...... To::orol, a new long-acting bronchodilator for

P. Arvidsson, S. Larsson, C-G. Lofdahl, 8. Melander, L. W~hlander , N. Svedmyr

11 1WW long-acting bronchodilaror for inllalario11. P. 1\rvidsson, S. Depts of Pulmonary Medicine and Qinical Phar· LOfdalll, B. Melandcr, L Wdlrlan.dt~r, N. Svedmyr. macology, Golhenburg University, Medical Dept, The aim or thJs study was to evaluate If treatment with Inhaled CIBA-Geigy, Sweden. Is appreciated by a.~tbmat lc s and whether lt ClHL'>CS taclty- Twenty s!Jtble asthmatics wen Included In a rnndomlzed, Conespondence: C-G. Lofdahl, Re~s trom s ka Hospital, Box 17301, S-40264 Goteborg, nd, crossover study. They were treated for two weeks either with Sweden. or snlbutamol, with one week washout lnbetween. T hey were rormoterol or 200 Ill twlc:e dally and Instructed to Keywords: Aslhma; fonnotcrol; salbutamol; fdd.IUOn,ru spray doses on demand. On a diary card they recorded the symptom score; visual analogue scale. o( doses, symptoms and peak expiratory now rule (PEFR) (FEV ) Received: April, t989; accepted after revision: e-very dose. Forcr.d expiratory volume In one second 1 dose­ curves ror salbutamol (total dose 1.3 mg) we re perrol'!11ed before November 10, 1988. eac h treatment perlod to evaluate development or tachyphytuxls. a !ilgnlnt'8nt difference In favour of rormoterul concerning P£FR recordings, spray consumption, and prefllrence. Flneen nr•• r.. rrHI rormoterol and twosalbutamot. The dose-response curves '"· - "'"•"' and before, as well as after salbutamol were utmost rormoterol the curve had changed ; both basal and ma:

nrmn•,.•·n• fumarate (BD-40A, YM-0 8316) is a new lO deJ.ennine whet11er patients would notice the prolonged ~noc:cpt or agonist which has been found in vitro effect and appreciate it when was given in a l 50 limes more potent than salbutamol on controlled study over a longer pcciod of time. We also smooth muscle (1, 2] and at least as 6-f studied whether this long-lasting stimulation of the .131 salbutamol and [2]. In vivo am• adrenoceptors of th e bronchi led to development of gave similar results [3, 4]. increased tachyphylaxis during two weeks of treatment, - 1986, formoterol has been registered for oral compared to their ordinary treatment with an inhaled 131 on in Japan. However, as an this stimulant. has not been tested in Japan. ~ier ~ t udy performed in Sweden has shown that Jnhalcd, the potency of fonnotcrol is 5-15 Limes Patients or salbu~nmo l , according to a double-blind, cumuJa· ~c:-rcsponse study, and studies in West Germany Twenty one patients with non-allergic bronchial asthma Slf!lllar resul ts rs, 6]. Mosl important, however, is using Bz·agonists by inhalation at least three times daily mg that the duration of effect or inhaled fomlOt· were included in the trial. A reversibility of FEY 1 of at is much longer than after equipotent doses of least 20% after inhalation of a 131-agonist was required on Eight hours after administration, forced the first day of the investi gation. One patient was ex· . volume in one second (FEY,) was still sig­ eluded as his reversibility was less than 20%. Twenty •ncrcased compared with the basal value. and patients are thus presented (table 1). Treatment with FEY lheophyUincs, inhaled steroids and inhaled anticholiner­ approximately 75% of the maximum 1 value. lnha lnt•on of salbutamol, FEY, returned to the basal gics in unchanged dosage was allowed during the trial. afler <•pproximately 4 h (5, 61. In other studies. a Oral 131 -agonists we~ withdrown. Thirteen patients used eftect nfter a single dose of inhaled forrnotcrol oral , fifteen patients i nh :~ l cd corticostcroids shown after 12 h [7, 8). and two patients inhaled anticholincrgics. prolonged bronchoclilating effect of inhaled Pregnant women, patients wi th serious diseases and ~ 11 "da'Ote r·nl , which has been demonstrated in studies over asthmatics on oral steroids or B-bloc.kers were excluded Y ~n~er laboratory conditions, may be of great from participation. Patients who were considered unable 81&n• ficance. The aim of the present study was to comply with the study protocol were not included. 326 P. ARV!DSSON ET Al.

Table 1. - Patient characteristics (n-20) mini peak_-flow ~eter was used. The patients were thorough InStructions about the recording technique. Mean Range best of two values was recorded on a diary cant ln way every additional dose was recorded. The vat Age yrs 48 43~6 Duration of disease yrs 16 2-42 the last 10 days of each treatment were eval ua~ FEY 44 Basal 1 % predicted 14-78 Reversibility % 44 20-80 Continuous recording of symptoms

Seventeen of the patients were men and five were smokers. The patients made subjective recordings of lhe Three patients had hypertension treated with or vera­ ity of their asthma every morning and evening on pamil. One patient had experienced slight cardiac decompensa­ diary card by using a four-grade scale: tion, treated with a . FEY : forced expiratory volume in 1 0 No symptoms, undisturbed sleep; one second. = 1 = Mild asthma, symptoms not interfering with or sleep; arm Methods 2 = Moderate asthma, symptoms only slightly ....., 11 with activities and sleep; The study was carried out as a randomized, double­ 3 = Severe asthma symptoms making daily ooutvtliiMII blind crossover study with two weeks of treatment with impossible and seriously disturbing sleep. either inhaled salbutamol or inhaled formoterol and with Recordings made during the 10 last days of the a washout period. of one week between treatment peri­ ment periods were used for the calculations. ods. The patients were examined before and after each treatment period, with FEV1 dose-response curves for Visual analogue scales salbutamol to evaluate tachyphylaxis. During the treat­ ment periods rate (PEFR) was Before and after each treatment period the patients recorded by the patients themselves before each dose of asked about their subjective view of symptoms the study . They also recorded on a diary card duration of effect of the sn1dy medication. Visual additional doses of the tested and symptom scores. logue scales were used for this investigation. The Asthma symptoms were also recorded using visual ana­ tients were asked to give their answers by logue scales at each visit, when side-effects were also on a lOO mm long horizontal line. Separate recorded. At the last visit, the patients were asked about paper were used for each question. The four l•u~:.:~ u~~J~t.; their treatment preference. asked are presented in figure 1. The study was approved by the Ethical Committee at the University of Gothenburg. Further interviews

PEFR values and needfor additional doses ofbronchodi­ At each visit the patients were asked for any lators effects that they considered attributable to the tested They were also asked to give their opinion ,.,. .. ,N•mnrw.-: PE~ was measured every morning and evening dur­ the duration of the effect by using a five-grade scale ing the study before lhe prescribed study medication was the following alternatives; 0-2 h, 2-4 h, 4-6 h, 6-8 b. taken. Recordings were also made before every addi­ and more than 8 h. At the last visit the patients welt tional dose (two puffs) of the study medication. A Wright asked which treatment period they preferred.

How has your asthma been during the last 2 weeks, compared with what lt Is usually like? Much worse 1------1 Much better Have you had problems with shortness of breath during the last 2 weeks?

A lot 1------1 Not at all How have you slept during the last 2 weeks?

Very badly Very well How long-lasting has the effect of the spray been during the last 2 weeks?

Very short Very long

Fig. I. - Visual analogue scales {0-1 00 mm). FORMOTEROL: A NI!W INHALED DRONCHOOILATOR 327

dose with a Yitalograph spirometer. The best of three values was used for calculations. lf the patient could not patieniS were treated with either salbut.amol from abstain from inhaled bronchodilators during the night 8erosol delivering I 00 ).1.8 per puff or formoterol before !he test, this was postponed . . Two puffs were given regularly morning A spacer, Volumatic4P, was used for the The patients were taught the correct inhala­ Statistics ue by an experienced assistant The patients msiiJU ~··"" to use additional when needed. The results were analysed with regard to interactions, the washout period, the patients used their ordi­ period and treatment effects according to Hiu..s and medication. ARMrrAGE (9]. Thus, while all the results given are based on the actually recorded unadjustcd figures, the p-values presented for treatment effects ore adjusted for period effects. Wilcoxon's mid rank-sum test was used studY the possibility of tachyphylaxis of the bron­ for comparisons between the sequences and p <0.05 was chosen as the level of significance. The SAS programme enCICCJ>tor·s, FEY1 dose-response curves for butamol were recorded before and after each package was used for all the calculations. period. The patieniS were asked to absmin ...... - ,~ bronchodilators during 12 h before the dose­ tests and from oml theophyllines for 36 h before Results They arrived at the laboratory at 7.30 am after breakfast without coffee or tea. The patients rested PEFR measurements for 50 min and. basal values for FEY l were then Two measurements were made wtth 20 rnin The highest and lowest PEFR values on each treat­ Salbut.amol was then given in three doses ment day were used in the calculation of data presented 300 and 900 ).l.g, respectively) at intervals of 20 in table 2. The table presents mean values for lhe last 10 The inhaled doses were given by a dose aerosol days of each treatment period. Maximum and minimum to a V olumatic~ spacer. Only 100 ).l.g salbutn­ values were significantly higher during formoterol cet(:asc:a illlo the space before each inhalation. treatment and the difference between maximum and unrmJauorts were supervised by an experienced ass is- minimum values decreased significantly during formot­ and the patient's mouth was rinsed with water after erol treatment, showing a decrease in diurnal variation

inhalation. FEV1 was recorded 12 min after each during that treatment.

Table 2.- Daily PEFR values, number of additional doses and symptoms, during salbutamol and formoterol treatment periods (mean±sEM)

Salburamol Formoterol Significance

Daily PEFR /·min·1 Maximal 344±22 357±21 p<0.05 Minimal 287±21 320±22 p

Additional doses Day ).55±0.33 0.78±0.32 p<0.001 (2 puffs each) Night 0.39±0.10 0.15±0.07 p<0.05 Total 1.94±0.35 0.92±0.33 p

Symptom score (0-3) Day 1.11±0.17 0 .77±0.13 p<0.05 Night 1.12±0.18 0.62±0.16 p<0.001 Total 1.11±0.16 0.69±0.14 p

Visual analogue scales (0-100 mm)

Asthma severity 55±5 71±3 p

Shortness of breath 52±5 74±4 p

Quality of sleep 64±6 77±5 p<0.05

Duration of spray effect 55±4 78±3 p

PEFR: peak expiratory flow rate. 328 P. ARVIDSSON ET AL.

Additional doses Durcstion of effect

Besides the regular inhalations of 2 puffs b.i.d. the The patient's awn opinion concerning the patients took. on average, 2 additional puffs 1.9 times effect of the tested drugs was estimated using -both···..u~ .... . during 24 h when treated with salbutamol, whereas their analogue scales and a fi ve-grade scale. Acco~:di ng average number of additional dosage occasions during vL~ ua l analogue scales. the patients experienced 24 h was 0.9 with formoterol. The number of additional cantJ y longer duration of effect with formotcrol doses (2 puffs each) both at night and day was signifi­ salbutnmol (table 2). There was also a significant cantly smaller during the formoterol treatment period ence in favour of formoterol when the five-grade (table 2). was analysed (table 3). During formot.erol treatment, patients estimated the duratiOn to be more lha:n whereas during salbutamol treatment only three P3tillllfi!411 Symptom evaluation gave the same estimate.

Mean values for each patient during the last 10 days of each treatment period were used for calculations of the Side-effects values presented in table 3. When treated. these patients had mild symptoms. reflected in low symptom scores. The patients had only slight complajnts. One During both day and night. the symptom scores were on salbutamol complained of slight significantly better dwing the formoterol lreatmenL pe­ tachycardia, and another patient on salbutamol of riod. The effect was most pronounced at night. ncss and coughing. On formoterol one patient cornpiJliftl• of dryness of the mouth in the morning. Table 3. - Subjective evaluation of spray duration (number of patients) Preferences Spray duration Salbulamol Formoterol After the last treatment period. we asked the 0-2 h 1 0 which of the two treatment periods they preferred_. 2-4 h 6 1 teen patients preferred the fonnoterol treatment 4-c6 h 6 3 6-8 h 4 8 two patients preferred the salbutamol period and >8 h 3 8 patients could not state a preference (p

Difference between drugs (p

1.7

1.2 0 100 400 1300 0 100 400 1300 Cumulative dose (J.!Q)

Pig. 2. - Mean dose-response curves for cumulative doses of s~Jbutamol perfonned before (o ) and after (•) 2 weeks of trealtllent with salbutamol or fonnoterol. FEV : forced expiratol}' volume in one second. 1 FORMOTEROL: A NP.W INHALP.D BRONCHODILAT0R 329

thl} fomlotcrol treatment period lhc FEY, curve severity in Sweden. Inhaled corticostcroids are the rec­ approximately the same level as the curves re­ ommended second choice after inhaled B1 adrenoceptor before and after the salbutamol treatment period. ogonists for the trea tment of asthma. This may have treatment for two weeks with fonnoterol both tlte blunted the development of tachyphylaxis [ 12]. How­ and maximal FEY, value were higher than the values ever, separate evatuntion of patients without inhaled before the fonnotcrol treatment pedod. TI1Us, treatment did not indicate tachyphylaxis. was no indication that fonnoterot produced a more Moreover. as this is the recommended treatment for this

Ulchyphylrut is to B2-adrcnoceptor stimulation type of patiem. our data elucidate the most important bronchial muscle of asthmatics than the B'l· question, namel y, whether a long-acting B.z-adrenoceplor agonists norm ally used. e.g. salbutamol. agonist such as fonnoterol induces tachyphylaxis in the stuctied separately the live patients who were clinical situation. However, studies of tachyphylaxis to with inhaled . Their dose­ t11is dntg in mild asthmatics without previous steroid or curves showed the same pattcm as those of the Bz-stim ulanl therapy would be of interest. group, i.e there was no indication of tac.hyphy- The dose of formoterol used in this study, 12 ~g. was ln thl'se patients either. chosen to be approximately equipotent with 200 ll& of salbutamol, with regard to the maximum bronchodilating effecL Actually, 200 J.L& salbutamot is somewhat more Discussion potent. This has been shown in a double-blind cumula­ tive dose-response comparison to salbutamol in asthmat­ study has demonslrated that the prolonged effect ics [5). Available data indicate tllatthe duration of effect formoterol shown in acute studies is also of l2 jlg fonnoterol would be I 2 h [7, 8]. For this reason longer periods or clinical use. The pa­ two administrations a day were chosen for continuous the long duration of effect and stated !hat use in this study. On average, the patients used formot­ lasted considerably longer than that of salbu­ crol once more per day. Our patients are used to talring also noted the longer duration of action or bronchodilators pr:ophylacticaJly when attacks can be os a need for fewer additional inhalations. anticipated, as for example before physical exercise. The patients included in this study had moderate to dose used may, therefore, have been slightly higher than severe asthma as evidenced by basal FEY, values, was actually needed. However. on the basis of data from no bronchodilators had been given since the previ­ this study. regular dosage of 12 Jl& formoterol 3 times No patients with the most severe form of dally can be expected to be a reasonable recommenda­ ipated, as patients on oral steroids were not tion for asthmatics witll moderate to severe asthma. The reason for their exclusion was the diffi- However, several patients in this study felt well on only ot studying patients with very severe asthma. as two doses of fonnoterol a day. lt was not the original rend to be unstable and unable to complete a intention of the present study to compare formoterot with study. This means, however. that we do not recommended salbutamol dosage. Such a comparison whether patients with more severe asthma will find seems possible, however. since the patients in this study as advantageous as the patients in the present took 200 J.L& salbutamot approximately 4 times daily, on average, which is in fact the recommended regular dose lll'nra nh t~il ators with a prolonged effect on the bron­ [16J. Our results indicate that 12 1.18 fonnoterol 3 times .::~tt,r.• n.nr~>ntnr~ may involve a greater risk of dail y is clearly superior to 200 jlg salbutamol 4 times ylaxis compared to the short-acting drugs. Stud­ daily with regard to symptom relief and improved PEFR tachyphylaxis to this new bronchodilator are values. essential. In this study, with a limited number The crossover design may give rise to certain prob­ , no evidence of tachyphylaxis to formoterol lems [9, lOJ. In this study a tendency towards interaction compared to their ordinary treatment with a between trea tment and treatment order was noticed, witll Fourteen days of treatment is a rather short respect to the dose-response recordings. This means that probably long enough for a study of tachy­ it cannot be ascertai ned that the change toward.-; "im­

Tachyphylaxis to 62-agonists develops very provement'' of the dose-response curves for FEY after after the start of ttcatment in almost all re­ the rormotcrot treatment period wns in fact caused by the

studied, except the bronchial 62-adrenoceptors therJpy. However. this is highly likely, since the same patients (11- 15]. It has been shown that healthy pattern wa$ evident when tlte results from Ule lirst treat· develop tachyphylaxis to the bronchial effects of mcnt period were analysed as a study with parallel groups. lsts (contrary to asthmatics) even after one week We are therefore inclined to believe !hat tlle high bnS31

I 12). It is therefore likely that tachyphylaxis values for FEV 1 after formoterol thernpy were caused by . developed in this group of patients within 14 remaining bronchodilatalion after the last dose. given •f such a development were to occur. The patients about 12 h before the test. study are now on continuous formoterol therapy It has been stated that a long-acting inhaled bronchocli­ one year and will be followed with repeated dose­ huor would improve astllma therapy significan tly I 171. curves to elucidate this matter further. This p::tpcr supports this assumption. The patients did not patients were treated with inhaled corticostcr- only notice the prolonged erfect of fomloterol, but also >Which is the standard treatment of asthma of this sUited that tlleir asthma was better controlled during both 330 P. ARVIDSSON ET AL.

night and day. Furthermore, they slept better and it was 12. Holgatc ST. Baldwin CJ, Tattcrsfield AE. _ B-ac~ten objectively demonstrated that their pulmonary function agonist resislance in normal human airways. Lancet 1917 was improved. The view that long-acting bronchodila­ 375-377. ' • tors are a major improvement appeared to be shared by 13. Harvey JE, Baldwin CJ, Wood PJ, Albcni KO the patients, as they strongly preferred this therapy. T altersfield AE. - Airway and metabolic rc.~pon siv Such clear-cut results are uncommon even in placebo­ intravenous salbutamol in asthma: effect of regular~ salbutamol. Clin Sci. 1981, 60, 579-585. controlled studies and it should be borne in mind that the 14. Harvey JE. Taucrsfield AE. - Airway response 10 comparison made in this study was with an active treat­ lam.ol: o(fcct or regular salbutamol inhalnt.ions in normli) ment, once a therapeutic breakthrough. and nsthmntic subjects. Thorax, 1982, 37, 280-287. 15. Larsson S, Svcdmyr N. 'T'hiringer G. - L:\Ck of br Acknowlrdgernents: We \hank B. Boquist and B. B -adrcnoceptor res i ~ t nnce in nsthmatics during long-term Oiofsson for e:~~pert technical assistance during \he 1 study. ment with tcrbutnline. J Allergy Clin lmm.unol, 19n, 59, 93-~ 16. Ulfdnhl CG, Svedmyr N. - Bronchodil:l[ors. /n: Ph cotherpy of respiratory disea.tes. J. Wilson ed., WiUiarna llill References WUkins. Sydn.ey, 1987, pp. 60-77. 17. Svcdmyr N, Ulfdahl CO.- Physiology and ph.umacoltt;. I. ldo H. - Comparison of oction of BD 40A and some other nctics or bcln-odrcnergic agonist$./n: therapy rur IISI!una. B-adrcnoceplor stimul1111ts on the isolated ltnchea. 1111d alrin of J.W. Jcnnc and S. Murphy eds, Ockkcr, New York, l987 - · the guinea-pig. Arz~im -Forsch ( D,ug Res). 1976, .526, 839-842. 177-211. • ..,... 2. Decker N. Quennedey MC, Rouo1 B, Schwnrt7. I, Velly J. - Effect of N-amkyl :;ubstitution of ll agonisls on alpha nnd beta-odrenoccptor sublypes: phamu1cologic.1J studies ond bind­ Le formt)le:ro/, UII II()UVeau brondwdilatateur aac tion proro,~; ing nssoys. J Phrnm Pharmocol. 1982, 34, 107- 112. en inlwlotion. Um! comparoison pendOJIJ deux j'eiTUJines, ~ 3. Id a H. - Cardiorcspimtory activities of 3-formyl:unino-4- etude de la tachypllylaxie. P. Arvidsson, S. Lor.rso11, C.(f. hydroxy-aJpha-(N -1-methyl-2-p-melhoxyphcnetylamin· LO[dahl, 8 . MeiOJuler. L. W4Jrlander. N. Sved.myr. omethyl)-ben7.yhdcohol-hemifumamt (BD 40A) and some other RESUME: L'objcctif de COliC etude est d'c!va.luer si lo lta!to. B-adrcnoceptor in conscious guine :~ - pigs . Arzm:im­ mcnt nu moyen du fonnoterol en inhalation est bien nppr6ci6 Forscll (Drug Res), 1916, 726, 1337-1340. par les asthmatiqucs, et s'il provoque une tnchyphyhuie. Noua 4. Wasserman MA, Griffm RL. - A new and highly potent nvons introduit 20 osthmatiqucs en etat sLoblc dans w1c &ucll bronchoselective beta-adrenergic stimulant. Pharmacologist, rnndomis~. en double anonymot, ayee permutation CTOis~c. 0. 1980, 22, 202. ont ete tr ru l ~ pendnnr deux sem aincs, soit pnr le fomtoL«<~ 5. Lofdahl CG, Svedmyr N. - Formotcrol fumarate, a new soil par le salbutamol, ovec une semaine intcmHI

31-adrenoceptor agonist. wa.shout. On leur a donne 12 ~g de formoterol ou 200 J.l& cfl 6. Lofdahl CG, Svedmyr N. - Effcel and dunnion of inhaled salbutnmol deux fols par jour et on leur a doMe corrune fonnoterol, a new Bt·adrenoceptor agonist, compBTed tO S11lbu ­ struction d'utiliser des doses complementaires d'aerosols a 11 tamol in asthmatic patients. Acta PJrarmacol Toxicol, 1986. dcmandc. lis ont note sur uno fiche d'observation quotidiCIUIJ (Suppl. 52), 229. le nombre de doses utilis~es. les symptOmes nsthmatiques, ainsl 7 ...... :: Bcrg A, Bcrdel D. - In: Comparison of a new B­ que le DEP avant chaque dose. Les courbes dose-rl!ponse du ugomsl with snlbutnmol in the treatment of in YEMS pour le salbutamol (dose totale l.3 mg) ont e~ real is&~ asthmatic children. XIT World Congress lnterasma. Barcelona, avant et apres chaque periode de traitement, pour evaluet .. 1987, Abstract. devcloppement d'une tachyphylaxie. On a note une dlff~ 8. Noho D. Rolke M. - In: Compt~tison of the bronchodi­ signilicative en favcur du fonnotcrol en cc qui conceme let lator effect or fomtoterol and over a 12-hour period. symptomes, les enregisltemenlS du DEP, la consomnnllion XIT World Congress 1nrcrasma. fbrcelonu. 1987, Abstract. d'acrosols, et la preference. Quinze patients preferaient le formo­ 9. Hills M, Armitagc P. - The tWo ·pcriod cross-over tri;1l. terol et deux le salbutamol. Les courbes dose-rcponse real~ Br J C/in Plwmtlcol, 1979. 8, 7-20. avant formoterol ainsi qu'avant et apres salbutamol, s'av~re:nl 10. V ere DW. -Validity of cross-over trials. Br J Clin Phar­ quasiment identiques. Apres formoterol, la courbe s'est modi· mocol, 1979, 8, 5-6. fice, Ios valeurs basales et maximales elant plus 6Jev6el ll. Svedmyr N. - Is belo-adrcnoceplor sensitivity a limiting qu'auparavant. On n'a done trouve aucune preuve de tochyphY• factor in asthma thernpy? In: Perspectives in asthma U. Bcta­ laxie par comparaison avec un traitement beta-stimulant clll• adrenoceptors in asthma. J. Moreley cd., Academic Press, Lon­ sique. don. 1984, pp. 181-199. Eur Respir J., 1989, 2, 325-330.