Comparison of Fluticasone Propionate with Beclomethasone Dipropionate

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Thorax 1993;48:817-823 817 Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from

L Fabbri, P S Burge, L Croonenborgh, F Warlies, B Weeke, A Ciaccia, C Parker on behalf of an International Study Group

Abstract Inhaled glucocorticosteroids are now consid- Background-High dose inhaled gluco- ered to be first line regular therapy for corticosteroids are increasingly used in asthma.' It is recommended that any patient the management of patients with moder- requiring daily relief with a /12 adrenoceptor ate to severe asthma. Although effective, agonist (fi2 agonist) should be considered for they may cause systemic side effects. inhaled prophylactic therapy (glucocortico- Fluticasone propionate is a topically steroids or sodium cromoglycate). This active inhaled glucocorticosteroid which would mean that between 50% and 75% has few systemic effects at high doses. of treated asthmatic patients may require Methods-Fluticasone propionate, 1.5 mg inhaled glucocorticosteroids (patient based per day, was compared with beclometha- data, AAH Meditel/Compufile, 1991). In sone dipropionate at the same dose for many patients reasonable management of the one year in patients with symptomatic disease can be achieved with doses of inhaled moderate to severe asthma; 142 patients glucocorticosteroid up to 400 ,ug twice daily. received fluticasone propionate and 132 It is generally agreed, however, that treatment received beclomethasone dipropionate. should be titrated according to the severity of The study was multicentre, double blind symptoms and that, in patients with persis- and ofa parallel design. For the first three tent asthma, the dose of inhaled steroid months patients attended the clinic every should be increased to achieve optimum con- four weeks and completed daily diary trol of the patient's condition.' Once the cards. For the next nine months they were patient's symptoms and peak flow rate have only seen at three monthly intervals in the improved, the dose is reduced to the mini-

clinic. mum required to maintain control. Higher http://thorax.bmj.com/ Instituto di Mallattie Results-During the first three months doses of inhaled steroid are also used in Infettive e diary card peak expiratory flow (PEF) patients who require a reduction in the dose dell'Apparato Respiratorio, rate and lung function measurements in of their oral steroid therapy.23 Universita di Ferrara, the clinic showed significantly greater Inhaled steroids are usually well tolerated Ferrara, Italy improvement in patients receiving fluti- but, as the dose increases, so too does the L Fabbri casone propionate (difference in morning likelihood of systemic side effects, particularly A Ciaccia PEF 15 Vmin (95% CI 6 to 25)), and these hypothalamic pituitary adrenal (HPA) axis Solihull Hospital, Solihull, West differences were apparent at the end of suppression, osteoporosis, and growth retard- on September 30, 2021 by guest. Protected copyright. Midlands, UK the first week. The improved lung func- ation.4 It is recognised that inhaled steroid P S Burge tion was maintained throughout the 12 therapy could be improved with the introduc- Inw-Longzieten- month period and the number of severe tion of drugs with higher topical potency and Astms, St and Augustlinuskliniek, exacerbations in patients receiving fluti- reduced local systemic side effects. Veurne, Belgium casone propionate was reduced by 8% Fluticasone propionate is a trifluorinated L Croonenborgh compared with those receiving beclo- glucocorticoid which has been developed for Lungen und methasone dipropionate. No significant use as an inhaled preparation for the treat- Bronchialkunde, differences between the two groups were ment of asthma. Fluticasone propionate has Berlin, Germany F Warlies observed in morning plasma cortisol chemical modifications which decrease min- Medical Dept TA levels, urinary free cortisol levels, or eralocorticoid activity and increase potency 7511, Rigshospitalet, response to synthetic ACTH stimulation. and lipophilicity. It has more than nine times Copenhagen, In addition, both the rates of withdrawal the activity of fluocinolone acetonide and Denmark and of adverse events were low, and there twice the activity of beclomethasone dipro- B Weeke were fewer exacerbations of asthma with pionate in the McKenzie skin vasoconstrictor Glaxo Group Research Ltd, Greenfo-.d, fluticasone propionate than beclometha- assay in humans.5 Furthermore, fluticasone Middlesex, UB6 OHE, sone dipropionate. propionate is poorly absorbed following oral UK Conclusions-This study shows that flu- administration. The small portion of drug C Parker ticasone propionate in a daily dose of which is absorbed is metabolised rapidly by Reprint requests to: Dr C Parker, Glaxo Group 15 mg results in a significantly greater the liver into inactive metabolites. The Research Ltd, Greenford, increase in PEF and asthma control than hepatic extraction ratio of fluticasone pro- Middlesex UB6 OHE the same dose of beclomethasone dipropionate is almost 100%, giving the drug an Received 14 September 1992 Returned to authors pionate, with no increase in systemic or oral bioavailability of <1%. This compares 9 December 1992 other side effects. favourably with the bioavailability of bud- Revised version received 10 March 1993 esonide (11%), flunisolide (20%), and dexa- Accepted 1 June 1993 (Thorax 1993;48:817-823) methasone and prednisolone (>80%).6 Since 818 Fabbri, Burge, Croonenborgh, Warlies, Weeke, Ciaccia, Parker

up to 90% of an inhaled dose may be ing potential were only included if the investi- swallowed if a spacing chamber is not used, gator considered that they were taking ade- fluticasone propionate appears to have an quate contraceptive precautions. All patients advantage over existing inhaled cortico- gave their informed consent and the study steroids. There is no evidence for local was approved by local ethical committees. Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from metabolism in the lung. This study was designed to compare the STUDY DESIGN efficacy and safety of fluticasone propionate During the two week run in period the with an equal daily dose of beclomethasone patients discontinued use of their usual dipropionate. Preclinical and clinical studies inhaled corticosteroid therapy and received have suggested that fluticasone propionate 1-5 mg beclomethasone dipropionate per day. has at least twice the potency of beclometha- The dose of all other asthma medication sone dipropionate with a greater local to sys- remained constant, except for inhaled /52 ago- temic activity ratio.5 Patients with moderate nists which were only to be continued on an to severe uncontrolled asthma taking a daily "as required" basis. If, during that period, the dose of at least 1000,ug beclomethasone patients achieved the criteria for randomisa- dipropionate or budesonide were recruited tion they entered the double blind portion of into a comparative study of fluticasone pro- the study. These patients were randomly allo- pionate, 1.5 mg per day, with beclometha- cated in a double blind manner to receive sone dipropionate, 1P5 mg per day, for 12 either fluticasone propionate, 1-5 mg/day, or months. Throughout the study period beclomethasone dipropionate, 1-5 mg per detailed assessments of asthma control were day, for one year. Investigators were, how- made for three months, and safety and lung ever, permitted to increase the dose of study function values were assessed for a further drug to 2 mg at any time after the first three nine months. months, either transiently or long term. For the first three months the patients attended Methods the clinic every four weeks and completed PATIENTS daily diary cards. After this they were seen at A total of 274 patients with symptomatic three monthly intervals in the clinic and did moderate to severe asthma aged between 17 not complete daily assessments. They were and 80 years recruited from 25 centres in 10 also seen at a follow up visit two weeks after countries were randomised to treatment. All withdrawal of study medication. patients were currently receiving at least 1000 ug/day beclomethasone dipropionate or Measurements budesonide. Following a two week run in Using the mini Wright peak flow meter, period on 1-5 mg beclomethasone dipro- patients measured their PEF in the morning pionate per day, patients were randomised to (between 07 00 and 08-00 hours) before http://thorax.bmj.com/ treatment with fluticasone propionate or using a bronchodilator, and in the evening beclomethasone dipropionate, 750,ug twice (19-00-20-00 hours), preferably not within daily, both administered via a pressurised four hours of bronchodilator therapy. On metered dose inhaler. Patients were allowed each occasion they took three readings and to use a spacer device but this was at the dis- entered the highest measurement on a daily cretion of individual physicians. One hundred record card on which they also noted the and forty two patients received fluticasone severity of their asthma symptoms by day and

propionate (15 mg/day) and 132 received at night, using four-point rating scales. on September 30, 2021 by guest. Protected copyright. beclomethasone dipropionate (15 mg/day). Symptoms during the day were rated as Patients were randomised if they had at 0 = very well, no symptoms; 1 = a few symp- least two of the following: mean morning toms (not troublesome); 2 = asthma trouble- peak expiratory flow (PEF) during the last some; or 3 = asthma bad, not able to carry seven days of the run in period .70% pre- out daily activities as normal. Symptoms dur- dicted; 15% reversibility of forced expiratory ing the night were rated as: 0 = slept through volume in one second (FEVI) following the night; 1 = slept well, woken early or once 200 ,ug salbutamol during the run in period or by asthma or cough; 2 = woken two or three within three months before the start of the times by cough or asthma; or 3 = bad night, study; 20% diurnal variation in PEF on at kept awake most of the night by asthma. least four of the last seven days of the run in Patients also recorded their use of the study period; asthma symptoms on at least four of medication and of the salbutamol inhaler. the last seven days of the run in period. At each of the clinic visits three measure- Exclusion criteria were as follows: treatments were made of PEF, FEV1, and forced ment with 2000 ,ug/day or more of vital capacity (FVC) and the best of the three beclomethasone dipropionate or budesonide; measurements were recorded. Where possible treatment with systemic corticosteroids these measurements were made at the same within one month of the study period or on time of day (preferably in the morning) on more than three occasions during the six each visit, and patients were asked not to use months before the run in period; treatment their inhaled bronchodilator for four hours with other investigational drugs within four before attending the clinic. Oropharyngeal weeks of the study; hypersensitivity to inhaled swabs to determine the presence of Candida corticosteroids; concomitant diseases likely to albicans were taken if there was clinical evi- complicate the evaluation of the study drug; dence of infection following visual examina- pregnancy or lactation. Women of childbear- tion. Flucticasone propionate and beclomethasone dipropionate in asthmatic subjects 819

Adverse events The occurrence of an exacerbation was not a At each clinic visit assessments of safety dropout criterion so the patient could con- were performed. All serious and minor tinue in the study at the doctor's discretion. adverse events were recorded, irrespective of The procedure to be followed in the event of their apparent cause in relation to the study an exacerbation of asthma was detailed in the Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from drug. protocol and explained to the patients. Patients who experienced worsening symp- Laboratory evaluations toms were instructed to increase their use of At the prestudy visit, at the end of the run in bronchodilator therapy and to report to the period, and after three, six, nine, and 12 hospital within 24 hours. The investigator months, patients were asked to collect a 24 would decide whether to commence oral hour urine sample for determination of uri- steroid therapy or increase the dose of inhaled nary free cortisol excretion. Blood samples for corticosteroid up to 2000 pg/day. If a short routine testing (haematology, biochemistry) course of oral corticosteroids was considered were taken between 08-00 and 10 00 hours at necessary patients took 30-40 mg pred- the clinic visits before and during treatment, nisolone daily for one week in addition to and at the follow up visit if any abnormal their trial medication. If their symptoms had results had been noted at the previous visit. improved and were stable for 48 hours the The samples were analysed locally. Plasma dose of oral corticosteroids was gradually cortisol concentrations were assessed from reduced and stopped. Those patients who did blood samples taken at the pretrial visit and not improve continued to take oral cortico- at all other visits throughout the 12 months of steroids for a further two weeks and were study. The plasma cortisol samples were reassessed. Patients who did not improve analysed by radioimmunoassay at the West after three weeks were withdrawn from the Middlesex Laboratory, UK using the coated study, as were patients who required systemic tube method with a between batch coefficient corticosteroids on more than four occasions of variation of 7%. during the study. In addition, at some centres patients had assessments of adrenal reserve made using a ANALYSIS short tetracosactrin test after 12 months of Data from the daily record cards completed treatment. Patients were asked to withhold during the last 14 days of the run in period treatment with inhaled glucocorticosteroids were used to establish a baseline. For the for at least 12 hours before the test. A blood treatment period data were analysed for sample was taken between 08-00 and 10-00 weeks 1-4, weeks 5-8, and weeks 9-12. A hours for determination of basal plasma corti- further analysis was undertaken using sum- sol concentration. Patients then received a marised data from the whole 12 week period. single intramuscular injection of tetracosac- To be included in the analysis of a variable, http://thorax.bmj.com/ trin 250 pg. Exactly 30 and 60 minutes later patients had to provide data for at least seven further blood samples were obtained for days during the run in period and for at least plasma cortisol measurements. 14 days in any treatment assessment period. The analysis presented here is that of the total Asthma exacerbations randomised population on an "intent to Asthma exacerbations were defined as treat" basis. increasing asthma symptoms requiring a Daily record card data were collected over change in therapy other than inhaled fl2 ago- the first 12 weeks of the study. Clinic lung on September 30, 2021 by guest. Protected copyright. nist rescue therapy, and these were recorded function measurements were recorded over throughout the study by the investigators. 12 months. The mean morning and evening PEF was calculated over each period for each patient and expressed as absolute values. Predicted lung function values were calcu- Table I Demographic details ofthe study patients randomised tofluticasone propionate lated from sex, age, and height using standard and beclomethasone dipropionate formulae.8 Diary card PEF rates and other Fluticasone Beclomethasone lung function values, together with plasma propionate dipropionate cortisol concentrations, were analysed by analysis of covariance using SAS-GLM pro- n 142 132 cedure Release 6 Tests for Withdrawals 25 (18) 18 (14) (SAS 04). inter- Male/female 91/51 (64/36) 64/68 (48/52) actions between baseline (the last 14 days of Age (range) (y) 17-77 19-80 the run in), country, use of spacer device, and Caucasian 137 (96) 130 (98) treatment were performed. Smokers 19 (13) 11 (8) Asthma >ly 139 (98) 129 (98) The non-parametric data such as symptom Asthma >1Oy 81 (57) 73 (55) scores and relief fl2 agonist use were analysed Spacer used 69 (49) 60 (45) by Wilcoxon rank sum test adjusted for coun- Mean morning PEF (1/min) 350 314 try by the van Elteren method.9 The adverse Mean morning PEF (% predicted) 74 73 events and withdrawals were analysed by the Prestudy asthma medications: Inhaled fi, agonist 124 (87) 119 (90) Mantel-Haenszel test'0 and Fisher's exact Oral f2 agonist 26 (18) 25 (19) test, respectively. In addition, exacerbations Methylxanthine 78 (55) 73 (55) reported as a single diagnosis were analysed Ipratropium bromide 29 (20) 35 (27) by the Wilcoxon rank sum test and the occur- Sodium cromoglycate 21 (15) 24 (18) rence of severe exacerbations by the Fisher's Values in parentheses are percentages. exact test. 820 Fabbri, Burge, Croonenborgh, Warlies, Weeke, Ciaccia, Parker

Diary card data The morning PEF values increased in both FP pm groups from the baseline value. The mean

P"P'o *i-'FP am differences between the treatment groups, Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from 400hi'vv-No however, at weeks 1-4, 5-8, and 9-12 were all significantly in favour of fluticasone pro- - -BDP pm pionate (fig 1). Overall the mean difference OOoOO 0°O 0OO 0°Oo°°o°°Ooo° was 15 I/min (95% confidence intervals (CI) w .. .. -4 . ... . o' . - . -..oO.oo °°°°°O., O..t°1 °6 to 25; p < 0005) when averaged over the .0. .. o -, , .. . ..- ;8 a 12 weeks of diary card completion and CL) iA- --X: :- ---e.BDP.a adjusted for differences in baseline values, a1) .:**BDP am -..z country, and use of spacer device. Analysis of 11 . f. : changes from baseline morning PEF values showed that the difference between treatments was significant for both days 1-7 (adjusted mean difference = 9 I/min; 95% CI 1 to 17; p < 0-05) and days 8-14 (adjusted I I 2 56 84 mean difference = 16 1/min; 95% CI 6 to 25; p = 0002). Moreover, these results were Days obtained after a two week run in period on Figure 1 Mean morning and eveningpeak expiraztoryflow (PEF) rates over baseline and 1500 pg/day beclomethasone dipropionate. 12 weeks treatment withfluticasone propionate 15(9Ouglday (FP) and beclomethasone Increases in mean evening PEF in favour dipropionate 1500Ipg/day (BDP). of fluticasone propionate were also observed throughout the 12 week period, the adjusted Results mean evening PEF being significantly greater Table 1 shows the demographic details of the on fluticasone propionate by 10 1/min (95% randomised patients. There were no apparent CI 0 to 19; p < 0 05). differences beitween the groups on entry to Patients in both treatment groups reported the study. App)roximately 50% of the patients fewer symptoms by day or night compared in each treatrnent group had been receiving with the run in values. The mean percentage >1 5 mg inhalced corticosteroid per day before of symptom free days was 19% and 22% dur- the run in per od ing the run in period for the fluticasone pro- During the trial 18 patients withdrew from pionate and beclomethasone dipropionate the beclomethasone dipropionate group and groups, respectively. This increased to 38% 25 from the fluticasone propionate group. and 41% over the 12 weeks, the differences One patient from the beclomethasone dipro- between the groups being not significant. The pionate and four from the fluticasone pro- mean percentage of symptom free nights was http://thorax.bmj.com/ pionate group,withdrew because of asthma. 47% and 50% during the run in period for Fifteen patientts in total, all in the fluticasone the fluticasone propionate and beclometha- propionate grc)up, temporarily increased their sone dipropionate groups, respectively. This study drug frc)m 1-5 mg/day to 2 mg/day to increased to 61% and 63% over the 12 control symptoms during the last nine weeks, again the mean differences not being months of tre,atment. This small number of significant between treatments. Patients in patients had jno apparent influence on the both treatment groups were well controlled. three monthly clinic lung function measure- For all treatment time periods analysed fewer on September 30, 2021 by guest. Protected copyright. ments or on the exacerbation rates. than 10% of patients given fluticasone propionate or beclomethasone dipropionate had median symptom scores of 2 or more. Both treatments also reduced the number of days and nights in which patients had to a1) FP use their salbutamol inhaler. The mean per- c BDP centage of f2 agonist rescue free days was .-0 20% and 13% during the run in period for EE'C the fluticasone propionate and belcometha- 0. L sone dipropionate groups, respectively. This a U- increased to 29% and 19% over the 12 CCL weeks. There were no differences M significant .E between treatments. The use of rescue medication was very low with /1, agonist require- (n-/A,C cj_ ment during the run in period varying from 25 to 27 times per week. During the treatment period patients on beclomethasone dipropionate tended to use more rescue medication than those in the fluticasone pro- I pionate treatment This difference was I9 12 group. significant for weeks 5-8 (p < 0 05). Months Clinic lungfunction Figure 2 Mean changefrom run in clinic peakflow recordedfor thefirst three months and 2 shows the mean from base- thereafter at three monthly intervals forfluticasone propionate (FP) and beclomethasone Figure change dipropionate (BDP) at 1 5-2 0 mglday (n = 112-137 throughout the 12 months). line values in clinic PEF values over the 12 Flucticasone propionate and beclomethasone dipropionate in asthmatic subjects 821

0-35- experienced was low with the majority (>70%) of patients experiencing no exacerba-

c 0-30 tions. There was significant difference in the distribution of exacerbations, reported as a Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from cn single diagnosis adverse event, between co 0.20BD patients receiving fluticasone propionate and these receiving beclomethasone dipropionate 0> (p < 0-02), with statistically fewer patients C WU 0-25 experiencing exacerbations in the fluticasone .C propionate group than in the beclomethasone 0-00f.. , | .~~~~~~~~~~~~~~~~~~~~~~~~~0 dipropionate group (p < 0-05). Furthermore, significantly fewer patients had severe exacer- 0005 bations on fluticasone propionate (3/142 patients, 2%) than on beclomethasone dipropionate (13/132 patients, 10%) (p < 0-02). 1 2 3 6 9 12 Months Cortisols Figure 3 Mean changefrom run in clinic FEV, value recordedfor thefirst three months Analysis of geometric mean plasma cortisol and thereafter at three monthly intervalsforfluticasone propionate (FP) and values at baseline and after three, six, nine, beclomethasone dipropionate (BDP) at 1-5-2-0 mglday (n = 112-137 throughout the 12 months). and 12 months include only those patients with data at baseline and at the specified visit. There was no difference between the geomet- month treatment period. The mean clinic ric mean plasma cortisol concentrations in PEF values, which were 369 I/min and patients receiving fluticasone propionate and 323 I/min at the end of the run in period for beclomethasone dipropionate at any of the fluticasone propionate and beclomethasone visits (table 3), nor were there any differences dipropionate groups respectively, increased in the percentage of patients with a plasma over the 12 months in both treatment groups cortisol level below the lower limit of normal to 405 I/min and 348 I/min. Analysis of the (150 nmol/1). Likewise there were no differ- results, which took baseline values, country, ences between treatment groups in the 24 and use of spacer into account, showed that hour urinary free cortisol levels; 25/110 the increase was significantly greater on fluti- (23%) patients treated with fluticasone pro- casone propionate by 20 I/min (95% CI 1 to pionate and 26/115 (23%) treated with 40; p < 0-05) at 12 months. beclomethasone dipropionate showed a The mean FEV, increased from 2-14 1 change from high or normal values to below and 1-81 1 for fluticasone propionate and the lower limit of the normal range. http://thorax.bmj.com/ beclomethasone dipropionate to 2-39 1 and The tetracosactrin test was performed in 1-97 1 respectively, over the 12 months (fig 35 and 30 patients in the fluticasone pro- 3), and the adjusted treatment difference was pionate and beclomethasone dipropionate greater on fluticasone propionate by 0-15 1 groups respectively, after 12 months of treat- (95% CI 0-01 to 0-29; p < 0-05). Significant ment. The results from both treatment treatment differences in favour of fluticasone groups showed a "normal response"-that is, propionate were also found after eight and 12 after 30 minutes mean plasma cortisol con- weeks of treatment (p < 0-05). centrations had risen by at least 200 nmol/l to Mean FVC values showed a similar almost 500 nmol/l and after 60 minutes were on September 30, 2021 by guest. Protected copyright. increase from 3-37 1 and 2-89 1 for fluticasone greater than 500 nmol/l. propionate and beclomethasone dipropionate groups to 3-56 1 and 3-04 1, respectively. The Adverse events adjusted mean differences, both between There were no consistent changes in bio- absolute values and as a percentage of pre- chemical or haematological indices on either dicted normal values, were not significantly treatment. During the study there were 276 different at any of the clinic visits. and 267 adverse events during treatment with fluticasone propionate and beclomethasone Asthma exacerbations dipropionate in 70% and 73% of patients, The number of patients experiencing an exac- respectively. This included serious adverse erbation of asthma during the study is shown events in 16% and 23% for fluticasone pro- in table 2. The number of exacerbations pionate and beclomethasone dipropionate respectively, leading to 8% of patients with- Table 2 Asthma exacerbations* drawing in both groups. There were three deaths during the study, two while receiving Fluticasone Beclomethasone p fluticasone propionate and one while receiv- propionate dipropionate ing beclomethasone dipropionate, none of n 142 132 which were asthma related. The adverse Total number of exacerbations 33 62 events which occurred most commonly-that Number of patients with exacerbation 23 (16) 37 (28) <0-05 Number of patients with severe is, more than 5%-and those which were exacerbations 3 (2) 13 (10) <0-02 pharmacologically predictable are shown in Number of patients with mild/moderate table 4. The most common were related to exacerbations 22 (16) 30 (23) NC the patient's disease (asthma, rhinitis). The *Exacerbation reported as a single diagnosis adverse event. Values in parentheses are incidence of expected pharmacologically pre- percentages. NC-not calculated. dictable adverse events such as Candida infec- 822 Fabbri, Burge, Croonenborgh, Warlies, Weeke, Ciaccia, Parker

Table 3 Cortisol values 12 months with no increase in adverse events or systemic effects in patients receiving fluti- Fluticasone Beclomethasone Ratio 950 confidence propionate (FP) dipropionate (FPIBDP)* interval casone propionate. In addition, the number (BDP) of severe exacerbations was significantly reduced in this group of patients. These data Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from Geometric mean plasma cortisol values 3 months are compatible with the clinical and pre- n 110 108 clinical studies5 which showed fluticasone Baseline (nmol/l) 251 283 propionate to be more potent than beclo- 3 months (nmol/l) 275 309 0-95 081 to 1 12 methasone dipropionate with less systemic 6 months activity. n 107 103 Baseline (nmol/l) 253 286 Beclomethasone dipropionate has been 6 months (nmol/l) 327 311 108 0-89 to 1-32 compared with budesonide over a wide range 12 months of doses which show that the two have similar n 96 92 effects on asthma control.'"'- Clinically sig- Baseline (nmol/l) 268 292 12 months(nmol/l) 351 322 110 089 to 1-37 nificant effects on the HPA axis have not Cortisol values below lower limit of normal in relation to total number ofpatients li whom been shown with either drug in doses up to cortisol data were available 1.5 mg/day.'4 In normal volunteers at high Baseline 23/121 (19) 18/115 (16) doses of 2 mg/day it has, however, been sug- 3 months 24/115 (21) 14/111 (13) 6 months 20/124 (16) 22/119 (18) gested that there may be greater systemic 12 months 18/112 (16) 18/107 (17) effects with beclomethasone dipropionate."5 In a recent study by Brown et al'4 more than *Ratio (FP/BDP)-ratio based on adjusted mean values (adjt.asted for baseline, country, 20% of their population of adult asthmatic and use of spacer device). Values in parentheses are percenta~ ges. None of these values were significantly different. patients taking long term high dose (>1500 ,ug/day) inhaled beclomethasone dipropionate were found to have adrenal sup- Table 4 Most common (>5%) and pharmacologically predicctable adverse events in the pression to an extent which may be of clinical treatment groups (values are percentages). relevance. In the 12 month study presented neither beclomethasone Fluticason eBeclomethasone here, however, dipro- propionate dipropionate pionate nor fluticasone propionate, in a dose of 1 5 mg/day, was associated with reduced Adverse event Asthma 17 28 HPA axis function as measured by serum cor- Respiratory infection 15 2 tisol levels or assessment of adrenal reserve by Bronchitis 8 7 the short tetracosactrin test as no firm con- Upper respiratory tract infection 6 5 clusions could be made from the 24 hour uri- Influenza 4 5 Headache 4 nary free cortisol data. Moreover, fluticasone Sore throat 5 2 propionate was well tolerated as indicated by Pharmacologically predictable adverse events the low incidence of adverse events. Further http://thorax.bmj.com/ Hoarseness 6 3 studies are required to establish the effects of Candidiasis 4 fluticasone propionate, if any, on other poss- None of these values were significantly different. ible systemic side effects such as growth retar- dation, osteoporosis, and skin thickness.'" Several national' and international'7 guide- tion and hoarse voice wrere not significant and lines recommend the use of inhaled glucocor- did not differ between the two treatment ticosteroid as first line prophylactic therapy. If

groups. these gain acceptance they will lead to greater on September 30, 2021 by guest. Protected copyright. numbers of asthmatic patients taking such drugs. Already in the UK more than 50% of Discussion treated asthmatic patients receive inhaled This study suggests 1that a daily dose of glucocorticosteroids. The guidelines recom- 1-5 mg fluticasone F)ropionate causes a mend treatment in a stepwise manner. To greater increase in boil i diary card and clinic achieve the goals of asthma management, lung function measurrements than 1-5 mg plans such as abolition of symptoms will beclomethasone dipr-opionate in adult therefore require that some patients receive patients with moderaite to severe asthma. higher doses of glucocorticosteroids than are Furthermore, the imp)rovement with fluti- currently given as maintenance. Indeed, this casone propionate was more rapidly apparent study has shown that patients taking at least than with beclometlhasone dipropionate, 1 mg/day beclomethasone dipropionate or occurring during the ffirst week. There was budesonide who, in addition, were regularly also a tendency for synnptom scores and res- taking / agonist and/or oral methylxanthines

cue /5, agonist use to be reduced more on showed considerable improvement in lung fluticasone propionate than on beclometha- function and symptom scores when their dose sone dipropionate, alti.iough only the differ- of inhaled glucocorticosteroid was increased. ence in 112 agonist use was significant. These The change to higher doses in greater num- improvements occurrecI in patients who were bers of patients will therefore require the use receiving between 10)00 and 2000,ug/day of drugs with the greatest margin of safety. beclomethasone diprop)ionate or budesonide The potential hazards from extended use of before entering the st:udy and then had a inhaled glucocorticosteroids were highlighted two week run in pieriod on 1 5 mg/day by Brown et al '4 and Boe and Skoogh'6 who beclomethasone diprop)ionate. The improve- concluded that more long term studies are ment in lung functionU was maintained over required. Flucticasone propionate and beclomethasone dipropionate in asthmatic subjects 823

The results of this study suggest that fluti- steroid): clinical developments in mild to moderate adult asthmatics. Eur Respir Jf 1990;3(Suppl 10):250s, casone propionate may be more effective than S924 (abstract). beclomethasone dipropionate. This, taken 8 Quanjer PH, Dalhuijsen A, van Zomeren BC. Summary together with the observation that it has mini- equations of reference values. Bull Eur Physiopathol

Respir 1983;19(Suppl 5):45-51. Thorax: first published as 10.1136/thx.48.8.817 on 1 August 1993. Downloaded from mal effect on the HPA axis function at high 9 Lehmann EL. Non-parametrics: statistical methods based on doses, suggests that fluticasone propionate ranks. San Francisco: Holden-Day, 1975:135. 10 Koch GG, Edwards S. Clinical efficacy trials with categor- will be of benefit in the long term treatment ical data. In: Peace KE, ed. Biopharmaceutical statistics of asthma. for drug development. New York: Dekker, 1988:403-57. 11 Willey RF, Godden DJ, Carmichael J, Preston P, Frame This study was funded by Glaxo Group Research Ltd. We M, Crompton, GK. Comparison of twice daily adminis- would like to express thanks to the following for their assis- tration of a new corticosteroid budesonide with tance with the study: Dr R Holzer, Dr G Kaik (Austria); Dr P beclomethasone dipropionate four times daily in the Zimmerman, Dr J Lee (Australia): Dr P Derudder, Dr R De treatment of chronic asthma. Br J Dis Chest 1982; Vogelaere (Belgium); Dr C De Socarraz, Professor F Patte, 76:61-8. Professor F Bonnaud (France); Professor L Allegra, Professor 12 Rafferty P, Tucker LG, Frame MH, Fergusson RJ, Biggs M Robuschi, Dr G A Rossi (Italy); Professor B de Almeida, B-A, Crompton GK. Comparison of budesonide and Dr F Pinto, Dr 0 Chiera, Dr M J Serra (Portugal); Dr G beclomethasone dipropionate in patients with severe Menz (Switzerland); Dr A F Henderson, Dr J Stradling, Dr I chromnc asthma: assessment of relative prednisolone- Starke (UK). sparing effects. BrJ7Dis Chest 1985;79:244-50. 13 Ebden P, Jenkins A, Houston G, Davies BH. Comparison 1 British Thoracic Society and others. Guidelines for man- of two high-dose corticosteroid aerosol treatments, agement of asthma in adults: I-Chronic persistent beclomethasone dipropionate (1500 pg/day) and budes- asthma. BMJ 1990;301:651-3. onide (1600 pg/day) for chronic asthma. Thorax 1986; 2 Smith MJ, Hodson ME. High-dose beclomethasone 41:869-74. inhaler in the treatment of asthma. Lancer 1983;i:265-9. 14 Brown PH, Blundell G, Greening AP, Crompton GK. 3 Laursen LC, Tamdor P, Weeke B. High dose inhaled Hypothalamo-pituitary-adrenal axis suppression in asth- budesonide in treatment of severe steroid-dependent matics inhaling high dose corticosteroids. Respir Med asthma. EurJ Respir Dis 1986;68:19-28. 1991;85:501-10. 4 Geddes DM. Inhaled corticosteroids: benefits and risks. 15 Ali NJ, Capewell S, Ward MJ. Bone turnover during high Thorax 1992;47:404-7. dose corticosteroid treatment. Thorax 199 1;46:160-4. 5 Phillips GH. Structure-activity relationships of topically 16 Boe J, Skoogh B-E. Is long-term treatment with inhaled active steroids: the selection of fluticasone propionate. steroids in adults hazardous? Eur Respir .7 1992;5: Respir Med 1990;84(Suppl A): 19-23. 1037-9. 6 Harding SM. The human pharmacology of fluticasone 17 International Consensus Report on Diagnosis and propionate. Respir Med 1990;84(Suppl A):25-9. Management of Asthma. National Institute of Health 7 Svendsen UG. Fluticasone propionate (a new inhaled Publication No. 92-3091. Eur Respiry 1992;5:601-41. http://thorax.bmj.com/ on September 30, 2021 by guest. Protected copyright.