Montelukast - NCBI

9~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

MontelukastNo current usefor asthma

Abstract

* Montelukast (Singulair®), an antiasthma drugbelonging to the leukotriene antagonist family, hastwo indications: as adjunctive treatment for mild-to-moderate chronic asthma when regular inhaledsteroid therapy and short-acting inhaled 02stimulants "on demand" are inadequate; and inprevention of effort-induced asthma.* The clinical file on montelukast contains nomethodologically acceptable comparisons withreference treatments.* Several placebo-controlled trials have shown theefficacy of montelukast, with improvement in clinicalscores and respiratory function tests in those withchronic asthma and prevention of effort-induced asthma.

* For chronic asthma, montelukast has not beencompared with oral or inhaled long-acting 02stimulants or with sustained-release theophylline inpatients inadequately controlled by steroid therapy.* For effort-induced asthma, only two trials havecompared montelukast with salmeterol. On the basisof preliminary results, the authors of both studiesconcluded that montelukast was superior.* Clinical trials showed no clear difference in thefrequency of side effects in patients takingmontelukast and patients taking placebo.Montelukast, however, might be associated withChurg-Strauss syndrome in rare cases.

* Montelukast is expensive.

Montelukast is indicated as adjunctive treatment for mild-to-moderate chronicasthma when regular inhaled steroid therapy and short-acting inhaled 12 Stimu-lants""o.n. .de .mand" fail t.o ontrol sym In this settngthe assessment file

...ils.to anwrayo h usIons:that aris inroutine pat1ice'..In the' scnd::.aitndica-tion(r....( ntio f e inducd a ?preliin sults of twofavour montelukast over salmeterol, but publication of final results must beawaited befbre determining the value of montelukast in this setting.

MontelukastTablets* H0 mg montelukast per tablet* 5 mg montelukast per tablet

Cost for once daily dosing for 1 month is $44.31 (with-out dispensing fee). Information is supplied by DavidFreeman, Pharmacist at the Orillia Soldiers MemorialHospital in Ontario.

Licensed indicationAdjunctive treatment of asthma for patients with mild-to-moderate chronic asthma inadequately controlledby inhaled steroid therapy and in whom short-acting 2agonists administered on demand do not provide ade-quate clinical control. Preventive treatment of effort-induced asthma. No particular risks have beendocumented in children, but experience in this popula-tion is limited.

Leukotrine antagonist; antiasthma drug

Long-term use of high-dose inhaled steroids or oralsteroids by patients with chronic asthma has a

number of disadvantages, such as the risk of local andsystemic adverse effects and of steroid dependency."

Oral montelukast (Singulair®, Merck FrosstCanada) is the second leukotriene antagonist to bemarketed in Canada (sidebar). It has two distinct indi-cations: continuous adjunctive treatment of mild-to-moderate chronic asthma when continuous inhaledsteroid therapy and short-acting inhaled 2 stimulantstaken on demand fail to provide adequate control; andpreventive treatment of effort-induced asthma.

This article examines the clinical assessment ofmontelukast for these two indications to determine therelative value of this new group of antiasthma drugs.We look at the possible effect of montelukast onrequirements of short-acting inhaled P2 stimulants,high-dose inhaled steroids, and oral steroids; and weconsider whether montelukast is a valid alternative tosustained-action inhaled [2 stimulants, oral [2 stimu-lants, sustained-release theophyliine, or even low-doseinhaled steroids.

86 Canadian Family Physician . Le Mtdecin defamille canadien * VOL46: JANUARY * JANVIER 2000

UU

The clinical file on montelukast is limited: pub-lished comparative trials are few and involve onlyplacebo-controlled comparisons.

Chronic asthma: few comparative trialsWithin the framework of adjunctive treatment forpatients with chronic asthma, trials assessing mon-telukast have involved subjects with mild-to-moderateasthma, most of whom were non-smokers. The degreeof severity of the asthma was generally well defined.On the other hand, patients included in several trialswere inadequately treated: for example, some patientswith chronic asthma were not receiving inhaledsteroids.

Three preliminary clinical pharmacology studiesinvolving a total of 21 asthma patients showed thesuperiority of a single daily dose of montelukast overplacebo in lessening bronchoconstriction, as shown bybronchial provocation tests based on inhalation ofeither an allergen or leukotriene D4."56

Dose-finding studies have shown that the activity ofmontelukast does not increase beyond a daily dose of10 mg in adults.6-10

Placebo-controlled trials. Four trials lasting 4 to 12weeks compared montelukast with placebo (a) 1114; twohave been published only as abstracts."1"12 The trialsinvolved 80 to 681 patients, with a total of 1323 (includ-ing 336 children). One of these studies involved onlyacetylsalicylic acid-intolerant patients." Three trialsinvolved adults receiving a daily dose of 10 mg of mon-telukast and one involved children aged 6 to 14 takinga daily dose of 5 mg of montelukast.13 Only in the twotrials published as abstracts were montelukast andplacebo plus inhaled steroid therapy routinely adminis-tered to all patients.""2 In the other two trials only afew patients were receiving inhaled steroids."1314

Three of these trials showed a statistically signifi-cant difference in favour of montelukast relative toplacebo for most of the end points studied, withimprovements in respiratory function test results(forced expiratory volume in 1 second [FEV1] andpeak flow rate) and some symptom and quality-of-lifescores (activity, nocturnal and diurnal symptoms, useof short-acting 12 stimulants on demand, exacerbationsof asthma). 11,13,14 These benefits were limited, however;for example, FEV1 increased from 1.85 L to 2.01 L(+8.23%) in the montelukast group and from 1.85 L to1.93 L (+3.58%) in the placebo group13; use of short-act-ing inhaled 12 stimulants on demand fell from approxi-mately five to four puffs a day in the montelukastgroup and changed little in the placebo group.14

The fourth trial showed that a substantially largerreduction in daily dose of inhaled steroids wasachieved with montelukast (from 976 to 526 ,ug, -46%)than with placebo (from 1079 to 727 ,ug; -33%)."2

Trials versus steroids. To establish the place ofmontelukast in the treatment strategy for asthma, weneed comparative trials with current reference drugs,such as inhaled steroids, at least in mild-to-moderatechronic asthma; long-acting bronchodilators in moder-ate-to-severe asthma; and other preventive treatmentsfor effort-induced asthma. Such trials are only just get-ting started.Two comparative unblinded trials have been

done.15"6 They involved patients who had previouslyparticipated in placebo-controlled trials."13"4 The firstinvolved 246 children aged 6 to 14 treated for 4 monthswith 5 mg/d of montelukast orally or 252 gg/d (approxi-mately) of inhaled steroids (drug not specified).15 Thesecond trial involved 373 adults treated for 9 monthswith 10 mg/d of montelukast orally or 400 gg/d ofinhaled beclomethasone.Y6 Another double-blind trialinvolving 895 adults treated for 12 weeks compared 10mg/d of montelukast, 200 ,ug of beclomethasone twice aday, and placebo.'7 The authors of the three trialsreported that montelukast had equivalent"",16 or lowerefficacy'7 than the inhaled steroid; however, two of thetrials were not blinded, meaning that the data must beinterpreted with care, especially as the results havebeen published only as abstracts.

In short. Montelukast relieves symptoms, regardlessof ongoing steroid therapy, but the degree of reliefremains to be documented. One trial showed thatmontelukast administration allowed the daily dose ofinhaled steroids to be reduced. The three trials usinginhaled steroids failed to show whether montelukastcan replace inhaled steroids in some types of asthma.

Prevention of effort-induced asthma:preliminary data onlyA clinical pharmacology study and a double-blind trialcompared the effect of montelukast and placebo inprevention of effort-induced asthma (b).'8" 9 Thepharmacology study involved 27 children treated for

a-We did not select a study lasting 10 days and involving29 patients in which the daily dose of montelukast was60 times higher than that in the product monograph.27b Two dose-finding studies involved 27 and 19 asthmapatients, but the second used a daily dose of montelukast10 times higher than that in the product monograph.8'28

VOL46: JANUARY * JANVIER 2000* Canadian Family Physician Le Medecin defamille canadien 87

U U

leukotrien

88 Canadian Family Physician Le Midecin defamille canadien * VOL 46: JANUARY * JANVIER 2000

......:,' ...................... ........;.>R

.kt~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.......

..........................................

F i jiLai; W l u l i . ? , , ,~~~~~~~~~~~~~~~~~~~~~~~~llw~l

i. : -...iiE~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. ...f i- =t...., | ib.....,R**:. .gaR?i?g! +; lH ..;.r .. dj .,<..*;. *,..,-.¢, ,.,: ,R,?g;:.. ,wd, .R......MA*-iY?d il !iE;! wair?i:<*a! .! ............................ ;j.;*..ati?R§ +i( ?!<R!w!Ud iX ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ......... .......

ii,::'; ,

.....

|,J aXa204f S ..''','.'....~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

:|l~~ ~ ~~~Vli mu".

.......... ... .W ..)

2 days in a crossover design.18 The clinical trialinvolved 110 patients from 15 to 45 years treated for 12weeks.19 In both cases, the benefit of montelukast wassignificantly superior to that of placebo in limitingbronchoconstriction due to effort (in terms of FEV1)and in shortening the time required for FEV1 to returnto normal after effort during the 24 hours followingadministration. In the clinical trial, 73% of patientsbelieved they were improved by montelukast com-pared with 44% of those taking placebo (P <.009). Withmontelukast, the number of patients needing P2 stimu-lants during exercise was also significantly lower.

Another two trials compared montelukast to salme-terol, a long-acting inhaled 2 stimulant, in prevention ofeffort-induced asthma. 221 Preliminary results from bothtrials showed the superiority of montelukast over salme-terol, but full results must be awaited before drawingconclusions on the relative. efficacy of the two drugs.

Few adverse effectsLimited follow up. In trials involving more than 2600adults older than 15 and approximately 320 childrenaged 6 to 14, the frequency of adverse effects differedlittle between the groups receiving montelukast (atvariable doses, sometimes high) and placebo.2224 The

most frequently reported adverse event washeadache.22 Follow up is limited to the duration of clini-cal trials, ie, 12 weeks for blinded trials, and 6 monthsand 1 year for two blinded trials with an unblindedpost-trial phase.

Risk of rare vasculitis? According to the productmonograph, "the possibility that leukotriene receptorantagonists are associated with onset of Churg-Strausssyndrome cannot be ruled out. Nevertheless, closeanalysis of clinical data on montelukast showed nosimilar cases or any evidence of a relationship betweenonset of the disease and drug administration" (c).23,24

c-Churg-Strauss syndrome, or allergic angiitis and granulo-matosis, is a rare and potentialy seriousform ofvasculitis simi-lar to polyarteritis nodosa; it differs from the latter in morefrequent pulmonary involvement in the initial phase of the dis-ease, before onset ofgeneralized vasculitis.9 A possible linkbetween zafirlukast (another leukotriene antagonist) andChurgStrauss syndrome was suggested on the basis ofsix casesobserved when the doses of oral steroids given concomitantlywith zafirlukast were reduced; as with montelukast, no causalrelationship between zafirlukast and the disease has been firmlyestablished. A protopathic bias was shown in two cases.26'30

VOL 46: JANUARY * JANVIER 2000 0 Canadian Family Physician . Le Midecin defamille canadien 89

In December 1998, Merck Sharp and Dohme-Chibret addressed a circular to United States healthprofessionals stating that cases of Churg-Strauss syn-drome had occurred in patients receivingmontelukast.25 In most cases, the disease occurred orworsened when the dose of continuous oral steroidswas reduced, and no cause-effect relationship withmontelukast treatment was established.

Montelukast might occasionally induce Churg-Strauss syndrome. These observations, however,might also be explained by a "protopathic" effect, inwhich montelukast would be prescribed for asthmapreceding the onset of Churg-Strauss syndrome. Thebeneficial effect of montelukast would allow thesteroid dose to be reduced, thereby unmasking thesymptoms of vasculitis that the steroid had previouslycontrolled along with the asthma. If this is so, it wouldbe wrong to attribute Churg-Strauss syndrome to mon-telukast; on the contrary, the disease itself would bethe "cause" of montelukast prescription. This secondhypothesis is supported by well-documented cases ofChurg-Strauss syndrome falsely attributed to zafir-lukast, another leukotriene antagonist.26 Active post-marketing vigilance must continue.

In practiceMontelukast slightly reduces short-acting P stimulantrequirements in patients with chronic asthma, butonly two trials have involved patients also insufficient-ly treated with inhaled steroids, as in the licensedindication. One trial suggests that montelukast admin-istration allows the dose of inhaled steroids to bereduced.

The assessment file fails to answer other key ques-tions, especially the place of montelukast relative tolong-acting bronchodilators (long-acting inhaled P2stimulants, oral 02 stimulants, and sustained-releasetheophylline).

The place of montelukast in effort-induced asthmaremains to be established relative to long- and short-acting inhaled P2 stimulants and to sodium cromogly-cate. Only preliminary comparative results have beenobtained with salmeterol, and these favour mon-telukast.

Montelukast has been well tolerated during clinicaltrials, but has been associated with rare cases ofChurg-Strauss syndrome.

In the current assessment file, montelukast has nodemonstrated role in management of asthma. ©PI

Translated from Rev Prescr 1999;19(195):323-7. Spelling, syntax,and reference style have been adapted to Canadian standards.

ReferencesOur literature search was based on continuous prospec-tive scrutiny of the contents of the main internationaljournals and Current Contents at the Prescrire library,and on reference texts in clinical pharmacology(Martindale-The extra Pharmacopoeia, etc). We alsoconsulted CD-ROM versions of MEDLINE (1990 toFebruary 1999), EMBASE and Excerpta Medica Drugsand Pharmacology (1991 to December 1998), Cochrane(1999, issue 1), and Reactions (1983 to December 1998).Merck Sharp and Dohme-Chibret sent us published andunpublished documents.

1. Fractures in adults on systemic steroid therapy. Prescr Int1999;8(43):153-6.

2. Systemic effects of inhaled steroids. Prescr Int 1995;4(17):83-4.3. Drug-induced cataract. Prescr Int 1994;3(11):79.4. Lipomatosis due to chronic steroid therapy. Prescr Int1999;8(41):84-5.

5. Diamant Z, Timmers MC, van der Veen H, De Smet M,LeffJA, Friedman BS, et al. Effect of oral montelukast (MK-0476), a potent leukotriene receptor antagonist, on allergen-induced airway responses in asthmatic subjects [abstract].Am JRespir Crit Care Med 1996;153:abstractA346.

6. De Lepeleire I, Reiss TF, Rochette F, Botta A, Zhang J,Kundu S, et al. Montelukast causes prolonged, potentleukotriene D47receptor antagonism in the airways of patientswith asthma. Clin Pharmacol 7her 1997;61(1):83-92.

7. Reiss TF, Altman LC, Munk ZM, SeltzerJ, Zhang J, Shingo S,et al. MK-0476, an LTD4 receptor antagonist, improves thesigns and symptoms of asthma with a dose as low as 10 mgonce daily [abstract]. Am JRespir Crit Care Med1995;151:abstract A378.

8. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. Dose-related protection of exercise bronchoconstriction by mon-telukast, a cysteinyl leukotriene-receptor antagonist, at the endof a once-daily dosing interval. Clin Pharnacol Ther1997;62:556-61.

9. Reiss TF, Sorkness CA, Sticker W, Botto A, Busse WW,Kundu S, et al. Effects of montelukast (MK-0476), a potent cys-teinyl leukotriene receptor antagonist, on bronchodilatation inasthmatic subjects treated with and without inhaled corticos-teroids. Thorax 1997;52(1):45-8.

10. Noonan MJ, Chervinsky LP, Brandon M, Zhang J, Kundu S,McBurney J, et al. Montelukast, a potent leukotriene receptorantagonist, causes dose-related improvements in chronic asth-ma. Eur RespirJ 1998;11: 1232-9.

11. Kuna P, Malmstrom K, Dahlen SE, Nizankowska E,Kowalski M, Stevenson D, et al. Montelukast (MK-0476),a cysLT1 receptor antagonist, improves asthma control inaspirin-intolerant asthmatic patients [abstract].Am j Respir CritCare Med 1997;155(Suppl 4):abstract A975.

90 Canadian Family Physician . Le Medecin defamille canadien * VOL 46: JANUARY * JANVIER 2000

I

12. Leff JA, Irael E, Noonan MJ, Finn AF, Godard P, Lofdahl CG,et al. Montelukast (MK-0476) allows tapering of inhaled corti-costeroids (ICS) in asthmatic patients while maintaining clini-cal stability [abstract]. AmJRespir Crit Care Med1997;155(4):abstract A976.

13. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC,Reiss TF, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. PediatricMontelukast Study Group.JAMA 1998;279(15):1181-6.

14. Reiss TF. Montelukast, a once-daily leukotriene receptorantagonist, in the treatment of chronic asthma. A multicenter,randomized, double-blind trial. Arch Intern Med 1998;158:1213-20.

15. Knorr BA, Matz J, Sveum RJ, Becker AB, Reiss TF,Seidenberg BC, et al. Montelukast (MK-0476) improves asthmaover 6 months of treatment in 6- to 14-year old patients[abstract]. EurRespirJ 1997;10(Suppl 25):219S.

16. Reiss TF, White R, Noonan G, Korenblat P, Hess J, Shingo S,et al. Montelukast (MK-0476), a CysLT1 receptor antagonist,improves the signs and symptoms of asthma over one year oftreatment [abstract]. Eur RespirJ 1997;10(Suppl 25):437S.

17. Malmstrom K, Guerra J, Rodriguez-Gomez G, Villaran C,Pineiro A, Gazzillo A, et al. A comparison of montelukast, aleukotriene receptor antagonist, and inhaled beclomethasonein chronic asthma. EurRespirJ 1998;12(Suppl 28):36-7S.

18. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF,Seidenberg BC, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children withasthma.J Pediatr 1998;133:424-8.

19. LeffJA, Busse WW, Pearlman D, Bronsky EA, Kemp J,Hendeles L, et al. Montelukast, a leukotriene-receptor antago-nist, for the treatment of mild asthma and exercise-inducedbronchoconstriction. NEngliJMed 1998;339(3):147-52.

20. Villaran C, O'Neill S, Helbling A, van Noord JA, Lee T,Chuchalin AG, et al. Montelukast compared to salmeterol inthe treatment of exercise-induced asthma (ETA) [unpublishedabstract]. World Asthma Meeting; Barcelona, Spain; 1998Dec 10-13. 1 page.

21. Turpin JA, Edelman JM, DeLucca PT, Pearlman DS, for theExercise Study Group. Chronic administration of montelukastis superior to inhaled salmeterol in the prevention of exercise-induced bronchoconstriction [abstract]. AmJRespir Crit CareMed 1998;157(Part 2):abstract A456.

22. Markham A, Faulds D. Montelukast. Drugs 1998;56(2):251-6.23. French Medicines Agency. Singulair 10 mg, comprime pel-

licule. In: French Medicines Agency. Summary ofproduct char-acteristics. Saint-Denis, France: French Medicines Agency;1998.

24. French Medicines Agency. Singulair 5 mg, comprime a cro-quer. In: French Medicines Agency. Summary ofproduct char-acteristics. Saint-Denis, France: French Medicines Agency;1998.

25. US Food and Drug Administration. Merck and Co. Dearhealthcare professional. Available from http://www.fda.gov. [Cited1998 Dec 10.]

26. D'Cruz DP, Barnes NC, Lockwood CM. Difficult asthma orChurg-Strauss syndrome? BMJ 1999;318:476-7.

27. Reiss TF, Altman LC, Chervinsky P, Bewtra A, Stricker WE,Noonan GP, et al. Effects of montelukast (MK-0476), a newpotent cysteinyl leukotriene (LTD4) receptor antagonist, inpatients with chronic asthma. JAllergy Clin Immunol1996;98:528-34.

28. Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, BronskyE, et al. Increased urinary excretion of LTE4 after exercise andattenuation of exercise-induced bronchospasm by montelukast,a cysteinyl leukotriene receptor antagonist. Thorax1997;52:1030-5.

29. Fauci AS. Allergic angiitis and granulomatosis (Churg-Strauss disease). In: Fauci AS, Braunwald E, Isselbadner KJ,Wilson JD, Martin JB, Kasper DL, et al, editors. Harrison's prin-ciples ofinternal medicine. 14th ed. New York, NY: McGraw-Hill; 1998. p. 1914.

30. Horwitz RJ, McGill KA, Busse WW. The role of leukotrienemodifiers in the treatment of asthma. AmJRespir Crit CareMed 1998;157:1363-71.

VOL46: JANUARY * JANVIER 2000 oCanadian Family Physician . Le Medecin defamille canadien 91

U

MontelukastL'utilit4 de ce produit dans l'asthme reste a preciser

RESUME

* Le montelukast (Singulair®), antiasthmatique dugroupe des antagonistes des leucotrienes, est officiel-lement indiqu6 d'une part en traitement additif dansl'asthme persistant l6ger a mod6r6, lorsque les trai-tements corticolde inhal6 regulier et beta 2-stimu-lant inhal6 d'action breve <a la demande>> ne sontpas suffisants, et d'autre part dans la pr6vention del'asthme d'effort.* Le dossier d'evaluation clinique du montelukast necomporte pas de comparaison m6thodologiquementacceptable avec des traitements de r6f6rence.* Plusieurs essais cliniques contre placebo ont 6t6favorables au montelukast: dans l'asthme persistant,am6lioration de scores cliniques et de mesures fonc-tionnelles respiratoires; protection contre l'asthmed'effort sup6rieure a celle obtenue avec le placebo.

* Dans I'asthme persistant, le montelukast n'a pas6t6 compar6 aux b6ta 2-stimulants d'action pro-long6e oraux ou inhal6s, ni aux th6ophyllines a lib6ra-tion prolong6e chez des patients insuffisamment con-tr6l6s par une corticotherapie.

* Dans I'asthme d'effort, seuls deux essais ont com-par6 le montelukast au salm6t6rol. Lors de la pr6sen-tation de leurs r6sultats pr6liminaires, les auteurs ontconclu a la superiorit6 du montelukast dans les deuxcas.

* Les essais cliniques n'ont pas montr4 une fr6-quence d'effets ind6sirables nettement diff6renteentre le montelukast et le placebo. On ne peutcependant exclure que, dans quelques cas, le monte-lukast soit associ6 a la survenue d'un syndrome deChurg et Strauss.

* Le montelukast est un m6dicament coOteux.

:.Lemontelukast est indiqu6 ofcielloment en traitemont additif dans l'"thmopersistant le6gr a moder6, lorsque les traitements corticoide inhale re6gulier-et bita 2-stimulant inha:ld'a.c on brAv ot Ia domande ne suffisont ... acontr6or.los symptbmes. Pour cette situaIon clinique,: son dos:sier.d'vua......-.......-:tion ne repond actuellement a aucune des questions qui se posent en prati-quo.Dans la socondoeindication,: leo traitement prventif do l'asthne d'effort.los r6sultats pr.limi:nais d.e..d.eux esss somblnt en fav ur d'uno sukrloridu montelukast sur le salm6t6rol. lI faut attendre la publication complete de.ces essais pour juger de. l'inte6r&it. 6ventuel. du montelukast.

s.....: _:

:..

........:*.:.:,

MontelukastComprim6s* I0 mg de montelukast par comprime* 5 mg de montelukast par comprime

Le cou't pour une posologie d'une fois par jour pour unmois s'eleve a 44.31$ (sans les frais d'ordonnance). Cerenseignement est fourni par David Freeman, pharma-cien a l'Orillia Soldiers Memorial Hospital en Ontario.

Indication officielieTraitement additif de l'asthme chez les patients pre-sentant un asthme persistant leger a modere insuffi-samment contr6le par corticotherapie inhalee et chezqui les beta-2 mimetiques a action immediate et decourte duree administres <<a la demande>> n'apportent

pas un controle clinique suffisant de l'asthme.Traitement preventif de l'asthme induit par l'effort.Remarque: il n'a pas et6 mis en evidence de risque par-ticulier chez l'enfant, cependant, l'experience acquisedans cette population est limitee.

Antagoniste des leucotrienes;antiasthmatique

T'utilisation des corticoides inhales a fortes dosesLou des corticofdes par voie orale, au long cours,chez les asthmatiques atteints d'asthme persistant,n'est pas denuee d'inconvenients: risque d'effets inde-sirables locaux ou systemiques, risque de corticode-pendance14.

Le montelukast par voie orale (Singulair®) est ledeuxieme antiasthmatique du groupe des antagonistes

VOL46: JANUARY * JANVIER 2000 * Canadian Family Physician Le Medecin defamille canadien 93

liii

I'll

s :..ies

94 Canadian Family Physician . Le Medecin defamille canadien + VOL46: JANUARY * JANVIER 2000

.~~e~3**~ **~~'~ zg! Eg

'F.~~~~~~~~~~~~~~~~~~~~~.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

~~W~~~E~~~keEX1~~~~~~ qued~~~~~~~au1resdeb~~~~.........

....~.......

us.~~~~~~~~~~~~~~~~~~

W ..

E Il&lUKA, WW"xEE

s2 X~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.........

i~~~...........'','.'.,..X.i..'.s.E.!ii'i~~~~... ....,.. .... .2 i

:.:::::::.:.!.:.;::-:::::

..'S'''''. {~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~....

7 .Z -.&.. P ... .I - ... 'desk. .^

*i..j vw.w...... ....

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~...,?

H! li'g ar li .'

|.? ......i.. ........'r~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ...

...: r;.....

:.;.:.-. . .: :: .

a~~~~~~~~~w~~~~~~ g~~~~~~~~d~~~~~~e1hi~~~~~~~~~~~~~s~~~~......MttlIna eAt~~~~~~~~~~~13~~~~$~~~d.w.p.....

oftmeat Thc~~~~~~~~~~~~~~~~~~~~~~~i4199?~~~~~~.. ...

I~~~~~Sr~~~~~~~uhL i#eS)1~~~~~~~~~~~~~~~~~~~~~~~......&..~~~d~~~~sMk~~~~~~~dmagew*t#fas*ma~~~~~~~~~~~~~~~~~~~~~~............

12.lo~~~~~~~~~iii11Ieu1, Lung .n&Blood~~~~~~~~~~~~~~. ........t~~~~ttite~~~~~~~~Globalieil~~~~~~~~~~~~~~~~,7aztkma~~~~......

....*...

4Ad1~~~~~~~~~~~t~~~~~t~~~~~0IM ~~ .. ... .......NHL .. ........../.....WHO...'50o ~#o~Bthaa d

NaI~~~~~~~~,nalInWkutee otl*~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~aIth;1995.~~~~~~~.... ...Nblicationiio. 95-3659.~~~~~~~~~~~~~~~~~~~~~~~... .. .. ....

..a.....a ...m

P~~~eveatk~~~~~~~~~~nNagram Cocrdhxating~~~~~~~~~~.......CorntE~~Ittee. ..0......f....q...SiDVE~~0d*~w.wgi~~g asth .a

eLdet~~~~~~~y.Berheeda, Md: National~~~~~~~~~~~~~~... ....

Itutesof&afth;~~~~~~~~~~~~~~~~~~~~~~~.. ...... ......Pul..a...no.96-3662~~~~~~~~~~~p.36..(.p.w....o.d 5 p gs... .... ...

.14,Nationaleuxt, Lung~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~andBlood~~~.... ..

199. N x no 9-3(59

des leucotrienes 'a disposer d'une autorisation de misesur le marche au Canada (lire en encadre), avec deuxindications distinctes: d'une part le traitement additifcontinu de I'asthme persistant leger 'a modere, lorsqueles traitements corticoide inhale continu et beta 2-stimu-lant inhale d'action breve pris 'a la demande ne permet-tent pas un contr6le suffisant de l'asthme; d'autre parten traitement preventif de I'asthme d'effort.

Quelle a ete l'evaluation clinique du montelukast dansces deux indications? Quel est l'interet et la place de cenouveau groupe d'antiasthmatiques? Le montelukastpermet-il de reduire la prise de beta 2-stimulant inhaled'action breve? Permet-il d'eviter ou de limiter le recours

aux corticoides inhales 'a forte dose, ou aux corticoidesoraux? Peut-il constituer une alternative aux beta 2-sti-mulants inhales d'action prolongee, aux beta 2-stimu-lants par voie orale ou aux theophyllines 'a liberation pro-longee, voire aux corticoides inhales 'a faible dose?

Le dossier d'Wvaluation clinique de ce medicamentest relativement faible: les essais comparatifs publiesen integralite sont peu nombreux, et ils concernentseulement des comparaisons versus placebo.

Asthme persistant peu de comparaisonsDans le cadre du traitement additif chez des patientspresentant un asthme persistant, les essais 6valuant le

VOL 46: JANUARY * JANVIER 2000* Canadian Family Physician Le Midecin defamille canadien 95

montelukast ont inclus des patients atteints d'asthmeleger a modere, non fumeurs dans la majorite des cas.Le niveau de severite de l'asthme y fut generalementbien defini. En revanche, les patients inclus dans plu-sieurs essais y furent insuffisamment trait6s, certainsd'entre eux, atteints d'asthme persistant, ne recevantpas de corticoide inhale.

Trois etudes preliminaires de pharmacologie cli-nique, ayant inclus au total 21 asthmatiques, ontmontre la superiorite du montelukast en une prise parjour sur le placebo pour attenuer la bronchoconstric-tion recherchee par tests de provocation bronchique,par inhalation soit d'un allergene, soit du leucotrieneD4"6.

Les etudes de recherche de doses ont montre quel'activite du montelukast ne semble pas augmenter au-dela d'une dose quotidienne de 10 mg chez l'adulteSl'.

Essais versus placebo. Quatre essais ont compare,durant 4 'a 12 semaines, le montelukast a un placebo(a)"'1-4, dont deux n'ont fait l'objet que de publicationspartielles sous forme de resumesl112. Les effectifs deces essais varient de 80 'a 681 patients, pour un total de1 323, dont 336 enfants. L'un de ces essais n'a inclusque des asthmatiques intolerants a l'aspirine". Troisessais ont et realises chez des adultes, avec une dosequotidienne de 10 mg de montelukast; un chez desenfants ages de 6 a 14 ans, avec une dose quotidiennede 5 mg de montelukastl3. C'est seulement dans les66*uu**00*000*0000

a-Nous n'avons pas retenu une courte etude de 10 jourssur 29 patients, dans laquelle on a utilise' une dose quoti-dienne de montelukast 60 fois superieure a celle figurantdans le resume des caracteristiques de Singulait027.b-Citons e'galement deux etudes de recherche de dosesrealises sur 27 et 19 asthmatiques, la seconde ayant utilisedes doses quotidiennes de montelukast lOfois superieures acellesfigurant dans le RCP de Singulaire®828.c-Le syndrome de Churg et Strauss, alias ange'ite aller-gique granulomateuse, est une vascularite rare, potentielle-ment grave, proche de la periarterite noueuse dont elle sedistingue en particulier par la plus grande frequenced'atteinte pulmonaire dans la premie're phase de la mal-adie avant l'apparition des signes cliniques de vascularitegeneralise'e9. Une association possible entre le zafirlukast(un autre antagoniste des leucotrienes) et le syndrome deChurg et Strauss a ete suggeree apres la survenue de six casde ce syndrome, lorsque les posologies de corticoides orauxassocies au zafirlukast ont e't diminue'es; comme pour lemontelukast, il n'a pu etre etabli de relation causale entrele zafirlukast et la survenue de ce syndrome. Un biais proto-pathique a me^me etie mis en evidence dans deux cas26'30.

deux essais publies sous forme de resumes que lemontelukast ou le placebo ont ete ajoutes a un traite-ment par corticoide inhale re,u systematiquement partous les patients""2. Dans les deux autres essais, seuleune minorite de patients recevait un corticoideinhalel6

Trois de ces essais montrent une superiorite statis-tiquement significative du montelukast sur le placebopour la majorite des parametres etudies: ameliorationde tests fonctionnels respiratoires (VEMS, debit depointe), amelioration de certains scores cliniques et dequalite de vie (prenant en compte l'activite, les symp-t6mes diurnes ou nocturnes, la necessite d'utiliser unbeta 2-stimulant d'action breve a la demande, les exa-cerbations de l'asthme, etc.)1"3"4 Ces benefices sonttoutefois modestes; par exemple: le VEMS passe de1,85 1 a 2,01 1 (+8,23%) dans le groupe montelukast,alors qu'il n'augmente que de 1,85 1 a 1,93 1 (+3,58%)dans le groupe placebo'3; l'utilisation de beta 2-stimu-lant inhale d'action breve a la demande passed'environ cinq a environ quatre bouffees par jour dansle groupe montelukast alors qu'elle varie peu dans le

14groupe placeboLe quatrieme essai montre une possibilite de dimi-

nution des doses quotidiennes de corticoide inhale,statistiquement plus importante avec le montelukast(de 976 a 526 jg, soit moins 46%) qu'avec le placebo(de 1 079 a 727 jg, soit moins 33%)12.

Essais versus corticoide. Pour etablir la place dumontelukast dans la strategie therapeutique del'asthme, il faudrait disposer d'essais comparatifs avecles medicaments actuels de reference: corticoidesinhales, du moins dans l'asthme persistant leger amodere; bronchodilatateurs d'action prolongee dansl'asthme persistant modere a severe autres traitementspreventifs de l'asthme d'effort; etc. Ces essais sont bal-butiants.

Deux essais comparatifs, non aveugles, ont eterealises1516. Ils ont inclus des patients ayant participeauparavant a des essais versus placebo13'4. Le premieressai a inclus 246 enfants ages de 6 a 14 ans, traitesdurant 4 mois par 5 mg par jour de montelukast per osou 252 jig par jour (environ) de corticofde inhale (nonprecis )15. Le second essai a inclus 373 adultes traitesdurant 9 mois par 10 mg par jour de montelukast peros ou 400 jigpar jour de beclometasone inhale'e6. Unautre essai a compare, en double aveugle chez 895adultes et sur 12 semaines, le montelukast (10 mg parjour), la beclometasone (200 jig deux fois par jour) etle placebo17. Dans ces trois essais, les auteurs font etat,avec le montelukast, de resultats egaux15'16 ou

96 Canadian Family Physician . Le Medecin defamille canadien * VOL46: JANUARY * JANVIER 2000

inf6rieurs" a ceux obtenus avec le corticofde inhale;ces resultats provenant d'essais non aveugles pourdeux d'entre eux sont 'a interpreter avec prudence et iln'est pas possible de les commenter au vu des seulsresumes publies.

En somme. La prescription de montelukast chez despatients traites ou non par corticoide permet unereduction des sympt6mes cliniques dont l'importancereste "a determiner. Un essai montre que la prise demontelukast permet de reduire la dose quotidienne decorticoide inhale. Les trois essais versus corticofdeinhale ne permettent pas de savoir si le montelukastpeut remplacer la prise de corticoide inhale dans cer-taines formes d'asthme.

Prevention de 1'asthme d'effort des donneesprelimmairesUne etude de pharmacologie clinique et un essai endouble aveugle ont etudie, versus placebo, l'effet dumontelukast en prevention de l'asthme d'effort (b)8"9.L'etude a inclus 27 enfants traites durant 2 jours selonle principe du traitement croise'8. L'essai clinique ainclus 110 patients de 15 'a 45 ans traites durant 12semaines'9. Dans les deux cas, un benefice du montelu-kast statistiquement superieur 'a celui du placebo pourlimiter la bronchoconstriction liee 'a l'effort (mesureepar le VEMS) et pour reduire le temps de retour duVEMS 'a la normale apres l'effort, a ete enregistre dansles 24 heures suivant la prise du medicament. Dansl'essai clinique, 73% des patients ont considere qu'ilsetaient ameliores par le montelukast, contre 44% par leplacebo (p <0,009). Sous montelukast, le nombre depatients ayant besoin d'un beta 2-stimulant durant unexercice a et6 statistiquement inferieur.

Deux autres essais ont compare le montelukast ausalmeterol, un beta 2-stimulant inhale d'action pro-longee, dans la prevention de l'asthme d'effort20e2.Dans les deux cas, sur la base de resultats prelimi-naires, les auteurs ont conclu 'a une superiorite du mon-telukast sur le salmeterol. II faut attendre la publicationdes resultats complets de ces essais pour conclure surl'efficacite comparee du montelukast et du salmeterol.

Peu d'effets indesirables, mais le recul est limiteDans les essais cliniques sur plus de 2 600 adultes deplus de 15 ans et environ 320 enfants de 6 'a 14 ans, lafrequence des effets indesirables a ete peu differenteentre les groupes montelukast (a' des posologies tresvariables, parfois elevees) et placebo2224. L'evnementindesirable le plus souvent signale a ete lescephalees22. Le recul est limite a la duree des essais,

soit 12 semaines pour les essais en aveugle (6 mois et1 an pour les deux essais realises en aveugle avec unephase d'extension non aveugle).

Un risque de vascularite rare? Selon le resume descaracteristiques (RCP) de Singulair®, <<l'eventualit6 queles antagonistes des recepteurs des leucotrienes puis-sent etre associes 'a l'apparition d'un syndrome de Churget Strauss ne peut etre eliminee. Neanmoins, l'analysedetaillee des donnees cliniques 'a partir des etudesmenees avec le montelukast n'a pas mis en evidence decas similaires ni d'element en faveur d'une relation entreson apparition et l'administration de Singulair>> (c)2324.

Une lettre des laboratoires Merck & Co a eteadressee en decembre 1998 aux professionnels desante des Etats-Unis d'Amerique25. Elle precise quedes cas de syndrome de Churg et Strauss ont ete noteschez des patients recevant du montelukast. Dans laplupart des cas, ce syndrome est apparu ou s'estaggrave lors de la reduction des doses de traitementscorticofdes oraux continus, sans qu'un lien causal soitetabli avec le traitement de montelukast.

Deux hypotheses peuvent etre emises. II est pos-sible que le montelukast induise dans de rares cas unsyndrome de Churg et Strauss. On ne peut pas exclurenon plus l'existence d'un biais dit oprotopathique>>: lemontelukast serait prescrit pour un asthme annoncia-teur d'un syndrome de Churg et Strauss. Son effetfavorable permettrait alors de reduire les doses de cor-ticoide demasquant ainsi les sympt6mes de vasculariteque le corticoide controlait, en plus de l'asthme. Dansce cas, attribuer le syndrome de Churg et Strauss aumontelukast serait une erreur car il preexisterait 'a laprise de montelukast et serait meme la cause de saprescription. Cette deuxieme hypothese est soutenuepar l'existence de quelques cas bien documentes desyndrome de Churg et Strauss faussement attribuesau zafirlukast, un autre antagoniste des leucotrienes26.

Ces phenomenes incitent pour le moins a une phar-macovigilance active apres commercialisation.

En pratiqueDans l'asthme persistant, le montelukast diminue demaniere modeste le recours aux beta 2-stimulants decourte duree d'action, mais seulement deux essais ontconcerne des patients traites par ailleurs par corticoidesinhales avec des resultats juges insuffisants (indicationofficielle). Un essai est en faveur d'un effet positif du mon-telukast sur la reduction de dose des corticoides inhales.

Le dossier d'ealuation ne repond 'a aucune autrequestion; et en particulier, on ne connait pas la place

VOL 46: JANUARY * JANVIER 2000 0Canadian Family Physician . Le Medecin defamille canadien 97

du montelukast par rapport aux bronchodilatateursd'action prolongee (beta 2-stimulants inhales d'actionprolongee, beta 2-stimulants oraux, theophyllines 'aliberation prolongee).

Dans l'asthme d'effort, la place du montelukastn'est pas non plus precisee par rapport aux beta 2-sti-mulants inhales d'action breve ou prolongee ou au cro-moglycate de sodium. On ne possede que des resultatspreliminaires versus salmeterol, favorables au monte-lukast.

Lors des essais cliniques, le montelukast a ete bientolere; mais on ne peut exclure formellement qu'ilpuisse etre associe dans quelques cas a l'apparitiond'un syndrome de Churg et Strauss. OLRP

Re&feencesNotre recherche documentaire a repose sur le suivi continu etprospectif des sommaires des principales revues internationaleset des Current Contents mis en ceuvre au sein du Centre dedocumentation Prescrire, ainsi que sur la consultation systema-tique d'ouvrages de reference en pharmacologie cinique(Martindale-The Extra Pharmacopoeia, etc). Nous avons con-sulte sur CD-Rom les bases de donnees Medline (1990 'a fevrier1999), Embase/Excerpta Medica Drugs and Pharmacology(1991 'a decembre 1998), Cochrane (1999, issue 1) et Reactions(1983 'a decembre 1998). Par ailleurs, les laboratoires MerckSharp & Dohme-Chibret nous ont communique divers docu-ments publies et non publies.

1. Fractures et corticotherapie generale chez l'adulte. Rev Prescr1999;19(193):207-11.

2. Effets systemiques des corticoides inhales. Rev Prescr1995;15(148):108-9.

3. Cataractes medicamenteuses. Rev Prescr 1994;14(137):85.4. Lipomatoses dues 'a la corticotherapie prolongee. Rev Prescr1998;18(188):678-9.

5. Diamant Z, Timmers MC, van der Veen H, De Smet M,LeffJA, Friedman BS, et al. Effect of oral montelukast (MK-0476), a potent leukotriene receptor antagonist, on allergen-induced airway responses in asthmatic subjects [abstract].AmJ Respir Crit Care Med 1996;153:abstract A346.

6. De Lepeleire I, Reiss TF, Rochette F, Botta A, Zhang J, KunduS, et al. Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma.Clin Pharmacol Ther 1997;61(1):83-92.

7. Reiss TF, Altman LC, Munk ZM, Seltzer J, Zhang J, Shingo S, etal. MK-0476, an LTD4 receptor antagonist, improves the signsand symptoms of asthma with a dose as low as 10 mg once daily[abstract].AmJRespir Crit Care Med 1995;151:abstract A378.

8. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. Dose-related protection of exercise bronchoconstriction by montelu-kast, a cysteinyl leukotriene-receptor antagonist, at the end of a

once-daily dosing interval. Clin Pharmacol Ther 1997;62:556-61.9. Reiss TF, Sorkness CA, Stricker W, Botto A, Busse WW,Kundu S, et al. Effects of montelukast (MK-0476), a potent cys-teinyl leukotriene receptor antagonist, on bronchodilatation inasthmatic subjects treated with and without inhaled corticoste-roids. Thorax 1997;52(1):45-8.

10. Noonan MJ, Chervinsky LP, Brandon M, Zhang J, Kundu S,McBurney J, et al. Montelukast, a potent leukotriene receptorantagonist, causes dose-related improvements in chronicasthma. EurRespirJ 1998;11:1232-9.

11. Kuna P, Malmstrom K, Dahlen SE, Nizankowska E,Kowalski M, Stevenson D, et al. Montelukast (MK-0476),a cysLT1 receptor antagonist, improves asthma control inaspirin-intolerant asthmatic patients [abstract]. Am j Respir CritCare Med 1997;155(Suppl 4):abstract A975.

12. Leff JA, Irael E, Noonan MJ, Finn AF, Godard P, Lofdahl CG,et al. Montelukast (MK-0476) allows tapering of inhaled corti-costeroids (ICS) in asthmatic patients while maintaining clini-cal stability [abstract]. Am JRespir Crit Care Med1997;155(4):abstract A976.

13. Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC,Reiss TF, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. PediatricMontelukast Study GroupJAMA 1998;279(15):1181-6.

14. Reiss TF. Montelukast, a once-daily leukotriene receptor anta-gonist, in the treatment of chronic asthma. A multicenter, rando-mized, double-blind trial. Arch Intern Med 1998;158:1213-20.

15. Knorr BA, Matz J, Sveum RJ, Becker AB, Reiss TF,Seidenberg BC, et al. Montelukast (MK-0476) improves asthmaover 6 months of treatment in 6- to 14-year old patients [abstr.].Eur RespirJ 1997;10(25 suppl):219S.

16. Reiss TF, White R, Noonan G, Korenblat P, Hess J, Shingo S,et al. Montelukast (MK-0476), a CysLT1 receptor antagonist,improves the signs and symptoms of asthma over one year oftreatment [abstr.I. Eur RespirJ 1997;10(25 suppl):437S.

17. Malmstrom K, Guerra J, Rodriguez-Gomez G, Villaran C,Pineiro A, Gazzillo A, et al. A comparison of montelukast, a leu-kotriene receptor antagonist, and inhaled beclomethasone inchronic asthma. Eur RespirJ 1998;12(28 suppl):36-7S.

18. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF,Seidenberg BC, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6-to 14-year-old children withasthma.J Pediatr 1998;133:424-8.

19. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J,Hendeles L, et al. Montelukast, a leukotriene-receptor antago-nist, for the treatment of mild asthma and exercise-inducedbronchoconstriction. N EnglJMed 1998;339(3):147-52.

20. Villaran C, O'Neill S, Helbling A, van Noord JA, Lee T,Chuchalin AG, et al. Montelukast compared to salmeterol inthe treatment of exercise-induced asthma (EIA) [unpublishedabstract]. World Asthma Meeting; Barcelona, Spain; 1998Dec 10-13. 1 page.

98 Canadian Family Physician * Le Midecin defamille canadien * VOL46: JANUARY * JANVIER 2000

21. Turpin JA, Edelman JM, DeLucca PT,Pearhman DS, for the Exercise StudyGroup. Chronic administration of mon-telukast is superior to inhaled salne-terol in the prevention ofexercise-induced bronchoconstriction[abstract].Am j Respir Crit Care Med1998;157(Part 2):abstract A456.

22. Markham A, Faulds D. Montelukast.Drugs 1998;56(2):251-6.

23. Agence fran,aise du medicament.Singulair 10 mg, comprim6 pellicule.Resume' des caracteristiques du produit.Saint-Denis, France: Agence fran,aisedu medicament; 1998. 10 pages.

24. Agence fran,aise du medicament.Singulair 5 mg, comprime 'a croquer.Summary ofproduct characteristics.Saint-Denis, France: Agence fran,aisedu medicament; 1998. 10 pages.

25. US Food and Drug Administration.Merck and Co. Dear healthcare profes-sional. Disponible 'a http://www.fda.gov.[consulte le 10 decembre 19981

26. D'Cruz DP, Barnes NC, LockwoodCM. Difficult asthma or Churg-Strausssyndrome? BMJ 1999;318:475-6.

27. Reiss TF, Altman LC, Chervinsky P,Bewtra A, Stricker WE, Noonan GP, etal. Effects of montelukast (MK-0476), anew potent cysteinyl leukotriene(LTD4) receptor antagonist, in patientswith chronic asthma.JAllergy ClinImmunol 1996;98:528-34.

28. Reiss TF, Hill JB, Harman E, Zhang J,Tanaka WK, Bronsky E, et al.Increased urinary excretion of LTE4after exercise and attenuation of exer-cise-induced bronchospasm by monte-lukast, a cysteinyl leukotriene receptorantagonist. Thorax 1997;52:1030-5.

29. Fauci AS. Allergic angiitis and granu-lomatosis (Churg-Strauss disease). In:Fauci AS, Braunwald E, Isselbadner KJ,Wilson JD, Martin JB, Kasper DL, et al,editors. Harrison's principles ofinternalmedicine. 14th ed. New York, NY:McGraw-Hill; 1998. p. 1914.

30. Horwitz RJ, McGill KA, Busse WW.The role of leukotriene modifiers in thetreatment of asthma. Am Respir CritCare Med 1998;157:1363-71.

FELODIPINE EXTNDED RELEASE TABLETS

2.5mg,5mgandlOmgAnIihpenIenm Agen0ihydripyridine Calcium Channel BlockerINDICATIONS AND CLINICAL USE PLENDIL (felodipine) is indicated in the treatment of mild tomoderate essential hypenension. PLENDIL shoul nomnaly be used in those patients in whom teatmentwith a diuretic or a beta-blocker was found ineffectiveor has been associated with unacceptable adverseeffects. PLENDIL can be tried as an initial agent in tose patients in whom the use of diuretics and/orbeta-blockers is contraindicated or in patients wifh medicd conditions in which these drugs frequerfycause serous adverse effects. Combination of PLENDIL with a thiazide diuretic or a bets-blocker hasbeen found to be compatible and showed an additive antihypertensive effect. Safety and efficacy ofconcurrent use of PLENDIL with other antihypertensive agents has not been established.CONTRAINDICATIOIS PLENDIL (felodipine) is contraindicated in:1) Patients wh a known hypersensitivity to felodine or other dihydropyndines.2) In women of childbearing potential, in pregnancy, and dunog lactation. Fetal malformations andadvense effects on pregnancy have been repoted in animals. Teralep Efec. Studies in pregnantrabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day (frmm 0.4 to 4 times the maxmumrecommended human dose on a mg/in basis) showed digital anomalies consisting of reduction in sizeand degree of ossification of the terminal phalanges in te fetuses. The frequency and severity of thechanges appeared dose-related and were noted even at the lowest dose. These changes have beenshown to occur with other members of the dihydropyridine class. Similar fetal anomalies were notobserved in rats given fteodipone. In a teratolgy study in cynomologus monkeys, no reduction in thesize of the termrinal phalanges was observed but an abnormal positon of the distal phalanges wasnoted in about 40 percent of the fetuses. Non4tralogenic Effecs. In a study on fertility and generalreproducitve perormance in rats, prolongation of paiturition with dfficuit labour and an increasedfrequency of fetal and eady postnatal deaths were observed in the groups treated with doses of9.6 mg/lkgday and above. Signifcant enlargement of the mammary glands in excess of the nonnalenlargement for pregnant rabbits was found with doses greater than or equal to 1.2 mg/kg/day. Thiseffect occurred only in pregnant rabbits and regressed during lactation. Similar changes in themammary glnds were not observed in rats or monkeys.WARNINGS Congeswe Hear Failure. The safey and efficacy of PLENDIL (felodipine) in pabents withheat failure has not been established. Cauton should, therefore, be exercised when using PLENDIL inhypertensive pabents with compromised ventricular tunction, padicublay in combination with a beta-blocker. Acute hemodynamic studies in a small number of pabents with New York Heat AssociationClass I or IlIl heast failure treated with felodipine have not demonstrated negative inotropic effects.Hypolension, pocardial Ischemia. PLENDIL may, occasionally, precipitate symptomatic hypotensionand rarely syncope. It may lead to reflex tachycardia which, particularly in patients with severeobstructive coronary aitery disease, may resuit in myocardial ischemia. Careful monitoring of bloodpressure durosg the inital administration and ittation of feldipmne is recommended. Care should betaken to avoid hypotension especially in patients with a history of cerebrovascular insufficiency, and inthose takn, medications known to lower blood pressure. DelaIlockIr Wndhwl. PLENDIL gives noprotecfion against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be agradual reduction of the dose of beta-blockers. Outlow Obs1ruction. PLENDIL should be used withcauton in the presence offed left ventricular ouow obstruction.PIEAUIIOONS Periphal Edema. MiH to moderat peripheral edema was the most common adverseevent in the clinical trials. The incidence of perpheral edema was dose-dependent. Frequency ofperipheal edema ranged rom about 10 percent in patients under 50 years of age takng 5 mq daily toabout 30 percent in tose over 60 years of age taking 20 mg daily. This adverse effect generally occurswithin 2-3 weeks of the initiation of treatment. Care should be taken to dfferentiate this peripheraledema from the effects of increasing ldff vents/cular dysfunction. Use in Elderly Patwets. Patientsover 65 years of age may have elevated plasma concentrations of felodipine and, therefore, mayrequire lower doses of PLENDIL (see ACTION AND CLINICAL PHARMACOLOGY -Pharmacokineticss). These paients should have their blond pressure monitored closely dudeg inoaladministration and after dosage adjustment of PLENDIL. A dosage of 10 mg daily should not beexceeded (see DOSAGE AND ADMINISTRATION - Use in the Eldedy). UsI in hUfents wfH ImpairedLiver Fundion. Patients with impaired liver function may have elevated plasma concentrations offelodipine and, therefore, may require lower doses of PLENDIL (see ACTION AND CLINICALPHARMACOLOGY- Pharmacokinetics'). These patients should have their blood pressure monitoredclosely during initial administration and after dosage adjustment 0 PLENDIL. A dosage of 10 mgdaily should not be exceeded (see DOSAGE AND ADMINISTRATION - Use in Patients with ImpairedLiver Function). Gialinal Hyperplasia. PLENDIL can induce gingival enlargement in patients witpronounced ngmitis and parodonittis. However, such changes may be reversed by measures of goodoral hygiene and mechanical debridement of the teeth. Pregnancy and Lactation. SeeCONTRANDICATIONS. Use in Chidrn. PLENDIL is not recommended in children since the safefy andeffcacy in children have not been established. Interaction with Grapetroit Juice. Published datashows that through inhibition of cytochrome P-450, graperuit juice can increase plasma levels andaugment pharmacodynamic effects of dihydropyndine calcium channel blockers. In view of theabsolute bioavailability of PLENDIL, the potential for a signigicant increase in pharmacodynamiceffects exists (see ACTION AND CLINICAL PHARMACOLOGY- Pharmacokinetics'). Therefore, theconsumption of grapefit juice p/or to or dunog treatment with PLENDIL shouo be avoided. DrugInteradtions. As with all drugs, care should be exercised when treating patients with multiplemedications. Dihydropyridine calcium channel blockers undergo biotransformation by thecytochrome P-450 system, mainly via the CYP 3M isoenzyme. Coadministration of felodipine withother drugs which follow the same route of biotransformation may resuff in aitered bioavailability offelodipine or these drugs. Dosages of similarly metabolized drugs, paiticulady those of lowtherapeutic ratio, and especially in patients with renal and/or hepatic impairment, may requireadjustment when starting or stopping concomitantly administered felodipine to maintain optmumtherapeutic blood levels. Drugs known to be inhibitors of the cytochrome P-450 system indude:azole antifungals, cimetidine, cyclosponne, erythromycin, quinidine, wadarin. Drugs known to beinducers of the cytochrome P-450 system include: phenobarbital, phenytoin, rifampin. Drugs knownto be biotransformed via P-450 include: benzodiazepines, flecainide, imipramine, propafenone,terfenadine, theophylline. Enzyme Inhibitors. Cimebdine: In healhy volunteers pharmacokineitcstudies showed an approximately 50 percent increase in the area under the plasma concentration timecurve (AUC) as wel as the C.of felodipne when given concomitanty with dmetidine. I is anticipatedthat a clinically significant interaction may occur in some hypeitensive patents. Therefore, it/srecommended that low doses of PLENDIL be used when given concomitantly with cimetidine.Erythromycin: Concomitant treatment with erythromycin has been shown to cause an increase infelodipine plasma levels. Enzyme Inducers. Phenytoin, Carbamazepine and Phenobarbital: In apharmacokineitc study maximum plasma concentrations of felodipine were considerably lower inepilepftic patients on long-term anticonvulsant therapy (phenyfoin, carbamazepine, phenobarbital) thanin heaithy volunteers. The mean amea under the felodipine plasma concentration-time curve was alsoreduced in epileptic patients to approximately 0% of that observed in healthy volunteers. S/nsa aclinically signfficant interaction may be ar/sc/paled, affernative antihypeitensive therapy should becons/dened in these patients. Alcohol: Alcohol can enhance the hemodynamic effects of felod/pine.Beta-Autconncegtor Blocking AgentS: A phanmacokinetic study of felodipine in conjunction withmetoprolol demonstrated no signfficant effects on the pharmacoW/netics of felodipine. The AUC andC., of metoprolol, however, were increased approximately 31 and 36 percent, respectively. Incontrolled din/cal trials, however, beta-blockers induding metoprobol were corcumeeffy administeredwith felodipine and were well tolerated. 0/gnx/n: When given concomitantly with felodipine as

convenfiomal tabletf the peak pbsma concentration of dgoxin was significantly increased. Wth theeotended release formuladon of faeodipine there was no signMcant change in peak plasma tevels orAUC of digoxin. Other Concomitant Therapy: In heeathy subects there were no clinically significantinteractons when fefdipne was giae concomitanly with indomethadn or spironoatctsne.ADVERSE REACTIONS In 861 essential hypedensive patients treated once daily with 2.5 mg to10 mg PLENDIL (felodipine) as monotherapy in controlled clinical trials, the moot common dinicaladverse events were perpheral edema and headache. Adverse events that occurred wih an incidenceof 1.5% or greater at any of the recommended doses of 2.5 mg to 10 mg once a day, without regardto causality, are listed by dose in Tablet below. These events are repoded from conhrolled clinicaltrials with patients who were randomized to either a fixed dose of PLENDIL or frated from an initialdose of 2.5 mg or 5 mg once a day. A doe a 21 mg one a day has been elusted in someclinial saldes. IUlho the antlbypedeniwe ettet at PlENDIL k incea at 20 mg one aday, there is a dismsportaonate lnease in adverse events, especially thIse associated withvasodilatoryettof (see DOSAGE AND ADMINISTRATION).Table 1. Percent of patients wih adverse everts in controlled trials of PLENOIL (N-861)'

as monotherapy without regard to causality (incidence of disconfinuatons shown inparentheses).

Body System Placebo 2.5 mg 5 mg 10 mgAdverse Events N-334 N-255 N-581 N=408Bodyas a WholePeripheral Edema 3.3 (0.0) 2.0 (0.0) 8.8 (2.2) 17.4 (2.5)Asthenia 3.3 (0.0) 3.9 (0.0) 3.3 (0.0) 2.2 (0.0)CardionwaslarPalpitahon 2.4 (0.0) 0.4 (0.0) 1.4 (0.3) 2.5 (0.5)Warm Sensation/flushing 0.9 (0.3) 3.9 (0.0) 6.2 (0.9) 8.4 (1.2)DigeslheNausea 1.5 (0.9) 1.2 (0.0) 1.7 (0.3) 1.6(6.7)Dyspepsia 1.2 (0.0) 3.9 (0.0) 0.7 (0.0) 0.5 (6.6)Constipation 0.9 (0.0) 1.2 (0.0) 0.3 (0.0) 1.5 (0.2)NervousHeadache 10.2 (0.9) 10.6 (0.4) 11.0 (1.7) 14.7 (2.0)Dimness 2.7 (0.3) 2.7 (0.0) 3.6 (0.5) 3.7 (0.5)Paresthesia 1.5 (0.3) 1.6 (0.0) 1.2 (0.0) 1.2 (0.2)RespiratoryUpper Respiratory Infection 1.8 (0.0) 3.9 (0.0) 1.9 (0.0) 0.7 (0.0)Cough 0.3 (0.0) 0.8 (0.0) 1.2 (0.6) 1.7 (0.0)SlnRash 0.9 (0.0) 2.0 (0.0) 0.2 (0.0) 0.2 (0.0)^ Some patents have been exposed to more than one dose level of PLENDIL.Adverse events that occurred in 0.5 up to 1.5 percent of patients who received PLENDIL in allcontrolled clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day are listedbelow. These events are listed in order of decreasing severity within each category regardless ofrelationship to PLENDIL therapy: Body as a Whole: Chest pain, facial edema, flu-like illness;Cardiovascuter Tachycardia, premature beats, postural hypotension, bradycardia; Gastrointestinal:Abdominal pain, diarrhea, vomiting, dry mouth, fiatulence, acid regurgitation, cholestatic hepatitis,gingial hyperplasia, salivary gand eniargement; Metbolic:ALT (SGPT) increased; Musculoskebtal:Arthralgia, muscle cramps, myalgia; Nervouu?sychiatric: Insomnia, depression, anxiety disorders,irritability, nervousness, somnolence, decrease in libido, tremor, confusion; Respiratory: Dyspnea,epistaxis; Dermatologic: Pruritis, erythema multiforme, erythema nodosum, urticaria,photosensitivity reactions; Special Senses: Visual disturbances; Urogenital: Impotence, urinaryfrequency, urinary urgency, dysuria, polyuria. Serious adverse events reported from controlledclinical trials and during marketing experience (incidence <0.5 percent) were myocardial infrction,hypotension, syncope, angina pectors, arrhythmia and anemia. Isolated cases of angioedema havebeen repoded Angioedema may be accompanied by breathing difficulty. Laboratory tests: Far thefllowing laboratory values statistically sgnificant decreases were observed; blirubin, red blood count,hemoglobin, and urate. Statistically signficant increases were found in erythrocyte sedimentation rateand thrombocyte count In isolated cases, there were increased liver enzymes. None of these changswere considered to be of clinical significance.DOSAGE AID ADNINISTRADON PLENDIL should be swallowed whole and not crushed or chewed.The usual recommended intial dose is 5 mg once dail (see DOSAGE AND ADMINISTRATION - Usein the Elderly, and - Use in Patients with Impaired Liver Function). Depending on the patientsresponse, the dosage should be adjusted accordingly. Dose adjustment, if necessary, should be doneat intervals of not less than two weeks. The maintenance dosage range is 2.5 mg to 10 mg oncedaily. In clinical trials, doses above 10 mg daily showed an increased blood pressure response but adisproportionately higher incidence of peripheral edema and other vasodilatory adverse events.Modficatin of the recommended dosage is usually not required in patients with renal impairment.Use in Me Elderly Patients over 65 years of age may develop elevated plasma concentrabons offelodipine. A stantng dose no higher than 2.5 mg once daily is recommended. A dosage of 10 mgdaily should not be exceeded (see PRECAUTIONS - Use in Elderly Patients). Use in Patents wthhImpaired Liver Funetion Patients with impaired liver function may develop elevated plasmaconcentrations of felodipine. A starting dose no higher than 2.5 mg once daily is recommended. AdosWe of 10 mg daily should not be exceeded (see PRECAUTIONS - Use in Patients with ImpairedLiver Functon).AVAILABILITY PLENDIL tablets are extended release, film-coated tablets, containing felodipine instrenghs of2.5 mg, 5 mg and 10 mg. APLENDIL 2.5 mg Tablet: A yelow, circular, bicorivex film-coted tabet, engraved FL on oe side and 2.5on the other. PLENDIL 5 mg Tablet A ink drcular, biconvexfilm ooated tbl engraved FM on one sideand 5 on he other. PLENDIL 16 mg Tablet:A red-brown, circular, biconvex film-coated tablet,engraved FE on one side and 10 ontheoher.Each blet strength is avaiabein blister pacages (30's) and in IOx 10 unit dose blister packages.NOTE: These eatended reteasetabletsmu not be dided, crushed or chewed.t Ful Product Monograph available on request.REFERENCES: 1. Hansson L, Zancheth A, Camuthers SG et at. for the HOT Study Group. Effects ofintensie blood pressure lowering and low-dose aspirin in patients with hypertension: principalresults of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.2. PLENDIL' (felodipine) Product Monograph, Astra Pharrna Inc. 3. Koolen JJ, Van Wezel HB,Piek J al. Effects of intracoronary felodipine versus nifedipine on left ventricular contractility andcoronary sinus blood flow in stable angina pectoris. The American Journal of Cardiology October1994;volume 74:730-32. 4. Liftle WC, Cheng C, Elvelin L et al. Vascular selective calcium entryblockers in the treatment of cardiovascular disorders: Focus on felodipine. Cardiovascular Drugs andTherapy 1995;9:557-563.

AstraZenecaeCMA

www.ma.ca/cpgs

PLENDIL' (felodipine) isoa registered trademark of the AstraZeneca group of companies. TheAstraZeneca logo is atrademark of AstraZeneca PLC and is used undertlicense by Astra Pharma Inc.and Zeneca Phanma Inc. Astra PharmmoInc., Mississauga, OnitarioLUYf1M4.

VOL 46: JANUARY * JANVIER 2000* Canadian Family Physician Le Medecin defamille canadien 99