : beclomethasone dipropionate (BDP) with chlorofluorocarbon (CFC) propellant 168-840; BDP with hydrofluoroalkane (HFA) propellant (QVAR) 40-320; BUD 200-1600; flunisolide (FLU) 500-2000; FP 88-660; triamcinolone acetonide (TA) 400-2000. All patients had been using their ICS on a twice-daily basis.

Written informed consent was obtained for all subjects. Treatment protocols were approved by the appropriate Institutional Review Board or Ethical Review Committee at each testing center, and were conducted in accordance with good clinical practice.

At the screening visit, each subject had to demonstrate a forced expiratory volume in 1 second (FEV^sub 1^) ≥ 60% of the predicted value. Prior to randomization, each subject also had to demonstrate an increase in absolute FEV^sub 1^ ≥ 12%, with an increase of at least 200 mL, following two puffs of a short-acting P2-agonist (SABA).

Excluded from the study was any subject who had been treated with cytotoxic agents within the past 3 months, required daily nebulized β^sub 2^-agonist or any long-acting inhaled β^sub 2^- agonist (LABA), was receiving immunotherapy, or had experienced a respiratory tract infection within 2 weeks of screening. A subject was also excluded if he/she had been hospitalized for asthma within the past 3 months, had received emergency treatment for asthma on two or more occasions in the previous 6 months, or had required ventilator support for asthma in the past 10 years. A smoker or ex- smoker who had smoked in the past 6 months, or who had a cumulative smoking history > 10 pack-years, was to be considered ineligible, as was any subject with clinically significant evidence of other respiratory disease which could interfere with the study.

Study design

The study was randomized, double-blind, and placebocontrolled. Subjects were randomized, in a 1:1:1:1:1 ratio, to 12 weeks of blinded treatment with: MF-DPI 200 μg qd PM, MF-DPI 400 μg qd PM as one inhalation (from a DPI delivering 400 μg/ inhalation), MF-DPI 400 μg qd PM as two inhalations (from a DPI delivering 200 μg/inhalation), MF-DPI 200 μg bid, or placebo. The AM dose was to be taken upon awakening, without regard to meals. Subjects were asked to take the PM dose in the late afternoon or early evening, preferably before dinnertime. The DPIs for all active treatments and placebo were indistinguishable from each other.

ICS reduction period

Prior to randomization, subjects completed an ICS reduction period lasting up to 4 weeks, to assure that randomized subjects were ICS dependent. The ICS reduction period was initiated by decreasing the ICS dose by 50% at the screening visit, after which specific asthma criteria had to be met in order to qualify for randomization. If after 1 week on this reduced regimen the subject did not meet the randomization criteria noted below, the ICS may have been reduced further or been discontinued, at the discretion of the investigator. After 4 weeks, a subject who did not meet randomization criteria was considered to be ineligible for randomization. Use of rescue medication (albuterol) was allowed and monitored during the entire study. If the subject met any of the following criteria during the ICS reduction period, he/she was to return to the office within 24 h to determine eligibility for randomization at that visit. The criteria included: use of ≥ 15 inhalations of rescue medication over the past 4 days (but ≤ 12 inhalations per day); total symptom score ≥ 4 since the last site contact, based on evaluations of wheezing, coughing, and difficulty breathing every morning and evening, with each symptom rated on a scale of O (none) to 3 (severe); ≥ 25% reduction in AM or PM peak expiratory flow rate (PEF) from the screening value; and at least one nocturnal awakening due to asthma symptoms that required use of a SABA. Subjects who met at least one of the symptom criteria during the ICS reduction period, and who also demonstrated a decrease in FEV^sub 1^ of ≥ 10% from the screening value and whose FEV^sub 1^ fell between 50% and 85% of predicted normal were randomized.

Subjects were discontinued if they experienced a clinically significant worsening of their asthma, which included emergency room care and/or hospitalization. Subjects could also be discontinued at the investigators' discretion if they had a clinically significant change in asthma control.

Spirometry was performed in accordance with ATS guidelines14. Calculations of percent predicted FEV^sub 1^ were made using Crapo formulas15 for subjects ≥ 18 years of age, Polgar formulas16 for subjects 12-17 years of age, and appropriate adjustments made for subjects of African descent (calculated val\ue 0.88).

Efficacy

The primary efficacy variable was the mean change in FEV^sub 1^ from baseline to endpoint (last post-baseline observation). secondary efficacy variables included: percent predicted FEV^sub 1^, forced vital capacity (FVC), forced expiratory flow between 25% and 75% of vital capacity (FEF^sub 25%-75%^), and physician's evaluation of response to treatment. Additional efficacy variables included weekly averages of AM and PM PEF, morning and evening asthma symptom scores, albuterol use, and nocturnal awakenings due to asthma that required albuterol use. Subjects rated and recorded on diary cards the daily occurrences of worsening asthma symptoms in the morning and evening using a scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe. Patient response to therapy was assessed by the evaluating physician (1 = much improved, 2 = improved, 3 = no change, 4 = worse, 5 = much worse). The PM symptom scores were recorded before taking the evening dose of study treatment.

Quality of life assessment

A self-reported, health-related quality of life (HRQOL) questionnaire, composed of the Medical Outcomes Survey 36-item Short Form (SF-36)17 and an asthmaspecific module based on the Asthma Quality of Life Questionnaire (AQLQ)18, were used to measure subjects' HRQOL in this study. Primary HRQOL variables were the physical component summary (PCS) score of the SF-36 module and the total domain of the asthma-specific module. Quality of life was assessed at baseline, Week 7, and the final visit. The primary HRQOL comparison was between MF-DPI 400 μg qd PM as 1 inhalation, and placebo.

Safety

Safety evaluations included diary records of adverse events, vital signs, clinical laboratory tests, and physical examination. The physician or a designee reviewed the diary cards at all visits post-screening, and relevant comments were documented.

Statistical analysis

The study was designed to yield at least 400 subjects who met the criteria for the evaluation of the primary efficacy variable with approximately 80 subjects per treatment group. The sample size was chosen to detect, with at least 90% power and 5% significance level, a clinically meaningful pair-wise difference in FEV^sub 1^ mean change from baseline (the primary efficacy variable) between any two treatment groups. This was defined as a pooled standard deviation of 0.48 L for FEV^sub 1^ change from baseline and a mean treatment difference of approximately 0.25 L or more between any treatment groups. Data from all centers were pooled for analysis. Primary efficacy analysis at endpoint was based on a two-way analysis of variance (ANOVA). Pair-wise comparisons were made using the least squares mean from the ANOVA model. Analyses and summaries of all efficacy and safety data were based on the intentto-treat principle. secondary efficacy variables and all other variables were analyzed using the same two-way ANOVA. A preliminary assessment of the consistency of results across centers was based on the significance of the treatment-by-center interaction for the primary efficacy variable, FEV^sub 1^. A primary comparison between MF-DPI 400 μg qd PM (one inhalation) and placebo was performed. If this was statistically significant, all other pair-wise comparisons were made at the nominal alpha level of 0.05 with no adjustment.

Results

Patient population

A total of 400 subjects aged 12-78 years, with a duration of asthma ranging from 1 to 71 years, were randomized at 45 study centers. No significant differences in baseline demographics were noted between treatment groups (Table 1). One patient randomized to MF-DPI 200 μg bid did not take any study medication and was not included in the efficacy analysis.

Lung function

The FEV^sub 1^ (% predicted) at screening was 77.8 9.6, 78.1 11.0, 78.6 11.0, 81.4 + 11.2, and 79.2 + 10.6 for the placebo, MF- DPI 200 μg qd PM; MF-DPI 200 μg bid, MF-DPI 400 μg qd PM (one inhalation) and MF-DPI 400 μg qd PM (two inhalations), respectively. The FEV^sub 1^ (% predicted) at baseline (after steroid reduction) was 65.1 9.6, 66.7 + 9.5, 66.4 9.3, 69.1 9.8, and 66.7 9.6 for placebo, MF-DPI 200 μg qd PM, MF-DPI 200 μg bid, MF-DPI 400 μg qd PM (one inhalation) and MF-DPI 400 μg qd PM (two inhalations), respectively.

Throughout the study and at endpoint (Figure 1), all MF-DPI treatment groups showed statistically significant increases in FEV^sub 1^ compared with placebo (p < 0.05). The mean a priori difference of 0.25 L was detected between each active treatment and placebo (Table 2); there was 98% post hoc power to detect this difference. Increases in FEV^sub 1^ for all MF-DPI treatment groups were comparable, with values reaching > 77% predicted at endpoint. Statistically significant increases in FEV^sub 1^ were observed as early as Week 1 and maintained at all time points (Figure 1) for all MF-DPI treatment groups compared with placebo (p < 0.05). All MF- DPI treatments significantly improved FVC and FEF^sub 25%-75%^ at endpoint compared with placebo (p ≤ 0.01; Table 2). The mean changes from baseline at endpoint for AM PEF and PM PEF were significantly improved for all MF-DPI groups compared with placebo at endpoint (p < 0.05; Table 2), and at individual time points (p < 0.04; Figure 2). Improvements at endpoint in AM and PM PEF were generally greater with MF-DPI 400 μg/day compared with MF-DPI 200 μg/ day, with statistically significant differences among active treatment groups (most involving comparisons to MF-DPI 200 μg qd PM) noted at scattered time points. There was no significant difference between MF-DPI 400 μg qd PM administered as one inhalation or two inhalations compared with MF-DPI 200 μg bid.

Table 1. Patient demographics

Asthma symptoms

Significant improvements in AM and PM asthma symptom scores were generally observed with all MF-DPI treatments, compared with placebo, at endpoint (Table 3). MF-DPI 400 μg qd PM administered as one inhalation or two inhalations significantly improved wheezing, coughing, and difficulty breathing compared with placebo (p ≤ 0.01). In addition, treatment with MF-DPI 200 μg qd PM significantly improved all symptom scores except PM wheezing at endpoint compared with placebo (p ≤ 0.05). The only significant difference among active treatment groups was a significantly greater (p ≤ 0.024) improvement of difficulty breathing scores with MF-DPI 400 μg qd PM administered as one inhalation compared with MF-DPI 200 μg qd PM.

Nocturnal awakenings, albuterol use

The number of nocturnal awakenings requiring albuterol use was significantly decreased at endpoint in all MF-DPI treatment groups compared with an increase in the placebo group (p ≤ 0.01; Table 3). Albuterol use was also significantly decreased at endpoint for all MF-DPI treatment groups compared with an increase in the placebo group (p ≤ 0.01; Table 3). Albuterol use was > 1 puff/ day at endpoint in all treatment groups (Table 3). There were no significant differences among MF-DPI treatments at endpoint in terms of nocturnal awakenings and albuterol use.

Figure 1. The effect of MF-DPI treatment on mean change in FEV^sub 1^. Mean changes in FEV^sub 1^ from baseline at each visit and at endpoint are shown. *p ≤ 0.001 versus placebo, [dagger]p < 0.05 versus placebo (for all MF-DPI treatment groups)

Figure 2. The effect of MF-DPI treatment on mean change in AM PEF. Mean changes in AM PEF from baseline at each study week and at endpoint are shown. Values shown are based on daily diary entries averaged over each 7-day interval. *p≤ 0.001 versus placebo, [dagger] p < 0.04 versus placebo (for all MF-DPI treatment groups)

Table 2. Effects on lung function

Table 3. Effects on asthma symptom scores and albuterol use

Asthma worsening, response to therapy

More subjects in the placebo group (n = 31) experienced asthma worsening than in any MF-DPI group (range, n = 12-18), including those treated with MF-DPI 200 μg qd PM (n = 14). Forty-eight percent of subjects in the placebo group discontinued treatment, compared with 17% in the MF-DPI 200 μg qd PM group, 15% in the MF-DPI 400 μg qd PM (one inhalation) group, 10% in the MF-DPI 400 μg qd PM (two inhalations) group, and 11% in the MF-DPI 200 μg bid group. Based on physicians' global evaluation of response to therapy, between 67% (MF-DPI 200 μg qd PM) and 81% (MF-DPI 400 μg qd PM, one inhalation) of MF-DPI subjects were considered to be improved or much improved with treatment, while 40% of placebo subjects were considered to be improved or much improved. Between 8% (MF-DPI 400 μg qd PM, two inhalations) and 17% (MF- DPI 200 μg qd PM) of MF-DPI subjects were considered to be worse or much worse, compared with 39% of placebo subjects considered to be worse or much worse.

Quality of life

The HRQOL questionnaire was administered to 376 of the 400 subjects randomized to treatment (Englishspeaking centers only). Of these 376 subjects, 369 (98%) completed both HRQOL modules at baseline and endpoint. Baseline scores indicated that asthma had a mild to moderate impact on subjects' HRQOL, with overall mean PCS scores below the national norm of 50 in all treatment groups. Analysis of the primary HRQOL variables (Table 4) showed significant (p ≤ 0.003) improvements compared with placebo in the PCS score and total asthma score in the two MF-DPI 400 μg qd PM groups and the MF-DPI 200 μg bid group. MF-DPI 200 μg qd PM treatment was associated with a significant improvement in the asthma total score (p < 0.001), but not in the PCS score. Scores in all of the asthma-specific domains decreased significantly with all MF-DPI treatments, including 200 μg qd PM, compared with placebo (data not shown); the greatest decreases were observed in the breathlessness domain.

Table 4. Health\-related quality of life scores (SF-36 and asthma- specific modules)

Table 5. Incidence of adverse events

Safety

All MF-DPI treatments were generally safe and well tolerated. Most of the adverse events were considered to be unrelated to treatment. Treatment-related adverse events (TRAEs) occurred at a similar incidence among groups taking higher doses of MF-DPI, with lower proportions of subjects reporting any treatment-related adverse events with MF-DPI 200 μg qd PM and placebo (Table 5). The only treatment-related adverse event occurring at an incidence > 5% with MF-DPI was oral candidiasis (6% overall). The incidence of treatmentrelated pharyngitis was < 2% overall with MF-DPI. Treatment- related adverse events were mild to moderate in severity, and very few subjects discontinued treatment due to adverse events. Five subjects reported serious adverse events, one each in the MF-DPI 400 μg qd PM (one inhalation and two inhalations) and MF-DPI 200 μg bid groups, and two in the placebo group. None of these was considered to be treatment related.

Discussion

The development of once-daily ICS therapy represents an important new option for asthma therapy. Our study found that once-daily MF- DPI (400 μg) is superior to placebo and comparable to twice- daily MF-DPI therapy in ICS-dependent patients. It also supports the concept of chronobiology in the treatment of asthma patients. Therapy with MF-DPI once daily restored lung function within 1 week after the ICS reduction/washout period. The ICS reduction/washout made the study more sensitive in terms of detecting differences between the treatment regimens. Furthermore, all MF-DPI treatments significantly improved FVC and FEF^sub 25%-75%^, at endpoint. These improvements in objective measures of asthma control were associated with improvements in asthma symptoms (AM and PM), nocturnal awakenings, rescue medication use, and HRQOL measurements. These findings are reassuring given that patients in the real world setting often present with acute changes in well-being; where the traditional approach to management has been twice daily or more frequent dosing of ICS to restore asthma control to desirable levels19,20. Note that the majority of subjects (> 85%) in this study were non-Hispanic Caucasians, and evaluation by race/ ethnicity was not meaningful.

Our study design allowed an examination of the efficacy and safety of different MF-DPI treatment regimens on common asthma control endpoints. The study was powered at the 90% level (5% significance level) to detect a clinically meaningful pair-wise difference in FEV^sub 1^ (mean change from baseline) between any two treatment groups. It is relevant to note that significant differences between the treatment groups and placebo were noted as early as the first week of treatment and maintained at all time points throughout the study. Our comparison of data between baseline and endpoint allowed inclusion of data from the maximum number of subjects regardless of when the data point was obtained; a strategy that was realistic given the high and not unexpected discontinuation rate in the placebo arm. Interestingly, the finding of a placebo effect in this study (Figure 1) is not uncommon21-23 and may in part be related to the high discontinuation rate in the placebo group that may have selected subjects whose lung function remained preserved at later time points. Despite the placebo response, all MF- DPI treatments were found to be significantly superior to placebo.

Given reports that indicate poor adherence to ICS use, which traditionally have been administered twice daily24, it has been suggested that decreasing the dosing frequency to once daily might enhance compliance25. Our study extends the findings in earlier studies of MF-DPI, which have shown that MF-DPI is an effective once- daily controller therapy for patients with mild to moderate persistent asthma at a dose as low as 200 μg qd PM10,11,13. The efficacy and safety of MF-DPI has also been demonstrated in studies in which FP, BUD, and BDP were used as active comparators in treating patients with mild to moderate persistent asthma who had previously been maintained on stable doses of twice-daily ICS26-29. The rapid response to MF-DPI therapy observed here has been noted in other controlled trials involving MF-DPI10,30. In our study, where ICS were reduced prior to active treatment, MF-DPI 200 μg qd PM showed significant improvement in the primary efficacy variable, FEV^sub 1^, as well as for FEF^sub 25%-75%^ and for FVC. Improvements in PM PEF were significant for all treatments at endpoint and at some, but not all, study visits in the MF-DPI 200 μg qd PM group. Furthermore, some improvements observed in subjects taking MF-DPI 400 μg qd per day were greater than those in subjects taking MF-DPI 200 μg qd PM. This suggests that while many patients may benefit from the lower starting dose of MF-DPI, some patients may need a starting dose of 400 μg qd PM. Based on the spirometry results in this study, which included an ICS washout/reduction period, MF-DPI 200 μg qd PM should be an effective starting dose for many patients. The efficacy observed at both the high and low evening doses may allow for flexible titration of ICS to maintain asthma control at the lowest effective dose.

Survey results31 indicate that a majority of patients report nocturnal awakenings at least once per week, and among patients who perceive their asthma to be mild, almost half report nocturnal awakenings at least 3 times per week. In the present study, MF-DPI 400 μg qd PM reduced night-time awakenings from 12 to 2 per month, and daytime and night-time symptoms of wheezing, coughing and difficulty breathing by 48%-55%, 46%-67%, and 46%-49%, respectively. These changes were also associated with significant improvements in quality of life. These data, along with objective improvements in lung function, highlight the efficacy of MF-DPI 400 μg qd PM.

In summary, once-daily evening dosing of MF-DPI at doses of 400 and 200 μg is effective at restoring lung function and improving nocturnal and daytime symptom control in subjects with asthma previously dependent on bid ICS therapy. Comparable effectiveness of a total daily dose of 400 μg was demonstrated between once daily in the evening and twice-daily administration. The results also confirm the effectiveness of MF-DPI 200 μg qd PM, the lowest dose studied.

Acknowledgments

Declaration of interest: Funding for this study was provided by Schering-Plough Corporation, Kenilworth, NJ, USA.

The authors would like to thank the investigators for their contributions to this study, Lucy Shneyer, MS, for biostatistical analysis of the clinical study data, and Ken Kauffman, BSc, for editorial assistance.

Some material contained in this paper has been presented at:

* The American College of Allergy, Asthma & Immunology, San Antonio, Texas, November 1520, 2002.

* The American Academy of Allergy, Asthma & Immunology, Denver, Colorado, March 7-12, 2003.

* The American Thoracic Society, Seattle, Washington, May 16-21, 2003.

* The European Respiratory Society, Vienna, Austria, September 27- October 1, 2003.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3095_4, Accepted for publication: 22 June 2005

Published Online: 14 July 2005

doi: 10.1185/030079905X56402

Anthony D'Urzo(a), Jill P. Karpel(b), William W. Busse(c), Louis- Philippe Boulet(d), Mary Ellen Monahan(e), Barry Lutsky(e) and Heribert Staudinger(e)

a Primary Care Lung Clinic, Toronto, Ontario, Canada

b North Shore University Hospital, Manhasset, NY, USA

c University of Wisconsin, Asthma and Allergy Research Unit, Madison, WI, USA

d Hpital Lavai, Centre de Pneumologie, Quebec City, Quebec, Canada

e Schering-Plough Research Institute, Kenilworth, NJ, USA

Address for correspondence: Anthony D'Urzo, MD, Primary Care Lung Clinic, 1670 Dufferin Street - Suite 107, Toronto, Ontario M6H 3M2, Canada; Tel.: +1 416 652 9336; Fax: +1 416 652 0218; email: tonydurzo@sympatico.ca

Copyright Librapharm Aug 2005

Source: Current Medical Research and Opinion

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