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Thorax 1990;45:259-261 259

Formoterol, a new long acting beta2 agonist for inhalation twice daily, compared with in the treatment of Thorax: first published as 10.1136/thx.45.4.259 on 1 April 1990. Downloaded from

Annika Wallin, Bo Melander, Leif Rosenhall, Thomas Sandstrom, Lars Wahlander

Abstract Methods Sixteen patients with stable chronic PATIENTS asthma participated in a double blind Eighteen patients with stable asthma were crossover study comparing the new entered in the study. None had had a res- inhaled long acting beta2 agonist formo- piratory infection for at least one month before terol with salbutamol. Inhaled (n = 15) the study. No patient had any concomitant and oral steroid (n = 1) treatment were disease apart from one who had mild hyperten- maintained at the same daily dose sion. Sixteen patients (five women, 11 men) throughout the study. For four weeks the completed the study. They had a mean age of patients received either formoterol 24 pg 62 (range 33-69 years), a mean duration of twice daily or salbutamol 400 pg twice asthma of 17 (range 2-48) years, a mean FEVy daily, plus additional puffs (with the same of600% predicted (range 33-106%), and amean drug) when needed. Asthma symptoms, percentage increase in FEVy after inhaling additional puffs of beta2 agonist, peak 400 pg salbutamol of 28% (range 16-71 O%). expiratory flow (PEF), and side effects All patients inhaled beta2 agonists regularly were recorded daily. During treatment and 15 also inhaled (daily dose with formoterol the patients used fewer 600-1600 pg), one taking oral steroids also. additional puffs of beta2 agonist, had The steroid dose was kept constant for four better symptom scores, less disturbed weeks before and during the study. One patient sleep, more days without additional inhaled an drug and six were aerosol, and higher PEF both morning treated with oral beta2 agonists and theo- and evening than during salbutamol phylline, two with oral beta2 agonists, and one

treatment. Thus formoterol 24 pg twice with . These drugs were with- http://thorax.bmj.com/ daily gave long lasting bronchodilatation drawn when the patient entered the run in and asthma symptoms were well con- period. The study was approved by the ethical trolled with regular twice daily adminis- committee ofthe University Hospital ofUmea. tration. STUDY DESIGN The study had a randomised double blind crossover design consisting ofa run in period of

two weeks followed by two treatment periods of on September 27, 2021 by guest. Protected copyright. four weeks each. During the run in period the Inhaled beta2 agonists are first line treatment patients were asked to inhale salbutamol 400 pg for asthma in most countries. One disadvantage (100 jug per puff) twice daily from a metered of currently available drugs is their relatively dose inhaler with a Volumatic spacer. Two short duration of action. If inhaled beta2 agon- additional puffs were taken from the same ist treatment is insufficient to provide good aerosol, but without the spacer, whenever control of asthma inhaled steroid treatment is needed. Peak expiratory flow (PEF) was taken usually added. Some patients will nevertheless as the best of three measurements with a mini need supplementary medication with a long Wright peak flow meter before the regular trial acting oral . Side effects often medication every morning and evening. Department of Lung Medicine, University limit the use ofsuch oral drugs. An inhaled long Asthma symptoms, side effects, additional Hospital, UmeA acting beta2 agonist that combined long lasting puffs of bronchodilator, and PEF were A Wallin bronchodilatation with few side effects would recorded daily. Asthma symptoms were L Rosenhall be useful for treating such patients. graded: 0 = none, 1 = mild, 2 = moderate, CIBA-Geigy, Formoterol is a new potent beta2 agonist that and 3 = severe. In the morning the patients V Frolunda B Melander is at least as beta2 adrenoceptor selective as also recorded whether they had woken up L Wihlander salbutamol in animal and human studies.'3 It is during the night because of asthma symptoms. Medical Division, about 50 times more potent than salbutamol All patients included in the active treatment National Institute of when given orally.34 Inhaled formoterol is 5-15 periods fulfilled the inclusion criterion of hav- Occupational Health, UmeA, Sweden times more potent than salbutamol in asthmatic ing taken at least four additional salbutamol T Sandstrom patients3 and the duration ofaction is usually at puffs per 24 hours during the last 10 days ofthe Address for reprint requests: least 8-12 hours.'57 run in period. Before randomisation patients Dr Annika Wallin, The aim of this study was to compare were balanced according to their additional Department of Lung Medicine, University formoterol withl salbutamol, given as aerosols, spray consumption during the run in period Hospital, Umea, Sweden. in patients with a proved high requirement for and a randomisation table was used for allocat- Accepted 3 January 1990 inhaled bronchodilator treatment. ing them to the two treatment groups. During 260 Wallin, Melander, Rosenhall, Sandstr6m, Wdhlander

the treatment periods the patients inhaled FEV1 salbutamol, four puffs (100 Mg a puff) twice daily, or formoterol, four puffs (6 pg a puff) twice daily, plus two additional puffs of the same aerosol whenever needed, for four weeks 2.6 Thorax: first published as 10.1136/thx.45.4.259 on 1 April 1990. Downloaded from followed by the other bronchodilator for four weeks. The aerosols were administered in the 2.4 same way and the diary cards were the same as during the run in period. 2.2 After the run in period and each treatment period patients were asked about side effects by 2.0 direct questioning and reversibility tests were performed. FEV1 was measured with a dry Before and after _ 400,ug salbutamlol spirometer (Vitalograph) before and 15 min- 1.8 I utes after inhalation of salbutamol 400 Mg with a Volumatic spacer. The patients were told not to take their inhaled beta2 agonist for at least After After After eight hours before the test. Serum potassium run in salbutamol formoterol concentrations were measured before and at the Mean (SEM) FEV, (litres) in reversibility tests performed after two weeks' run in period and afterfour end of the study. Blood samples were taken 20 weeks' treatment with salbutamol andfour weeks' minutes after beta2 agonist inhalation. formoterol. FEV, values were recorded at least eight hours after the last dose of the test medication and STATISTICAL ANALYSIS 15 minutes after inhalation of 400 pg salbutamol. For calculations based on the patients' own recordings mean values or sum totals were agonists was 1 9, compared with 6-2 during the used. The last 10 days of the pretreatment salbutamol treatment period, and patients had period were used for the description ofpatients a mean number of 1-3 nights with disturbed and the last 14 days ofeach treatment period for sleep compared with 4 9 nights when taking analysis of efficacy. Significant interactions salbutamol. They had a mean number of 6-6 and period or drug effects were sought accord- (range 0-14) days when they did not require ing to Hills and Armitage.! Differences in additional aerosol inhalations when taking for- efficacy (as judged by number of additional moterol, compared with 10 (range 0-5) days puffs of beta2 agonist, number of disturbed when receiving salbutamol. Ten patients man- nights, asthma symptom scores, PEF, FEV1) aged more than five days without additional between patients taking the drugs in different puffs during the last two weeks ofthe treatment period while having formoterol but none while sequence were assessed by the Wilcoxon rank http://thorax.bmj.com/ sum test; data on preferences were analysed by having salbutamol. the sign test. The mean basal value of FEV1 before the reversibility test was higher after four weeks' Results treatment with formoterol (p < 0-05). The Two patients were withdrawn during their first reversibility was greater after four weeks' treat- treatment period, one in each treatment group, ment with salbutamol than after formoterol, owing to deterioration of their asthma. the difference corresponding to the increased During treatment with formoterol 24 Mg basal value of FEV1 after formoterol. There twice daily there was a significant reduction in was no significant difference between the mean on September 27, 2021 by guest. Protected copyright. the number ofadditional puffs ofbeta2 agonists maximum FEV, values after inhaled sal- used, lower asthma symptom scores, higher butamol (figure). PEF values, and less disturbed sleep due to Side effects were mild and few with both asthma compared with the salbutamol treat- treatments (table 2). No significant changes in ment period (p < 0 01 in each case; table 1). serum potassium concentrations were observed During the formoterol treatment period the after the two treatments (table 3). mean total number of additional puffs of beta2 When patients were asked after completing treatment Table 1 Additional inhalations ofbeta2 agonists, number ofnights with disturbed sleep, the study which period they symptom scores, andpeakflow duringfour weeks' treatment with salbutamol and with preferred, 13 said they preferred formoterol formoterol: mean (SEM) valuesfor the last 14 days ofboth treatment periods and the and one salbutamol, and two had no preference last 10 days of the run in period (p < 0-01). p value: salbutamol v Run in Salbutamol Formoterol formoterol Table 2 Number ofpatients who reported side effects during the last 10 days of the run in period and during the No of additional inhalations last two weeks of each treatment period Day 6-5 (0 6) 4-4 (0-9) 1-6 (0-4) Night 24(05) 18 (08) 03(02) Total/24 h 89 (10) 62 (16) 19 (05) < 001 No ofpatients Formoterol No ofnights with disturbed sleep 6-1 (1-0) 4-9 (1-5) 1-3 (0-9) < 0 01 Run in Salbutamol Symptom score (4 point scale) Any side effect 8 6 6 Day 1 1 (<0 1) 1 1 (<0 1) 0-6 (<0 1) Night 0-8 (<0 1) 0-5 (<0 1) 0.2 (<0 1) Palpitation 3 1 1 Mean/24h 10(<01) 08(<01) 04(<01) < 001 Tremor 3 2 3 Muscle cramps 2 1 1 Peak flow (1/min) Anxiety 2 0 0 Morning 363 (23) 374 (25) 432 (24) < 001 Headache 5 4 3 Evening 397 (23) 394 (25) 443 (24) < 001 Others 3 2 3 Formoterol, a new long acting beta2 agonistfor inhalation twice daily, compared with salbutamol in the treatment of asthma 261

Table 3 Mean (SEM) serum potassium concentrations beta2 agonist. After four weeks' treatment with before and after the study in thegroups treated with was salbutamolfollowed byformoterol and withformoterol formoterol the mean basal value of FEV1 followed by salbutamol considerably increased, however, despite the eight hour interval, presumably owing to the Serum potassium concentration (mmol/l) residual effect of the last dose, as the duration Thorax: first published as 10.1136/thx.45.4.259 on 1 April 1990. Downloaded from Salbutamoll Formoteroll of action is at least 8-12 hours. The mean formoterol salbutamol maximum value was about the same for both treatment limbs. Before study (n=8) 4-17 (0-17) 3-91 (017) After study (n=8) 4-16 (0-15) 4-14 (0-17) The timing of the reversibility test was not ideal for assessing tachyphylaxis but for these patients, with their high requirement for a beta2 Discussion agonist, it was clinically impossible to withhold In this study formoterol 24 pg had a longer bronchodilator treatment for at least 12 hours. duration of action, and when given twice daily We believe that if clinically important tachy- led to less need for additional puffs of beta2 phylaxis had developed both the baseline and agonist than salbutamol 400 pg. The doses of the maximum value would have diminished formoterol and salbutamol were based on the after four weeks' treatment with formoterol, results of a cumulative dose-response study by which they did not.617 Lofdahl et al,3 in which formoterol 24 pg We conclude that formoterol 24 pg gave a caused at least as much bronchodilation as long lasting bronchodilator effect and that, salbutamol 400 pg; and our findings agree with with regular twice daily administration, asthma those of their study and of others.7 They symptoms were well controlled in a group of indicate clinical benefit in terms of less aerosol asthmatic patients with a frequent daily use, fewer day and night time symptoms, and requirement for inhaled salbutamol despite better lung function with the formoterol treat- regular treatment with inhaled steroids. ment. To compare a long acting with a short acting bronchodilator we selected the patients on the basis of a high requirement for additional beta2 1 Ida H. Comparison ofthe action ofBD 40 A and some other f,2-adrenoceptor stimulants on the isolated trachea and agonist aerosol despite regular treatment with atria of the guinea pig. Arzneim-Forsch 1976;26:839-42. twice daily regimen using 2 Decker N, Quennedey MC, Rouot B, Schwartz J, Velly J. inhaled steroids. A Effects of N-aralkyl substitution of ,B-agonists on a-and salbutamol was insufficient for these patients, 0-adrenoceptor subtypes: pharmacological studies and to use binding assays. J Pharm Pharmacol 1982;34:107-12. and they were therefore told additional 3 Lofdahl C-G, Svedmyr N. Formoterol fumarate, a new aerosol whenever they needed it. The greater beta-2-adrenoceptor agonist. Allergy 1989;44:264-71. 4 Ida H. Cardiorespiratory activities of 3-formylamino-4- need for additional aerosol during salbutamol hydroxy-alpha-(N-1-methyl-2-p-methoxyphenethyl- treatment was expected. We had anticipated aminomethyl)-benzylalcohol-hemifumarate (BD 40A) http://thorax.bmj.com/ a greater salbutamol would lead to and some other ,B-adrenoceptor stimulants in conscious that need for guinea pigs. Arzneim-Forsch 1976;26:1337-40. a similar degree of asthma control with the two 5 Nolte D, Rolke M. Comparative trial of the acute broncho- treatments. patients used spasmolytic action of formoterol versus over 12 Even though the hours. In: Sybrecht G, ed. Formoterol-a new longacting considerably more aerosol during the sal- bronchodilator. Toronto: Huber, 1988:24-31. treatment period, however, asthma 6 v. Berg A, Berdel D, Buhr W. Ein inhalatives #2-Adren- butamol ergikum mit Langzeitwirkung in der Akut- und Dauer- control and lung function were much better therapie beim Asthma bronchiale im Kindesalter. Atem- during the treatment period. wegs-und Lungenkrankheiten 1988;14(suppl 2):128-32. formoterol 7 Arvidsson P, Larsson S, Lofdahl C-G, Melander B, Early morning dyspnoea in asthmatic W&hlander L, Svedmyr N. Formoterol, a new longacting on September 27, 2021 by guest. Protected copyright. patients relates to a circadian rhythm in airway bronchodilator for inhalation. Eur Respir J (in press). 8 Hills M, Armitage P. The two-period cross over trial. Br J calibre.910 Oral theophylline, oral beta2 agonists Clin Pharmac 1979;8:7-20. and beta2 agonists by metered dose 9 Hetzel MR. The pulmonary clock [editorial]. Thorax 1981; high dose 36:481-6. inhaler at bedtime have up to now been the 10 Smolensky MH, Reinberg A, Queng JT. The chronobiology treating this and chronopharmacology of allergy. Ann Allergy 1981; therapeutic approaches for 47:234-52. sometimes dangerous symptom.11"'5 Long act- 11 Postma DS, Koeter GH, Keyzer JJ, Meurs H. Influence of would be expected slow-release on the circadian variation of ing inhaled catecholamines, histamine, and lung function in non- to be beneficial in these circumstances, and our allergic patients with partly reversible airflow obstruction. more during JAllergy Clin Immunol 1986;77:471-7. patients had undisturbed nights 12 Postma DS, Koeter GH, Mark TW, Reig RP, Sluiter HJ. the formoterol treatment period. The effects of oral slow-release terbutaline on the cir- The duration of bronchodilation with for- cadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction. Chest 1985; moterol has not yet been compared with oral 87:653-7. beta2 agonists in sustained release forms but it 13 Barnes PJ, Neville L, Greening AP, Timmers J, Poole GW. Single dose slow release at night prevents seems to be of the same magnitude. As the side nocturnal asthma. Lancet 1982;i:299-301. effects with formoterol 24 were similar to 14 Fairfax AJ, McNabb WR, Davies HJ, Spiro SG. Slow pg release oral salbutamol and aminophylline in nocturnal those with inhaled salbutamol 400 pg, the use asthma. Thorax 1980;35:526-30. 15 Prior JG, Nowell RV, Cochrane GM. High dose inhaled of formoterol may improve patients' com- terbutaline in the management of chronic severe asthma. pliance. _ Thorax 1982;37:300-3. Reversibility tests were performed after the 16 Tattersfield AE. Tolerance to beta-agonists. Eur Physiopathol Respir 1985;21:1-5. treatment periods to investigate whether tachy- 17 Svedmyr N, Lofdahl C-G. Physiology and pharmaco- developed (figure). The tests were dynamics of beta- agonists. In: Jenne JW, phylaxis Murphy S, eds. Drug therapy for asthma. New York: made at least eight hours after inhalation of the Dekker, 1987:177-21 1.